- On the therapy side, the last day of IDF featured a brilliant talk by King’s College London’s Dr. Janaka Karalliedde on the promise of GLP-1 agonists and SGLT-2 inhibitors for renal protection in diabetes. A poster on the real-world DISCOVER study (which was presented in full in a separate symposium on Tuesday) showed how patients taking sulfonylureas as first-line faced a ~4x risk for hypoglycemia vs. patients taking metformin as first-line. As even more data accumulates linking sulfonylureas to costly complications like hypoglycemia (not to mention weight gain, beta cell burnout, and possible CV harm), both from head-to-head RCTs and real-world observational studies, we hope HCPs, payers, and guideline-writers are watching, as we feel very strongly that SFUs should no longer be used, since the class would no longer be approved today. Although it is easy to say they must be used for some due to cost, we do not have the same arguments about dialysis or heart failure or heart attacks or strokes (“they are too expensive”). The right therapy must begin to be viewed in investment, not cost, terms.
- Big picture, Dr. David Napier reviewed the Cities Changing Diabetes (CCD) approach to research on diabetes prevention, which quantifies the social, cultural, environmental, and other determinants of health that are often eliminated or ignored in RCTs. He shared that the four new CCD participants are Hangzhou, Beijing, and Xiamen in China, plus Leicester in the UK. A debate on the efficacy of a soda tax proved disappointing, though the President of the Mexican Diabetes Federation pointed out that government corruption and a lack of substitutes may be hindering progress in his country.
- Exhibit hall: We visited 13 booths in the small but very well balanced and well attended exhibit hall. On the tech front, we heard Eversense Senseonics rollout updates from a Roche rep (France, Czech Republic launches next year; n=300 RCT next year in France – although we followed up with the company later and these details were not verified) and learned of Alere’s (now Abbott’s) pharmacy A1c screening program in India. A highlight on the therapy side was Novo Nordisk’s conference debut of Tresiba’s hypoglycemia claim in Europe, showing significantly lower risk for hypoglycemia vs. Sanofi’s Lantus (an FDA decision on this label claim is expected in 1Q18).
IDF 2017 has come to a close, but we have one last installment of highlights for you, from day #5 of this outstanding conference. See below for seven of our top takeaways from our last day in Abu Dhabi, and take a look back at our previous coverage here: day #1, day #2, days #3-4.
Top Seven Highlights
1. Could GLP-1 Agonists and SGLT-2 Inhibitors End a Dry Spell (17 Years and Counting) of No New Drug Approvals for Diabetes-Related Kidney Disease?
Dr. Janaka Karalliedde (King’s College London) 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.
2. DISCOVER Poster Attributes Hypoglycemia Risk to SUs as First-Line, Prior Micro/Macrovascular Disease
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.
3. Dr. Napier Explains Cities Changing Diabetes Program and the Research Underlying Vulnerability Assessments; Hangzhou, Beijing, Xiamen, Leicester Announced as New CCD Participants for a Total 12 Cities and >100 Million People
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).
4. Disappointing Debate on Soda Tax, but President of Mexican Diabetes Federation Says Gov’t Corruption + Lack of Substitutes Hampering Success in His Country
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.
5. Prof. Speight on #LanguageMatters: How the Words We Use Can Influence Stigma, Well-Being, & Treatment Intensification
Promoting the use of non-judgmental, person-first language in diabetes care, Professor Jane Speight aptly argued that the words we use in talking about diabetes influences experiences of stigm and diabetes distress, as well as the clinician-patient relationship and attitudes toward treatment regimens. Prof. 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.
- Prof. 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 people with diabetes agree with care decisions, she explained, pointing to a study by Prof. Tim Skinner in which patients/clinicians showed mutual recall of only ~half of all treatment decisions made in a consultation – many decisions were made but not recalled, recalled but not actually made, or not made clear to the other party. This, suggested Prof Speight, highlights how unrealistic the concept of “compliance” is, not to mention that almost no-one with diabetes is given a clear and detailed recipe for managing diabetes by their clinicians. Words like “control,” Prof. Speight continued, don’t acknowledge the unpredictability of diabetes, as well as its progressive nature and the fact that it gets even more difficult to manage over time. Health professionals and researchers often refer to people as “failing,” for example, their oral medications, to lose weight, or to meet targets – thus projecting this “failure” onto the person they are trying to help, who often go on to internalize that sense of failure. This leads to a low sense of self-efficacy, and a reluctance to intensify treatments in the case that intensification itself symbolizes their acceptance of themselves as a failure. Prof. Speight also reminded us that referring to people with diabetes as “diabetic” is defining them by their disease, which runs the risk of ignoring their humanity and the complexity of the life in which they are trying to manage their diabetes. This is 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 also be used to reinforce what people with diabetes do well, and focus respectfully on their strengths, which is both more empathetic and likely to be more productive – when things are not going well, people rarely respond well to criticism and negativity.
- As Prof. 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-clinician interactions and the everyday experience of people living with diabetes. Prof. 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.
6. Workplace Wellness Study Using CGM Reveals Glycemic Improvements for Type 2 Diabetes Patients with Overweight/Obesity Who Reduce Sitting Time
Dr. David Dunstan presented hot-off-the-press results of a wellness 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 full 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 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.
7. FIGO and IDF Sign COnsensus Statement on Universal Gestational DIabetes Testing; Maternal Health is Key to Reduce Diabetes Prevalence
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.
Exhibit Hall – Technology
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.
Exhibit Hall – Therapy
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 Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Maeve Serino, Adam Brown, and Kelly Close