In this final report, we bring you our full coverage of the International Diabetes Federation (IDF) World Diabetes Congress, held at the Abu Dhabi National Exhibition Center from December 4-8, 2017. We congratulate the organizers on a terrific meeting in such an interesting location, and we’re already looking forward to IDF 2019 in Busan, South Korea! This year’s conference drew ~7,500 attendees, down from the ~8,00 registrations for IDF 2015 in Vancouver and ~10,000 for IDF 2013 in Melbourne.
Our commentary is split into four sections, including:
Diabetes Therapy Highlights
Symposium: Latest Diabetes Clinical Trials
The DISCOVER Study Program: Rationale and Importance
Linong Ji, MD (Peking University Diabetes Center, China)
Dr. Linong Ji provided an introduction to the real-world DISCOVER study, which began in 2014 (the first participant was enrolled in December that year) and completed recruitment in July 2016. The last patient visit is expected mid-2019, with a mean follow-up of three years for all type 2 diabetes patients enrolled. Dr. Ji presented the primary objective of DISCOVER – to describe diabetes management patterns and disease evolution over three years for people initiating a second-line glucose-lowering therapy – and also reviewed secondary aims – to assess clinical outcomes like achievement of glycemic targets (A1c), BMI, blood pressure, incidence of micro and macrovascular outcomes, incidence of hypoglycemia, patient-reported quality of life, healthcare resource use, and factors associated with treatment choices. One year in, this is already a very rich dataset, and it could potentially shed light on how different therapies affect micro and macrovascular outcomes in the real world (this isn’t exactly a head-to-head trial, but it could certainly illuminate advantages/disadvantages of different treatment options relative to one another, which is something we desperately need in the push for personalized medicine). Dr. Ji announced that 15,992 participants have been recruited for DISCOVER from 38 counties, mostly low- and middle-income. This study size is impressive; Dr. Ji described it as “ambitious,” especially considering the standardized data capture from very different healthcare systems around the world. More specifically, DISCOVER includes 2,002 type 2 diabetes patients from the Americas (but notably, not the US), 811 from the continent of Africa, 3,480 from Europe, 2,183 from the Eastern Mediterranean, 4,156 from the Western Pacific, and 3,360 from Southeast Asia – this is truly a global investigation, creating a realistic picture of what diabetes care looks like in different places around the world.
The DISCOVER Study Program: Methods and Baseline Patient Characteristics
Kamlesh Khunti, MD (University of Leicester, UK)
Dr. Kamlesh Khunti described study methods and baseline patient characteristics for the DISCOVER program (n=15,992 from 38 countries), pointing to considerable treatment inertia on a global scale. DISCOVER used a standardized case report form to collect information on demographics, physical exam and lab test results, first- and second-line treatment, treatment changes and reasons for change, hypoglycemia and vascular complication incidence, and, notably, patient-reported outcomes. Variables were all measured according to standard clinical practice – importantly, these standards may have differed from region to region, although the study was designed to maximize consistency in data capture. DISCOVER enrolled 4,156 participants from the Western Pacific, 3,480 from Europe, 3,360 from South East Asia, 2,002 from the Americas (no US), 2,183 from the Eastern Mediterranean, and 811 from Africa. Dr. Khunti pointed out that while >90% of patients had a reported systolic blood pressure and BMI, fewer had a recorded A1c (77%), LDL or triglycerides (60%), serum creatinine (55%), or albuminuria (15%) measurement, with wide variation across geographies. Mean diabetes duration was 5.6 years, mean A1c 8.4%, and mean BMI 29.6 kg/m2; these were reasonably constant across regions. Health insurance coverage was split between public/governmental (55%), private (16%), mixed (3%), and no insurance (26%); 48% were employed or self-employed, 23% retired, and 29% not working. Inclusion criteria were broad and included type 2 diabetes, age >18 years, and status of initiating a second-line therapy (adding or switching) after first-line oral treatment. Patients were excluded for type 1 diabetes, pregnancy, chemotherapy and steroid use, dialysis or renal transplants, if first-line treatment was injectable or herbal, interventional trial participation, and conditions that might cause early loss to follow up. Sites were selected to represent a country’s diversity of treatment (e.g. spanning urban and rural locations in the right proportion); 673 sites have been involved, including 41% PCP offices, 42% endocrinology practices, 15% internal medicine, 1% cardiology, and 1% other.
The DISCOVER Study Program: Baseline A1c Control and Prevalence of Complications
Mikhail Kosiborod, MD (University of Missouri, Kansas City, MO)
Dr. Mikhail Kosiborod presented key findings from the DISCOVER study so far, emphasizing a few key messages: (i) mean worldwide A1c for the type 2 diabetes population is far above goal, (ii) global complication rate is high, despite this population having a relatively short duration of diabetes (4-7 years, 5.6 years on average), and (iii) there’s evidence for broad treatment inertia, given that people starting a second diabetes drug displayed high A1c and frequent complications. First off, <80% of participants had a recorded A1c assessment, which Dr. Kosiborod described as an important finding in itself, revealing gaps in screening and monitoring. A1c screening rate was lowest in Africa at 57%, followed by Southeast Asia at 61%, ranging up to the Eastern Mediterranean with 94%. When screening was defined as A1c or fasting plasma glucose evaluations, the rate increased, but was still <90% globally. During later Q&A, Dr. Kosiborod pointed out that patients in some parts of the world have to pay out of pocket for screening, delivering this powerful quote: “This has been an eye-opening experience for someone who practices in the US. What we think of as basic measures, this is something that people pay out of pocket for in large parts of the world, so it’s not surprising that we see low rates of screening.” Mean A1c across the entire global study population was 8.4%, from a high of 8.7% in the Eastern Mediterranean to a low of 8.1% in Europe. Nearly one-third of the population had A1c ≥9%, while 55% had A1c ≥8%, and only 15% met an A1c target <7%. This is highly indicative of treatment inertia, Dr. Kosiborod explained, because major guidelines recommend second-line therapy initiation after ~three months not at glycemic goal, and it’s disheartening to see so many individuals waiting until they surpass an A1c of 9% before adding a second agent. The prevalence of microvascular complications (CKD, albuminuria, retinopathy, retinal laser photocoagulation, autonomic neuropathy, peripheral neuropathy, or erectile dysfunction) was 18% globally, ranging from 13% in the Americas to 22% in Southeast Asia. Macrovascular complications were defined broadly (coronary artery disease, stroke, transient ischemic attack, carotid artery stenting, carotid endarterectomy, peripheral artery disease, diabetic foot, amputation, defibrillator use, or heart failure) and appeared in 13% of the overall study population, ranging from 10% in Africa and the Americas to 18% in Europe. Dr. Kosiborod’s main takeaway from this outcomes data was that a large proportion of patients relatively early in the course of diabetes present with microvascular disease, macrovascular disease, or a combination of both. We already see meaningful implications of this finding: As one example, many thought leaders have argued that diabetes CVOTs are hardly generalizable to the real-world diabetes population because they enroll very high-risk patients, but DISCOVER suggests that the real-world diabetes patient is actually quite likely to have existing micro or macrovascular disease. Dr. Kosiborod listed four correlates for both micro and macrovascular complications: (i) male gender, (ii) older age, (iii) smoking, and (iv) a history of hypoglycemia (we find this last one particularly notable, in the movement for glycemic outcomes beyond A1c). He spoke to the “remarkable opportunity for aggressive risk factor screening and modification early in the disease process.” Indeed, while one objective of this program was to reveal the true global picture on diabetes, the researchers also anticipate many actionable insights, and the need for better screening (of glycemia, of micro and macrovascular risk factors) is one of them.
The DISCOVER Study Program: First- and Second-Line Treatment
Kamlesh Khunti, MD (University of Leicester, UK)
Dr. Khunti took the stage once again to discuss first- and second-line therapy choices in the DISCOVER study population. There was regional variation, but the most common first-line treatment across the board was monotherapy, ranging from 87% of regimens in Africa to 52% in Southeast Asia, where fixed-dose combinations are common according to Dr. Khunti. More specifically, 61% of all individuals enrolled in DISCOVER took metformin as first-line; 17% received a metformin/SU combination upfront, and 8% were prescribed SU monotherapy. Second-line therapies were more typically combinations, ranging from 71% in the Western Pacific to 85% in the Eastern Mediterranean. Insulin was used as second-line in 5% of Southeast Asian patients, up to 15% of patients in the Western Pacific, and 9% of cases overall. Second-line use of metformin/SU co-administration was seen in 24% of patients globally, while 23% of all participants took a metformin/DPP-4 inhibitor combination as second-line. Additionally, a multinomial regression model with region as a fixed effect examined individuals receiving metformin monotherapy as first-line treatment and found that region was an important predictor of second-line treatment. The Americas favor SUs over DPP-4 inhibitors and insulin, while Southeast Asia and the Western Pacific heavily favor DPP-4 inhibitors over SUs (this would be our preference as well, given the hypoglycemia, weight gain, beta cell burnout, and possible CV harm associated with sulfonylureas). DPP-4 inhibitors were a more likely addition in the elderly than SUs, and SUs were in turn more likely than insulin. At higher A1c, SUs were more likely to be added than DPP-4 inhibitors, but insulin was a more likely addition than SUs in those with A1c ≥9%. Follow-up analysis for DISCOVER is currently underway, and will reveal more about the clinical effects of various second-line treatment options over three years. This could be incredibly important insight for the diabetes field, in differentiating between drug classes and matching the right therapy to the right patient at different stages of disease.
The DISCOVER Study Program: Discussion
Naveed Sattar, MD (University of Glasgow, UK)
Glasgow’s Dr. Naveed Sattar presented strengths and limitations of the DISCOVER study, finding more strengths in this analysis overall. He highlighted the value of real-world data from diverse parts of the world, including regions that have never before been represented in a diabetes study. He called out the standardized data capture, which allows for comparisons between geographies, and discussed the potential for one area to learn from another (what strategies are working elsewhere for population-level diabetes management?). Dr. Sattar also summarized the important insights gained on prevalence of diabetes complications, patterns of glycemia and risk factors, and quality of care around the world. As for limitations, he shared an earlier concern he had that DISCOVER would enroll patients who are more educated than average. However, after seeing the full presentation, he noted a high percentage of individuals who had no formal schooling. Lastly, Dr. Sattar mentioned the gaps in data: Not everyone in the study had an A1c reading, but this too was telling, revealing how so many people with diabetes around the world aren’t properly screened, let alone treated. Ultimately, he described the DISCOVER program as a “much-needed snapshot of diabetes care standards for people transitioning from first-line therapy to second-line therapy,” and we certainly appreciate the massive effort behind this global, real-world study, which has already provided new knowledge on diabetes care around the world and which will hopefully reveal strategies for improvement in the prospective follow-up.
Questions and Answers
Dr. Sattar: Gentlemen, were any of you surprised by any of the findings?
Dr. Kosiborod: I’m not sure if surprised is the right word – more like “unexpected” – but participants in this study were relatively young, with relatively short duration of diabetes, and still we saw complication rates that are quite high. We’re used to seeing high event rates in diabetes CVOTs, which specifically select for high-risk patients. DISCOVER enrolled a very, very different patient population. There was no requirement for individuals to have vascular disease at baseline, and overall, these patients would be considered low-risk. So, are we missing the boat? Are we thinking of these patients as low-risk when in fact they aren’t? What can we do to minimize the risk of complications? Very shortly, we’ll have one-year data from DISCOVER, and this will be one of the most insightful takeaways.
Dr. Khunti: My surprise was that we go to all these diabetes meetings, and we look at these fantastic RCTs showing how we can improve care, but this global population is not receiving the basic care they need. Look at lipids, albuminuria. These are basic standards of care that every patient in the world should get.
Comment: Congratulations on a really wonderful session. This is the type of study that is much-needed in diabetes. I do want to point out that Sub-Saharan Africa was not represented, so that may be an issue. It’s important to encourage those regions with the lowest resources to participate in these types of studies going forward. But this is a great start.
Q: I was struck by the map of macrovascular complication rates around the world. Prevalence was high in Russia, for example. Are there other risk factors besides diabetes that are more common there and explaining this?
Dr. Kosiborod: You make a keen observation. It’s important to keep in mind that there are many reasons why there could be higher macrovascular prevalence in any given region. Screening strategies are different in different parts of the world. So, you can imagine a scenario where someone screens aggressively for complications, and complications are thus reported as high, but that doesn’t mean the quality of care is suboptimal for patients there. It also depends what kind of healthcare setting patients come from (rural, urban, etc.).
Dr. Ji: This program will most likely be adapted by IDF, and it could be expanded into other regions for a more global picture on diabetes management.
Q: I’d also like to highlight that only 2.3% of participants were Black, which shows the under-representation of Sub-Saharan Africa. Also, the US wasn’t represented. This is a big country with a very heterogeneous patient population. That would have helped the final result.
Dr. Kosiborod: There’s a very good reason for this exclusion. There’s a parallel registry program called the Diabetes Collaborative Registry – now with nearly 2 million patients enrolled – between the ACC, ADA, AACE, Joslin Diabetes Center, and American College of Physicians (APA) that’s collecting this data in the US. This US data will complement the findings from DISCOVER.
Q: Drawing on Steno-2, when multifactorial intervention led to better outcomes, what is most important? Is it to control A1c with any drug, or to focus on the pathophysiology of diabetes?
Dr. Khunti: This study was not looking at the therapies in terms of how they’re being used. One of the primary reasons for doing this research is access to care – the basic level of care that some patients are getting is quite low. Certainly, we’ll look to see newer therapies coming onto the market in our prospective follow-up, but it’s more about the quality of life that these patients are getting. And, this is the first time we’re getting data from some countries that have never been represented in any study previously.
Q: I was surprised that the influence of cost on choosing a second-line drug was actually quite low in this study. How can you explain this, even though the study was conducted in low- to middle-income countries?
Dr. Khunti: Some places have a minimum number of drugs available – maybe only metformin, sulfonylureas, and insulin. So these professionals won’t say that cost comes into the equation, because it doesn’t.
Dr. Sattar: Two final questions for the panel. Why was albuminuria collection so low, only 16%? And what are the specific aims of three-year follow-up?
Dr. Khunti: These are basic quality of life measures that patients should be getting, and it’s just not happening, especially in lower-income countries.
Dr. Kosiborod: Let me double up on what Kamlesh just said – this has been an eye-opening experience for someone who practices in the US. What we think of as basic measures, this is something that people pay out of pocket for in large parts of the world, so it’s not surprising that we see low rates of screening (for albuminuria, and for other complications). It’s not because clinicians aren’t thinking of it. Patients may choose not to do it because of other priorities and limited resources. For me, the most interesting question to look at in follow-up will be: What’s the incidence of diabetes complications in people who didn’t have complications before? What are the predictors of that? Having this rich dataset will allow us to better determine who develops a complication vs. who doesn’t. And we’ll be able to see what treatment patterns make an impact.
The DiRECT Trial: Finding a Practical Management Solution for Primary Care: The Primary Outcome Results of DiRECT
Mike Lean, BChir (University of Glasgow, UK)
Dr. Mike Lean presented highly-anticipated one-year data from the DiRECT trial (n=298), reporting that 24% of participants receiving intensive weight loss intervention (36 out of 149) achieved ≥15 kg (~33 lbs) weight loss, and that 46% of this treatment arm (68 individuals) achieved diabetes remission. No member of the control group achieved that level of weight loss (p<0.0001 for comparison), though 4% (6 out of 149) did achieve diabetes remission with a mean 5% body weight reduction (p<0.0001 for comparison). In DiRECT, intensive weight loss intervention was a combination of withdrawal of anti-diabetic and anti-hypertensive drugs, total diet replacement with an ~800 calorie/day meal plan for three-five months, stepped food reintroduction for two-eight weeks, and structured support for long-term weight maintenance. Average weight loss for the intervention group was 14.5 kg (~30 lbs) after meal replacement, and average weight regain at 12 months was ~2 kg (~4.4 lbs). In those losing ≥15 kg, a striking 86% achieved diabetes remission. These results have been discussed some time, with talks describing the aims of DiRECT at Diabetes UK 2017 and EASD 2017, and we must say, we did not necessarily expect such encouraging success from the trial – we will be very interested to see longer-term results, of course. An intervention delivered by modestly-trained usual care providers that eliminates current and future need for pharmacotherapy is very intriguing, particularly from a health economic perspective as well as a health equity perspective – we also would’ve been interested in understanding what might’ve been possible with a combination approach with metformin and other easy drugs to prescribe and take that will be going generic over the next decade, like SGLT-2 inhibitors (particularly since some in this class now have established cardioprotection). We’ll be curious to see cost-savings projections for these 149 intensively-treated patients, and Dr. Lean announced that economic analyses are underway. That said, this protocol will be difficult for many to follow – Dr. Lean shared that 32 participants dropped out due to the intervention’s demands, or, presumably, lack of appeal. Ultimately, it only seems applicable in diabetes that has been diagnosed relatively recently – Dr. Roy Taylor shared in discussion that shorter duration of diabetes predicted responders vs. non-responders in a subgroup of DiRECT. Overall, Dr. Lean later clarified that people with longer duration of diabetes who lose a substantial amount of body weight can achieve diabetes remission, although the best results appear in individuals with shorter disease duration. All participants were from the UK, so it’s unclear how calorie reversal would affect diabetes status in more diverse populations (not that the UK isn’t diverse). Two- and three-year data from DiRECT are still being collected, and we look forward to future readouts. All in all, we did find these to be inspiring results – in the words of Dr. Lean, “as good as or even better than results from bariatric surgery.” We don’t expect mainstream diabetes remission clinics to pop up anytime soon, but this does seem to be a fruitful area of research, particularly given increased interest in “intermittent” fasting, etc. Notably, one-year DiRECT findings were simultaneously published in the Lancet online, alongside a positive editorial: “Remission of type 2 diabetes: mission not impossible.”
Symposium: Latest Cardiovascular Clinical Trials
New Insights from EXSCEL
Angelyn Bethel, MD (University of Oxford, UK)
EXSCEL investigator Dr. Angelyn Bethel presented new analyses excluding drop-in medication use in the placebo group. When SGLT-2 inhibitors, SUs, or “any medication” were excluded, AZ’s GLP-1 agonist Bydureon (exenatide once-weekly) gave a significant reduction in three-point MACE. Session chair Dr. J Hans DeVries reminded the audience that EXSCEL reported neutral CV results at EASD, although the p-value was “marginal” for CV superiority (HR=0.91, 95% CI: 0.83-1.00, p=0.06 for superiority). The new results announced at IDF indicate that concomitant medication use in the placebo arm of EXSCEL – which was at the discretion of the usual care provider, and only prohibited GLP-1 agonists – may have had small effects on risk, theoretically reducing the detectable effect size. Indeed, metformin, SUs, insulin, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists all had at least 5% drop-in rates in the placebo group. Analyses censoring these patients at time of drop-in were used to estimate new hazard ratios and 95% confidence intervals. When censoring sulfonylurea use out of the placebo arm, the hazard ratio point estimate for three-point MACE became 0.89 (95% CI: 0.81-0.98, p=0.022). For SGLT-2 inhibitors, the hazard ratio post-censoring became 0.91 (95% CI: 0.83-1.00, p=0.046). And for “any medication,” the hazard ratio post-censoring became 0.88 (95% CI: 0.80-0.98, p=0.022). Thus, the magnitude of the hazard ratio/risk reduction was not changed, but statistical significance did increase, with a shift to the left of unity in favor of Bydureon. Results on all-cause death were consistent with primary results (HR=0.88, 95% CI: 0.77-0.97, p=0.016): Significant effects were seen from censoring SUs (HR=0.84, 95% CI: 0.75-0.95, p=0.007), SGLT-2 inhibitors (HR=0.86, 95% CI: 0.77-0.97, p=0.016), and any medication (HR=0.84, 95% CI: 0.73-0.96, p=0.009), but also from censoring DPP-4 inhibitors, insulin, GLP-1 agonists, and GLP-1 agonists + SGLT-2 inhibitors. While EXSCEL was not properly powered for these analyses, which assume that new medications were continued once started (Dr. Bethel identified this as a limitation before diving into the post-hoc findings), we do find the results compelling. EXSCEL’s narrow miss for superiority has been attributed, by many thought leaders, to the pragmatic nature of the trial (the intervention was delivered in usual care settings), a larger primary prevention cohort (27% of participants), a lack of patient-friendliness in dosing Bydureon (lengthy mixing/reconstitution was required with the single-dose kits), and the wide range of concomitant drug use allowed – this last suspicion is at least partially validated by these results. This post-hoc analysis joins one presented by Dr. Robert Mentz at AHA 2017, showing that Bydureon’s effects were consistent across baseline risk quintiles. We eagerly await more looks at the data to come over the next few years, which will hopefully clarify the benefits of exenatide across a diverse spectrum of clinical scenarios.
Dr. Bethel also presented a meta-analysis of four reported CVOTs for a GLP-1 agonist, suggesting significant class effects on three-point MACE (non-fatal MI, non-fatal stroke, or CV death), CV death, and all-cause death. The results were simultaneously published online in the Lancet Diabetes & Endocrinology. For three-point MACE, a 10% relative risk reduction was calculated (HR=0.90, 95% CI: 0.82-0.99, p=0.033). Tests for heterogeneity among trials were moderate (Q-test p=0.11, I2=50%), indicating that the meta-analysis was statistically appropriate and this effect was likely robust for the GLP-1 agonist class. Of note, the ELIXA CVOT for Sanofi’s lixisenatide used a primary outcome of four-point MACE (also including hospitalization for unstable angina) – Dr. Rury Holman thus excluded ELIXA and presented a meta-analysis of LEADER (Novo Nordisk’s liraglutide), SUSTAIN 6 (Novo Nordisk’s semaglutide), and EXSCEL (AZ’s exenatide) in his commentary at EASD, reporting a relative risk reduction of 12% for three-point MACE across the three longer-acting agents (HR=0.88, 95% CI: 0.81-0.95, p=0.002). All-cause death was reduced by 12% across the four trials vs. placebo (HR=0.88, 95% CI: 0.81-0.95, p=0.002, Q-test p=0.63, I2=0%), and CV death was reduced by 13% vs. placebo (HR=0.87, 95% CI: 0.79-0.96, p=0.007, Q-test p=0.43, I2=0%). We’ve come to think of EXSCEL for AZ’s Bydureon (exenatide once-weekly) as confirming CV safety while hinting at CV efficacy for GLP-1 agonist agents, and this meta-analysis supports this overarching message, though of course the limitations of meta-analysis must be considered in interpreting the results. By nature, a meta-analysis can be driven by particularly strong – perhaps outlier – results in one direction or the other, but on the whole, we’re encouraged by what Dr. Bethel called fair heterogeneity among the trials.
- Safety endpoints of particular interest were also positive. The odds ratio was 0.93 for severe hypoglycemia with any GLP-1 agonist product vs. placebo (95% CI: 0.74-1.18), 0.90 for pancreatitis (95% CI: 0.63-1.28), and 0.83 for pancreatic cancer (95% CI: 0.33-2.11). There was a neutral effect overall on fatal and nonfatal MI (HR=0.94, 95% CI: 0.86-1.03), fatal and nonfatal stroke (HR=0.87, 95% CI: 0.75-1.00), hospitalization for heart failure (HR=0.93, 95% CI: 0.83-1.04), and hospitalization for unstable angina (HR=1.09, 95% CI: 0.90-1.32). Notably, where SGLT-2 inhibitors are showing efficacy in reducing heart failure for people with diabetes, GLP-1 agonists are firmly demonstrating safety. At ESC 2017, Dr. Naveed Sattar mentioned the very low likelihood that any company will launch a dedicated study of a GLP-1 agonist in heart failure, in contrast to the recently-initiated outcomes trials of SGLT-2 inhibitors Jardiance (Lilly/BI’s empagliflozin) and Farxiga (AZ’s dapagliflozin) toward a heart failure indication.
New Insights from the ACE TRIAL
Rury Holman, MD (University of Oxford, UK)
Dr. Rury Holman presented new analyses of ACE, the CVOT of Bayer’s alpha-glucosidase inhibitor Glucobay (acarbose) which reported neutral CV outcomes vs. placebo but significant risk reduction for new-onset type 2 diabetes in a population with prediabetes in China (n=6,526). Full results from the trial were presented at EASD 2017 in Lisbon, and Dr. Holman expanded on these prior data with a new on-treatment analysis and a new reverse analysis – that is, how many individuals were able to revert to normoglycemia? After five years, 59% of acarbose-treated patients presented a normal result on a glucose tolerance test vs. 54% of placebo-treated patients, corresponding to a favorable rate ratio of 1.26 (95% CI: 1.13-1.40, p<0.0001). This lends further support to the notion that acarbose could have applications in prediabetes, following the initial finding of an 18% relative risk reduction for new-onset diabetes over five years (HR=0.82, 95% CI: 0.71-0.94, p=0.005). An on-treatment analysis for new-onset diabetes showed “even more impressive results,” according to Dr. Holman, with a rate ratio of 0.79 (95% CI: 0.68-0.92, p=0.0017). Notably, participants enrolled in ACE had a prior history of CV events, and delaying/preventing type 2 diabetes in this population could be especially important because further progression of hyperglycemia would greatly exacerbate their CV risk (a diabetes diagnosis confers similar risk for premature death as having a previous MI). ACE represents a successfully completed outcomes study in a prediabetes population, which should also set an example for the field as we push for more clinical research into effective strategies for earlier intervention – not only to avoid diabetes, but also to avoid hard outcomes like stroke, MI, hospitalization for unstable angina or heart failure, and CV death. J&J announced plans for a prediabetes CVOT of SGLT-2 inhibitor Invokana (canagliflozin), though we’ve heard no updates on this project since the company’s 3Q16 update, while Novo Nordisk just recently announced plans for an obesity CVOT of GLP-1 agonist semaglutide (now FDA-approved for type 2 diabetes as Ozempic). Dr. Holman established the high unmet need for prevention efforts in China, where almost half of the adult population has prediabetes – that’s ~500 million people! We’d very much like to see pharmacotherapy utilized for diabetes prevention in China and elsewhere, and to this end, we’ll be curious to see if ACE results extend to a more diverse, global population outside of China, as prediabetes is certainly a worldwide epidemic by this point.
- During Q&A, Dr. Holman shared his view that prediabetes is indeed a CV risk marker. Several sessions at IDF have focused on CV risk reduction for people even before they progress to diabetes (see our coverage of a talk by Dr. Jaakko Tuomilehto in this report), and we wonder if this interest from thought leaders foreshadows additional clinical trials in prediabetes populations. We see tremendous value in these investigations, especially when they collect data on outcomes more so than biomarkers, because there’s no reason we should be waiting until patients exhibit multiple CV risk factors before we intervene to prevent CV morbidity/mortality.
Symposium: Prediabetes and Macrovascular Impact
Is Prediabetes a Cardiovascular Risk State or Only a Transient State to Indicate Progression to Type 2 Diabetes?
Jaako Tuomilehto, MD, PhD (Dasman Diabetes Institute, Kuwait City, Kuwait)
Dr. Jaakko Tuomilehto, a highly-esteemed expert in diabetes prevention, showed how postprandial glucose (measured by a two-hour post-meal test) may be the best predictor of CV outcomes in people with prediabetes. The overarching takeaway from his talk was that prediabetes itself confers CV risk – many of these individuals will have a CV event before onset of type 2 diabetes, so we should be intervening earlier with CV risk reduction strategies. Dr. Tuomilehto focused most of his presentation on the DECODE study (n=55,000 people across 22 sites and 11 countries in Europe), but also called out recently-published EUROSPIRE IV (n=4,004), in which two-hour postprandial glucose was significantly correlated with CV outcomes in a population with coronary artery disease but no diabetes, while neither A1c nor fasting plasma glucose showed a statistically significant association with MACE (non-fatal MI, non-fatal stroke, CV death, or hospitalization for heart failure) over two years. In DECODE, researchers found a linear relationship between two-hour postprandial glucose and all-cause mortality. If the risk of death with known diabetes is mapped to a hazard ratio of 1.00, then a two-hour postprandial reading <95 mg/dl was associated with a hazard ratio of 0.47, a reading between 95-112 mg/dl was associated with a hazard ratio of 0.50, and this increased steadily until a reading >200 mg/dl was associated with a hazard ratio of 0.92. No such linear relationship was seen between fasting plasma glucose and all-cause mortality. For example, fasting glucose <85 mg/dl mapped to a hazard ratio of 0.58, fasting glucose between 85-105 mg/dl mapped to a slightly lower hazard ratio of 0.52, and a fasting glucose between 105-110 mg/dl mapped to a slightly higher hazard ratio than that, at 0.56. Dr. Tuomilehto also broke down DECODE results by different categories of death. When impaired glucose tolerance was defined by a two-hour meal test, the rate ratio for CV death was 1.34, and this was barely changed when also adjusting for fasting plasma glucose (1.32). The rate ratio was 1.26 for fatal stroke, and this was barely changed to 1.21 when also adjusting for fasting plasma glucose, suggesting that the latter has little to no effect in linking prediabetes hyperglycemia to mortality outcomes. Notably, UNC’s Dr. John Buse presented a contrasting opinion at Keystone 2017, arguing that A1c is a better predictor of CV events for people with prediabetes, rather than fasting or two-hour glucose. Italy’s Dr. Antonio Ceriello spoke right after Dr. Tuomilehto during this IDF symposium, and also pointed to some conflicting evidence, ultimately concluding that it’s still “an open question” whether postprandial glucose is an independent risk factor for CV disease. That said, he acknowledged that evidence is accumulating, and indeed, with a growing emphasis in the field on prediabetes and prevention, we’re hoping that further analyses and meta-analyses will elucidate answers here.
- Above all, Dr. Tuomilehto, Dr. Buse, Dr. Ceriello, and numerous other thought leaders agree that prediabetes should be considered a risk state for CV morbidity/mortality. As Dr. Ceriello put it, “CV risk mitigation is becoming a central goal in diabetes management, and maybe it should also be the goal of prediabetes management.” This consensus is very important. The correlation with macrovascular outcomes could compel payers and regulators to recognize prediabetes as a disease. This would make it easier to get drugs indicated for prediabetes, and that might prompt more real-world HCPs to treat for prevention, while also encouraging people at-risk for diabetes to seek care sooner. Turning to a Finnish study (n=504), Dr. Tuomilehto reported a CV event rate of 8 per 1,000 patient-years across the cohort with prediabetes, which rose only to 9.3 events per 1,000 patient-years when looking at all participants with prediabetes or diabetes. Again, the key takeaway was that CV risk is already substantially elevated for the individual with hyperglycemia even if it’s not quite at the level where we define type 2 diabetes. “There are people with impaired glucose tolerance who are developing CV disease before they develop diabetes,” Dr. Tuomilehto explained, and added “this is a category where we should focus interventions, because it’s where things happen.”
Symposium: New Pharmacologic Approaches to Treatments of Type 2 Diabetes
Antiglycemic Medication: What is in the Pipeline
J Hans DeVries, MD, PhD (Academic Medical Center, Amsterdam, Netherlands)
Dr. J Hans DeVries shared exciting details on Novo Nordisk’s oral insulin and on Merck’s glucose-responsive insulin, suggesting that both represent promising future innovations in diabetes therapy. Shortly after Novo Nordisk discontinued its oral insulin candidate 338 in 3Q16, management attributed this decision not to lack of efficacy in phase 2 trials, but to cost of goods. Dr. DeVries confirmed this in his presentation, showing how you need ~350x the amount of insulin in an oral capsule to achieve the same pharmacokinetics as a subcutaneous insulin injection (absorption is significantly slower through the GI tract – still, this surprised us). He highlighted key advantages of oral insulin, which are pretty obvious – namely, that oral administration is more patient-friendly than injectable administration, and that it’s actually more physiologic since subcutaneous insulin bypasses hepatic clearance and therefore presents at much higher concentrations in the blood – but underscored that these benefits come at a high price for the manufacturer. On the (very) bright side, Dr. DeVries announced that Novo Nordisk is likely working to make the absorption process more efficient to reduce ~350x to a more reasonable level, and a more reasonable cost of goods (this was also unsurprising given that otherwise it would be impossible to commercialize). Overall, we’ve gathered from management at the company that they haven’t shut the door on oral insulin despite the 3Q16 discontinuation, given how transformative this could be for people with diabetes, and we were thrilled to hear further assurance of this from Dr. DeVries. He also reviewed preclinical results on Merck’s glucose-responsive insulin (GRI) candidate, presented on a poster at ADA 2017 (study in eight dogs). Notably, Merck discontinued its phase 1 glucose-responsive insulin MK-2640 in 2Q17, and this data was on another agent which doesn’t yet appear on the company’s pipeline page. According to Dr. DeVries, however, Merck has initiated phase 1 clinical studies of this other GRI, which will hopefully be presented at a scientific meeting in 2018. This was a second piece of good news on the diabetes pipeline, since we weren’t sure if Merck would invest further in glucose-responsive insulin following the discontinuation of MK-2640. Both oral and glucose-responsive insulin are challenging therapeutic propositions, but the payoff of these drugs could be tremendous, reducing injection burden (and daily burden of diabetes), improving quality of life, and enhancing the overall quality of diabetes care available to patients in the real world. These candidates are early-stage, and it’s important to note that neither actually appears in the public-facing pipeline from Novo Nordisk or Merck, so we’ll try to temper our enthusiasm for now.
GLP-1 RA and Insulin Combination
Samit Ghosal (Nightingale Hospital, Calcutta, India)
Dr. Samit Ghosal captured the benefits of basal insulin/GLP-1 combination therapy by focusing on the composite endpoint of proportion of patients who reach A1c goal <7% without weight gain or hypoglycemia. A meta-analysis published in 2012 (by first author Dr. Bernard Zinman) found that 40% of patients (n=1,513) randomized to 1.8 mg liraglutide (Novo Nordisk’s GLP-1 agonist Victoza) achieved this metabolic composite vs. 33% of patients (n=1,077) on 1.2 mg liraglutide, 15% of patients (n=225) on basal insulin glargine (Sanofi’s Lantus), and only 8% of patients randomized to placebo (n=505). Summarizing data from the DUAL program on Novo Nordisk’s Xultophy (insulin degludec/liraglutide fixed-ratio combination), Dr. Ghosal showed how 80% of participants randomized to the combination product achieved A1c <7% without weight gain or hypoglycemia – he added that this is “not something we’ve been able to achieve with traditional molecules.” This metabolic composite has clear clinical relevance, as glucose control, weight control, and risk reduction for hypoglycemia are all key components of diabetes management. Dr. Ghosal cited ADA, EASD, and AACE guidelines, all of which recommend treating to target A1c while also prioritizing weight loss (or at the very least, avoiding weight gain) and minimizing hypoglycemia. Moreover, weight gain and fear of hypoglycemia are common factors contributing to low medication adherence, to treatment dissatisfaction, and to poor quality of life for people with diabetes. By establishing the value of this composite endpoint, and by demonstrating that we now have an emerging therapy class that shows greater benefit on this endpoint than any drug that has come before, Dr. Ghosal made an extremely compelling case for basal insulin/GLP-1 fixed-ratio combination products (the class also includes Sanofi’s Soliqua, a fixed-ratio of insulin glargine/lixisenatide). By and large, thought leaders have expressed enthusiasm for Xultophy and Soliqua, and Dr. John Buse went so far as to suggest that Novo Nordisk’s IDegLira may be “the most effective anti-hyperglycemic agent on the planet.” Still, commercial uptake of these products has been sluggish to-date (mainly due to perceptions of combos and Novo Nordisk’s decision to price the basal/GLP-1 combo very high and to emphasize the specific components of Tresiba and Victoza more than the combo), and we can only hope that improved reimbursement and greater HCP familiarity with fixed-ratio combinations leads to a steeper incline in volume/sales for the class in 2018. Dr. Ghosal emphasized the cost issue, explaining that >90% of his patients in India pay out of pocket for drugs, which keeps basal insulin/GLP-1 combinations (or even co-administration of the two agents separately) out of reach.
- Dr. Ghosal called DUAL VII, comparing Xultophy vs. basal-bolus therapy (insulin glargine/insulin aspart), “the most ambitious study” in this clinical program, and then proceeded to review the positive results. Novo Nordisk simultaneously issued a press release highlighting this data. Full results from DUAL VII were a major highlight at this year’s ADA Scientific Sessions, when Dr. Liana Billings reported non-inferior A1c-lowering, half-size total daily insulin dose, greater weight loss, and less hypoglycemia with Xultophy vs. basal-bolus. At IDF, Dr. Ghosal specifically called out the “practically negligible” GI side-effects with Xultophy compared to a standalone GLP-1 agonist. Patient-reported outcomes from the trial also favored Xultophy over a basal-bolus regimen: After 26 weeks of the study, 85% of people in the Xultophy arm were “very” or “extremely” willing to continue treatment vs. 68% of people in the basal-bolus arm, and mean improvement on diabetes management, treatment burden, and compliance (quantified by the Treatment-Related Impact Measure-Diabetes questionnaire and the Short Form Health Survey 36 v2) was significantly greater with Xultophy vs. basal-bolus therapy.
Symposium: Cardiovascular Benefit of Glucose-Lowering Agents
Hirotake Watada, MD, PhD (Juntendo University, Tokyo, Japan)
Dr. Hirotaka Watada presented two Japanese studies demonstrating beneficial effects of alogliptin (Takeda’s DPP-4 inhibitor Nesina) and sitagliptin (Merck’s Januvia) in reducing carotid intima-media thickness (cIMT) vs. placebo in patients with type 2 diabetes and no established CV disease. He pointed to a potential CV benefit when these agents are used early in the course of disease – which, coincidentally, is when thought leaders recommend them the most. While the SAVOR-TIMI, EXAMINE, and TECOS studies of Onglyza (AZ’s saxagliptin), Nesina, and Januvia all found a resoundingly neutral impact of these DPP-4 inhibitors on three-point MACE (despite mixed and controversial results on heart failure), Dr. Watada presented a series of compelling studies that aim to reopen the book on cardioprotection for the class. While the aforementioned CVOTs only enrolled high-risk patients or those with established CV disease, who would tend to have advanced atherosclerosis, Dr. Watada published two papers last year evaluating DPP-4 inhibitors earlier in the course of diabetes, both using cIMT as a measure of atherosclerosis. The SPEAD-A trial (n=322) randomized patients with type 2 diabetes not in glycemic control and free from apparent CV disease to two years of either alogliptin or conventional treatment, measuring cIMT at intake and one and two years. At 102 weeks, the treatment effect of alogliptin was -0.031 on mean IMT (95% CI: -0.058 to -0.005, p=0.019), -0.065 on right max-IMT (95% CI: -0.114 to -0.016, p=0.01), and -0.070 on left max-IMT (95% CI: -0.114 to -0.014, p=0.008). Similarly, the SPIKE trial (n=274) enrolled patients with type 2 diabetes not in glycemic control and on insulin, without apparent CV disease, and randomized them to either sitagliptin or placebo. At 102 weeks, the treatment effect of sitagliptin was -0.029 on mean IMT (95% CI: -0.090 to -0.016, p=0.005) and -0.065 on left max-IMT (95% CI: -0161 to -0.014, p=0.021). Right max-IMT was not significantly reduced with sitagliptin. Thus, two DPP-4 inhibitors have been shown to attenuate the progression of atherosclerosis in common carotid arteries vs. placebo in patients with type 2 diabetes without established CV disease. These effects are all the more important when one considers the increase in IMT seen in the placebo group. That said, the beneficial reductions in atherosclerosis with alogliptin and sitagliptin have not been directly linked to improved macrovascular outcomes, making the clinical significance unclear. While these are relatively short and small trials (compared to a full CVOT) in a very homogeneous Japanese population, we are encouraged to see evidence supporting the early use of DPP-4 inhibitors for CV benefit. Moreover, this trial could have particular implications in Japan, where DPP-4 inhibitors are often-prescribed. Also to his point, Dr. Watada mentioned a cohort study (n=~104,000) in Taiwan, published in 2016, showing a significant CV benefit with sitagliptin. We wouldn’t be surprised if trial design were a big factor in demonstrating benefit here, and we’ll keep our eyes peeled for more on this front.
Symposium: The Role of the Brain in Metabolic Regulation
UCSF’s Dr. Allison Xu and University of Ulsan College of Medicine’s Dr. Min-Seon Kim presented riveting data investigating the role of the brain in metabolic regulation. While still very early-stage, these exciting developments may point to new therapies, promising highly specific drug targets. This important research also underscores the substantial complexity of obesity – as Dr. Xu noted, our bodies fiercely defend an adiposity set point via myriad pathways, making it extremely difficult to lose weight. Read on for some of our top takeaways of the session.
Adaptive Mechanisms Underlying Body Adiposity Linked to Ageing to Diet-Induced Obesity
Allison Xu, PhD (University of California, San Francisco, CA)
Dr. Xu presented fascinating data on the cellular mechanisms underlying body adiposity, highlighting AgRP neurons as likely first responders to short-term metabolic changes, and POMC neurons as engaging in long-term energy homeostasis alterations. Following consumption of a high-fat diet, changes in AgRP neurons were quickly exhibited in mice, with severely reduced leptin signaling observed at just two days; POMC neurons took longer to reveal an impact, demonstrating only moderate decreased signaling (albeit significant) at two weeks. As a reminder, leptin is a key hormone in metabolic homeostasis that promotes feelings of fullness. Here, the brain is shown to ignore these signals in response to a high-fat diet, prompting the mice to continue eating.
- Dr. Xu also detailed pathways contributing to age-dependent increases in body adiposity. In mice, both body fat and leptin levels increase with age under normal feeding conditions. This struck Dr. Xu as odd –if leptin is increasing, which ostensibly signals the individual to feel full, shouldn’t body fat decrease? Dr. Xu reasoned there must be some counter-regulatory mechanism antagonizing leptin’s anorexigenic action. Interestingly, in middle-age mice, AgRP neurons are observed to concentrate to specific targets in the brain, a process known as innervation. POMC neurons are among these targets of age-specific AgRP innervation, and as a result are shown to decrease firing frequency. The same phenomenon occurs in young mice on a high-fat diet, suggesting diet-induced obesity to operate via a similar pathway as age-dependent adiposity.
The Role of Hypothalamic Inflammation in Diet-Induced Obesity
Min-Seom Kim, PhD (Ulsan College of Medicine, South Korea)
Dr. Kim discussed how microglia, astrocytes, and macrophages contribute to hypothalamic inflammation, known to be associated with diet-induced obesity by resulting in impairment of leptin and insulin signaling. Microglia are rapidly activated in the hypothalamic arcuate nucleus following a high-fat diet, suppressing POMC neuronal function. Inhibiting microglia action prevents weight gain in mice on a high-fat diet, strongly suggesting their role in diet-induced obesity. While microglia show increases at three days due to a high-fat diet, macrophages are also present at higher concentrations in the arcuate nucleus of diet-induced obese mice, but lag slightly behind, taking roughly two weeks to exhibit enhanced proliferation. Astrocytes increase quickly in the hypothalamus in response to a high-fat diet. By suppressing the macrophage response in diet-induced obese mice, hypothalamic leptin resistance is improved, resulting in decreased food intake and body weight.
Symposium: New Insulins and Innovative Insulin Delivery
Options to Improve Insulin Absorption in the Subcutaneous Tissue
Lutz Heinemann, PhD (Profil Institute, Neuss, Germany)
Dr. Lutz Heinemann covered current efforts to accelerate insulin absorption and action. He reviewed Adocia’s BioChaperone insulin lispro, shown to result in a 61% reduction in postprandial glycemic excursions, as well as Novo Nordisk’s Fiasp (faster-acting aspart), which he believes has a particularly bright future. He was also encouraged by Lilly’s ultra-rapid insulin, just moved into phase 3, which uses a substance known to treat pulmonary hypertension. While he was optimistic regarding these attempts to improve insulin formulation, he was not so positive about advances in mechanical delivery systems. Insuline’s InsuPad, a disposable patch for insulin injections, automatically delivers localized heat to the injection site, aiming to increase internal blood flow and accelerate insulin absorption. The patch received its CE mark back in 2008, but has been off the radar for a few years now. Dr. Heinemann noted its initial commercial success, but confessed he is unsure of InsuPad’s future – as far as we know, the device has not been cleared in the US, and we imagine wearing something else on the body for incremental benefit is a deal-breaker for most. Intradermal application (as opposed to traditional subcutaneous injection) via 1-1.5mm microneedles has also been shown to induce enhanced insulin absorption. BD cancelled this project, though there are some such applications in development within academia level. Dr. Heinemann also noted data suggesting that “insulin spreading” results in faster absorption, referencing a study demonstrating nine injections of two units to act faster than one injection of 18 units. This is a product of larger surface area:volume ratio, and a piece of the rationale behind the sprinkler-type infusion set cannulas. A needle-free system promoting insulin spreading has been tested, but was ultimately not brought to market due to an unpleasant noise upon injection. While the lack of tangible progress for patients is unfortunate, we’re seeing more investment in this area than we have historically. For now, we can only preach good practices: Site rotation, 4-mm needle, etc.
- Dr. Heinemann also highlighted his study aiming to visualize lipohypertrophy via thermography. The prevalence of lipohypertrophy varies significantly, ranging from 16%-60%. Dr. Heinemann believes this is likely because lesions are often not visible, requiring palpation to detect. Lipohypertrophy can pose substantial challenges, as insulin injected into affected skin areas exhibits decreased absorption rates, translating to higher postprandial glycemic excursions. Dr. Heinemann hopes his approach will improve identification of lipohypertrophy by distinguishing cooler areas in the patient’s body.
- In the same session, Dr. Jothydev Kesavadev reviewed previous, current, and future insulin delivery systems. He was particularly excited about Medtronic’s Advanced Hybrid Closed Loop (previously called “690G”) with Dreamed’s Fuzzy Logic, referring to the promise of automated correction boluses as a “dream come true.” Dr. Kesavadev was also very encouraged by Bigfoot’s hybrid closed loop efforts, underscoring the benefits of the company’s auto-titration system (“Inject”) to MDI users. He also spoke highly of Beta Bionics’ system, which he considers to be highly effective and especially user-friendly, as it requires minimal user input and is easy to set up (just body weight). In addition to advances in delivery devices, Dr. Kesavadev also covered new insulins, noting that Fiasp will be the insulin of choice for both pumps and hybrid closed loop systems.
Teaching Lecture: Novel Advances in Treatments for Diabetic Nephropathy
Novel Advances in Treatments for Diabetic Nephropathy
Janaka Karalliedde, BChir (King’s College London, UK)
Dr. Janaka Karalliedde suggested that GLP-1 agonists and SGLT-2 inhibitors may hold the greatest promise for the next generation of therapies for diabetes-related nephropathy. He provided a thorough tour of the diabetic nephropathy competitive landscape, specifically noting AbbVie’s phase 3 endothelin-receptor antagonist atrasentan and several late-stage mineralocorticoid receptor antagonists, including Bayer’s phase 3 finerenone and Daiichi Sankyo’s phase 3 esaxerenone. Still, Dr. Karalliedde was most impressed by the renal risk reduction seen in recent GLP-1 and SGLT-2 CVOTs. Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) showed a significant 22% relative risk reduction for the composite renal outcome (new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement therapy, or death due to renal disease) in LEADER (HR=0.78, 95% CI: 0.67-0.92, p=0.003), while the company’s second-generation GLP-1 agonist semaglutide (recently approved as Ozempic) showed a 36% relative risk reduction for nephropathy in SUSTAIN 6 (HR=0.64, 95% CI:0.46-0.88, p=0.005). To-date, all reported CVOTs of an SGLT-2 inhibitor have reported evidence of renal protective effects. This includes a 39% relative risk reduction for nephropathy in the EMPA-REG OUTCOME trial of Lilly/BI’s Jardiance (empagliflozin), as well as a 40% relative risk reduction for the composite renal outcome (renal death, renal replacement therapy, or 40% reduction in eGFR) in the CANVAS trial of J&J’s Invokana (canagliflozin). To this end, all three SGLT-2 inhibitors on the market have a dedicated renal outcomes trial either planned or ongoing: The CREDENCE trial for Invokana is enrolling patients with comorbid type 2 diabetes/kidney disease, and is expected to complete the soonest, in June 2019. The Dapa-CKD trial for AZ’s Farxiga (dapagliflozin) is enrolling patients with CKD both with and without type 2 diabetes, and is expected to complete in November 2020. Lastly, a soon-to-begin trial of Jardiance will recruit patients with CKD both with and without type 2 diabetes; Lilly/BI have not yet specified timing. Interestingly, SGLT-2 inhibitors are currently contraindicated in patients with low eGFR, but Dr. David Fitchett clarified at ESC 2017 that this is not because of safety concerns, but rather a presumed loss of efficacy with impaired kidney function. Dr. Fitchett hinted that people with diabetes and eGFR <60 ml/min/1.73m2 may actually stand to benefit the most from SGLT-2 therapy, in terms of CV and renal outcomes alike, and Dr. Karalliedde expressed similar, distinct optimism for the renal protective benefits of SGLT-2 inhibitors, as well as GLP-1 agonists. The potential for these advanced diabetes drug classes in nephropathy is noteworthy, especially as dedicated drug development for kidney disease has been slow, with no new therapies approved since irbesartan and losartan in 2000. We also appreciated Dr. Karalliedde’s mention of atrasentan. Separately, we’re intrigued by this candidate as AbbVie’s phase 3 SONAR study has a unique trial design, excluding early non-responders to demonstrate maximum efficacy in responders.
Meet-the-Expert: Incretins and their Pleiotropic Actions
Tina Vilsbøll, MD (University of Copenhagen, Denmark)
The great Dr. Tina Vilsbøll argued that a GLP-1 agonist needs to be continuously available and acting to have a significant impact on CV disease, which could explain the mix of positive and neutral CVOT results for the class. Sanofi’s Adlyxin (lixisenatide) is short-acting – and the agent showed no CV benefit in ELIXA – while Novo Nordisk’s liraglutide (Victoza) and semaglutide (Ozempic; just FDA-approved!) are long-acting, and demonstrated CV efficacy in LEADER and SUSTAIN 6 respectively. The REWIND study for Lilly’s Trulicity (dulaglutide) will shed more light on this hypothesis (expected to complete in July 2018), as dulaglutide is another long-acting GLP-1. Interestingly, Novo Nordisk CSO Dr. Mads Thomsen has speculated that REWIND will report neutral findings on the primary outcome of three-point MACE because of the low baseline A1c (mean ~7.3%), relatively short duration of diabetes (mean ~10 years), and large size primary prevention cohort (only ~31% of study participants had established CV disease at baseline). That said, if Dr. Vilsbøll’s proposed explanation is correct, might we see significant risk reduction in the secondary prevention cohort of REWIND on par with LEADER and SUSTAIN 6? Dr. Vilsbøll made clear that there are key molecular differences between liraglutide, semaglutide, and dulaglutide, even though they all have greater homology to human GLP-1 vs. exendin-4-based exenatide and lixisenatide. Novo Nordisk has been promoting this molecular variation between human GLP-1-based agents and exendin-4-based agents for some time, and while this opinion has generated a fair amount of controversy in the field (with some thought leaders downright rejecting it), there is inherent logic in Dr. Vilsbøll’s argument: You should get more benefit when a drug is active all the time. To Dr. Thomsen’s point, trial design is clearly an important factor in whether a CVOT will demonstrate benefit. Dr. Vilsbøll noted that EXSCEL for AZ’s Bydureon (exenatide once-weekly) met its primary endpoint when patients in the placebo group taking SGLT-2 inhibitors were removed from analyses, but added “that’s not the way we do science.” Another valid claim, though we do think it’s meaningful that EXSCEL might have shown CV efficacy with some tweaks to the CVOT design, as this keeps very open the possibility of a cardioprotective class effect for GLP-1 agonists. To this end, we should also mention that neutral trials like ELIXA and FREEDOM-CVO for Intarcia’s ITCA 650 were designed purely as safety studies.
- Dr. Vilsbøll made a compelling case for widespread use of liraglutide and semaglutide with number needed to treat (NNT) data. She shared that the NNT to prevent one CV death, non-fatal MI, or non-fatal stroke was 66 patients for three years with liraglutide and 45 patients for two years with semaglutide. While these numbers may seem high, Dr. Vilsbøll aptly pointed out that the NNTs for statins and ACE inhibitors are actually higher, but those medications are still prescribed nearly ubiquitously.
- Dr. Vilsbøll also presented preclinical evidence supporting an anti-atherosclerotic mechanism for the CV benefit seen with GLP-1 agonists. In mouse models, liraglutide has been shown to inhibit early atherosclerotic lesion development, and both liraglutide and semaglutide have been shown to reduce aortic plaque lesion area in mice on a high fat, high sugar diet. While these experiments could never be done in humans, observational data can provide marked insight. In a study of atherosclerotic plaques collected during carotid endarterectomy from patients without diabetes (n=30), with diabetes who have never used incretins (n=28), and with diabetes who were current incretin users (n=24), significant differences were seen in plaque stability. Inflammation (TNF-alpha) and oxidative stress (nitrotyrosine) were significantly reduced in current incretin users vs. never users, though both groups were higher than controls. Current incretin users also had significantly higher collagen content than never users; both were lower than controls. While this is a small, non-randomized, non-controlled group, it’s not the first suggestion we’ve heard for the anti-atherosclerotic effects of GLP-1 agonist products, and it contributes valuable mechanistic knowledge to our understanding of this class and its groundbreaking CV benefits.
Debate: Should SGLT-2 Inhibitors be the First-Line Therapy for Type 2 Diabetes?
André Scheen, MD, PhD (University of Liege, Belgium) & Guntram Schernthaner, MD (Rudolfstiftung Hospital Vienna, Austria)
In front of a packed room, Drs. André Scheen and Guntram Schernthaner debated a provocative question currently facing the diabetes field: Should SGLT-2 inhibitors be first-line therapy? Dr. Scheen spoke first, taking the “pro” stance, highlighting the clinical benefits to SGLT-2 inhibitors, the limitations of metformin (to say nothing of SFU’s!), and the limitations of incretin-based drugs (that part was more surprising). Dr. Schernthaner followed, arguing that there’s insufficient evidence for SGLT-2 inhibitors to replace metformin as the first-line therapy recommendation in diabetes treatment guidelines, though he supported the use of SGLT-2 agents as second-line therapy for people with established CV disease.
- Yes: Dr. Scheen started his answer with a question of his own – what are the main objectives in treating type 2 diabetes? In the age of diabetes CVOTs, there’s certainly been a shift toward greater emphasis on outcomes, on micro and macrovascular risk reduction. Lowering A1c is one component of this, but a glucose-centric view of diabetes is no longer acceptable among thought leaders, Dr. Scheen asserted and he posited that SGLT-2 inhibitors show the greatest efficacy in micro and macrovascular risk reduction. There is strong evidence from EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin), from CANVAS for J&J’s Invokana (canagliflozin), and from CVD-REAL, the AZ-sponsored real-world study evaluating outcomes with all SGLT-2 inhibitors, including Farxiga (dapagliflozin). Dr. Scheen speculated that the class may show benefits in primary CV prevention as well, based on the fact that only 13% of CVD-REAL participants had established CV disease at baseline. A recent post-hoc analysis of CANVAS also found that heart failure and renal outcomes were reduced with canagliflozin in the study’s primary prevention cohort. Moreover, SGLT-2 agents have demonstrated profound weight reduction and blood pressure-lowering. Dr. Scheen alluded to the common safety argument in defense of metformin as first-line (i.e. this agent has been on the market for ~60 years and its safety/tolerability is thus well-established), but suggested that SGLT-2 inhibitors are very safe as well, with a manageable risk for genital mycotic infections in females (he didn’t mention the CANVAS amputation signal, which Dr. Schernthaner picked up on during his remarks). Metformin’s positioning as first-line treatment for diabetes is largely based on UKPDS, Dr. Scheen explained, which should be challenged by the current data on SGLT-2 inhibitors. These agents weren’t on the market at the time of UKPDS, but have churned out impressive outcomes data in the past couple years. He also pointed out that baseline A1c in UKPDS was relatively low, at 7.2%, which isn’t the case for the average real-world patient today – and a higher starting A1c is all the more reason to use a more effective therapy as first-line. Dr. Scheen acknowledged the powerful efficacy of GLP-1 agonists, but highlighted their ~three-fold cost vs. SGLT-2 inhibitors as well as their injectable administration, which would deter some people from starting on a GLP-1 as their initial medicine for diabetes.
- No: Dr. Schernthaner refuted that SGLT-2 inhibitors show superior glycemic effects vs. metformin in all cases, and in fact, he called into question the durability of A1c-lowering with SGLT-2 agents. He pointed out that real-world treatment discontinuation is more common for SGLT-2 inhibitors (25%) compared to metformin (only 8%), GLP-1 agonists (20%), and DPP-4 inhibitors (17%), which suggests safety/tolerability concerns, from genital mycotic infections, to dehydration, to DKA, bone fractures, and amputations. Notably, the FDA has only issued a black box warning for lower limb amputations on the Invokana label, but the EMA has applied the same warning across the class. Cost was Dr. Schernthaner’s most compelling argument, in our view though with SGLT-2s going generic in the next decade and DPP-4s even sooner, we don’t think cost should be the primary determinant, particularly since the cost of the drugs is dwarfed by the costs of complications they could avoid. As we’ve learned in our explorations of why sulfonylureas still appear in treatment algorithms, guidelines cannot ignore cost considerations, since the vast majority of type 2 diabetes patients face some sort of access/affordability issues in their medical care. To this end, we’d love to see a cost-savings analysis on first-line intervention with SGLT-2 inhibitors, because annual hospitalizations for heart failure also run an astronomical bill. We appreciated Dr. Schernthaner’s balanced view (he even highlighted the increased longevity associated with metformin in some studies of people without diabetes), and his ringing endorsement of SGLT-2 inhibitors as second-line treatment in patients with established CV disease. We’re glad to hear that SGLT-2 therapy for CV protection is not as controversial as the first-line debate, considering the promising support for a class effect from EMPA-REG, CANVAS, and CVD-REAL, not to mention the high unmet need in addressing residual CV risk in people with diabetes.
Using Advanced Machine Learning to Predict HbA1c Control with Basal Insulin and Glucagon-like Peptide-1 Receptor Agonist (P-0488)
K Rhee, A Shaunik, D Alevras, S Balodi, J Thellin Skyberg, S Kumar, T Fan, F Barbe, J Beers, I Dankwa-Mullan, C Brulle-Wohlheuter
In this busy poster, lead author Dr. Kyu Rhee (IBM Chief Health Officer) and colleagues used advanced machine learning techniques on the IBM Explorys dataset (n=~108,000 T2D patients on insulin+GLP-1 combo therapy from EMRs of 39 major integrated care systems in US) to identify clinical and nonclinical factors affecting response to basal insulin+GLP-1 combo therapy. 3,300 of the 7,600 patients (43%) included in the study with valid A1c results achieved “successful A1c control,” defined as A1c ≤7% or ≥1% drop in A1c over at least a 180-day continuous treatment without DKA or hyperosmolar syndrome. Pictured below are the top 20 predictive factors of success after intensification to the combo therapy, and the authors singled out a few: (i) A trend of decreasing systolic blood pressure in the year prior to the start of the therapy; (ii) Decreasing BMI or a high standard deviation of BMI; (iii) Increasing A1c in the year prior to treatment; (iv) Patients in higher population density areas saw greater success; and (v) Patients whose last treatment was ≤50 days prior to combo therapy saw greater success. Interestingly, variability of body surface area and body weight in the year prior to the start of the period are the strongest predictors of success – the directionality is not specified, i.e., is low standard deviation positively correlated with success, or high? We imagine the latter, given the BMI trend noted above – though neither were discussed in the poster. The authors were careful to point out that this was a retrospective, population-level study that can’t be validated at the individual level, and called for future studies using large real-world clinical datasets with long term data to explore additional factors. There is clearly much work to be done, but we love the data driven approach to precision care – and the fact that all of the inputs are already in the EMR means that providers wouldn’t have to take on more work to reap the benefits should algorithms be implemented. The vision here is very compelling: IBM Watson could recommend a treatment at the point-of-care, given a patient’s recent history and what it knows about other patients. This is what Watson does in oncology and we see very obvious, high potential value in type 2 diabetes prescribing. Moving forward, we’d like to see other medicines included in the analysis, and hopefully outcomes beyond A1c one day (if they ever make it into EMRs). What if the patient and provider could together choose the suite of outcomes that matters to them, and then have the algorithm churn out the best drug to help that patient meet her goals? Clearly, we’re excited about the possibilities…
- We are dying to know how much this analysis costs to perform. It seems like a no-brainer to use cognitive computing to get to the heart of what treatment is best for what patient and when, and at the advantage of not having to enroll a single patient or pay for a single drug. We also wonder what the partnership between Sanofi and IBM Watson looks like – how does it compare to the Novo Nordisk and Medtronic partnerships? Is the Sanofi iteration more of an R&D effort, while the others are more commercial?
- The authors emphasize that the results can’t be validated at the individual level, but we wonder just how predictive they are. If a patient who had decreasing systolic blood pressure, decreasing BMI, and lives in an area of high population density, what is the probability she will respond well to basal insulin+GLP-1 therapy? What if she lives out in the countryside (low population density), but has all the other things in place – what is the probability that she will respond now?
Real-World Observational Study to Evaluate Probability of Achieving Glycaemic Control in Patients with Type 2 Diabetes (P-0489)
L Blonde, L Meneghini, A Boss, K Rhee, A Shaunik, I Dankwa-Mullan, S Kumar, S Hensley Alford, S Balodi, M Chorev, C Brulle-Wohlheuter, R McCrimmon
Ochsner’s Medical Center’s Dr. Lawrence Blonde et al. analyzed clinical EMR data from 5,936 type 2 diabetes patients in the IBM Explorys dataset – each had intensified treatment from an oral to a first basal insulin prescription with or without oral continuation. They assessed time to reach “glycaemic control” (A1c ≤7%) and percentage of patients reaching A1c ≤7%. From a baseline of mean ≥9.2% (depending on medication subcohort; a high baseline probably reflecting clinical inertia), ~20% of patients had reached goal after six months of treatment; at 12 months, ~29% had reached goal. After six months, the probability that patients would achieve target within the next three-month period dropped considerably: 10.9% in months 6-9, 5.7% in months 9-12, and just 1.9%-3.5% over the next year (see below). The results are not limitation-free, but taken as is, there are two main, potentially antagonistic, takeaways: (i) The data suggest that, if target A1c hasn’t been met as early as 6-12 months after basal insulin initiation, alternate therapeutic strategies should be investigated, or (ii) insulin doses are not being up-titrated aggressively enough. To the first point, there are now fixed-ratio combination therapies that show much greater efficacy and ease of use with less hypoglycemia and less weight gain, and to the second point, the data remind us that insulin is still an incredibly difficult drug to dose safely and starting conservative makes a lot of sense – assuming the doses are quickly and continuously updated if glucose does not get to target. We see tremendous potential for basal insulin titration software to empower physicians and patients, make them feel more secure using insulin, and thereby reduce clinical inertia. We would also love to know which insulins were used by the patients in the study – is goal achievement more likely with newer insulins?
Semaglutide is More Efficacious than SGLT-2 Inhibitors in Patients with Type 2 Diabetes Inadequately Controlled with Metformin: A Network Meta-Analysis (P-0013)
S Kanters, L Wilkinson, S Lopes, E Popoff, JP Jansen, M Barazandegan, UJ Ploug
A Novo Nordisk poster compared GLP-1 agonist semaglutide vs. SGLT-2 inhibitors, finding more powerful A1c-lowering efficacy in type 2 diabetes for the GLP-1 – which, coincidentally, was just FDA-approved as Ozempic. This meta-analysis encompassed 19 phase 3 studies (n=13,329), all of which enrolled participants with type 2 diabetes inadequately controlled on metformin, and all involving randomization to either semaglutide (0.5 mg or 1 mg) or an SGLT-2 inhibitor (canagliflozin 100 mg and 300 mg, dapagliflozin 2.5 mg, 5 mg, and 10 mg, and empagliflozin 10 mg and 25 mg). As illustrated in the figure below, both doses of semaglutide showed greater A1c reductions than any of the SGLT-2 inhibitors at both 26 weeks and 52 weeks. Interestingly, dapagliflozin showed the most modest effect on A1c, with slightly greater A1c-lowering efficacy for canagliflozin and empagliflozin on an absolute numeric basis (although this analysis was not meant to show statistical differences between different SGLT-2 inhibitors, and this wasn’t reported). In line with semaglutide’s superiority in reducing A1c from baseline, both doses of the agent were statistically superior to all SGLT-2 inhibitors in achieving the target A1c of ≤7% at 26 weeks. In fact, further mathematical modeling demonstrated that semaglutide has between 70%-80% higher probability of achieving this A1c goal than any of the SGLT-2 inhibitors. Novo Nordisk’s clinical program for semaglutide has included a number of head-to-head comparisons, and Ozempic has now shown superior glycemic efficacy to AZ’s GLP-1 agonist Bydureon (exenatide once-weekly), to Lilly’s GLP-1 agonist Trulicity (dulaglutide once-weekly), to Merck’s DPP-4 inhibitor Januvia (sitagliptin), and to Sanofi’s basal insulin Lantus (insulin glargine) in RCTs, in addition to this meta-analysis pointing to advantages over SGLT-2 inhibitors. Demonstrating superiority to some of the most commonly-used diabetes drugs and to some of the most advanced is no small feat, bolstering Ozempic’s already-impressive clinical profile. That said, we note that this poster should not diminish our impression of the clinical benefits of SGLT-2 inhibitors, which set a high bar for semaglutide to top.
- This meta-analysis also evaluated weight loss with semaglutide vs. SGLT-2 inhibitors. Semaglutide 1.0 mg was significantly more efficacious in reducing body weight relative to all SGLT-inhibitors at 26 weeks (~11 lbs with semaglutide vs. ~4-8 lbs with an SGLT-2 inhibitor), but lost significance for the comparison with respect to dapagliflozin 5 mg at 52 weeks. At ~8 lbs decline in body weight, semaglutide 0.5 mg also had a favorable weight loss profile at both 26 weeks and 52 weeks, but only achieved statistically significant superiority with respect to dapagliflozin 2.5 mg and empagliflozin 10 mg (both at 26 weeks). Notably, semaglutide is being developed for a dedicated obesity indication, and the phase 3 STEP program is scheduled to begin in 1H18. In our view, these results indicate the weight loss efficacy of SGLT-2 inhibitors as well, but there’s no doubt from clinical data collected so far that semaglutide comes with a meaningful weight loss benefit. Novo Nordisk also plans to conduct a CVOT of semaglutide in obesity; this would be the first study to establish medical obesity as a chronic disease.
Risk Reductions Across Hypoglycemia Definitions with Insulin Degludec vs. Insulin Glargine U100 in SWTICH 1 and 2
J Gumprecht, C Wysham, W Lane, LN Troelsen, D Tutkunkardas, S Heller
A new post-hoc analysis of the SWITCH 1 and 2 trials found that Novo Nordisk’s Tresiba (insulin degludec) was associated with fewer hypoglycemia episodes vs. Sanofi’s Lantus (insulin glargine) for people with type 1 and 2 diabetes alike, regardless of A1c. The results, presented on a poster and also highlighted in a company press release, demonstrate that the estimated rate ratios for severe, nocturnal, and overall hypoglycemia for people with type 1 and type 2 diabetes in the SWITCH program (all of which favor the next-gen Tresiba over current standard of care Lantus) were identical after statistical adjustment for fluctuations in A1c throughout the trial, as illustrated in the table below. These rate ratios reflect a significant risk reduction for hypoglycemia with Tresiba across all categories for people with type 1 diabetes in the SWITCH 1 trial, and for overall and nocturnal hypoglycemia for people with type 2 diabetes in the SWITCH 2 trial (risk reduction for severe hypoglycemia trended in favor of Tresiba, but did not reach statistical significance). Furthermore, the analysis indicates that there was less hypoglycemia with Tresiba regardless of whether participants had an A1c above or below the target of 7%. For people with type 1 diabetes and an A1c ≤7%, observed rates of hypoglycemia were numerically lower with Tresiba vs. Lantus (overall [22 vs. 26 events per patient-year of exposure], nocturnal [2 vs. 4], and severe [0.6 vs. 0.9]) and the same held true for their counterparts with A1c >7% (overall [22 vs. 22], nocturnal [3 vs. 5], and severe [0.8 vs. 0.9]). This was also the case for people with type 2 diabetes and A1c ≤7% (overall [1.6 vs. 2.8], nocturnal [0.5 vs. 1.0], and severe [0.09 vs. 0.1]) as well as A1c >7% (overall [2.1 vs. 2.5], nocturnal [0.6 vs. 0.9], and severe [0.01 vs. 0.06]). Hypoglycemia and fear of hypoglycemia are major barriers to initiation and adherence in the context of insulin therapy – by reducing this risk, Tresiba represents a major win for patients. It’s certainly reassuring to know that Tresiba’s hypoglycemia benefit is consistent regardless of A1c. These results add to the impressive body of evidence around hypoglycemia risk reduction for this next-generation basal insulin. To this end, a hypoglycemia claim for Tresiba has been approved in the EU and an FDA decision on a similar revision to the US label is expected in 1Q18, based on the SWITCH studies as well as the landmark DEVOTE trial.
Factors Associated with Hypoglycemia in 12,679 Patients Starting Second-Line Therapy: The Global DISCOVER Study (P-0101)
W Rathmann, B Charbonnel, MB Gomes, N Hammar, K Khunti, M Kosiborod, O Kuss, MV Shestakova, H Watada, I Shimomura, F Tang, L Ji
A poster displayed results from the real-world DISCOVER study correlating first-line sulfonylurea use with increased hypoglycemia. This program was presented in full during a Tuesday afternoon symposium at IDF, and Dr. Linong Ji reviewed background and rationale for the study, including one aim to assess hypoglycemia (among other relevant clinical outcomes) in 15,922 diabetes patients initiating second-line therapy around the world (from 38 different countries, to be exact). Dr. Ji also presented this poster focused on hypoglycemia findings from the global sample, and showed how individuals prescribed an SU as first-line treatment were nearly four times as likely to experience an episode of hypoglycemia vs. individuals prescribed metformin first-line (odds ratio=3.71, 95% CI: 3.04-4.53). People taking an SU/DPP-4 inhibitor together as first-line were still more than twice as likely to experience hypoglycemia vs. people taking metformin first-line (odds ratio=2.43, 95% CI: 1.43-4.15). In this sample, 7,712 people took metformin as their first agent for diabetes, while 3,514 took a sulfonylurea either alone or co-adminstered with another drug, and 273 took SU/DPP-4 combination therapy. In the overall DISCOVER study, 17% of participants were prescribed a combination of metformin/sulfonylureas as first-line, while 8% were prescribed SU monotherapy. A recent Diabetes Care paper reported that 8% of adult patients in the US took sulfonylureas as first-line therapy in 2016, and that sulfonylureas remain the most common second-line agent, accounting for 46% of second-line prescriptions. This all goes to show that sulfonylurea use is still widespread and pervasive, despite evidence highlighting the significant hypoglycemia risk. The class has also been associated with weight gain, beta cell burnout, and possible CV harm, and as we understand it, cost considerations are the only factor keeping these agents in rotation for diabetes care. As even more data accumulates linking sulfonylureas to costly complications like hypoglycemia, both from head-to-head RCTs and real-world observational studies, we hope HCPs, payers, and guideline-writers are watching, and are switching patients from sulfonylureas to a safer alternative that’s also more effective in the long term (since beta cell burnout leads to an attenuation of the glucose-lowering effect over time). TZDs come to mind as another now-generic therapy class (low-dose pioglitazone has even shown CV risk reduction in the IRIS trial), and our fingers are crossed that as generic DPP-4 inhibitors arrive on the market in the next ~5-10 years, that these weight-neutral, hypo-neutral oral agents will replace sulfonylureas as earlier interventions for diabetes. That said, IDF also featured an engaging debate on whether SGLT-2 inhibitors should be first-line in diabetes management, now that multiple products have demonstrated cardioprotection and a meaningful heart failure benefit. As newer, more advanced agents, SGLT-2 inhibitors are more expensive, but we imagine the profound weight loss, A1c-lowering, and CV/renal protection could absolutely be cost-saving in the long run for certain patients when initiated early.
- Hypoglycemia was more common in individuals with a history of microvascular (odds ratio=1.33, 95% CI: 1.07-1.65) or macrovascular disease (odds ratio=1.31, 95% CI: 1.03-1.66), highlighting the overlap between hypoglycemia and other diabetes complications. The relationship between hypoglycemia and adverse CV outcomes has been of particular interest since a post-hoc DEVOTE analysis (for Novo Nordisk’s next-gen basal insulin Tresiba) found heightened risk for CV death in the aftermath of severe hypoglycemia (HR=2.14, 95% CI: 1.37-3.35). This finding adds weight to the importance of outcomes beyond A1c, including glycemic variability, and we imagine it’ll be immensely valuable for the beyond-A1c movement going forward to have real-world evidence (like DISCOVER) corroborating conclusions from RCTs.
- This poster also showed how experiencing even a single hypoglycemia episode caused a significant increase in related worries and behaviors (including therapy avoidance) as measured by the Hypoglycemia Fear Survey-II (HFS-II). Worries rose 2.5x with a prior hypoglycemia event (odds ratio=2.51, 95% CI: 1.23-3.79) while behaviors + worries rose nearly four-fold (odds ratio=3.96, 95% CI: 1.75-6.18). Drawing on these results, Dr. Ji emphasized the importance of considering hypoglycemia risk and fear in making treatment decisions for the individual patient. Indeed, these findings fall in line with the commonly-cited data that 58% of type 2 diabetes patients lower their insulin dose following a severe hypoglycemia episode, and that 72% of PCPs and 79% of diabetes care specialists would treat hyperglycemia more aggressively if fear of hypoglycemia wasn’t a factor.
Efficacy and Safety of Dapagliflozin +/- Saxagliptin versus Glimepiride as Add-On to Metformin in Type 2 Diabetes (P-0106)
D Müller-Wieland, M Kellerer, K Cypryk, D Skripova, K Rohwedder, E Johnsson, R Garcia-Sanchez, R Kurlyandskaya, CD Sjöström, S Jacob
A poster comparing combination therapy with AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) + DPP-4 inhibitor Onglyza (saxagliptin) vs. glimepiride pointed to the inferior glycemic efficacy, significant weight gain, and significant hypoglycemia risk associated with sulfonylureas. This study, DapaZu, was completed in March 2017 according to ClinicalTrials.gov, randomizing 939 patients on background metformin to dapagliflozin, dapagliflozin + saxagliptin, or glimepiride for 52 weeks. The average participant was 57-59 years-old with an A1c of 8.3%, fasting plasma glucose of ~190 mg/dl, body weight between ~202-213 lbs, and BMI of 33 kg/m2. After one year of treatment, the combination approach showed superior A1c reductions vs. glimepiride (1.2% vs. 1%, p<0.001), while dapagliflozin monotherapy was non-inferior to glimepiride on this endpoint (0.8% vs. 1%). Fasting plasma glucose declined by a mean ~35 mg/dl in the combination arm vs. ~25 mg/dl in the SU arm (p<0.001), and standalone dapagliflozin again showed non-inferiority. Both dapagliflozin-containing regimens did significantly better on weight loss compared to the sulfonylurea: Body weight dropped ~8 lbs for patients on dapagliflozin only, while patients on glimepiride gained ~4 lbs on average over 52 weeks (p<0.001). The magnitude of weight loss was just barely smaller in the dapagliflozin/saxagliptin group, at ~7 lbs, but this was still superior to weight gain with glimepiride (p<0.001). Hypoglycemia was much more common in the SU arm of the trial, with symptomatic events <70 mg/dl occurring in 216 of 312 patients (a whopping 69%) – only 7 of 312 people in the combination group (2%) and only 1 of 313 people in the SGLT-2 only group (<1%) experienced this endpoint. In our view, the weight gain and hypoglycemia associated with sulfonylureas are enough to deter patients/HCPs from this drug class, and we note that glimepiride is actually one of the “better” agents in the class according to thought leaders. Dr. Irl Hirsch has suggested that glimepiride confers the least hypoglycemia risk of all sulfonylureas, and still 69% of study participants taking it had one or more episodes. On the flip side, DapaZu underlines the weight loss efficacy of SGLT-2 inhibitors, to say nothing of the profound A1c-lowering that occurs without excess hypoglycemia. As head-to-head data vs. sulfonylureas accumulates (we saw a fair amount at EASD this year), we’re hoping that more patients are switched to a safer, more effective diabetes therapy. SUs remain the most-often prescribed second-line diabetes drug in the US and are also very commonly prescribed globally. This poster was particularly intriguing to us because both SGLT-2 inhibitors and DPP-4 inhibitors have been proposed as alternative first-line agents (though metformin is the recommended first-line currently, 8% of first-line diabetes prescriptions in the US were for sulfonylureas in 2016).
- Sulfonylureas have also been associated with attenuated glycemic efficacy over the long term, as they spur beta cell burnout. For this reason, we imagine that longer study duration may have revealed significantly superior A1c-lowering for dapagliflozin vs. glimepiride as well as dapagliflozin/saxagliptin vs. glimepiride. Two ongoing outcomes studies promise to illuminate this longer-term impact of SU treatment: (i) Lilly/BI’s CAROLINA CVOT compares DPP-4 inhibitor Tradjenta (linagliptin) head-to-head vs. glimepiride, and is expected to complete in March 2019, while (ii) the NIH-funded GRADE study compares outcomes between basal insulin, DPP-4, GLP-1, and SU, and the last patient visit is expected around April 2021.
- AZ has also developed Qtern, a fixed-dose combination of dapagliflozin/saxagliptin. The product is available in Europe, though it has not yet launched in the US despite FDA approval in March 2017.
Effect of Ertugliflozin on A1c, Body Weight, and Systolic Blood Pressure: Results from the VERTIS Program (P-0104)
R Pratley, B Lauring, S Terra, R Calle, S Huyck, J Liu, H Makimura, J Mancuso
A meta-analysis covering six phase 3 studies of Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin was presented on a poster. All part of the VERTIS clinical program, these studies enrolled 4,395 adults with type 2 diabetes in total. Across VERTIS MONO, VERTIS MET, VERTIS SITA, VERTIS SITA2, and VERTIS FACTORIAL, ertugliflozin demonstrated superior A1c reductions vs. its comparator. The only exception was VERTIS SU, the focus of an oral presentation at EASD by Dr. Brett Lauring, in which 15 mg ertugliflozin demonstrated non-inferiority vs. glimepiride on the primary A1c endpoint after 52 weeks (as we note in our coverage of an AZ poster above, sulfonylureas are thought to cause beta cell burnout over the long term, leading to attenuated glycemic efficacy – were VERTIS SU a longer trial, it may have produced a different result, perhaps superiority for the SGLT-2 inhibitor). Weight loss was consistently greater with ertugliflozin vs. its comparator in all six trials, as was systolic blood pressure decline. Safety findings were as expected, with no major imbalance in adverse events with the exception of genital mycotic infections occurring more often in the ertugliflozin group. The timing of this meta-analysis is noteworthy, as an FDA decision on ertugliflozin is expected by end of year (Merck/Pfizer’s New Drug Application was accepted for active review this past March). The candidate’s clinical profile seems to match what we know about the SGLT-2 class, with profound benefits to A1c, body weight, and blood pressure. The VERTIS CV study is ongoing to evaluate CV safety (or possible cardioprotection), with an expected completion date of October 2019.
Satellite Symposium: Evolving Strategies for Early, Effective Glycemic Control in Type 2 Diabetes (Sponsored by Sanofi)
A Sanofi-sponsored symposium was rich with real-world data on next-gen basal insulin Toujeo, as speakers dissected the results of the LIGHTNING study and the DELIVER-D study, two retrospective observational analyses comparing the safety/efficacy of Toujeo vs. Novo Nordisk’s Tresiba based on electronic medical records and claims data. The LIGHTNING study (which boasts the title of largest real-world comparative study in diabetes to-date) evaluated EMR data from April 2015 to December 2016 from >130,000 adults with type 2 diabetes who switched from one basal insulin to another. In this real-world setting, rates of severe hypoglycemia were significantly lower in participants who switched to Toujeo vs. those switching to Lantus (3.6 vs. 9.7 events/100 patient-years, p=0.009) or Levemir (3.6 vs. 15.1 events/100 patient-years, p=0.002), and were comparable vs. those switching to Tresiba (3.4 vs. 5.3 events/100 patient-years, p=0.37). The risk reduction for severe hypoglycemia with Toujeo vs. Lantus and Levemir occurred without any compromise to glycemia, as A1c did not change significantly after any basal insulin switch. Notably, this is just the tip of the iceberg for the LIGHTNING project (we first heard about this exciting endeavor at EASD), which is expected to produce more data over the coming months utilizing machine learning techniques to define the patient segments in which Toujeo provides the greatest hypoglycemia differentiation vs. comparators, and to evaluate the medical cost-savings for these populations. Similarly, the DELIVER-D study evaluated data from a different EMR source, evaluating 2,893 people with type 2 diabetes who switched their basal insulin prescription to Toujeo or Tresiba from March 2015 to December 2016. After adjusting for baseline hypoglycemia, the overall hypoglycemia event rate was equivalent between Toujeo and Tresiba arms (0.50 vs. 0.51 events per person per year, p=0.88), as was the event rate for hypoglycemia associated with hospitalization (0.17 vs. 0.18 events per person per year, p=0.82). Furthermore, both Toujeo and Tresiba produced a significant 0.5% improvement in A1c over six weeks of follow-up, and participants on Toujeo and Tresiba were equally likely to attain the A1c targets of <7% (13% vs. 16%, p=0.24) and <8% (44% vs. 45%, p=0.92). Presumably, these real-world findings bode well for Sanofi and for the Toujeo business. Still, we can’t imagine DELIVER-D would have the same commercial influence as a hypoglycemia claim for Tresiba (approved in the EU, decision on US label expected in 1Q18) based on the RCT DEVOTE. Still, the health economic analysis from LIGHTNING could well have substantial impact, unveiling cost-savings in specific patient segments, which should be appealing to payers.
- To complement this real-world data, the symposium also covered the recent BRIGHT study, the first RCT to compare the next-generation basal insulins Toujeo and Tresiba head-to-head; full results are expected in 2018. The study randomized people with type 2 diabetes (n=929) to Toujeo or Tresiba for 24 weeks; all participants were naïve to insulin therapy with an A1c above goal on oral agents or a GLP-1 agonist. Sanofi also announced topline findings in a press release yesterday, underscoring that the BRIGHT study met its primary endpoint of similar A1c reductions with Toujeo vs. Tresiba. Secondary endpoints include the percentage of participants experiencing adverse events, the rate of hypoglycemia episodes, and a variety of patient-reported outcomes from the Diabetes Treatment Satisfaction Questionnaire (DTSQ). We have long speculated about how the two next-generation insulins stack up against one another, so needless to say we are eagerly awaiting the readout of this first head-to-head RCT. Still, we must keep in mind that this is a Sanofi-sponsored trial, so we’ll have our eyes peeled for any elements of study design that might favor Toujeo over Tresiba or the opposite. Our interest is especially piqued for the secondary endpoint of hypoglycemia: To-date, Tresiba appears to have the edge on this front, boasting an impressive hypoglycemia benefit vs. Lantus in both the DEVOTE trial and the SWITCH 1 and 2 trials, but it is impossible to be sure since Tresiba and Toujeo have never been directly compared in the same RCT. From our view, it’s critically important not to miss the forest for the trees we believe both insulins are much better than predecessors Lantus and Levemir and both would be major advantages.
Satellite Symposium: Fixed-Ratio Combinations: A Practical Approach to Individualized Care (Sponsored by Sanofi)
Individualizing Care Through Titratable Fixed-Ratio Combination Treatment Approaches
Juan Frias, MD (National Research Institute, Los Angeles, CA)
During a Sanofi-sponsored symposium, Dr. Juan Frias reviewed key data on fixed-ratio combination Soliqua (basal insulin glargine/GLP-1 agonist lixisenatide), highlighting the drug’s benefits to A1c, adherence, patient quality of life, and the composite outcome of A1c ≤7% without weight gain or hypoglycemia. He discussed post-hoc analyses of the phase 3 LixiLan program showing dramatic A1c reduction for Soliqua-treated patients with baseline A1c ≥9%. From a mean of 9.5% at baseline, this cohort reached a mean 7% A1c with Soliqua vs. 7.6% with Lantus (insulin glargine) after 30 weeks. Soliqua demonstrated superior glycemic efficacy vs. component monotherapies in all subgroups regardless of baseline A1c, but Dr. Frias suggested that HCPs should particularly consider the fixed-ratio combination product for their patients with very high starting A1c. He positioned Soliqua as a simpler option for treatment intensification vs. basal-bolus therapy, given the single injection. In his slides, he included graphs displaying the inverse relationship between complexity of medication regimen and adherence: Patients prescribed one dose/day take 79% of doses on average (which we point out is already rather low), and adherence declines to an abysmal 51% when patients are prescribed four doses/day. Dr. Frias established the importance of adherence for long-term clinical outcomes in diabetes. Drug tolerability is another critical aspect to patient quality of life, and he explained how GI side-effects (nausea, vomiting, diarrhea) are much milder with insulin glargine/lixisenatide together vs. lixisenatide alone, because Soliqua allows for very gradual dose escalation of the GLP-1 component. He emphasized the decreased frequency of hypoglycemia and the neutralized weight gain with the fixed-ratio combination vs. basal insulin monotherapy, which are extremely important outcomes beyond A1c. Considering all these factors together, Dr. Frias shared that ~33% of Soliqua-treated patients achieved A1c ≤7% with no weight gain or severe hypoglycemia. He seemed quite impressed with this number, although Dr. Samit Ghosal announced on day #2 of IDF that ~80% of patients on Novo Nordisk’s fixed-ratio combination Xultophy (insulin degludec/liraglutide) achieved the same composite. In response, Dr. Frias emphasized the different definitions of hypoglycemia used in the LixiLan program for Soliqua (<70 mg/dl) vs. the DUAL program for Xultophy (<56 mg/dl) – on the surface, this would lead to more recorded hypoglycemia in the LixiLan trials, and Dr. Frias cautioned against over-comparison between “apples and oranges.” To be sure, there’s been no head-to-head study comparing Soliqua and Xultophy, and there’s a lack of standardization across these clinical trials. Moreover, we don’t think the focus should be on in-class competition at all, but rather whole class growth, since sales of both Soliqua and Xultophy have trended below expectations since launch in January and May 2017, respectively. We did find it notable that both Dr. Frias and Dr. Ghosal underscored the effects of basal insulin/GLP-1 fixed-ratio combos on the composite endpoint of A1c ≤7% without weight gain or hypoglycemia, as this could be considered the sweet spot for this emerging therapy class.
Satellite Symposium: Improving Cardiovascular Outcomes in Patients with Type 2 Diabetes: Applying New Evidence in Practice (Sponsored by BI)
Heart failure and kidney disease in type 2 diabetes: where can new evidence lead us?
Subodh Verma, MD, PhD (St. Michael’s Hospital, Toronto, Canada)
If there was any doubt that heart failure imposes a huge burden for people with diabetes, University of Toronto cardiologist Dr. Subodh Verma set the record straight. In fact, he advocated for much more focus on non-ischemic CV events from the diabetes field. He displayed graphs showing how rates of atherosclerotic CV events, namely MI (heart attacks) and stroke, have actually declined somewhat in the past 20 years for even the diabetes patient population. Meanwhile, heart failure has been contributing more to CV mortality among people with diabetes. In another study, heart failure was found to be the most common CV complication associated with diabetes, and Dr. Verma emphasized that it was also the most “disabling” and “deadly” – not only is the frequency of heart failure elevated for the diabetes patient population, but the prognosis is poor. The takeaway from this data, as Dr. Verma put it, is that both ischemic and non-ischemic CV events are a challenge in diabetes care: he showed near-equivalent prevalence of heart failure and ischemic complications. Despite recent gains in cardioprotective therapy (Dr. Verma specifically mentioned better anti-platelet agents and better stents), people with diabetes still face high residual risk for stroke/MI compared to the background population, and we’re certainly not done optimizing anti-atherosclerotic treatment for diabetes patients. But Dr. Verma referred to heart failure as “the elephant in the room,” too long ignored as an important CV outcome in the context of diabetes. He suggested that the field has been “fixated” on ischemia, and that this has largely overshadowed heart failure. Indeed, there’s nothing in the FDA’s 2008 CVOT guidance that stipulates heart failure should be investigated, and the most common primary endpoint in diabetes CVOTs completed so far has been atherosclerosis-oriented three-point MACE (non-fatal MI, non-fatal stroke, and CV death). We’ve heard arguments from many thought leaders recently that heart failure should be a primary endpoint in diabetes CVOTs (Dr. Jens Øllgaard at EASD 2017, who pointed out the irony of heart failure being left out of the FDA guidance, Drs. Bertram Pitt and John McMurray at AHA 2017, among others), and DECLARE (for AZ’s SGLT-2 inhibitor dapagliflozin) will be the first. This commentary is certainly valuable in increasing awareness of the diabetes/heart failure overlap (which is clearly necessary, given how the heart failure burden persists), and we’re pleased to see this education happening from day #1 at IDF.
- Dr. Verma elaborated that there’s a high rate of subclinical heart failure in diabetes patients. Compared to atherosclerosis, diastolic dysfunction appears earlier on in the course of disease progression. He outlined the mechanistic underpinnings: heart failure arises in diabetes due to the direct effects of glucotoxicity and insulin resistance on the myocardium, leading to diabetic cardiomyopathy. According to Dr. Verma, this timeline occurs much earlier than the timeline of atherosclerosis in diabetes, and it occurs independently from coronary disease. In a study like CANVAS (CVOT for J&J’s SGLT-2 inhibitor canagliflozin), even people in the primary prevention cohort may have had underlying diastolic dysfunction. “We call them primary vs. secondary prevention, but that’s from an atherosclerotic point of view,” Dr. Verma explained. To this end, he highlighted a recent post-hoc analysis of CANVAS presented at AHA, which found that canagliflozin’s beneficial effects on heart failure hospitalization appeared in both primary and secondary prevention subgroups. The hazard ratio for this endpoint was 0.68 in the secondary prevention cohort (95% CI: 0.51-0.90) vs. 0.64 in the primary prevention cohort (95% CI: 0.35-1.15). In contrast, the primary prevention subgroup did not experience significant benefit with canagliflozin on three-point MACE (HR=0.98, 95% CI: 0.74-1.30). Dr. Verma described how people labeled “primary prevention” weren’t truly primary prevention for heart failure. He reminded the audience that these participants weren’t newly-diagnosed, as they had long duration of diabetes, and this often implies the development of diastolic dysfunction even in the absence of overt atherosclerotic disease.
- During the ensuing panel discussion, Dr. Verma asked “why not?” in considering SGLT-2 agents as first-line treatment for type 2 diabetes, with the caveat that as a cardiologist he’s more accustomed to seeing patients with longer duration of diabetes. Even if this class doesn’t show cardioprotection in a primary prevention population, he suggested that the weight loss, lack of hypoglycemia, and hope for CV benefit should be enough to introduce an SGLT-2 inhibitor into a patient’s medication regimen early on. Once again, he called attention to the recent CANVAS post-hoc, showing canagliflozin’s significant and meaningful risk reduction for heart failure hospitalization regardless of a patient’s history of stroke/MI. The implication here is exciting – if heart failure appears earlier in the course of diabetes development, before atherosclerosis and ischemic events, a pill that counteracts this elevated risk for people with recent-onset diabetes would be tremendous. From this standpoint, SGLT-2 inhibitors as first-line products seems like a no-brainer to us as well, but we await a debate on this topic scheduled for Tuesday at IDF for in-depth arguments and counter-arguments.
- Another key focus of Dr. Verma’s remarks was the tight link between heart failure and renal disease. On one memorable slide, he showed how type 2 diabetes in the absence of kidney disease increases 10-year mortality rate by ~4%. Add albuminuria to diabetes, and this 10-year mortality rate rises ~18%. Add impaired eGFR, and the rate grows to ~24%. With type 2 diabetes, albuminuria, and impaired eGFR, the 10-year morality rate is 47% higher vs. the background population, and is nearly 10x that of people with diabetes but without kidney disease. Moreover, Dr. Verma underscored how heart failure increases risk for renal disease, which in turn worsens prognosis for heart failure events. He established the importance of preventing both these complications in approaches to diabetes management. Interestingly, the same CANVAS post-hoc analysis from AHA found similar risk reduction with canagliflozin for the composite renal outcome as well in both primary and secondary prevention cohorts: The hazard ratio was 0.59 in the secondary prevention subgroup (95% CI: 0.44-0.79) and was 0.63 in the primary prevention subgroup (95% CI: 0.39-1.02), compared to a 40% relative risk reduction across the entire study population (HR=0.60, 95% CI: 0.47-0.77).
- Dr. Verma summarized key details on the ongoing clinical trials of SGLT-2 inhibitors in heart failure and in CKD: EMPEROR HF-Preserved and EMPEROR HF-Reduced for Lilly/BI’s Jardiance (empagliflozin) in heart failure, Dapa-HF for AZ’s Farxiga (dapagliflozin) in heart failure, CREDENCE for J&J’s Invokana (canagliflozin) in diabetic kidney disease, Dapa-CKD for Farxiga in CKD (participants with and without diabetes), and a planned outcomes study of Jardiance in CKD (~5,000 participants with and without diabetes). We highly-recommend a recent JAMA viewpoint authored by Dr. Verma, Dr. John McMurray, and Dr. David Cherney on SGLT-2 inhibitors as a possible “sweet spot” in heart failure management.
- Dr. Verma ended his pre-conference presentation with a powerful quote, calling on cardiologists to adopt cardioprotective diabetes therapies like SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) into their clinical practice: “EMPA-REG OUTCOME reminds me of the 4S study, when we cardiologists were forced to begin understanding that statins now had to be part of our toolbox. We cannot be laggards when it comes to empagliflozin – not too much that we do today can reduce CV mortality by 38%.”
Diabetes Management in the Era of Cardiovascular Outcomes Trials
Steven Kahn (University of Washington, Seattle, WA)
In reviewing the current state of the field on diabetes CVOTs, the very highly regarded Dr. Steven Kahn elucidated fundamental differences between trials – in study design, baseline population, etc. – affirming our strong sense that there’s a lack of standardization around CVOT design, making it difficult (or, pretty much impossible) to compare among studies and come to strong conclusions. In considering the two SGLT-2 inhibitor CVOTs that have reported full results so far, Dr. Kahn pointed out that CANVAS (for J&J’s canagliflozin) enrolled only 66% of patients with established CV disease, while 99% of participants in EMPA-REG OUTCOME (for Lilly/BI’s empagliflozin) started the trial with a history of CV events. Jardiance (empagliflozin) gave a 14% relative risk reduction in three-point MACE (non-fatal MI, non-fatal stroke, or CV death) but Dr. Kahn underscored that only the 38% relative risk reduction in CV death was significant on its own – and only this component of MACE was included on the updated Jardiance label. Non-fatal MI trended in favor of empagliflozin in EMPA-REG OUTCOME, while non-fatal stroke trended in favor of placebo (again, neither of these effects reached statistical significance). In CANVAS, Invokana (canagliflozin) showed a similar 14% risk reduction in three-point MACE, but no component was significant on its own, though all trended in favor of the SGLT-2 inhibitor. Dr. Kahn posited that these varying results could be due to differences in population: More patients in CANVAS had no prior CV events, possibly contributing to a significant reduction in three-point MACE without any component on its own being significant (i.e. with a larger primary prevention cohort, we might expect a lower event rate for CV death and thus less statistical power to show superiority on this component endpoint relative to EMPA-REG). Turning to the GLP-1 agonist CVOTs, Dr. Kahn summarized the positive findings from LEADER (for Novo Nordisk’s liraglutide) and SUSTAIN 6 (for Novo Nordisk’s semaglutide) vs. the neutral findings from EXSCEL (though AZ’s Bydureon only narrowly missed the threshold for superiority) and ELIXA (for Sanofi’s lixisenatide). The differences in trial design and protocol between EXSCEL and LEADER are notable, with a larger primary prevention cohort (27% vs. 19% in LEADER), no run-in period to exclude individuals with low medication adherence, a wide range of concomitant medications allowed (including DPP-4 inhibitors, which were prohibited in LEADER), etc. Dr. Kahn pointed to another notable incongruity between LEADER and SUSTAIN 6: While liraglutide’s MACE benefit was driven by a 22% risk reduction for CV death (other components were not significant), semaglutide’s most impressive CV benefit was a 39% risk reduction for non-fatal stroke. Dr. Kahn didn’t provide an explicit hypothesis to explain this divergence of findings, but we note that SUSTAIN 6 was a small, pre-market trial (n=3,297 vs. 9,340 in LEADER), which introduces more room for chance. Dr. Kahn warned against over-comparison between diabetes CVOTs, even those investigating agents in the same class, and we continue to believe that real clinical pearls would come from one large head-to-head CVOT that compares all drugs, within-class and between-class. As we push toward personalized medicine in diabetes, HCPs need actionable insights on which therapy to match to which patient, and to this end, we need more head-to-head evaluations if not more standardization of CVOT design.
- With a nod to the future, Dr. Kahn expressed excitement for the CARMELINA and CAROLINA, PIONEER 6, and CREDENCE trials. CAROLINA, in particular, could lay to rest the debate over the impact of sulfonylureas on CV events, as this Lilly/BI-sponsored CVOT compares DPP-4 inhibitor Tradjenta (linagliptin) head-to-head vs. glimepiride. While we wouldn’t hope any participants experience CV harm, we do see value in this study for potentially pushing SUs out of treatment algorithms – that said, we also strongly believe the “real-world” experience of SU’s vs. a RCT experience will be different. As a reminder, SU’s have been associated with hypoglycemia, weight gain, beta cell burnout over the long term, and possible CV harm. All this is true even though they remain the most common second-line diabetes prescription in the US due to their low cost. CAROLINA could finally provide the concrete evidence that regulators, payers, and guideline-writers need to see in order to de-prioritize this class; actually, we’d love to see it fall out of use entirely. While many say that is impossible given cost, we’d love a more robust view on the cost front to examine short- and long-term costs associated with SU use.
Satellite Symposium: The Transition to Injectable Therapies: Navigating Clinical and Emotional Challenges in T2DM (Sponsored by Lilly)
Patient Case #1: The Path to Insulin Treatment
Bill Polonsky (University of California, San Diego, CA)
Dr. Bill Polonsky shared major takeaways from the EMOTION study, namely that demonstrating the injection process, explaining the benefits of insulin, and adopting a collaborative communication style are the most effective strategies for getting patients to start and continue on insulin therapy. The EMOTION study (about which we will hear much more this IDF) features a 37-question survey asking 594 geographically diverse type 2s who recently started taking insulin after initial reluctance what convinced them to eventually take the plunge. The results were not surprising, but as Dr. Polonsky pointed out, these are the first ever studies dissecting the factors – bright spots – that help people to start taking insulin. Participants rated providers demonstrating the injection process a 3.07/4 in terms of helpfulness, explaining insulin benefits a 2.97/4, and having a collaborative style a 2.77/4. Dispelling insulin myths (2.77/4), and interestingly, an “authoritarian style” (2.63/4), were also highly rated. Encouragingly, the top three highly-rated actions were also the most commonly observed. Digging a little deeper, demonstrating the injection process was the only action referred to in the survey that was useful in the initiation of insulin, while explaining the benefits of insulin and a collaborative style were more beneficial in preventing the discontinuation of insulin use. A recently-published paper by Dr. Polonsky et al. goes in depth on the question of how to start and maintain insulin therapy, emphasizing that it’s a continual process of proactive follow-up to re-encourage the patient, review injection technique, review the logbook and titrate dose as necessary, and address questions and concerns. Above all, Dr. Polonsky stressed that as busy as “we” (providers) are, it’s always important to take time to be a good listener. The perils of clinical inertia and then maintaining an insulin regimen are all too well documented, so we are very happy to see Dr. Polonsky, UCSF’s Dr. Lawrence Fisher, and others look for what is working. How great would it be if insulin manufacturers began including these tips, and others as they are plucked from the EMOTION results, in supplementary materials targeted at providers? Higher sales volume for pharma, better outcomes for patients, and physicians who are and feel more successful – a winning combination!
- Dr. Polonsky poignantly reminded the audience, to a sea of nods, that people act rationally given their beliefs. In this framework, proper education is one of the best weapons against resistance to starting insulin. “Everyone with diabetes is educated about their diabetes – it just happens that many are mis-educated.” Countless people are under the impression that once they start insulin they won’t be able to stop, insulin therapy will restrict their lives, that they are failures, etc. On the more extreme side, reluctant patients in one study were >2x more likely to believe that insulin can cause blindness. Dr. Polonsky commented that such sentiments are often accompanied by a story – e.g., they know someone who had type 2 diabetes for 30 years without healthcare intervention and without an issue, and then went to a doctor, started on insulin, and developed complications of the feet, kidneys, and eyes. Without proper education, it isn’t too far a leap to surmise that insulin caused these complications. Correcting these misconceptions in a gentle way can go a long way. The devil is in the details from our view; while few would disagree, how can HCPs be systematically trained to address this problem?
Patient Case #1: The Path to Insulin Treatment
Mohamed Hassanein (Dubai Hospital, UAE)
Dubai Hospital’s Dr. Mohamed Hassanein endorsed the International Hypoglycemia Study Group’s glucose level-independent definition of severe hypoglycemia, implying that widely implementing such a definition may attenuate fear of starting/continuing insulin because of hypoglycemia concerns. To support this point, Dr. Hassanein showed un-published data; a six-month retrospective + four-week prospective study of the rates of self-reported severe hypoglycemia and hospitalization in thousands of insulin users at 300 sites in nine countries. As seen in the figure below, across all data sets (type 1, type 2, retrospective, prospective), only ~3%-19% of severe hypoglycemia cases resulted in hospitalization. In other words, being told that they had three severe hypoglycemia episodes in the last week – despite no hospitalizations – may cause patients to experience excessive distress and a desire to discontinue insulin. On the other hand, if glucose levels less than 70 mg/dl are referred to as “alert” or “level 1” hypoglycemia, and levels less than 54 mg/dl are referred to as “clinically important” or “level 2” hypoglycemia (as recommended by the International Hypoglycemia Study Group), patients may not be as fearful of insulin. This idea is ripe for an RCT. We acknowledge that patients in the study may have been (a) under-hospitalized and/or (b) surrounded by very capable assisters, thus preventing hospitalization, but we can get on board with the idea of re-framing low blood glucose values in the interest of keeping patients on insulin.
- A survey conducted by Mark Peyrot et al. found that 31% of people who stopped insulin did so because of hypoglycemia – only 48% of those who fell into this group actually reported hypoglycemia during insulin use. Fear, even of the unknown in ~50% of cases in the survey, is enough to deter people from insulin use. This underscores the tremendous need for education, blood glucose monitoring, and effective algorithms to help people dose more safely and with less anxiety.
- The CREED study of hypoglycemia during Ramadan showed the importance of risk-stratifying based on factors such as lifestyle (religion): The study found that Ramadan-observing (fasting) individuals who experienced no episodes of hypoglycemia in a period before Ramadan (n=3,012) were very unlikely to have hypoglycemia during Ramadan (only 5% did). Contrarily, 35% of people who experienced ≥1 episode of hypoglycemia before Ramadan (n=238) had ≥1 episode during Ramadan. Prioritizing the education of people in the latter group leading up to the fasting month would clearly be a wise allocation of resources.
Patient Case #2: Beyond Oral Therpay: GLP-1 Agonists as Potential Injectable Options
Francesco Giorgino (University of Pisa)
In a Lilly-sponsored symposium, Dr. Francesco Giorgino lambasted the negative impact that clinical inertia has on patient outcomes in diabetes, using this to frame the benefits of the GLP-1 agonist class. He presented compelling data to show that a one-year delay in treatment intensification for a patient with high A1c is associated with a 67% increase in MI, a 51% increase in stroke, and a 64% increase in heart failure. Clinical inertia has also been linked to increased incidence of diabetes-related retinopathy and shorter time to progression of retinopathy. Enter GLP-1 agonists, known for their profound A1c-lowering efficacy (to reduce microvascular risk) and possible cardioprotective effects (for fewer macrovascular complications). Dr. Giorgino emphasized the agents’ broad range of biologic activity, associated weight loss, lower risk of hypoglycemia compared to insulin, and A1c-lowering efficacy at least on-par with insulin. He also discussed how GLP-1 agonists are differentiated based on administration: Lilly’s Trulicity (dulaglutide) is the only product in this class that does not require a needle to be attached (it’s part of the device), and to be sure, we’ve heard an abundance of positive patient feedback on the IDEO-designed Trulicity pen. Novo Nordisk management has shared that Ozempic (semaglutide, FDA approval anticipated by year-end) will be available in a FlexTouch only, which requires only 1-2 newtons of force to inject vs. ~15 with the FlexPen; the potential downside is that the FlexTouch is an inherently costlier device, so we’re not quite sure how Ozempic will be priced relative to Victoza – we would love to see the pricing remain consistent with Victoza even though short-term margins would go down.
AZ’s Bydureon BCise autoinjector is another substantial improvement over the single-dose reconstitution kits or dual chamber pen for Bydureon, offering more patient-friendly, adherence-prone administration (the device was FDA approved in October and US launch is slated for 1Q18). We certainly see potential for more patient-friendly devices to reduce clinical inertia in diabetes care, encouraging patients/providers to try treatment intensification earlier on if there’s less overall injection burden. We continue to believe that many more patients should be taking a GLP-1 agonist – this class accounted for only 7% of second-line diabetes prescriptions in the US in 2016 – and while inertia is only one aspect of this (we can’t ignore access/reimbursement issues), more advanced, efficacious products with ease of administration could start to shift prescription habits for the better.
- When Dr. Giorgino polled the audience on where they find it most challenging to intensify treatment, a striking ~85% voted “adding injectable to second oral anti-diabetic medication.” This underscored for us how seriously injection burden – including the impact it has on lifestyle, the discomfort patients feel, and concerns about side-effects – can impact the overall quality of diabetes management, often delaying the initiation of a drug that could greatly improve an individual’s A1c, body weight, and risk profile for microvascular and macrovascular events. While once-weekly GLP-1 formulations can reduce this burden, these aren’t always the best choice for all patients in terms of adherence (some thought leaders have suggested that once-weekly doses are harder to remember vs. once-daily doses though presumably there is technology that can help with this). Still, as far as injectable therapies go, GLP-1 agonists hold particular advantages over insulin because they offer similar glucose-lowering capacity and promote weight loss rather than weight gain, don’t increase hypoglycemia risk, and in many cases can be more flexibly-dosed. Although they are, admittedly, far less affordable as things stand, we hope to see far more investment in getting more patients onto GLP-1, particularly given the cardiovascular risk reduction benefits of Victoza and others that trend toward risk reduction.
- We were also struck that ~34% of the audience picked “CV prevention/safety” as the most important characteristic they consider when selecting a GLP-1 agonist. This implies that HCPs can compare CV outcomes among agents, which we do not think is possible at this stage. Efficacy edged this out with ~40% of the vote, and dosing frequency followed at a distant 13%. We were very surprised that so many providers in the room were so keen on CV risk reduction with GLP-1 agonists and very glad to see this. This paradigm shift in diabetes management, where CV risk mitigation is at the center, may be seen by some as inevitable, but we imagine it will take time and concerted effort to get this changed mindset/approach disseminated widely among all the real-world HCPs who treat diabetes. Following the addition of a first-ever GLP-1 agonist CV indication for Victoza (Novo Nordisk’s liraglutide), we’ve been watching provider uptake of this agent for reducing CV risk in patients with established CV disease. At the company’s recent Capital Markets Day, Novo Nordisk management described the “re-launch” of Victoza with its CV indication, including direct-to-consumer advertising and directed HCP campaigns. We would like to see investment in a CVOT with multiple GLP-1 agents and SGLT-2s – rather than industry sponsored, perhaps this could be investigator initiated.
- Dr. Giorgino mentioned diabetes-related retinopathy multiple times throughout his presentation, which we found notable in light of the safety signal for retinopathy seen in SUSTAIN 6 for Novo Nordisk’s once-weekly GLP-1 agonist semaglutide. While panelists at the recent FDA Advisory Committee meeting for semaglutide overwhelmingly felt that this risk would be manageable in the real world with screening and monitoring (suggesting that the safety concern should not hinder approval), we imagine that some patients and HCPs will exhibit some worry about GLP-1 agonists/retinopathy. It’s thus important to discuss risk mitigation strategies and protocols, even though we don’t believe the retinopathy signal holds a candle to semaglutide’s remarkable potency in glucose-lowering, weight loss, and possible cardioprotection.
Satellite Symposium: Shaping the Future of Type 2 Diabetes Management: What Next? (Sponsored by Takeda)
A Takeda-sponsored symposium offered a deep dive into DPP-4 inhibitor/TZD dual therapy, focusing especially on the clinical benefits of combining Takeda’s Nesina (alogliptin) with Actos (pioglitazone; now generic). Overall, we have been surprised that this combination has not done better commercially though it probably mainly reflects negative perspectives on TZDs. Dr. Guntram Schernthaner framed the logic of the DPP-4/TZD combination in terms of the “ominous octet,” noting that together, alogliptin and pioglitazone target six of the eight pathophysiological defects in type 2 diabetes, including insulin resistance. Alogliptin enhances the incretin effect in the gut and decreases pancreatic glucagon secretion, pioglitazone decreases hepatic glucagon secretion and increases muscular glucose uptake, and both agents increase pancreatic insulin secretion. Indeed, three phase 3 studies of alogliptin/pioglitazone combination therapy (as an add-on to metformin, as initial combination therapy, and as an add-on to metformin/pioglitazone therapy) all found superior glycemic efficacy with both agents vs. either monotherapy. Moreover, the combination with alogliptin also neutralizes some side-effects of pioglitazone, including bone fracture risk and elevated LDL cholesterol and triglycerides. Both DPP-4 inhibitors and TZDs have been the subject of considerable controversy when it comes to CV safety, but cardiologists on the panel assured that they don’t find these concerns especially compelling. Thought leaders seem largely worry-free on DPP-4 agents and heart failure hospitalization, although in a conservative move, FDA did recently add heart failure warnings to all DPP-4 inhibitor product labels (including Merck’s Januvia, Lilly/BI’s Tradjenta, AZ’s Onglyza, and Takeda’s Nesina). This followed a signal for heart failure hospitalizations associated with Onglyza (saxagliptin) in the SAVOR-TIMI study, but panelists agreed that this broad-sweeping warning is an overstep when all data suggests that the safety signal is unique to Onglyza. Speakers at this Takeda symposium cited no significant heart failure risk in the EXAMINE trial of Nesina (though results did trend in favor of placebo for this outcome), and also emphasized the resoundingly neutral hazard ratio of 1.00 for heart failure hospitalization seen in the TECOS trial for Januvia (sitagliptin). They also reviewed meta-analyses showing no signal across the DPP-4 inhibitor class as a whole. On TZDs, esteemed cardiologist Dr. Robert Chilton lamented the bad reputation this class has been assigned following the infamous rosiglitazone scare (rosiglitazone’s link to increased risk of MI and CV death was major inspiration for the FDA’s 2008 guidance mandating diabetes CVOTs). He noted that this, too, appears to be an agent-specific and not class-wide effect, and he argued that it’s an oversimplification to equate pioglitazone’s tendency to increase fluid retention with any additional risk of heart failure. We’ve heard Dr. Chilton remark on this important point several times before, and particularly appreciated his remarks at EASD 2017 that a diuretic would likely be an effective risk mitigation strategy for heart failure in the context of TZD therapy.
- Beyond CV safety, the panelists went as far as to suggest that pioglitazone and alogliptin may even have beneficial CV effects – this is not surprising in light of the PROactive trial results that Dr. Schernthaner pointed to, which demonstrated a definitive 16% risk reduction for the secondary outcome of three-point MACE with pioglitazone (HR=0.84, 95% CI: 0.72-0.98, p=0.027). We note this was a secondary endpoint and can’t be considered truly significant because the study’s primary seven-point MACE outcome did not reach statistical significance. We think this is a classic example of the pitfalls of what Dr. David Matthews memorably termed “statistical fundamentalism” and regret that this statistical formality is reinforced so rigidly in the interpretation of clinical trials, preventing wider discussion of this benefit for pioglitazone. Furthermore, both Drs. Sanjay Rajagopalan and Stefano Genovese pointed to a significant 24% risk reduction in the primary composite endpoint of fatal and non-fatal stroke and MI in the IRIS trial (HR=0.76, 95% CI: 0.62-0.93, p=0.007) in people with insulin resistance (but no overt diabetes) and a history of recent stroke or transient ischemic attack. Dr. Rajagopalan went as far as to say that “pioglitazone needs to be considered in all our patients with existing CV events,” and Dr. Genovese raved “I love pioglitazone and think it’s one of the best drugs we have for people with diabetes.”
- On DPP-4 inhibitors, Dr. Chilton highlighted the SPEAD-A trial, in which alogliptin decreased carotid intima-media thickness, indicating a protective effect against atherosclerosis, an important precursor of CV events. We were encouraged to hear reinforcement of the CV safety of pioglitazone and alogliptin reiterated by these experts in no uncertain terms. That said, the evidence for CV benefit with these agents remains rather less certain to date in comparison to the rich body of evidence for the cardioprotective effects of GLP-1 agonists and SGLT-2 inhibitors. Still, the speakers made a compelling point that the cost-effectiveness of now-generic TZDs and to a lesser-extent DPP-4 inhibitors makes them the best therapeutic option for many people with diabetes. While we’re incredibly fortunate to live in a time when diabetes drugs that have CV safety as well as a possible CV benefit are more widely accessible, we hope for a future in which cost is not part of the equation when it comes to determining optimal diabetes therapy (in other words, the safest, most effective medicines should be accessible to all patients in-need).
Symposium: Prevention in the Workplace and Productivity
Standing Time at Workplace for Diabetes Prevention
David Dunstan, PhD (Baker Heart and Diabetes Institute, Melbourne, Australia)
Dr. David Dunstan presented hot-off-the-press results of a wellness[DWD1] program, just published in Diabetologia, showing how reduced sitting time in the office leads to glycemic improvements for people with type 2 diabetes – lower 22-hour glucose, mean nocturnal glucose, and mean overall glucose. People with type 2 diabetes and overweight/obesity (n=24) spent three days at Australia’s Baker Heart and Diabetes Institute, rotating through different conditions over a simulated eight-hour workday: three-minute bouts of light intensity exercise (walking) every 30 minutes, simple resistance activities every 30 minutes, or a control condition of prolonged sitting. All participants wore CGM for all study visits. To control for the influence of eating behavior, meals and meal times were standardized. CGM data revealed that just one day of interrupting sitting with either walking or resistance activities produced meaningful glycemic improvements. Compared to prolonged sitting, both the walking and resistance activity conditions significantly reduced 22-hour glucose (160 mg/dl and 157 mg/dl respectively vs. 209 mg/dl, p<0.001) and nocturnal mean glucose (146 mg/dl and 149 mg/dl respectively vs. 191 mg/dl, p<0.001). Mean overall glucose was sustained at a lower level until the morning in both conditions of interrupted sitting (both -49 mg/dl vs. control, p<0.001). These findings highlight the immediate and lasting glycemic benefits associated with breaking up prolonged sedentary time, validating the the potential usefulness within workplace wellness interventions that aim to reduce time spent sitting. In fact, Dr. Dunstan showed evidence that increased occupational sitting time is one of the main consequences of the overall declines in total physical activity across recent decades.
- Dr. Dunstan contextualized these findings with an overview of the detriments of prolonged inactivity. Sitting for >8 hours/day is associated with 2x the risk of diabetes, 2x the risk of CV disease, and 1.5x the risk of premature death vs. the recommended <3 hours/day of sitting. Frighteningly, sitting is now our dominant waking behavior in the Western world. A 2015 study found that Australians spend just over nine hours/day sitting on average (four hours in prolonged >30 minute bouts and five hours in shorter <30 minute bouts) vs. a mean six hours in light intensity activity and only 36 minutes in moderate to vigorous activity. Only very high levels of exercise (60-75 minutes per day of moderate-vigorous activity) during non-sitting time appears to neutralize the risks associated with prolonged periods of sitting. Thus, Dr. Dunstan underscored the value of frequent rather than sporadic activity for metabolic health, in addition to engaging in regular health enhancing exercise.
- Dr. Dunstan also highlighted the Baker Diabetes and Heart Institute’s new Rise & Recharge app, which helps users become “chair aware” by tracking the number and length of sitting bouts, reminding users when they have been sitting too long. This tracking of sitting time is also a feature of Fitbit and other wearables, but Rise & Recharge specifically awards users with stars each time they interrupt a sitting bout in each 30 minute period by taking at least 15 steps. We at Close Concerns have been consciously trying to stand/walk intermittently since Dr. Dunstan’s talk, and we have to admit that it has been much more difficult to achieve the recommended 24+ sitting breaks since returning to the office vs. strolling the halls of the IDF conference center (even with our office treadmill desks and affinity for walking meetings!). This underscores the importance of increased awareness about the sheer amount of time most workers spend sedentary, and the need to design workplaces (and schools, and the built environment more generally) in a way that promotes frequent, regular activity.
Symposium: Diabetes and Technology
Update on Glucose Sensors in Everyday Life
Raimund Weitgasser, MD (Clinic Diakonissen, Salzburg, Austria)
Dr. Raimund Weitgasser presented an in-press sub-analysis from Abbott’s IMPACT RCT of FreeStyle Libre in low-A1c type 1s, demonstrating MDI participants (n=167, or 75% of the full study participants) saw significant reductions in hypoglycemia after 26 weeks using the sensor. He didn’t break out numbers, but based on a figure (below), we estimate that patients in the experimental arm dropped from ~3.5 hours/day below <70 mg/dl at baseline to ~1.9 hours/day <70 mg/dl, a ~46% reduction translating to ~1.5 hours fewer in hypoglycemia every day. The SMBG comparator arm saw no such decrease. Time below 55 mg/dl (~30 min less per day) and 45 mg/dl (~40 min less per day) also shrunk considerably in the MDI cohort using FreeStyle Libre, while remaining stagnant in the SMBG group. Scanning rate was sustained above 15/day for the duration of the study, replacing SMBG almost entirely. These results are in line with the overall study population (pumpers and MDIs; n=221 total), where patients using FreeStyle Libre spent ~1.2 hours fewer per day <70 mg/dl relative to controls, ~49 minutes fewer per day <55 mg/dl (a 50% reduction) and ~33 minutes fewer per day <45 mg/dl. We look forward to seeing more results – A1c, time-in-range, hyperglycemia, data by time of day, etc. – published in Diabetologia soon. At this point, this analysis adds to the evidence base in favor of CGM in type 1s on MDI, along with the Dexcom DIaMonD and GOLD trials, which were published side-by-side in JAMA in January. There’s no question about it – the field is on a roll to combat the historical “pump first, CGM second” mindset. Ultimately, companies need to influence HCPs to change their prescribing, and then influence payers that CGM is a better investment than a pump for many patients.
Meet-the-Expert: Diabetes Tools and Apps
What’s New, What Works, and What Do Patients Really Want
Adam Brown (Close Concerns, San Francisco, CA)
Our own Adam Brown reviewed the latest in diabetes tools and apps, condensing areas of promise into three Cs: CGM, Clever insulin delivery, and Coaching/remote care. Download a PDF of his slides here, and see the bullets below for more depth on each of the areas, as well as Adam’s six-tem shopping list of where diabetes tech still needs to improve. Adam grounded his presentation with a couple visual examples to demonstrate what a great diabetes tool or app might do – (i) turn a mountainous, curvy road on a foggy day into a flat, straightway road on a sunny day; and (ii) turn that feeling of blind floundering in the darkness to confidently walking down a well-lit path. In short, he said, diabetes tools and app will add value to patients if they deliver outcomes and/or reduce burden – ideally, they will do both. By both outcomes and burden, Adam emphasized this isn’t just glycemia (A1c, time-in-range), but a broader box that might include weight loss, mindset, energy, better sleep, cost, time, finger pokes/injections, and frustrating conversations. He noted that, while there has been a steady progression toward better outcomes thanks to better diabetes technology, they have often come with more burden (e.g., pumps and CGMs). “I hope we’re entering the era of better outcomes with increasingly less burden.” Amen!
- Adam spent most of his talk on CGM’s increasing evidence base, user base, and published outcomes data. He showed strong adoption curves for Dexcom CGM (sales) and Abbott’s FreeStyle Libre (users), and covered recent studies showing strong health and cost benefits – but estimated that <0.5% of people with diagnosed diabetes globally are using CGM. Assuming roughly 15% of people with diagnosed diabetes are on insulin worldwide, he continued, then just ~2-3% of insulin users are using CGM. (For the initial calculation, Adam estimated from recent Abbott and Dexcom user base updates and Medtronic sales data that ~0.7-1.0 million people are on CGM – the denominator, 212 million people diagnosed worldwide, came from the 8th IDF Atlas.) Strikingly, this <0.5% penetration says nothing of the 212 million undiagnosed and 352 million people with impaired glucose tolerance, all of whom could potentially benefit from CGM as well. CGM clearly has a massive runway, which Adam characterized as “both exciting and daunting.” With an eye toward access and affordability, he suggested that professional CGM (FreeStyle Libre Pro) is a great option in lower resource settings, and that the smaller/less costly Dexcom/Verily sensors (in-development) “will really expand the market in a big way.” With data supporting clinical and economic outcomes, burden and price coming down, growing payer interest (see remote care below), and data getting easier to understand (with AI, such as Medtronic/IBM Watson’s Sugar.IQ), adoption should continue to improve.
- To support the health and financial benefits of CGM, Adam pointed to a slew of recently published or presented data: (i) Abbott’s IMPACT and REPLACE studies, plus real-world data from now 200,000+ users (DTM); (ii) Dexcom’s DIaMonD and GOLD studies (here and here); (iii) A Belgian reimbursement study from EASD demonstrating strong decreases in hospitalizations and work absenteeism with CGM; (iv) the CONCEPTT study of CGM in pregnancy – the first study to indicate potential for improvements in non-glycemic health outcomes from CGM use,” in this case costly neonatal outcomes such as lengthy NICU admissions and neonatal hypoglycemia; and (v) the IN CONTROL study showing CGM reduces incidence of severe hypoglycemia in people with hypoglycemia unawareness.
- Within “clever insulin delivery,” Adam (i) exclaimed that he is “really excited” for smart pens to provide injection data; (ii) shared enthusiasm for the power of insulin titration to continuously update doses; and (iii) highlighted a slew of commercial closed loop systems in development. For each, he displayed slides with graphic versions of Close Concerns’ competitive landscapes – smart pens/pen attachments (led by Companion Medical, which is set to launch this month in the US); insulin dose titration; and automated insulin delivery. After alluding to a Common Sensing poster from ADA with overlaid CGM and injection data, Adam noted that smart injection devices are not widely available at the moment, but “could be even bigger than closed loop with pump and CGM.” No doubt that connected pens and decision support will be more prevalent, and we look forward to finding out how far smarter open loop can go. How will patients segment between MDI+advice and pump+CGM hybrid closed loop? Will anyone run a head-to-head study once commercial systems are out? (Bigfoot/Abbott and Lilly/Dexcom both plan to have a system in each category.)
- The big question with coaching and remote care, according to Adam, is can it scale? We’re not sure yet. He discussed some of the solid outcomes demonstrated by Livongo, mySugr, One Drop, and Virta, cautioning that much of the data is from observational, real-world studies where there is not control group. He argued that we DO need these studies, though payers will likely want to see real-world data and RCTs (more in Q&A). Do the reductions translate to the broader population? Can these interventions scale? Crucially, can they get reimbursed? One good sign, Adam said, is that payers are getting interested – in just the past couple of weeks, Dexcom and UnitedHealth Group announced an unprecedented pilot of CGM and coaching in 10,000 type 2s, Onduo and Blue Cross Blue Shield announced a pilot of Onduo’s (“Virtual Care Clinic”) in three southern states, and Sanofi and Innovation Health (Aetna+Inova Health Systems) launched a pilot with Common Sensing and One Drop. Do these payer-based coaching setups have a better chance of reaching more people? How will the companies support the needs of the patients? How does Dexcom/a UnitedHealth coach interact with the provider that a patient has traditionally seen? There are a lot of questions in this nascent area, but closing the gaps between infrequent clinic visits is seemingly a no-brainer success; at this point, it’s about establishing successful workflows, incentive structures, risk-stratification, and program tailoring.
- Despite progress in the three Cs, Adam identified six areas in which we still need massive innovation: (i) Cost and access globally – most diabetes tech is limited to developed countries; (ii) more simplicity, seamless, “it just works – magic!” experiences; (iii) More medication dosing guidance including oral medications – e.g., “this patient should take a higher metformin dose” or “this one should add a GLP-1 agonist to her regimen”; (iv) more implementation in different systems and patient populations (especially type 2s); (v) Improving providers’ efficiency, scaling their expertise and limiting administrative hassle; and (vi) designing for more delightful, bright spots moments “where you’re like ‘Yeah – awesome!’” Adam related a story about how he had his glasses prescription refilled at home using the brilliantly innovative Warby Parker Prescription Check app – the app interfaced with his computer, guided him with videos, helped him measure the distance, and allowed him to complete an eye-chart-like test by swiping on his phone. Those “WOW, this is awesome!” moments rarely happen in diabetes tech, but they could!
- Drawn in by the “you might also like” section of the online Wall Street Journal, Adam recently stumbled upon an article about drones delivering blood to remote locations in Rwanda by a startup called Zipline. With this system, delivering blood takes 10-15 minutes, whereas it used to take three hours. What if we used this technology to deliver insulin or diabetes supplies? On day #1 of the conference, we chatted with a doctor now based in Fiji, who told us that people were scattered across 100 islands in the nation and many times without refrigeration … Brian pointed out that drone delivery would make a huge difference, especially in extreme cases like Fiji! Adam wondered how other mainstream consumer tech could similarly be leveraged in diabetes to great effect (e.g., 3-D printing, VR, etc.).
Questions and Answers
Q: Lot of things need to be done before we progress in diabetes technology – evidence generation, reimbursement issues…the results you showed are often not enough. With observational studies, there are lots of confounders. How do we collect more evidence in medicine?
Adam: We could do a whole session on that. There are a couple challenges in tech. CGM was plagued for a number of years because studies took so long to do that devices were outdated by the time the study was published. It colored the field a lot. Now we’re starting to see a mix of RCTs that take time to do but are published (DiaMonD, GOLD, IMPACT, REPLACE), and real-world data. That may be one reason why diabetes technology is starting to see more reimbursement, especially in the EU – we’re seeing this nice mix of both data. It’s a really good sign to me, a canary in the coal mine (in a good way), that payers are now testing CGM and remote care and insulin titration in pilots. Reimbursement will naturally always lag behind new stuff; I think that’s okay, but it does put pressure on companies to build solid evidence as soon as possible. And I think they get it. I’m not an expert on the right balance between real world data and RCTs, and I also don’t know what payers think about this question.
Q: I don’t have a specific question, but can you talk about barriers related to medicolegal issues? What about providers that don’t trust algorithms?
Adam: Whenever there’s new technology, many are scared of what they don’t understand. There was recently a really cool New York Times Magazine article, about whether AI can explain itself. The idea with AI is you feed it data sets, it learns, and then it can make smart decisions. But for a court of law or a healthcare provider, you have to explain how the decision was arrived at. So there’s a big debate in AI in healthcare: If the algorithm can’t explain how it arrived at a decision, where does that leave us? This NYT piece covered the beginnings of this field called “explainable AI” (XAI for short). One of my favorite examples in the piece was an expert on XAI, who said “the solution to XAI is just more AI.” Some researchers are now lashing two algorithms together, one that makes the decision, the other that watches that algorithm and explains the decision making. I think whenever tech is new, many people are naturally scared of it. We hear it at digital health conferences too as it relates to radiology. The IBM Watson computer can read image scans pretty accurately and far quicker than a human – what does that mean for radiology? Well, perhaps it changes the way people work – just like the industrial revolution and the agricultural revolution – I hope tech will allow providers to do less monotonous tasks. What if an Amazon Echo could listen to the consultation and capture what was said? Providers do a lot of mundane stuff, and tech should help with that. There’s a big question on liability I don’t know the answer to – what about when a company takes care of a patient through one of these remote care models? Who’s accountable in that system, and who do I listen to – the company or my own HCP? I don’t know.
Debate: Diabetes Technology – We’re Not Waiting vs. Why Are We Waiting
Dana Lewis (OpenAPS, Seattle, WA)
OpenAPS’ Dana Lewis made a persuasive “pro” case for the #WeAreNotWaiting movement, citing the enormous glycemic and quality of life benefits from do-it-yourself (DIY) automated insulin delivery systems. She noted over 500 people worldwide are using various DIY “Loop” systems (likely an underestimate), which totals ~2.8 million hours of closed loop experience in her estimate – an order of magnitude larger than the ~267,000 hours that could be gathered in a single company’s 124-patient, three-month pivotal study. She shared a number of moving DIY user stories from social media, including a very compelling side-by-side retina scan – one DIY user’s retinal swelling declined markedly after starting on closed loop (picture below)! Ms. Lewis emphasized the “overwhelming health benefits” of these systems (A1c, time-in-range, sleep, stress, diabetes burden), something she couldn’t justify keeping to herself. She has now gone ~ 105 days without taking a bolus, a testament to continuous improvements in the OpenAPS algorithm (e.g., “eating soon mode”). Ms. Lewis concluded her part of the debate with a good point – DIY systems are not for everyone, but patients “now have a choice” on whether to use them (i.e., it’s an individual benefit/risk decision). Indeed, many will continue to use OpenAPS and Loop, even with the MiniMed 670G on the US market and other commercial systems coming. A broader AID portfolio will be great for patient choice, and we’ll be fascinated to see if the field evolves to a mix of commercial and Open Protocol-enabled AID systems.
- In Q&A, Ms. Lewis highlighted out the Bluetooth-enabled Dana insulin pumps (R and RS), which are being used by many Android APS users in Europe and Asia – these allow for direct Android smartphone app communication to the pump (no communication relay bridge), an even bigger user experience win. Ms. Lewis lamented that in the US, out-of-warranty Medtronic pumps are what DIYers are forced to use – she hoped the JDRF Open Protocol AID Initiative will encourage more pump companies to include Bluetooth for interoperability with DIY systems. We hope so too, as this community is incredibly innovative and will enhance the value of pumps and CGMs with excellent software. As Ms. Lewis said, “We’re going to keep doing this (DIY) – we would all love to use an in-warranty pump and we’d be happy to give you money to do so.”
- Ms. Lewis highlighted the dramatic shrinkage in communication hardware form factor (see picture below), and noted an incredible ecosystem of software around OpenAPS – e.g., Auto Tune to optimize pump settings, a user can “text” their pancreas with Siri and inform it of upcoming events (“getting ready to speak”, running, eating soon.), etc.
Retinal Scan – Before and After DIY Closed Loop
Text My Pancreas – Software Ecosystem Example
The Burden Liftoff, Especially for Parents
Why We’re Waiting
Ms. Annabel Astle, mother of a 14-year-old girl with diabetes, explained why she is happy to wait (counter to the #WeAreNotWaiting DIY movement): Risk aversion and a desire to guarantee continuity of care for her daughter. Ms. Astle isn’t 100% risk averse, she pointed out – her daughter wore a Dexcom sensor off-label as a child, and today wears it on her arm. But she calculates the risk of off-label CGM to be extremely small, since insulin isn’t being directly delivered off-label (though CGM probably informs dosing). With DIY automated insulin delivery systems, however, she perceives higher risk, and she said it comes down to being a parent: “You need to be aware of a number of things when caring for a child with diabetes – if she were an adult, it’d be very different. The decision would be hers, and I would support her either way.” Certainly, choosing how to deliver a dangerous drug to your child is an enormously difficult decision, so we understand the desire to stick “on label” and proceed with caution – of course, to have diabetes is to be forced to accept significant baseline risk, and a DIY system in the hands of many will reduce that risk (especially overnight). According to Ms. Lewis, there have been no adverse events reported to date for OpenAPS users related to under- or over-delivery of insulin, though admittedly, there is no single responsible party that tracks them. But as Ms. Lewis pointed out, the systems are widely used in very young pediatrics, with set up done by a mix of tech-savvy and non-tech-savvy parents. As for continuity of care, Ms. Astle pointed out that she can’t guarantee a supply chain of parts if the off-warranty Medtronic pump or computer breaks, and she wonders how going back to “analog” care from Looping would impact her daughter’s emotional wellbeing (especially if she’s happy with her current regimen the moment). The question is a complex one: Is this a “better to have loved and lost…” situation, or is it better to maintain the current level of satisfaction if things seem fine? This status quo bias is one that may impact diabetes technology uptake for several years –“I don’t want to try to something new or switch, because what I have works.” Ms. Astle also likes that her daughter has products with warranties, rigorous testing, guarantees, and assurances – a fair point and one out-of-warranty Medtronic pumps and DIY algorithms cannot attest to at this point. Again, this is a very difficult choice for a parent to make. Many find DIY automated insulin delivery systems to be very safe (basal modulation only, and lots of constraints can be set by the user), but not everyone will be comfortable without regulatory approval. This adoption cycle is natural in any market!
Adjunctive Therapy with Dapagliflozin Improves Full Closed Loop Post Prandial Glycemic Control in Type 1 Diabetic Young Adults – The DAPADream
T Biester, A Nieswandt, S Biester, K Remus, R Nimri, I Muller, E Atlas, M Phillip, T Battelino, M Scheerer, O Kordonouri, T Danne
A poster presented findings from a double-blinded, randomized controlled cross-over trial (n=15) showing that AZ’s SGLT-2 inhibitor dapagliflozin (DAPA; Farxiga) significantly increased overall and postprandial time in range (70-180 mg/dl) combined with the DreaMed system in full closed loop (FCL) mode. 15 young adults with type 1 diabetes (mean age: 19 years-old; baseline A1c: 8.3%) used the “DreaMed Substance Administration System” (we haven’t heard this branding before) for 24 hours and randomized to receive either 10 mg DAPA or placebo twice. Two unannounced mixed meal tests were performed. Average time in range increased an impressive 4.3 hours/day in the DAPA group compared to the placebo, a notable 18-percentage point boost (68% vs. 50%; p<0.001)! The curve below (pink=placebo, blue=DAPA) depicts statistically significant reductions in postprandial glycemic excursions, decreases in glycemic variability, and a lower mean blood glucose in the DAPA group. These are good outcomes, though since this was full closed loop, the meal excursions were quite big (>250 mg/dl), and the placebo group was at a big disadvantage with the current speed of insulin. Indeed, time in range during the day (7AM-7PM) was 42% with DAPA vs. just 19% for placebo, a ~2.7 hours gain in the DAPA group (p<0.001). There was no significant difference in time in-range overnight, when the system alone kept people in range an impressive average of 91% of the time. However, it is worth noting that mean time in range in the DAPA group was 100%. Time in hyperglycemia (>180 mg/dl) was the big driver of DAPA’s benefit, significantly decreasing by nearly four hours relative to control (29% vs. 45%; p<0.001). No increases in hypoglycemia or serious ketosis were observed – there appears to have been very little hypoglycemia at baseline. Further, total insulin dose decreased by ~30% with DAPA use, from a total daily dose of ~39 units to 28 units. The strong in-patient data led the esteemed investigators to conclude that DAPA is a safe and effective adjunction to FCL, benefiting time in range. We would add that a diminished dose of insulin is very desirable as it can lead to less weight gain, and the SGLT-2 inhibitor can cushion post-prandial excursions on fully closed loop, making up for the speed of insulin. Of course, removing the need to announce meals will also do much to decrease hassle and burden – carbohydrate counting and bolusing still take up headspace for those on hybrid closed loop systems. We’re glad to see such promising results in such a short study and hope to see the data replicated in a longer outpatient study moving forward. Should that happen, we’re also intrigued by commercial opportunities – is there a path forward for a device-pharma partnership to package an SGLT-2 inhibitor and a closed loop system?
Satellite Symposium: Shaping the Future of Integrated Diabetes Management Solutions and Clinical Treatment for Patients with Type 2 Diabetes (Sponsored by Roche)
Steven Russell, MD, PhD (Massachusetts General Hospital, Boston, MA)
In a Roche symposium, MGH’s Dr. Steven Russell shared new comparative accuracy data from a six-week outpatient Bionic Pancreas study. Each patient wore Senseonics’ Eversense, Dexcom’s G5, and Abbott’s FreeStyle Libre Pro. Eversense recorded an MARD of 14.8% vs. 16.8% for Dexcom’s G5 vs. 18% for Abbott’s FreeStyle Libre Pro – each patient wore all three sensors, with CGM values compared to fingersticks taken via Nova StatStrip Xpress (n=829 paired points; p<0.008 vs. Eversense). When data was only compared with five-minute sample intervals, Eversense had a similar 15.1% MARD vs. 16.9% for G5 (n=2,277; p<0.0001 vs. Eversense). Based on this strong Eversense performance – it was statistically superior to G5 and Libre Pro – MGH and Beta Bionics are now “exploring” the device as an “additional sensor option,” supplementing Dexcom. FDA discussions are just beginning, but the hope is to include Dexcom’s G6 and Senseonics’ Eversense in the Bionic Pancreas pivotal trial (per the last update, this is expected to start at the beginning of 2019). If it comes to fruition, Beta Bionics could be the only AID system that offers two different companies’ sensors.
- This “Monitoring Study” will be presented as an oral at ATTD 2018 – the trial actually tested the Bionic Pancreas in both insulin-only and bihormonal configurations with vs. without remote monitoring. (This sensor comparison was a side benefit.) The team didn’t have access to FreeStyle Libre real-time for this study, which is why Libre Pro was used. Per the US label, Libre real time has slightly better accuracy (MARD: 9.7%) than Libre Pro (MARD: 12%), as the real-time version has a 12-hour warmup. For a six-week study, we assume the number of paired points was so low because fingersticks were only taken a couple times per day for device calibration – i.e., not for frequent sampling like in a traditional CGM accuracy study.
- Beyond the head-to-head comparisons, the other obvious takeaway is how far real-world CGM performance can differ from clinical trial performance – Eversense had an 8.8% MARD in its US pivotal vs. 14.8% here; G5 has a 9% MARD in its label vs. 16.8% here; and FreeStyle Libre Pro has 12% in its label vs. 18% here. This presumably reflects dirty fingers and other real-world issues that may be avoided in best-case-scenario accuracy studies.
- It was notable to hear Dr. Russell’s positivity on Eversense – he highlighted the accuracy, no acetaminophen interference (Dexcom will have this fixed soon but doesn’t yet), adhesive/wear flexibility, and simple outpatient insertion procedure. Dr. Russell said he has inserted the second-most Eversense sensors in the world (according to Senseonics), and once he has the skin site scrubbed and draped, it takes him “less than two minutes” to implant a sensor. (As a reminder, it requires lidocaine, a small incision in the upper arm, and is closed without sutures using a Steri Strip bandage. It can be done in an office visit.) Dr. Russell likes that the Eversense on-body transmitter adhesive can be changed every day, a plus for patients plagued by skin reactions or adhesive failures. Moreover, since the Senseonics transmitter doesn’t actually have to be adhered to the skin – it just has to be over the sensor implantation site – it is possible to hold it in place with a “sleeve” and not use any adhesive at all. We hadn’t realized this point and like the idea! Dr. Russell concluded that Eversense will be another great CGM option on the US market, pending approval – as a reminder, an FDA advisory committee is expected in 1Q18 (see Senseonics 3Q17). In Europe, Roche and TypeZero are using the 180-day version of Eversense in their AID system, expected to start its pivotal study in 2018.
Symposium: Hypoglycemia and Time-in-Zone – Wim Wientjens Memorial Symposium
Time in Range: Beyond HbA1c
Bart Van der Schueren, MD (University of Leuven, Belgium)
University of Leuven’s Dr. Bart Van der Schueren announced that EMA’s updated diabetes drug development guidance will be out for public comment in January. In a major victory, he gave a preview of the hypoglycemia section, which has been updated since his EASD talk to align with the consensus definitions of <54 mg/dl, <70 mg/dl, and severe hypoglycemia. (At EASD, the slide included less than or equal to.) It’s great to see EMA is now consistent with the two just-published Diabetes Care statements from ATTD and JDRF et al. – “It’s very important that we align throughout the world.” Dr. Van der Schueren clarified the exciting Beyond-A1c implications in Q&A: “Previously, any additional treatment had to show a change in A1c. Now if we include hypoglycemia into the guidance, the idea is to foster development of therapies that would lead to less hypoglycemia. Therefore, we would recognize that in the label. That also means you could get approved on that basis, even if you didn’t show a difference on mean glycemic control.” What a major victory! Indeed, <54 mg/dl is characterized as “Serious, clinically important hypoglycemia,” a clear sign EMA believes it matters and might approve a therapy on this basis. (Take note, FDA CDER!) Dr. Van der Schueren added in Q&A that time-in-range is not in the updated EMA drug guidance, as there is debate on what the high threshold should be. (Perhaps some think >180 mg/dl is not serious enough?) In other words, based on the current draft guidance, time-in-range data could not be included in a label. Still, we’re glad to see hypoglycemia is firmly in place, and we hope EMA receives many positive comments in January on these thresholds and the benefits of using CGM to characterize drugs. Perhaps advocates will also recommend time in 70-180 mg/dl as a meaningful endpoint to be included in the final guidance. We also hope this EMA guidance encourages the FDA to update its own outdated diabetes drug guidance.
- Specific patient-reported outcomes (PRO) instruments are not specified in the updated EMA guidance. Dr. Van der Schueren said “they are not currently robust enough,” and there is obviously no consensus on which instruments should be included. We believe this is a solvable problem, but one that will demand as much commitment as the drive to standardize CGM thresholds (and perhaps more, since there seems to be less clarity in that field than in CGM).
- For context, EMA released its last diabetes drug guidance in 2012 (which included CGM already), and is already updating it five years later. Meanwhile, FDA’s 2008 diabetes drug development guidance (still “draft”) will have its ten-year anniversary in March! Boy have the drug and device fields changed a lot since then…
Impaired Hypoglycemia Unawareness
Simon Heller, MD (University of Sheffield, UK)
In a compelling talk on impaired hypoglycemia awareness, Dr. Simon Heller emphasized a major gap – rates of severe hypoglycemia have not fallen in clinical practice, despite therapeutic advances. He emphasized the clinical trials like STAR-3 underestimate the current real-world burden of severe hypoglycemia – see the slide below, where the rate of severe hypoglycemia in recent studies is still double that of DCCT’s intensive group and roughly 10x the level seen in STAR-3. In a 2012 Denmark Study and a 2007 UK Hypoglycemia Study, frequency of severe hypoglycemia was more than 1 episode per patient-year, compared to 0.62 in DCCT’s intensive groups. In those two studies, 22%-46% of type 1s were affected by severe hypoglycemia, a staggering number. (Assuming 1/event/patient-year is true in the US, that means people with type 1 diabetes alone experience ~1.5 million severe hypoglycemia episodes per year in the US – to say nothing of type 2 diabetes.) Dr. Heller noted impaired awareness of hypoglycemia affects 20-25% of adults with type 1 and ~10% of people with insulin-treated type 2 diabetes. These individuals have a 3-6 fold greater risk of severe hypoglycemia. Dr. Heller emphasized that for society, hypoglycemia is a much more important problem in type 2, given the greater number of events – we agree and think this point deserves far more attention. He lamented that “rates of severe hypoglycemia in our clinics have not really changed,” though Dr. Heller was optimistic that structured education (e.g., DAFNE), new therapies (insulin analogs), and new technology (CGM, AID) can reduce risk.
Hypoglycemia – It is Personal for Me!
Kelly Close (The diaTribe Foundation & Close Concerns, San Francisco, CA)
To open the hypoglycemia session, our own Kelly Close shared a wide-ranging perspective on the field (download her slides here and her talking points here): (i) hypoglycemia is still a huge problem worldwide, as shown in global studies like HAT (Khunti et al., Diabetes Obes Metab. 2016); (ii) there are many faces to a 7% A1c – time-in-range gives us critical information about quality of A1c; (iii) recent evidence suggests A1c levels are not related to hypoglycemia (Munshi et al., J Diabetes Complications 2017); and (iv) CGM is THE tool to help us answer meaningful questions related to hypoglycemia. She recapped the compelling real-world data we saw at EASD from the Belgian experience with CGM – 12 months of CGM use dramatically improved days in the hospital for hypoglycemia/DKA (-67%) and days of work absenteeism (-53%). Still, Ms. Close lamented how much is spent on diabetes every hour – over $150 million globally! – and wondered how much of this $1.3 trillion annual expense (Bommer et al., Lancet Diabetes & Endocrinology 2017) could be avoided with smarter investment in CGM, drugs that reduce the risk of hypoglycemia, and better research. She highlighted the dQ&A patient priorities data presented at several venues this year (ADA 92-LB, AADE, Outcomes Beyond A1c Workshop), and posed several research questions for the Beyond A1c movement:
- Which drugs have the most and least hypoglycemia?
- Is it possible that time-in-range or hypoglycemia might influence adherence?
- How much time do insulin users spend in hypoglycemia at work? How does this impact their productivity?
- Is there a link between hypoglycemia and long-term complications or mortality? What about time-in-range?
Questions & Answers
The selected Q&A below addressed some of the key issues in the Beyond A1c movement: benchmarking outcomes, patient-reported outcomes (PROs), and future research. This came from the all-star hypoglycemia session, on which other highlights appear directly above and below this one.
Kelly Close: It was great to hear you talk about fostering development of therapies that reduce hypoglycemia. What about PROs? What instruments should be used? Are they sensitive enough?
Dr. Van der Schueren: We knew we needed to include endpoints not directly related to glycemic control. Then, when we started to look at PROs used by companies – and which to use –it became a very traumatic experience. We decided we would do it on a case by case basis. Dulaglutide (Lilly’s Trulicity) included a PRO in section 5.1 of its summary of product characteristics (page 16 here). But we are not able to tell companies what PRO to use in their clinical development program. (Although the hypoglycemia fear survey has been widely used.) We should move in the next couple of years to make this happen. I think it’s very important that treatments improve quality of life of patients – this is crazy that’s it’s not there.
Dr. Heller: We know PROs are very affected by the way medication is sold to them. If you don’t have a double-blind study, there are serious questions over PROs. It would be interesting to hear a regulatory comment on that.
Dr. Van der Schueren: We would only include PROs from placebo controlled studies.
Kelly: We’ve come to conclusions on how hypoglycemia can be measured and monitored. I’m hopeful about this for Pros. It’s going to require some investment in better understanding it.
Q (JDRF Australia): What single trial, analysis, or study, could be the most influential to bring this topic further into the public eye?
Dr. Van der Schueren: We should perform a DCCT with glycemic variability in it, confirming that glycemic variability has an influence on harder endpoints. This will validate it more for regulatory agencies. That’s one of the first things I would prioritize.
Dr. Heller: We are looking at a changing landscape. BGM was introduced in ~1977. In the next five years, in type 1 diabetes, patients are not going to participate in regulatory trials because they have to measure glucose with fingersticks. Many in Europe will be using CGM. The large companies developing these products, have failed to use CGM to date. I know that because I participate in those trials. They have sub-studies where a few people use it. Those data are never published. It’s extraordinary. They don’t have the experience, and many of the centers don’t know how to use CGM. For me, it’s taking the new tech and incorporating it into regulatory studies that EMA and other regulators need. We can look at glycemic variability. For me that is a fundamental thing we need to do.
Adam Brown: What should the benchmark goal be for time spent <70 mg/dl? Should it be <3%? <5%? <10%?
Dr. Heller: We don’t know. We need more research. I think the critical thing is the between 70 and 55 mg/dl range. If you spent 5% of the time at that level (55-70), there is very little evidence that you’ll impair responses. I think it’s around the 5% mark. Watching people use Dexcom G5, they see how much hypoglycemia they have at night – it’s transformative. It’s why I think CGM is so helpful. I think the 5%-10% mark, and for under 55 mg/dl, we should be stopping it completely. More than 2-3% would be very concerning. For 55-70 mg/dl, I’m not so worried – lower than that is the issue. Above it, 5% is where we might aim.
Adam: If we need more research, what would that trial look like, to help us understand a proper benchmark for time in hypoglycemia?
Dr. Heller: If people drop under 55 mg/dl, they develop unawareness, which drives risk of severe hypoglycemia. With large numbers and very good CGM, we can begin to measure what the consequences are of clinical episodes in that range. In the lab, we could even measure awareness thresholds. It would be great to know whether 5% between 55-70 adversely impact awareness thresholds – I don’t know. But let’s be clear, in five years’ time, in type 1 diabetes, everybody will be using CGM in the trials. There is a huge amount we will learn.
Symposium: The Role of Society in Primary Prevention in Diabetes: Health in All Policies
A Comprehensive Approach to Primary Prevention of Type 2 Diabetes
David Napier, PhD (University College London, UK)
University College London’s Dr. David Napier gave on overview of the Cities Changing Diabetes research model for vulnerability assessment, which identifies segments of the population most vulnerable to diabetes within an urban area. Dr. Napier described a disconnect between medical research and public health solutions. While RCTs remain the gold standard for developing therapies, these clinical trials are designed to eliminate some of the confounding variables that matter most in real-world diabetes prevention. These include sociocultural factors (religious beliefs, traditional meals, societal norms around health engagement – are people taught only to visit a doctor when they lose sensation in their foot?), economic circumstance, traffic patterns (are people spending many sedentary hours in a daily commute?), and proximity to health services based on geographic location – to name a few. Quantifying all these complex variables is a daunting task, but Dr. Napier asserted that “we can bring lived experience to the level of evidence.” To-date, the Cities Changing Diabetes team has conducted >740 vulnerability assessments in five cities, unveiling the greatest vulnerability points for a city, but also cataloguing existing services and levels of resilience to diabetes. Novo Nordisk EVP Ms. Camilla Sylvest announced at the recent Cities Changing Diabetes Summit in Houston that the company would support vulnerability assessments in at least five more cities in 2018.
- Ms. Sylvest also shared that four new cities would join the program, and Dr. Napier’s slides listed all four: Hangzhou, Beijing, and Xiamen in China, plus Leicester in the UK. Activities in Hangzhou were just launched earlier in the week. In total, the 12 urban participants in Cities Changing Diabetes now cover a population upwards of 100 million people, according to Dr. Napier. The three new cities in China alone cover a population of ~34 million (~9 million from Hangzhou, ~21.5 million from Beijing, and ~3.5 million from Xiamen). Certainly, there is potential here to make a dent in the population-level diabetes epidemic, and we applaud Novo Nordisk for this ongoing commitment to prevention. The focus on cities is strategic. Dr. Napier reminded the audience that cities hold two-thirds of the world’s population with type 2 diabetes, and that they’re also the ideal setting for stakeholder engagement, where policymakers can have a meaningful impact on the health of their local citizens. “Why cities?” was also a key theme at the recent Cities Changing Diabetes Summit.
- During Q&A, several audience members expressed concern bordering on outrage that this very important session on diabetes prevention was scheduled for the last day at IDF. We agree that this is an all-important topic, one that deserves to take center stage. As type 2 diabetes prevalence continues to rise (projected to reach ~one in nine people by 2045 if we take no action, according to Novo Nordisk/Cities Changing Diabetes, and projected to reach 629 million adults globally by 2045 according to the most recent IDF Atlas), it’s becoming increasingly clear that treatment alone will not “bend the curve” without concerted efforts aimed at prevention. As a first step, it was great to see IDF congress attendees advocating passionately for more discussion around prevention, and we hope to see more talks like Dr. Napier’s throughout the agenda at IDF 2019 (not to mention the many other diabetes conferences we’ll attend between now and then).
Symposium: Language Matters: When Speaking To and About People with Diabetes
Language Matters: Words Reflect and Foster Attitudes that Impact Diabetes Care
Jane Speight, PhD (National Diabetes Services Scheme, Australia)
Promoting the use of non-judgmental, person-first language in diabetes care, Dr. Jane Speight aptly argued that the vocabulary we use in talking about diabetes influences experiences of stigma, diabetes distress, anxiety, and depression, for better or for worse. Dr. Speight was the lead author of Diabetes Australia’s groundbreaking 2012 position statement on language in diabetes, so she spoke with authority on this all-important topic. She pointed to a study from Dr. Bill Polonsky demonstrating that “feeling guilty or anxious when you get off track with your diabetes management” is the second most important issue contributing to diabetes distress, ranked ahead of coping with complications and worrying about hypoglycemia. New measurement scales for diabetes stigma have found elevated stigma in one in six adults with type 1 and one in five adults with type 2 diabetes. Moreover, stigma has been significantly associated with depressive and anxiety symptoms, lower self-esteem, and diabetes distress.
- Dr. Speight outlined how words contribute to stigma, but also how they can help ameliorate it. Terms like “compliance” and “adherence” assume that instructions are given clearly and that patients agree with care decisions, she explained, pointing to another study in which patients/providers showed mutual agreement with only ~half of all treatment decisions. Words like “control,” Dr. Speight continued, fail to acknowledge the unpredictability of diabetes, as well as its progressive nature and the fact that it gets even more difficult to manage over time. Thus, patients who struggle to manage their diabetes can project their “failure” onto themselves – this leads to a low sense of self-efficacy, and it often compels people to define themselves by their disease, which runs directly counter to the goal of person-first language. To be sure, if words have the power to harm, they can also do good: Words can reinforce what patients do well, can explain the physiological reasons why diabetes is so difficult to manage, and can involve patients in all of their care decisions.
- As Dr. Speight highlighted, the ADA and AADE recently published their own joint paper echoing the sentiments laid out by Diabetes Australia. Recently, the New York Times also published a piece about how to talk to children with excess weight. We’re excited to see this field of research garnering more mainstream attention, and we fully believe this work holds enormous potential to improve patient-provider interactions and the everyday experience of people living with diabetes. Dr. Speight noted that Dr. Polonsky once called the clinician-patient relationship the least explored complication of diabetes, and we imagine improving that relationship could have positive downstream effects on every aspect of diabetes management. We’ve certainly started to watch our own words more closely than ever in light of this research and these position statements.
Symposium: Challenges in Diabetic Retinopathy – What to Do in Low and Middle Income Countries
Promoting Awareness of Screening in Patients and Providers
Pablo Aschner, MD (Javeriana University, Colombia)
Javeriana University School of Medicine’s Prof. Pablo Aschner explained how training GPs in his clinic to screen people with diabetes for eye disease cut down on ophthalmologist referrals significantly. While the cost of a retinal camera is certainly a major investment, Prof. Aschner emphasized that the value gained in the long-term far outweighs the initial financial burden: Among those with a diabetes duration less than one year, only 30% had abnormal retinal readings and were referred to an ophthalmologist, seriously cutting down on visits. As diabetes duration increased, so, too did the frequency of abnormal readings requiring referrals, leading Prof. Aschner to suggest that those with a diabetes duration of more than ten years should be sent directly to an ophthalmologist. Prof. Aschner was prompted to advocate for early screening by less-specialized providers by a finding that 11% of newly diagnosed individuals at a diabetes care center in Colombia already had retinopathy – compared to 0% at a center in Canada. Upon seeing these results, he recommended immediate screening up on diagnosis for type 2 patients, and screening beginning five years post-diagnosis in type 1 diabetes. We are equally concerned by the 11% rate of retinopathy at diagnosis, which uncovers a larger problem; perhaps earlier glucose tolerance or fasting glucose tests are required so people can be diagnosed and complications can be prevented. Early retinopathy screening is an investment; so, too, is earlier diabetes screening (of course, we recognize this is easier said than done). Apart from reduced ophthalmologist usage (cost) and therefore better resource allocation to those who really need it, we wonder if Prof. Aschner’s work has led to a decrease in retinopathy prevalence in his clinic.
- We were surprised to see data reflecting substantial global variation in diabetic retinopathy awareness. A meta-analysis of 15 articles revealed that among those with diabetes, between 29% and 84% were aware diabetes could affect vision. Awareness among general practitioners was also found to be variable, with 44% of general practitioners in Myanmar lacking awareness of vitreous hemorrhage and retinal detachment as possible diabetes complications, and only 34% of physicians surveyed in the Latin American Congress on Diabetes reporting correct referral of type 1 patients for eye exams. Prof. Aschner emphasized the need for education, highlighting rampant levels of misinformation and lack of information.
Symposium: Value Health Care in Diabetes and Real-Life Evidence
How to Design and Monitor Population Based Intervention – The New Frontier of Medical Research: Real Life Evidence
Josip Car, MD, PhD (Imperial College London, UK)
Imperial College London’s Dr. Josip Car found the lack of patient education and empowerment worldwide to be particularly striking. To this end, he showed a Google search trend (recreated and adapted below) demonstrating substantially (infinitely?) higher and more dynamic interest in “Kim Kardashian” (in blue) compared to “diabetes prevention” (in red) over the past year. Interestingly, a deeper analysis of the Google trends for the term “diabetes prevention” revealed that the most searches derive from Nigeria, followed by the Philippines, India, and the US. Considering diabetes prevalence continues to grow, it’s especially disappointing that interest in prevention has remained so stagnant, though we can’t say we’re surprised that a socialite garners more public interest than something few people are even aware of before it’s too late for them to take advantage. Our own analysis shows that the term “diabetes” (in yellow) is actually quite well-represented in the world’s searches (more so than Ms. Kardashian), and significantly more common than “flu” (green) and “Zika” (purple). This is, in a microcosm, the apex of the problem: Humans are reactive, and only take interest in something when they are directly affected by it. We can’t expect everyone to become a hypochondriac and Google everything that they could possibly be afflicted with every day, but we certainly do need a global shift in mindset toward prevention.
- Dr. Car was not hopeless regarding prevention, advocating for a population health approach to promote health and prevent disease from cradle to grave – a population level approach is necessary, he said, because 83 countries are already below the WHO’s recommended threshold of 23 skilled healthcare professionals for every 10,000 individuals. The strategy will require comprehensive mobilization of resources, including active participation from schools, organizations, communities, cities, regions, and national governments. Traditional population health interventions focus on leveraging communication and education to: (i) change norms; (ii) establish standards; and (iii) manage outliers. The rise of smartphone use for healthcare may serve to enhance these methods – Dr. Car noted that among smartphone owners, 77% of 18-29 year-olds, 68% of 30-49 year-olds, and 39% of 50+ year-olds used their phone for information about a health condition. Dr. Car believes there’s huge opportunity for real world evidence (RWE) from apps and sensors to help move the needle, yet stipulated that the current promise of technology, particularly smartphones, to improve healthcare is just that – promising, but not yet a reality. He expects the greatest challenge will not be to make big data meaningful, but instead to integrate data streams into routine clinical care.
- Dr. Car highlighted the importance of app accreditation to provide clinical assurance regarding quality and safety, increasing the likelihood of promotion and adoption by healthcare professionals and patients. He detailed a much-discussed UK study published in BMC Medicine reviewing 46 insulin dose calculator apps, which unfortunately identified only one (unnamed) app as completely issue-free. 44 apps had issues affecting data input, 42 failed to validate numeric inputs, 22 violated “basic clinical assumptions,” and only 14 provided the formula used to suggest the insulin dose. We’re reminded of a talk from this year’s EASD meeting, during which a predominately international panel expressed concern regarding the regulation of mHealth apps. While of course we encourage a healthy dose of skepticism, we’d note that there are a few apps that are delivering outcomes and publishing in peer-reviewed settings, though the majority of these are not just an standalone app now, but an app plus coaching, a connected device, and a subscription package.
Symposium: IDF-FIGO Joint Symposium – Detection and Diagnosis of Abnormal Carbohydrate Metabolism During Pregnancy
In a packed session, the International Federation of Gynecology and Obstetrics (FIGO) and IDF signed a consensus statement advocating for universal gestational diabetes testing of all pregnant women using a single step 75 gram oral glucose tolerance challenge. Because risk factor-based screening fails to identify 50% of women with hyperglycemia in pregnancy, FIGO states that risk factors should only be used to identify women in need of more intensive testing. Insulin resistance and compensatory increased insulin secretion in pregnant women reach significant levels by 24-28 weeks, making this timeframe the best in which to screen for hyperglycemia. However, in those with additional risk factors, decompensation (a lack of sufficient compensatory insulin secretion) may occur earlier, warranting earlier testing. Dr. Anil Kapur (Chairman of the Board of Directors, World Diabetes Foundation) shared data indicating that 38% of women test positive for hyperglycemia before 24 weeks, and 42% test positive in the second trimester (~weeks 13-28) – that is to say, that nearly 40% of cases of gestational diabetes can be detected before the fetus is the size of a cantaloupe. When good care is provided early (0-23 weeks of gestation vs. 24+ weeks), birth weight is shown to be ~300g (~10.6 oz) lower, strongly indicating the benefits of early screening. The standard of care surely doesn’t call for CGM currently, though the positive results from the JDRF-funded CONCEPTT trial make a strong case for CGM in pregnancy (even though the study looked exclusively at mothers with type 1). Still, many barriers exist around the world, including scarcity of equipment, lack of qualified staff, and patient transportation and hassle. The FIGO guidelines attempt a pragmatic approach, describing alternate strategies to consider in resource-constrained settings. One tip we found particularly clever was to support postpartum follow up through child vaccination visits. Several studies demonstrate postpartum intervention for type 2 diabetes prevention to be highly cost effective in both high- and low-income countries, yet mothers often struggle to prioritize their own health. However, if the child’s care team is involved, more women with gestational diabetes can receive appropriate management to reduce progression to type 2 diabetes.
- In a sobering reminder of how much there is still to be done in gender equality, Prof. C. N. Purandare, President Elect of FIGO, argued that women and girls should be empowered with equitable access to knowledge aimed at strengthening their capacity to prevent diabetes. According to Prof. Purandare, diabetes has greater adverse impacts on women’s health, resulting in reduced fertility and poor pregnancy outcomes, just to name a few. Women with gestational diabetes have up to a 16-fold increased risk of developing type 2 diabetes, making maternal health a priority for anyone hoping to make a dent in diabetes prevalence. As Prof. Purandare noted, pregnancy should be considered a window of opportunity to improve the future of metabolic health, not just for the women themselves, but also their offspring. In fact, according to Dr. Kapur, offspring of mothers with diabetes are at a greater risk of developing type 2 diabetes themselves (OR: 3.9; no p-value specified) – this risk skyrockets if the mother has obesity as well as diabetes (OR: 19.2; no p-value specified). Additionally, a woman with a maternal history of diabetes has a three-times greater risk of developing gestational diabetes than if she has a paternal history.
- Gestational diabetes prevalence is on the rise, attributed to the fact that the age of diabetes onset is decreasing while childbearing age is increasing. Indeed, coronary artery disease and stroke in women with gestational diabetes is projected to be the leading cause of death in women in India in 2050.
Award Lecture: The Robin D Lawrence Outgoing IDF President’s Award Lecture
Education is Empowering
Shaukat Sadikot, MD
Outgoing IDF President Dr. Shaukat Sadikot delivered a compelling keynote address, urging that we shift discussions of diabetes care “from ivory towers to on-the-ground realities.” Drawing upon decades of work in rural, underserved communities in India, Dr. Sadikot suggested that the current discourse around diabetes focuses too much on developing new medicines and updating treatment guidelines, and not enough on action that will directly help people with diabetes – 80% of whom live in low- and middle-income countries where the newest diabetes drugs are out of reach and major treatment guidelines are hardly applicable (this certainly seems to be the case based on an IDF survey of care centers from 90 different countries – see below for our coverage of this). According to Dr. Sadikot, people in this field must understand that “diabetes is not solely a matter of medicine, medicine, medicine,” because there are many other factors that determine health, including socioeconomic conditions and their effect on healthcare access and health literacy. To drive this message home, Dr. Sadikot told a story from his early years of medicine: After hosting a session in a rural Indian village to educate people about diabetes-friendly dietary recommendations, a man approached him and said “Doctor, thank you for telling me what to eat. My problem is that I don’t know whether my family will have anything to eat today.” He surmised, “You’re not a diabetologist unless you understand that it’s about much more than blood glucose.”
- “We are here to fight a war against diabetes, and PCPs and diabetes educators are on the front lines.” Beyond empowering patients and becoming champions of policies to lessen healthcare disparities, Dr. Sadikot also emphasized the importance of empowering PCPs, nurses, and educators, who provide care to a majority of the world’s people with diabetes. Under Dr. Sadikot’s leadership, the IDF has developed the “Best of IDF” program, which provides free educational content on diabetes to providers. Dr. Sadikot also spearheaded the IDF School of Diabetes, which offers intensive six-month courses in diabetes management tailored for diabetes educators, PCPs, and specialists. Currently, the programs are free to anyone living in a low-income country or working for a government health center.
- Dr. Sadikot acknowledged that diabetes is one of the most challenging public health issues of our time, deeply entangled with complex issues of poverty and disparities in access to healthcare. Thus, to meaningfully confront the diabetes epidemic will require a more expansive approach than our traditional efforts for scientific advancement on top of already-excellent therapies, he argued. He pointed out that within the past decade, every international organization has come out with academic guidelines and advisories, dozens of new diabetes medications have hit the market, and several diabetes conferences occur every month – and yet the fact remains that the majority of people with diabetes are not at optimal control, and most are not even near optimal control. We have tools to manage diabetes, but what’s missing is widespread education and empowerment, in Dr. Sadikot’s view.
- This emphasis on the different stories of diabetes in developed vs. developing regions of the world is certainly important and appropriate for an international meeting like IDF. Every sentiment in Dr. Sadikot’s remarks rang true, although we’re not sure everyone would agree that our diabetes toolkit is stocked with already-excellent therapies. In other words, even the most advanced treatments available today are not to the point where they’re lowering the burden of diabetes and maximizing patients’ quality of life (so that they can live as they would without diabetes). Slowing innovation, or investing less in it, is not the answer from our perspective. That said, while manufacturers continue to improve diabetes treatment to be safer, more effective, and easier to use, we also need all stakeholders (including industry) to lend a hand in promoting screening/monitoring (for diabetes, for complications) and education in harder-to-reach pockets of the globe.
Meet-the-Expert: Access to Care and Medicines
Access to Diabetes Medicines and Supplies: A Perspective from IDF Members
Belma Malanda, MD (International Diabetes Federation, Belgium)
IDF’s Dr. Belma Malanda illuminated stark disparities in access to diabetes medicines/supplies around the globe by presenting survey data from a spectrum of IDF-member care centers across 90 countries. Availability (as defined by presence in the supply chain) of basal insulin, rapid-acting insulin, metformin, and sulfonylureas exceeded 90% in high-income countries, ranged from 75%-95% in middle-income countries, and ranged from only 40%-50% in low-income countries. Provision of these medicines (whether by a governmental agency, private insurance, or another source) was lower across all geographies, but followed the same expected pattern: 70%-80% in high-income countries, 50%-60% in middle-income countries, and 10%-20% in low-income countries. The gap between availability and provision reflects a worldwide disconnect between the presence of these medicines and access to them. What’s more, this survey didn’t even include advanced therapy classes such as DPP-4 inhibitors, SGLT-2 inhibitors, or GLP-1 agonists, and we can only imagine that provision for these drugs comes in at even lower percentages. Dr. Malanda discussed barriers to insulin access in particular. Lack of diabetes education emerged as the greatest challenge for insulin access in high-income and low-income countries alike, with 45% of the surveyed IDF-member care centers ranking this as a major barrier. Notably, diabetes education is an even greater challenge in low-income countries, ranked as such by 70% of care centers, though this is outmatched by the high cost of insulin, ranked by 80% of surveyed care centers. These statistics are hard to stomach, but Dr. Malanda noted that the reality is probably even worse, since only IDF-member centers were surveyed, leaving out responses from less-engaged areas (even less likely to have diabetes education, availability, or provision). Overall, these findings underscore the sheer magnitude of the systemic barriers preventing people with diabetes from accessing the essential medicines they need. As we continue to grapple with IDF’s latest statistics on the size of the global diabetes epidemic, it is clear that meaningful improvement will require seismic shifts on the health policy front. Dr. Malanda left us with a compelling call-to-action: the first step in addressing disparities is high-quality data, which is the only way we’ll fully understand the scope of this problem to develop precise and maximally-effective strategies for improving access.
Debate: Does a Sugar Tax Affect Obesity Rates?
Juan Jose Irazabal Lujambio (Mexican Diabetes Federation, Mexico)
In a wholly disappointing debate on the efficacy of a tax on sugar-sweetened beverages (SSBs), Mexican Diabetes Federation President Mr. Juan José Irazabal Lujambio pointed to two major roadblocks to success in his country: Government corruption and a lack of substitute beverages.
“Categorically, in Mexico, we’ve been living with soda taxes for four years and it hasn’t worked. Fiscal authorities say the moneys go in one box, and they decide how to use it. We haven’t seen all the money return into the health system – which is very disturbing; very sad. Unfortunately, these sorts of legislative actions may be good in countries where there is no corruption. Unfortunately, I live in a country where corruption is strong. This would probably work if we had another type of government, another type of country… The other thing is that soda manufacturers are very powerful enterprises – they’re in the system. More than them manufacturing healthier or unhealthier products, what would really work is if all that money the government is getting – it’s 10% taxation, so the government is making a lot of money with this – if all of these moneys returned into health system, that would make a big difference. If there was really clean drinking water, even in schools, that’d make a difference. But many schools in Mexico don’t have water. Kids have to go to soda pop or whatever is available.”
These factors are both, of course, extremely concerning, and we wonder to what degree they are true. Corruption and a lack of substitutes, if pervasive, color otherwise positive data published earlier this year showing that the tax lowered soda consumption by 7.6% in its first two years. Was the higher cost of SSBs forcing people to drink unclean water, or even face dehydration, instead? (Other data says bottled water consumption has gone up 7% in Mexico, though presumably from a lower base than soda’s 7.6% decline.) Secondary to reducing consumption, a big promise of an excise tax on SSBs is to funnel revenue back into social support, education, awareness campaigns, and even city planning to further healthy behaviors – where has the money in Mexico actually gone? How much of it has been pocketed by politicians and others? Looking to other locations where the tax has been implemented – Philadelphia, Boulder (CO), Albany (CA), Oakland, San Francisco, and Seattle in the US; France, Norway, and Hungary outside of the US, to name a few – to what extent do they face a lack of substitutes, and how much of the tax revenue is going to improving health? This seems like an area deserving of external investigation, though it demands expertise well beyond the bounds of public health.
- Mr. Lujambio’s actual argument against the SSB tax was elementary and faulty – he suggested that, since obesity has continued to rise in Mexico since 2014 (when the tax was implemented), the tax has been a failure. The unsophisticated analysis lacks a control group and doesn’t answer the question of what the rates would have done in the absence of a soda tax – climbed even faster? To expect obesity trends to reverse in just ~four years after beginning to tax SSBs is extremely over-optimistic. A 2016 study estimated that the tax would prevent 89,300 type 2 diabetes cases, 20,400 strokes and myocardial infarctions, and 18,900 fewer deaths from 2013 to 2022, saving the country $983 million. A 2017 study found a 6.3% reduction in soft drinks in 2014 compared to expected purchases that year based on historical trend data, with the greatest reductions in lower-income households, urban areas, and households with children. Further, there was a 16.2% overall increase in water purchases that year. Despite Mr. Lujambio’s valid concerns, the data indicates that the tax is acting at least somewhat as intended.
- Danish Diabetes Association’s Ms. Charlotte Rullfs Klausen, Mr. Lujambio’s counterpoint for the debate, showed that sales of SSBs grew by 5.4% in 2014 vs. 2013 – a tax was introduced in 2013 and then cancelled in 2014. We and the Danish Diabetes Association are strong advocates that it be re-implemented, particularly as one in two children and one in three adults in the country exceeds daily recommendations for sugar intake. In Europe, Denmark is surpassed only by Finland in candy consumption, and only Germany and Belgium for soft drink consumption.
- Mr. Lujambio’s speech raised the question: What needs to be in place in order for a soda tax to be successful? Availability of substitutes; a non-corrupt government; elastic consumption (a small change in price accompanied by a large reduction in consumption); the tax must be passed down to consumers (as opposed to incurring internally by a soda company or distributor); and sufficient enforcement against arbitrage (sold across borders due to price difference). These (and surely others not listed) must be considered and/or addressed before implementing a tax in a specific locale.
Debate: Hypoglycemia and Macrovascular Outcomes
Brian Frier, MD (University of Edinburgh, UK)
A debate between Prof. Brian Frier and Prof. Markolf Hanefeld left most thinking that the association between severe hypoglycemia and macrovascular complications is causal (rather than correlational), despite a lack of bona fide evidence. Unfortunately, at this point, it seems that the field doesn’t have the data to make a judgement call – Prof. Frier suggested that an expensive, labor-intensive prospective study using simultaneous CGM and Holter monitoring for EKG would be the only way to firmly establish causation. (We’d note Dr. Irl Hirsch tried this in the FLAT-SUGAR pilot study, but showing big differences in glycemic variability/hypoglycemia for the same A1c was challenging.) Prof. Frier believes a trial would actually reveal that the answer to the debate probably lies “somewhere in the center ground,” and he acknowledged that many of the large studies that show an association between hypoglycemia and CV mortality are just as likely to show that hypoglycemia is an index of poor cardiovascular prognosis as hypoglycemia being the direct cause of the adverse outcomes. University of Dundee’s Prof. Rory McCrimmon told us separately that groups will be getting together to discuss large trials with CGM, which we’d certainly welcome! We’ve noticed some advocating for a modern-day DCCT with CGM, while others think such a trial would be a waste of time. Would such a trial really move the needle? What would the randomization arms look like? The cost and size of such a long-term study would have to be weighed against the opportunity cost of other things that could be funded. This may be the prime opportunity for a registry study, perhaps in the context of a payer who could link claims and glucose data. Would it not be in a payer’s interest to randomly select a number of patients in its population to wear CGM, and then track hypoglycemia (and time in zone and glycemic variability) in concert with CV events? (Perhaps Dexcom/UHC’s pilot in type 2 will do just this.)
- Prof. Frier plainly stated that the relationship between hypoglycemia and adverse vascular events is complex and trials thus far haven’t been conclusive, but made the case for causality based on secondary analyses from RCTs and physiological/electrical evidence. On the trial front, he pointed to VADT (severe hypoglycemia was the strongest predictor of CV death, above previous CV event and A1c); ACCORD (patients with severe hypoglycemia had higher mortality, though only in the non-intensive group); the Edinburgh Type 2 Diabetes Study (severe hypoglycemia associated with CV events and mortality); and a six-study meta-analysis from 2013 finding that severe hypoglycemia was strongly associated with higher risk of CVD, and comorbid severe illness couldn’t explain this higher risk. The problem of course is that all of this evidence is totally circumstantial, and one could make a strong argument for occurrence of severe hypoglycemia being a marker for frailty and vulnerability to poor health outcomes. To indirectly bolster his point of view, Prof. Frier went the mechanistic route, pointing out that hypoglycemia has many detrimental effects on vasculature, including endothelial dysfunction, hemodynamic changes/rhythm abnormalities/heart rate variability, blood coagulation abnormalities, and inflammation. These effects, he went on, last for several days, which could explain difficulties in attributing sudden death directly to severe hypoglycemia – it may be setting the patient up for a CV event days later. Further, there is evidence that hypoglycemia is associated with pro-arrhythmogenic changes in EKG. Finally, since many people with diabetes already have established CV disease, Prof. Frier proposed that severe hypoglycemia may often just be the smoking gun that causes death, exacerbating cardia and autonomic dysfunction.
- Prof. Frier laid out a number of limitations to the available data with respect to searching for a link between hypoglycemia and adverse CV events: (i) Evidence comes from secondary analyses of RCTs recruiting high-risk patients; (ii) Large outcome trials can’t prove causality between hypoglycemia and macrovascular events; (iii) Cardiac events are rare, severe hypoglycemia is uncommon in many individuals, and hypoglycemia is under-reported (he dismisses claims about hypoglycemia and CV outcomes in DEVOTE for this reason).
It Doesn’t Damage
Markolf Hanefeld, MD, PhD (Technical University Dresden)
To counter Prof. Frier’s argument, Prof. Hanefeld cited numerous studies showing increased (non)-severe hypoglycemia along with neutral or improved CV outcomes. In the DCCT, there was a three-fold higher incidence of severe hypoglycemia in the intensive arm, but this arm also had 30% CV risk reduction. There were similar stories in UKPDS and ORIGIN (the latter saw neutral effects of CV events despite more mild and severe hypoglycemia). In DPP-4 inhibitor trials SAVOR TIMI 53, EXAMINE, and TECOS, CV outcomes were all neutral despite less hypoglycemia in the DPP-4 arms. In DEVOTE, there was a clear benefit for Tresiba with respect to severe hypoglycemia, but there was no difference in CV outcomes or A1c. Finally, in the ARIC study (of older individuals), in the one year since a hypoglycemic event, risk was actually higher for cancer mortality than it was for coronary heart disease, heart failure, and CV mortality – in other words, severe hypoglycemia may be a sign of declining health, particularly in the elderly.
- In hallway chatter, University of Dundee’s Prof. Rory McCrimmon told us he believes this debate may have been viewing the relationship too simplistically. First of all, he doesn’t believe that the effects of non-severe hypoglycemia were discussed sufficiently. Second, he thinks that the context within which the hypoglycemia occurs, and overshooting the target range on the recovery from hypoglycemia may be more relevant factors than hypoglycemia itself – a great point! At EASD, he discussed how hypoglycemia may be deleterious only in the context of hyperglycemia, and today he proposed that hyperglycemia after a bout of hypoglycemia may be damaging. He alluded to literature suggesting that people with hypoglycemia but no diabetes (hyperglycemia) actually live longer. One thing’s for sure, without the CGM data, we won’t know for sure the impact of any “real-time” glycemic metric on overall or CV-related mortality.
Launch Session: IDF Diabetes Atlas – The Global Burden of Diabetes
The New Edition of the IDF Diabetes Atlas
Nam Cho, PhD (Ajou University, South Korea)
The latest edition of the IDF Atlas – see our coverage here – was presented today in a high-level session kicking off with remarks from the newly-elected IDF President Prof. Nam Cho. Prof. Cho highlighted that the values in the IDF Atlas are still estimates, with gaps in data collection and quality prohibiting the release of more accurate figures. Although he did not provide a specific timeline or action plan, Prof. Cho mentioned that he hopes improvements in diabetes research and epidemiology will eventually lend itself to the Atlas using actual values. We suspect that such developments will require significant energy and time and likely will be reserved as a long-term project – enhanced data capture via EHR and other digital tools are only just starting to gain ground in some high-income countries. How much value would actual figures add, anyway? The most valuable aspects of the Atlas are in showing trends and acting as a periodic thermometer for how the world is doing in diabetes care. Prof. Cho also stressed the major discrepancies that exist in healthcare expenditure related to diabetes, as well as the startling rates of undiagnosed diabetes. As a reminder, one in two people with diabetes is undiagnosed, with a large proportion (85 million people, or 40%) residing in the Western Pacific – the IDF region with the greatest number of people currently living with diabetes. The complete 8th edition of the IDF Atlas is now available in English, Spanish, French, and Arabic for free download here, or see our detailed coverage here.
- Dr. Alireza Estaghamati (Tehran University of Medical Sciences) provided additional color to estimates for the Middle East and North Africa (MENA) region. MENA is estimated to have the second highest diabetes prevalence following North America. Currently, there are 39 million people living with diabetes in MENA, predicted to skyrocket to 82 million by 2045. While prevalence increases with age, females are more affected across every age group and experience higher rates of mortality. There are likely several reasons for the gender disparity: In addition to cultural factors and education inequity, hyperglycemia in pregnancy (HIP) is a probable contributor. Only three countries (Iran, the UAE, and Qatar) in MENA have data sources for gestational diabetes, estimating 3.8 million live births to be affected by HIP, for which the age-adjusted prevalence is nearly 18% overall and 17.3%, 37.1%, and 25.5% respectively by country. Dr. Estaghamati called for more collaboration, cooperation, strategies, and dedicated, focused plans to combat diabetes in the region.
- Prevalence of undiagnosed diabetes in the MENA region, estimated to be 49%, is on par with the worldwide average. Major discrepancies exist, with people in Pakistan and Egypt least likely to know they have diabetes. Substantial variation across countries is also seen for impaired glucose tolerance testing, as well as diabetes-related healthcare expenditure, accounting for a staggering $21.3 billion overall or 17% of the total spend in MENA. This level of spend is obviously too high (compared to a diabetes-free world), but it is shockingly just over 6% of what the US spent in 2017 ($348 billion).
- Algeria, Saudi Arabia, and Morocco are the MENA countries with the highest number of children and adolescents (ages 0-19 years) with type 1 diabetes, totaling 42,500, 35,000, and 31,800, respectively. Interestingly, none of these countries are amongst those with the highest number of adults with diabetes, although Saudi Arabia does have one of the highest age adjusted comparative diabetes prevalences in MENA at 17.7%.
Open Forum: General Practitioners and Primary Care: Strengths, Focus, and Function in Diabetes Care
A fascinating discussion – during which speakers and audience members discussed hope (or lack thereof) for diabetes prevention, an interesting take on precision medicine, and the need to change systems via legislation – followed a forum on the function of GPs in diabetes. We’ve provided the entire transcript below. After a Ugandan provider asked the panel if there was reason to be optimistic despite climbing diabetes rates even in the best care settings, conversation turned to systems, policy, and the detrimental effects of modernization. VU University Medical Center’s Dr. Petra Elders seemed to place the onus on society to find ways to do better, while chair Dr. Ali Khalil focused on “business-minded multi-national companies” like McDonalds and Coca Cola, and a “macro environment where we involve government and push them very strongly against certain things that we know as professionals is actually causing disease…” Dr. Elders proposed that even in countries, like Uganda, where elaborate diabetes care networks haven’t been established, that society-level prevention strategies may be a solution. The whole discussion is worth a read, including Dr. Elder’s comment that she doesn’t expect much from precision medicine based on genetics – while this may help a few, it is not entirely feasible at this point in time outside of academia, and she believes broader strokes are sufficient for most people (exercise sufficiently, “eat less than your predecessors”). Of course, determining the appropriate strategies to promote a healthier lifestyle for an individual by definition requires some sort of precision medicine, but “deep phenotyping” and behavioral analysis could be even more informative than genomics. However, when it comes to picking the right medication, we still believe that –omics will have a lot to offer.
Q: I practice in Uganda, where our dream is that, if we had the resources that you do in the Northern European setting, we could stop diabetes. Even in your environment, diabetes is still going up. Is there hope? Do we still have a chance of ever bringing diabetes down, if we’re going up even in the best environment?
Dr. Petra Elders (VU University Medical Center, Amsterdam, Netherlands): Since you’re here and I’m here and there are people in the audience, we still have hope. It has something to do with patient awareness – we as doctors can prevent complications. Guide glycemic control, blood pressure, lower lipids, prevent complications, and have a multidisciplinary approach to treat complications. But we’re past this. Now the public has to do something. It’s a societal question, whether we as mankind are able to stop eating horrible foods. And if we don’t have to move to survive, we prefer to sit on our chairs. We need a new view and new solutions, I think that’ll take a long time.
Dr. Ali Khalil (Imperial College London Diabetes Center, Abu Dhabi, UAE): The big issue is the elephant in the closet – the big problem is not with the physicians, and it’s not with the population. It’s the business-minded multi-national companies – McDonalds, Coca Cola – despite our best efforts, they are able to advertise their products better than we can advertise ours (healthy eating and exercise). Unfortunately, we’re going in the wrong direction. Now we don’t even have to get out of chairs to get food because its delivered right to our doors. The problem is even being propagated now. 30 years ago when I went to China, there were bikes everywhere. Then eight years ago, I didn’t see any bikes in Beijing. They’re coming back again, but that whole issue of modernization, what we call modernization, that’s plaguing us.
Dr. Elders: And maybe even in the countries where diabetes care still has to be established, maybe even finding societal solution in reducing consumption there might be a solution, but still small steps and we have a lot left to do.
Dr. Ed Fisher (UNC, Chapel Hill, NC): In your presentation, precision medicine touched on a whole number of things, many related to phenotype. Talk about precision medicine in US focus mostly on genotype directed care. Can you talk a little more about that?
Dr. Elders: As a GP, I’m realizing that the gene pool is not changing so much over time, but I’m also realizing that we are having an epidemic of diabetes. To be very honest, I don’t expect much from genetic research. Maybe a little for small select segments, but for the broad population, things will probably remain very practical – exercise sufficiently, eat less than your predecessors. Sorry, GPs usually give very flat answers. One thing we can make a lot of headway in is patient input – in western countries, we tend to send out a lot of input, but in activating patient input, getting patients to take care of their own issues, we have a long way to go.
Dr. Fisher: Both of your presentations point to importance of understanding systems of care rather than thinking healthcare will be solved by individuals trying harder and being smarter. We are trained as professionals to think that we as individuals can make a difference, but it’s important to realize that we need systems to make us more effective.
Dr. Khalil: I came to UAE from Canada. It was very different when I came here. We were part and parcel of people who started programs here, developing specialized medicine for diabetes or diabetic centers because of the high prevalence here. The sad part is a lot of it starts at youth – we’re seeing type 2 diabetes at the ripe age of 25. Not even caught up with complications yet, but they’re about to come. As members of a medical community, we need to push legislation really, much more so than working on our own environment. We need to have a macro environment where we involve government and push them very strongly against certain things that we know as professionals is actually causing disease and problems for indigenous populations who had never had to deal with onslaught of different foods and changes in their environment. That’s the biggest challenge in developing world. We need to develop some sort of structured methodology, but that works separately in different areas. It’s a whole different mental status in the Netherlands and the UAE. Understanding the population and getting through to them is primary. But aside from that, it’s not always the public’s fault. Given the choice between high calorie food that you can chow down in five minutes and having to wait three to four hours for a smaller meal, most will choose the faster option, and face the consequences later. In the UAE, we set up a lot of these legislations through regulatory bodies to educate the population in a much stronger way as opposed to leaving that and going with specialized centers.
Media Event: Uncovering Insights Related to Cardiovascular Disease Among People with Type 2 Diabetes – Are We Doing Enough?
Novo Nordisk and IDF announced interim results from their co-sponsored “Taking Diabetes to Heart” survey: One-third of respondents considered their CV risk to be low (“minor” or “marginal”), and one in six have never talked to a healthcare provider about how their type 2 diabetes confers risk for CV disease. The 27-question online survey, open to everyone with type 2 diabetes, found that while 52% of people with diabetes learn about CV disease before diagnosis, 12% never learn about it, 7% learn only when diagnosed with CV disease, and 14% learn several years after diabetes diagnosis. Further, while 27% of patients discuss CV disease with their provider at time of diabetes diagnosis, 16% never have, 5% did several years after diagnosis, and 3% did only when diagnosed with CV disease. These results represent an overall lack of awareness of the overlap between diabetes/CV disease, as well as subpar patients/provider conversations with respect to CV disease and risk factors. In a panel convened to discuss the results, Professor Eduard Montanya (University of Barcelona, Spain) shared that patients in clinic frequently ask about eye problems and weight, but not about CV risk, even though it is most likely to lead to death (indeed, CV morbidity remains the leading cause of mortality for the diabetes patient population, and thought leaders are issuing passionate wake-up calls that diabetes should be considered a CV disease in and of itself). According to Professor Montanya, the focus on microvascular complications is partially responsible for unawareness around CV risk. As we learned in examining the CANVAS results on J&J’s SGLT-2 inhibitor Invokana, there are some complications (e.g. amputations) that affect people more viscerally than others (e.g. the possibility of a future stroke or heart attack). We didn’t find the Novo Nordisk/IDF results entirely surprising, especially in light of data from a similar Lilly/BI-sponsored survey conducted in the US (66% of people with type 2 diabetes were unaware of their elevated risk for CV death). In some ways, the interim results from the global survey are even better than we may have expected, though we recognize the potential for selection bias, with more engaged patients than average (and those with internet access) completing the voluntary exercise. These analyses were based on 943 responses from 32 countries, but 83% of respondents are from Denmark, followed by 6% from the US, 5% from Belgium, and 1% from the UK. That said, statistician Dr. Nafeesa Dhalwani noted that analyses including and excluding Denmark gave very similar results. Data collection will continue through March 2018 (the survey was launched in September 2017), and full results are expected at EASD 2018, followed by a full report in October 2018.
In the Alere booth (now owned by Abbott), we learned about an extraordinary effort to increase (pre)diabetes screening in India called Testing at Pharmacies (TAP). The Afinion 2 analyzer, which gives an A1c reading in three minutes, a lipid panel in five, and a CRP value in three, has been placed in a “good number” of pharmacies (as the name implies), and the program intends to scale. We couldn’t get more information about the program from the rep and couldn’t find any materials online – how much does the test cost the screenee, if anything? – but we love the idea of boosting awareness and placing the test in a location that people come across frequently. India is in sore need of early diagnosis and prevention, as it currently has the second highest number of people with diabetes (73 million), with >60 million more diagnoses expected in the next 30 years, according to the Eighth IDF Diabetes Atlas. We hope the program can reach sufficient scale to curb this impending avalanche, and that there are good triage, referral, and treatment systems in place for those who are told that they have or are in danger of developing diabetes.
Boasting one of the larger booths in the exhibit hall, BD advertised its 4mm pen needle as the shortest in the market, and also the size recommended by FITTER experts. The booth also displayed BD’s safety devices, including Autoshield Duo, compatible with all insulin pens, as well as the Safety Glide, which fits over syringes. Company representatives were unable to comment on BD’s partnership with Medtronic and could not provide timing regarding the MiniMed Pro-set with BD FlowSmart technology. Last we heard during BD’s November earnings call, the additional clinical trial conducted due to higher-than-anticipated user complaints surrounding kinked cannulas and elevated blood glucose levels had been completed. The most recent timing update came in August, when the company expected launch to resume in FY18 (October 2017-September 2018). This wide window seems very doable, and armed with additional information to ensure that customers are more successful with the set the second time around, we look forward to seeing the re-entry. (On the downside, Medtronic’s recent calls have noted declining prices and pressure on infusion set sales – how this will impact BD is unclear, though its set is priced roughly at parity to Unomedical.) Kudos to BD and Medtronic for undertaking an additional study when it was called for. Representatives also could not comment on BD’s type 2 basal-bolus patch pump, although one noted it is “still in development.” As of November, the pump’s launch has been delayed to FY19 (October 2018-September 2019), pushed back from previous 2H18 timing.
We thought we were in the Twilight Zone when we came across the UK-based Evia booth and saw their EGM 1000 non-invasive ear clip glucose monitor, which strongly resembled Integrity’s GlucoTrack product, to put it lightly (see pictures below). The rep was familiar with GlucoTrack, but told us that they were not distributing Integrity’s monitor and that the products are distinct, suggesting that the sensors are different. Based solely on appearances, we assume they are the same. The rep told us repeatedly that the sensor was “97.3% accurate,” but didn’t offer units. We assume he meant that 97.3% in zones A and B of the Clarke Error Grid. Whether the same or slightly different from GlucoTrack, there are many questions that remain – apart from the non-invasive perk, form factor, user-friendliness, target market, and beyond will need to be addressed. While the non-invasive piece is nice, the lengthy measurement time (one minute) and high visibility of taking a measurement (clipping to an ear lobe) could hinder adoption. There is certainly potential for an easy-to-use non-invasive diabetes screening product, but even GlucoTrack/Evia would not be accurate enough for that indication and the calibration process would limit widespread use. Until these monitors become more discreet and less time-consuming to use, we remain skeptical.
Optomed displayed Aurora, its fifth-generation automated screening tool for diabetic retinopathy, priced at €7,500. The non-mydriatic (no dilating eye drops required) digital fundus camera is portable, handheld, and the only device on the market with a 50-degree field of view. The camera uses a rechargeable battery and includes a screen to automatically display the image for quick analysis. Images can also be uploaded via WiFi or USB to Optomed Avenue, a real-time software for automatic screening of early stage diabetic retinopathy. The platform performs risk stratification, suggesting referral to an ophthalmologist if any alterations are flagged. Given the limited supply of ophthalmologists, we’re very excited to see how this program may serve to reduce burden and improve screening rates. We do wonder what kind of training is needed to operate the camera, and whether health or social systems would be willing to invest in the moderately expensive hardware to prevent costs on the back end…
Owen Mumford, a UK-based company specializing in drug delivery devices, advertised its single-use safety lancets Unistik 3 and Unistik Touch. Unistik 3 is designed for use with BGMs and is available in five gauges depending on the blood volume required. Comfort Zone Technology (eight raised dots at the tip of the lancet) is meant to mask the pain stimulus from the needle, said the rep, citing pain gate theory. (FreeStyle Libre’s inserter has a similar technology, though we’re not sure if it drives the lower pain or if it’s something else in the design.) The needle is discharged by pressing the release button, minimizing applied pressure. Unistik Touch includes the same Comfort Zone Technology as Unistik 3, but is cheaper and contact-activated, requiring more pressure. It is available in four gauges.
Roche – Senseonics Eversense
Senseonics’ Eversense was the star of the Roche exhibit, with attendees swarming that part of the booth. We received a number of updates on the sensor’s EU rollout: France entry early next year, Czech Republic toward 3Q18, and the 180-day XL sensor has rolled out in the UK (on track with previous expectations) with the next wave to come “mid-next year [at the] latest.” There will also be a randomized, controlled study in France (18 months, n=300 according to the rep) with the goal of demonstrating improved outcomes with the implantable CGM. Nice! This could help with achieving difficult national reimbursement in France (where there are “hundreds of thousands” of type 1s and 2s who use insulin multiple times a day, according to an Abbott a press release upon FreeStyle Libre’s national reimbursement). However, we later followed up with the company and these details could not be verified. Eversense has performed very well in terms of accuracy in both the EU and US pivotal trials and a recent MGH study where it edged out FreeStyle Libre Pro and Dexcom’s G5, and real-world usage is quite high, but this will be the first RCT to investigate outcomes. With respect to pricing, the rep suggested that Eversense would be comparable to Dexcom’s G5, but (naturally) more expensive than Abbott’s FreeStyle Libre. The launch is moving along, and as of Senseonics’ 3Q17 call, ~75% of the user base had previous CGM experience – this will be a key metric to follow, as Senseonics will need to push that number down if it wants to grow the market. This was the third time we’ve seen Eversense in a Roche booth, Day #2 was the second time we’ve seen Eversense prominently featured in a Roche symposium, and reps continue to tell us that the sensor fits in with Roche’s connected ecosystem vision – is an acquisition a possibility? As a reminder, Roche already has a broad distribution agreement with Senseonics and invested $30 million in the company in May.
- We asked about US regulatory status but the rep simply shrugged. Per the last update, projected approval has been pushed back to early 2018, and management anticipates an Ad Comm in 1Q18.
AZ’s sprawling booth featured its trio of main diabetes products: GLP-1 agonist Bydureon (exenatide-once-weekly), the SGLT-2 inhibitor Farxiga (dapagliflozin) franchise also including Xigduo (dapagliflozin/metformin), and the DPP-4 inhibitor Onglyza (saxagliptin) franchise also including Kombiglyze (saxagliptin/metformin). On one large poster, Bydureon was promoted as an injectable treatment intensification option to be used before insulin, and a panel around the side promoted EXSCEL as the largest CVOT to be conducted with a GLP-1 agonist (n=14,752). AZ’s new autoinjector Bydureon BCise was recently approved by the FDA and was accepted for active review by the EMA, but did not make an appearance in the company’s IDF booth. Farxiga was featured opposite Bydureon, with emphasis on the number of patients (1.5 million) who have used dapagliflozin, and on the associated A1c reduction and weight loss. Off to the side, booth visitors could read information on the DapaCare program – which is enrolling 30,000 patients across Dapa-HF, Dapa-CKD, and three mechanistic trials, and which also includes CVD-REAL, DECLARE, and DELIGHT. Around the back side of the booth, a large screen took attendees through the company’s 100+ years of experience in CV medicine. AZ seems especially focused on showing CV and renal benefits to dapagliflozin therapy, hence the massive investment in DapaCare and the emphasis not only on diabetes, but on the triad of cardio-renal-metabolic syndrome in this exhibit.
Lilly hosted a large booth in the IDF exhibit hall, easily recognizable for its signature red color scheme. Free-standing wall displays radiated outward from the center, outlining information on the company’s various diabetes products. GLP-1 agonist Trulicity (dulaglutide) and BI-partnered SGLT-2 inhibitor Jardiance (empagliflozin) were given prime location at the front corners of the booth. Promotional materials for Jardiance’s new CV death indication were out in full force, with the bold slogans we’ve seen at many cardiology conferences of-late, such as “CV death has a new opponent.” Behind these displays, smaller sections featured DPP-4 inhibitor Tradjenta (linagliptin), fixed-dose combination Glyxambi (empagliflozin/linagliptin), basal insulin Basaglar (biosimilar insulin glargine), the Humulin U500 KwikPen, and the Humalog (insulin lispro) U200 KwikPen. Each section contained an interactive touchscreen where booth visitors could learn more about the clinical data for each product. Panels titled “Have You Seen a Patient Like…?” offered information on the typical patient profile who might benefit the most from each of Lilly’s diabetes therapies – we loved this nod to personalized medicine. As the backdrop of the medical information booth, we found a timeline of developments at Lilly, starting with its 1876 founding and detailing an amazing history of pharmaceutical advances. A decently-sized corner of Lilly’s booth was dedicated to patient education, with reps on hand to walk attendees through a colorful array of conversation mapping tools to address healthy eating with diabetes.
Adjacent to Lilly’s booth, a partnered Lilly/BI exhibit drew attendees with a large overhead banner decorated with pictures of animals, accompanied by lower banner that read “Now That I Have Your Attention,” the companies’ signature marketing scheme for Basaglar (biosimilar insulin glargine). Inside the booth, insulin initiation was likened to an airplane flight. Reps described the patient support kit for Basaglar as a suitcase to ease the “turbulence” of starting insulin therapy. Since US launch of the biosimilar in December 2016, Lilly/BI have been promoting basaglar.com, which offers detailed answers to the most pressing questions for a patient switching or starting insulin therapy. This theme of patient support also came across clearly in Lilly/BI’s IDF exhibit hall booth. SGLT-2 inhibitor Jardiance (empagliflozin) and DPP-4 inhibitor Tradjenta (linagliptin) were represented, too, with a touchscreen “clinical trial tree” infographic detailing every single clinical trial of the agents – roots represented phase 1, the bark represented phase 2, and leaves and apples on the tree represented phase 3.
Merck brought a compact booth to IDF, but it was hard to miss on account of the bright purple, yellow, pink, and teal color scheme. The exhibit was entirely dedicated to Glucophage (metformin), which has now been on the market for 60 years. On a central pillar, a dozen monitors played videos on loop, taking viewers through the history of the product and the evidence supporting the glycemic and CV benefits of metformin. Booth visitors were also invited to put on virtual reality headsets to learn more about metformin’s efficacy in the Diabetes Prevention Program – the drug isn’t yet indicated for prediabetes, but given solid evidence from DPPOS, we are keen to see metformin prescribed earlier in the progression of hyperglycemia. MSD, which manufactures DPP-4 inhibitor Januvia (sitagliptin), did not host a booth at IDF. We wonder if this is because of the uniquely international focus of this meeting, with Glucophage prescribed at higher volumes outside the US vs. within the US, although ~49% of Januvia franchise sales also come from ex-US markets. We did find Januvia’s absence from the exhibit hall floor quite surprising, since the product is by far the market leader for DPP-4 inhibitors, capturing 61% of pooled class sales in 3Q17.
Novartis’ booth celebrated 10 years of DPP-4 inhibitor Galvus (vildagliptin) and highlighted “patient trust” in this product. Tall panels promoted the once- or twice-daily oral drug for use early in the course of disease – this echoes what we’ve heard from thought leaders on when DPP-4 inhibitors are most appropriate, and it represents one piece of the company’s three-pronged strategy on marketing Galvus (also for the elderly and for patients with renal impairment). Galvus took home 12% of the ~$10 million DPP-4 inhibitor market in 3Q17. We were a bit surprised not to see any information on Lucentis, which Novartis markets ex-US and which is actually a bigger commercial product for the drug maker. Lucentis is one of three anti-VEGF therapies on the market for diabetes-related retinopathy and macular edema. Given that retinopathy affects nearly one in four people with ≥ten years diabetes duration, we see it as a missed opportunity that Novartis dedicated no booth space to Lucentis.
Novo Nordisk hosted one of the most popular (i.e. crowded) booths on the exhibit hall floor, giving each portfolio product its own section (Victoza, Tresiba, Ryzodeg, Xultophy, and NovoRapid – but no Fiasp). We found the Tresiba section particularly eye-catching, with its emphasis on the EMA-approved hypoglycemia claim – an FDA decision on this label change is expected in 1Q18. Bold signs showed 40% risk reduction for severe hypoglycemia and 53% risk reduction for severe hypo overnight vs. standard of care Lantus in DEVOTE. Visitors were directed to the medical information booth to see the full European summary of product characteristics (SmPC), and it’s great to see that Novo Nordisk has swiftly launched provider education efforts around Tresiba’s hypoglycemia benefit. A basal insulin offering that reduces hypoglycemia risk will be enormously valuable for patients, and getting DEVOTE data on the Tresiba label makes it much more likely that HCPs will heed this new knowledge in their clinical practice. The Victoza section matched what we’ve seen from the company at recent cardiology conferences (most recently, AHA 2017), with banners announcing that liraglutide is the first and only GLP-1 agonist approved for CV risk reduction. GLP-1 agonist Saxenda was featured in its own booth nearby, highlighting Novo Nordisk’s commitment to obesity as well as diabetes.
Sanofi’s square booth was split into four triangles, with two dedicated to next-gen basal insulin Toujeo (glargine U300), one focused on fixed-ratio combination Soliqua (insulin glargine/lixisenatide), and the fourth covering the MyStar device business. Notably, Soliqua is available in two pens outside the US, each with a unique fixed-ratio. The 2:1 Soliqua Pen dispenses two units of basal insulin glargine per microgram of GLP-1 agonist lixisenatide, and is recommended for patients currently taking 20-30 units of total daily insulin. The 3:1 Soliqua Pen dispenses three units of glargine per microgram of lixisenatide, and is recommended for patients currently taking 30-60 units of total daily insulin. The FDA approved only a single pen for Soliqua, and so we don’t see this detail at US conferences, but company reps in the IDF booth were heavily promoting the variety of dosing options and the flexibility this affords to prescribing HCPs. Moreover, messaging on Soliqua emphasized the “simplicity” and familiarity of the SoloStar device, which was promoted as the most widely-used insulin pen worldwide. In the Toujeo half of the booth, visitors could play an interactive game to stay-in-range, and we appreciated this nod to glycemic outcomes beyond A1c. One poster displayed real-world findings from DELIVER 2 (first presented at ENDO 2017), showing lower hypoglycemia risk for patients switching to Toujeo vs. other basal insulins. DELIVER is just one component of Sanofi’s real-world evidence campaign around Toujeo, which was the subject of a Tuesday evening corporate symposium at IDF. There was no mention of Insulin lispro Sanofi (called Admelog in the US), the recently-approved biosimilar rapid-acting insulin, which is also available in the familiar SoloStar device at a discount to Lilly’s Humalog (insulin lispro). This was a noticeable absence, in our view, since the biosimilar was a major focus of Sanofi’s exhibit hall presence at EASD 2017.
-- by Adam Brown, Ann Carracher, Abigal Dove, Brian Levine, Payal Marathe, Maeve Serino, and Kelly Close