- Diabetes/obesity therapy: You’ll find 12 highlights below on diabetes/obesity therapy, starting with a debate on simultaneous vs. sequential approaches to treatment, featuring Drs. Carol Wysham and Silvio Inzucchi. We saw full phase 2 data on Novo Nordisk’s GLP-1 agonist semaglutide in obesity (27% of people on the highest dose experienced ≥20% weight loss), and learned about a planned CVOT for metformin in prediabetes (VA-IMPACT), which could have significant implications in getting healthcare stakeholders to accept prediabetes as its own disease. Dr. Steven Nissen shared a critical view on the ODYSSEY Outcomes subgroup analysis reporting almost all the CV benefit in patients with baseline LDL ≥100 mg/dl; he attributed this finding to dose confounding and suggested that the CVOT was poorly designed. Obesity experts Drs. Donna Ryan and Steven Kahan presented during a Novo Nordisk symposium, on lifestyle intervention and language, respectively. We also attended a fascinating Salix-sponsored product theater led by Dr. James Gavin, who reviewed the data on Cycloset suggesting possible cardioprotection (and, somewhat unbelievably, we learned from the company afterward that a CVOT for Cycloset may be coming soon. If it does, we hope they will use KOLs to develop “guidelines” for how a CVOT would optimally be run – adjudication, etc.).
- Diabetes tech & hypoglycemia: On the tech front, it was a light couple of days headlined by a phenomenal talk from NIDDK’s Dr. Judith Fradkin in which she laid out her CGM-heavy research agenda for hypoglycemia. In the spirit of federal interest in hypoglycemia, FDA’s Dr. Christine Lee discussed an encouraging risk-stratification initiative. Joslin’s Dr. Lori Laffel made two appearances, discussing the latest in AID (not seamless yet!), CGM (how to increase penetration?), and pumps (need more competition!).
- Big picture: We were blown away by Dr. Fran Kaufman’s keynote at the Women in Endocrinology annual meeting – she delivered a passionate call-to-action for women (and men) in the field to advocate for equal pay, as well as patient-centered and value-based care. Wharton’s Dr. David Asch discussed behavioral economics and how it applies to healthcare and diabetes, and ADA President Dr. Jane Reusch argued firmly that “lifestyle is medicine.”
- Exhibit hall: Companion Medical’s InPen is still in <500 patient hands, but reimbursement is solid (85% of people covered with mean $40 copay – not bad!) and many are still paying out of pocket; the company is working diligently on an Android app (late Q2), expanding to all insulins, and an imminent time-in-range study. Glooko’s new transmitter has begun to roll out (aiming for total replacement by EOY), and the company is seeking pilot sites for its FDA-cleared MIDS titration system. The Medtronic booth was abuzz with excitement over the 670G and newly-FDA-approved Guardian Connect mobile CGM. On the therapy side, it was hard to miss Ozempic – not just within the Novo Nordisk booth, but all around the exhibit hall floor. Reps emphasized head-to-head data showing semaglutide’s superiority over other diabetes drugs, including Lilly’s Trulicity in SUSTAIN 7. Novo Nordisk was also eagerly promoting Tresiba, and we’re waiting anxiously to see what FDA decides on the requested hypoglycemia claim by end of 1Q18 – this should be in the next ten days! Sanofi’s booth highlighted Toujeo, Lantus, Apidra, and Soliqua, with some advertisements for a SoloStar Max pen “coming soon” (though details were scarce). Merck debuted SGLT-2 inhibitor Steglatro in its exhibit, though the product was nowhere to be seen in Pfizer’s booth. We also visited Amgen, AZ (the company seems to be all-in on Bydureon BCise), Janssen, Lilly, and Rhythm.
Greetings from Chicago! We spent this past weekend soaking up all the learnings that ENDO 2018 had to offer. You’ll find 23 highlights below – 12 on diabetes/obesity therapy, six on diabetes technology and hypoglycemia, and four on big picture topics (including an outstanding keynote lecture by Dr. Fran Kaufman on women in endocrinology).
In case you missed it, here’s our first highlights report on ENDO 2018, which officially began on Friday with preconference sessions. Dr. Irl Hirsch reviewed the landscape of injectable diabetes therapies, returning to cost issues, and Dr. Vivian Fonseca discussed typical and atypical complications of diabetes. We’ll be back soon with even more on ENDO – this year marks the 100th annual meeting – and in the meantime, you’ll find our preview here.
- Diabetes/Obesity Therapy Highlights
- 1. Debate on Simultaneous vs. Stepwise Treatment Covers Cost & Outcomes; Drs. Wysham and Inzucchi Present; Time for a New Algorithm Based on CV/Renal Risk Rather than Starting A1c?
- 2. Full Phase 2 Results on Novo Nordisk’s Semaglutide in Obesity: Incredibly Impressive Efficacy, with 27% of Patients on Highest-Dose (0.4 mg Once-Daily) Achieving ≥20% Weight Loss from Baseline
- 3. VA-IMPACT CVOT Will Study Metformin vs. Placebo in ~8,000 Adults with Prediabetes + CV Disease; Expected to Begin in 2018 and to Report Results in 2024-2025; Major Implications for Understanding and Treatment of Prediabetes as a Disease
- 4. Dr. Nissen’s Critical Take on ODYSSEY Outcomes: Greater CV Benefit in Higher Baseline LDL Subgroup (≥100 mg/dl) Was a Product of Dose Confounding; Argues for Lower LDL Targets
- 5. Ozempic Has Arrived! Dr. Wysham-Led Product Theater Highlights Superior A1c-Lowering/Weight Loss vs. Trulicity (SUSTAIN 7 Results), CV Safety but Not Efficacy (Per FDA Product Label)
- 6. Dr. James Gavin Intrigued and Encouraged by Cycloset, Cardioprotective Potential; CVOT Reportedly in the Works, Not Likely to Start in Next Six Months
- 7. In-Patient Glycemic Outcomes Worse with U500 than Non-U500 Insulins in UVA Retrospective Study
- 8. The “Hidden Secret” of Endocrinology? Dr. Busch Enthusiastic About SGLT-2 + GLP-1 Combination Therapy; Highlights Renal Protection of SGLT-2 Class; Presents Meta-Analysis Comparing Canagliflozin vs. Empagliflozin and Dapagliflozin
- 9. Dr. Ryan on Novo Nordisk’s Planned Obesity CVOT for Semaglutide – “A Game-Changer” That Could “Really Legitimize Our Field”; Suggestions on Making Lifestyle Intervention Successful in the Real World
- 10. Dr. Kahan Highlights Significant Weight-Based Bias Among HCPs, Another Systemic Challenge for Obesity; Evokes Language Movement
- 11. “We’re Not Going to Treat Our Way Out of the Obesity Epidemic.” Obesity Expert Dr. William Dietz Advocates for Prevention Initiatives
- 12. Amgen Symposium Highlights Access Challenges for PCSK9 Inhibitors; How Will ODYSSEY Outcomes Results Influence Class-Wide Reimbursement?
- Diabetes Tech & Hypoglycemia Highlights
- 1. NIH’s Dr. Judith Fradkin lays out CGM-Heavy Hypo Research Agenda: Rates/Predictors of Non-Severe Hypo, “Frailty”+Hypo+CV risk, Racial Disparities, + More
- 2. Dr. Lori Laffel on AID: “Not Seamless” (Yet), but “Remarkable” DIY!; CGM: How to Increase Penetration? Pumps: More Competition!
- 3. FDA’s Safe Use Initiative + Hypo Risk Stratification Tool Tested at Mayo & KP; Social Media Listening Project Harnesses Unstructured Diabetes Data – Twitter is Most Popular Place to Talk DM!
- 4. Drs. Laffel and Aleppo Review G5 Arrow Dosing Guidelines in Relation to Other Methods (DirecNet, Edelman/Pettus, Scheiner, Klonoff/Kerr)
- 5. Dr. Jeffrey Boord on the Hypoglycemia Quality Collaborative; Six Key Domains to Address Hypoglycemia
- 6. 12- and 20-Week Texting Programs Enhance Weight Loss and A1c Reductions Achieved in Medical Group Visits
- Big Picture Highlights
- 1. Dr. Fran Kaufman Keynote: Women are the Future of Endocrinology, But the Fight for Equality in Pay and Treatment is Ongoing Across Medicine
- 2. Wharton Behavioral Economist: Using Behavioral Reflexes to Encourage Healthy Decisions; Regret Lottery Improves Medication Adherence; Social Incentives More Potent than Financial Compensation in Reducing A1c
- 3. ADA President Dr. Jane Reusch and Dr. Jack Leahy: “Lifestyle is Medicine”
- 4. Dr. Tamara Hershey Discusses Potential Memory-Impairing Effects of DKA in Youth with Type 1 Diabetes
- 5. Very-Low Calorie Diet Leads to Restored Normoglycemia in UCLA Pilot; Promises Significant Cost Reductions vs. Bariatric Surgery
- Exhibit Hall
Diabetes/Obesity Therapy Highlights
Drs. Carol Wysham and Silvio Inzucchi argued for a simultaneous vs. stepwise approach to type 2 diabetes treatment, respectively, in an engaging debate session. The discussion covered cost, outcomes, the pathophysiology of diabetes (how can we best address the ominous octet?), clinical inertia, medication adherence, and more, culminating in Dr. Inzucchi’s proposal of revised guidelines that recommend therapy based on a patient’s CV and renal risk factors rather than A1c. We would love to see this, and we’re happy to note steps in the right direction with ADA’s 2018 Standards of Care recommending that type 2s with A1c ≥9% and established CV disease start immediately on a combination regimen of lifestyle + metformin + a GLP-1 agonist or SGLT-2 inhibitor (ADA specifically names liraglutide and empagliflozin). On the whole, we’re inclined to think combination treatment is under-utilized in diabetes given the known prevalence of clinical inertia, as Dr. Wysham highlighted, plus persistence of poor outcomes at the population level (>30% of type 2s in the US have A1c >9% according to HEDIS). Dr. Wysham also pointed out that HCPs in breast cancer would never try one treatment at a time – that field relies on an aggressive initial approach, a cocktail of therapies, and starting three drugs simultaneously from diagnosis results in the best outcomes. That said, Dr. Inzucchi also presented a very compelling argument centered around cost and gaps in the current data. He outlined the hypothetical study that we need in order to determine empirically whether simultaneous or sequential treatment makes the most sense for the majority of patients with type 2 diabetes, and he expressed skepticism that a simultaneous approach would come out on top. We dive into both sides of the debate in more detail below.
- Cost: If recently-diagnosed (within the last three years) patients in ADOPT were prescribed two branded diabetes drugs on top of metformin, one being a GLP-1 agonist, Dr. Inzucchi showed that this would raise the cost per patient by $55,800 over 45 months, which is the average time it took for someone on metformin in the trial to climb back up to A1c >7%. That’s $1,240 more spending per month, and enough to purchase 45 months of metformin for 310 patients. And yet, 80% of ADOPT participants randomized to metformin monotherapy maintained fasting blood glucose <140 mg/dl after five years, suggesting that the now-generic drug performed quite well. Dr. Inzucchi thus questioned whether initial combination therapy is necessary or feasible at the population level. To be sure, there are so many people with type 2 diabetes who can’t access or afford any branded medications, hence the high rates of sulfonylurea use and rising rates of human insulin use. This doesn’t mean, however, that simultaneous treatment isn’t beneficial for those who can access/afford it, and we note that initial dual therapy would be cheaper than Dr. Inzucchi’s calculated figures for initial triple therapy. While guidelines must absolutely consider cost, we believe it would also be helpful if initial combination therapy were stated as a clear option in managing type 2 diabetes (AACE seems to have embraced this, and ADA is starting to). Dr. Wysham also made the interesting point that simultaneous treatment offers a great value proposition if you consider improved adherence and subsequently, better patient outcomes and cost-savings for the payer. It’s important to acknowledge the health economic burden of diabetes as well: According to IDF’s 2017 Atlas, diabetes accounted for $727 billion globally in direct costs, including $348 million (48%) in the US. Furthermore, a recent Diabetes Care article projected that direct and indirect costs of diabetes will hit $2.1 trillion by 2030 under the best-case scenario, a steep 62% climb from $1.3 trillion in 2015. Clearly, our current level of diabetes spending is unsustainable. From this perspective, Dr. Inzucchi’s cost calculations make a stronger argument in our view. That is to say, we have to look at financial burden on the health system as well as the individual patient, and Dr. Inzucchi’s message is an important one, that we can’t expect population-level recommendations without more data on cost-savings with advanced therapy classes. We think (and hope) that this data is coming.
- Outcomes: Dr. Wysham presented several slides showing superior A1c-lowering with combination therapy vs. monotherapy. For example, all SGLT-2/metformin combinations (canagliflozin/metformin, dapagliflozin/metformin, and empagliflozin/metformin) achieved greater A1c decline vs. metformin alone (all p<0.05) in clinical studies. Additionally, patients on the combo were more likely to meet target A1c <7%: 57% of people on canagliflozin/metformin vs. 43% on metformin alone; 47% of people on dapagliflozin/metformin vs. 35% on metformin alone; and 66% of people on empagliflozin/metformin vs. 56% on metformin alone. Dr. Wysham reviewed similar data on DPP-4/metformin combinations, covering alogliptin, linagliptin, saxagliptin, and sitagliptin. She also shared results on AZ’s Qtern (saxagliptin/dapagliflozin fixed-dose combination) and Lilly/BI’s Glyxambi (linagliptin/empagliflozin), each demonstrating A1c superiority vs. their component monotherapies (all p<0.05). We’re certainly excited about this fixed-dose SGLT-2/DPP-4 class because of the added benefits of two pills in one, although real-world uptake has been sluggish so far, suggesting HCP resistance to consider earlier combination therapy (alongside poor reimbursement). The same goes for fixed-ratio basal insulin/GLP-1 combos, with very underwhelming real-world uptake compared to the hype surrounding this class prior to November 2016 FDA-approval. Dr. Wysham also summarized the EDICT study, which evaluated initial triple therapy with metformin + TZD pioglitazone + GLP-1 exenatide. She specifically pointed to greater weight loss with triple therapy (-2.6 lbs) vs. stepwise treatment with metformin, followed by SU glipizide and basal insulin glargine (+9 lbs), although Dr. Inzucchi swiftly refuted this during his remarks, highlighting that the comparator arm featured two older agents associated with weight gain (the sulfonylurea and the insulin). He called the EDICT trial “so 1980s,” suggesting that we now have better drugs that promote weight loss (SGLT-2s, GLP-1s) even when prescribed as standalone.
- Dr. Inzucchi focused on A1c as a limited endpoint. He suggested that we need a study comparing simultaneous initiation of three drugs vs. stepwise introduction of the same three drugs on meaningful outcomes – durability of A1c effect over longer-term follow-up, need for insulin rescue, costs, CV events, and new or worsening CKD. This trial hasn’t been conducted to-date, so even if people have an intuition that early combination therapy is better, Dr. Inzucchi underscored that this isn’t grounded in hard evidence. Given glucose control, weight loss, and CV/renal protection associated with SGLT-2s and GLP-1s, we’d anticipate results that favor simultaneous treatment overall, with particularly positive data on cost (i.e. fewer hospitalizations, less productivity loss), CV death, three-point MACE, and new or worsening CKD; we might even add hypoglycemia and time-in-range, if we can get CGM into this hypothetical study. Dr. Inzucchi implied that this may not be the case, that with a 6-12 month delay, stepwise treatment would deliver the same A1c and frequency of micro and macrovascular complications as simultaneous treatment. Even so, would there be appreciable cost-savings over those 6-12 months with earlier combination therapy? How might early combo therapy improve patient quality of life and motivation? Would there be any legacy effects? In our view, there are far too many unanswered questions here to be addressed by speculation alone, and we’re eager for this hypothetical study to become a reality. Seeking any sponsors (or ideas for sponsors)…
- Pathophysiology: Drs. Wysham and Inzucchi agreed that combination therapy is logical when you consider the multifaceted defects underlying type 2 diabetes. Dr. Wysham explained that metformin + GLP-1 covers six out of eight aspects of Dr. Ralph DeFronzo’s ominous octet. We’ve heard a similar rationale for introducing a GLP-1 agonist from other thought leaders as well, and at AADE 2017, Dr. Susan Cornell described how GLP-1s (i) lower endogenous glucose production from the liver, (ii) enhance insulin and amylin secretion from pancreatic beta cells, (iii) increase amylin in the brain to stimulate satiety, (iv) slow gastric emptying from the GI tract, (v) impair glucagon secretion from pancreatic alpha cells, and (vi) improve glucose uptake in muscles via weight loss. Dr. Wysham additionally suggested that insulin + GLP-1 together address many components of the ominous octet. Dr. Cornell has advocated for GLP-1 + SGLT-2 to tackle all eight defects underlying diabetes, and at CODHy last month, Dr. DeFronzo presented his “Fab Four” diabetes drugs (SGLT-2 + GLP-1 + TZD pioglitazone + metformin). Dr. Inzucchi acknowledged that “initial combination therapy is definitely more satisfying from a pathophysiological standpoint.”
- Clinical inertia: Dr. Wysham established clinical inertia as a major challenge in diabetes care today. She cited a 2013 study using the UK Clinical Practice Research Datalink (n=81,573), which found “huge delays” in adding drugs to a patient’s medication regimen, even after months or years above target A1c. For example, there was a median 2.9 years until treatment intensification for people with A1c >7% on one oral diabetes drug. To illustrate the adverse impact of these all too common delays, Dr. Wysham reviewed results from a 2015 study showing a 62% elevated risk for CV events (MI, stroke, and heart failure) over 5.3 years with clinical inertia (defined as A1c ≥7% and not intensifying therapy within one year); risk for MI was increased by the greatest margin, 67% higher with clinical inertia. Another 2016 study found significantly heightened risk for retinopathy with clinical inertia over 60 months (p=0.02). Dr. Wysham framed initial combination therapy as a way to circumvent clinical inertia, since starting two (or more) diabetes drugs from the outset eliminates the lag time between treatments that aren’t working. We see this as an excellent strategy to break the treat-to-fail paradigm in diabetes management, particularly with fixed-dose and fixed-ratio combination products now on the market (provided patients can access/afford them).
- Adherence: Dr. Wysham elaborated that initial combination therapy can also help sidestep the adherence issue in diabetes care. She discussed clinical trial data showing 7%-8% better adherence with fixed-dose vs. loose dose combinations, although Dr. Inzucchi pointed out that no long-term data has been collected to show that this holds up over time. Nonetheless, we think the early results are promising. Dr. Wysham highlighted the potential for fixed-dose and fixed-ratio combo products to simplify medication regimen. Indeed, fixed-dose SGLT-2/DPP-4s decrease pill burden and even more importantly, fixed-ratio basal insulin/GLP-1s decrease injection burden, which is generally appealing for people with diabetes. These therapies allow for more aggressive glucose-lowering (and weight loss) without making the patient feel like they’re on multiple drugs soon after diagnosis (although the field also needs to break the mental association between more prescriptions and patient failure), and there’s certainly value for patients in facing one co-pay instead of two. We definitely believe adherence should be a factor considered in the simultaneous vs. sequential debate, and in shared decision-making on treatment plan between HCPs/patients. As Dr. Wysham underscored, this is a major problem in type 2 diabetes – 31% of new prescriptions for diabetes drugs are never filled, and discontinuation within 60 days is high (42%) even for a well-tolerated therapy like DPP-4 inhibitor sitagliptin.
Dr. Patrick O’Neil presented full data from a phase 2 dose-ranging study of GLP-1 agonist semaglutide in obesity. Novo Nordisk management has already referenced the positive topline results multiple times, since semaglutide’s demonstrated safety/efficacy in this trial (n=957) led to plans for a robust phase 3 program in obesity (n=~4,500), which will launch later this year. Dr. O’Neil shared more granularity on the data. On the primary endpoint of weight loss after 52 weeks (baseline 244 lbs and BMI 39 kg/m2), all doses of semaglutide were superior to placebo. Mean weight loss was 6% with 0.05 mg semaglutide injection once-daily (p=0.01 vs. placebo), 8.6% with 0.1 mg semaglutide (p<0.0001), 11.6% with 0.2 mg semaglutide (p<0.0001), 11.2% with 0.3 mg semaglutide (p<0.0001), 13.8% with 0.4 mg semaglutide (p<0.0001), and only 2.3% with placebo. Moreover, one treatment arm received high-dose liraglutide (Novo Nordisk’s Saxenda, already marketed for obesity), and mean weight loss within this group was 7.8%; Dr. O’Neil affirmed that this finding was consistent with what was seen in phase 3 for Saxenda. Novo Nordisk CSO Dr. Mads Thomsen has alluded to a “new level of weight loss efficacy” with second-gen GLP-1 agonist semaglutide, better than anything that’s currently available, including Saxenda. Interestingly, thought leaders have suggested that the next major innovation in obesity pharmacotherapy should be a drug that produces >10% weight loss, and Dr. O’Neil presented very positive results to this end. Among patients on 0.4 mg semaglutide (the highest dose administered in phase 2), 83% achieved ≥5% weight loss vs. 23% of placebo-treated patients (p<0.0001); 66% of patients on Saxenda achieved ≥5% weight loss (p<0.0001 vs. placebo). A weight loss target of ≥10% was met by 65% of people on 0.4 mg semaglutide vs. 10% of people on placebo (p<0.0001) and 34% of people on Saxenda (p<0.0001 vs. placebo). But Dr. O’Neil didn’t stop there – 41% of patients on 0.4 mg semaglutide experienced ≥15% weight loss vs. 5% of patients on placebo (p<0.0001) and 15% of patients on Saxenda (p<0.05 vs. placebo), while 27% (!) of patients on 0.4 mg semaglutide achieved weight loss ≥20% (remarkable) vs. 2% of patients on placebo (p<0.0001) and 4% of patients on Saxenda (not statistically different from placebo). Dr. O’Neil also showed graphs of weight loss over time. He emphasized that there was no attenuation of weight loss effect with semaglutide over the course of one year, and excitingly, patients on the highest dose still seemed to be losing weight at week 52 in the on-treatment analysis. This would be another significant advance over current obesity therapies, which all do show attenuated efficacy over time, starting around 26-30 weeks according to Dr. O’Neil. Weight loss doesn’t seem to plateau as quickly with semaglutide (it continued well past the 30-week mark), and Dr. O’Neil explained that longer-term data is necessary to figure out when the body weight change does start to level off. The phase 3 STEP studies planned for semaglutide, as well as the SELECT CVOT (n=~17,500 people with obesity), will illuminate this.
- Turning to safety, Dr. O’Neil underscored that there was no unexpected imbalance in adverse events in this phase 2 trial. In the on-treatment analysis, 90%-96% of semaglutide-treated participants experienced any adverse event compared to 85% of Saxenda-treated participants and 79% of the placebo pool. Dr. O’Neil emphasized that only 3% of all reported adverse events were severe in nature. The most common adverse events were GI-related, which is a known side-effect of GLP-1 agonists. Between 62%-82% of the semaglutide groups experienced a GI side-effect, on par with 75% of the Saxenda group; 38% of the placebo group experienced a GI side-effect. There was a relatively high rate of treatment discontinuation in the highest-dose semaglutide arm due to GI side-effects, with ~14% of patients randomized to this 0.4 mg dose discontinuing by week 52; the vast majority of these discontinuations happened by week 16. Dr. O’Neil reported a dose-dependent relationship between semaglutide treatment and nausea, but also underscored that this usually occurred when patients were starting/up-titrating therapy, “dissipating as they arrived at their target dose of the drug.” Additionally, he explained that the majority of nausea events were considered mild rather than moderate or severe. Since nausea and other GI effects are associated with all GLP-1 agonists, we don’t see this as a cause for concern, though treatment discontinuation will be something to watch closely for in phase 3. To be sure, semaglutide is an extremely potent molecule, which leads to enhanced efficacy (both glucose-lowering and weight loss) but perhaps more side-effects as well, especially immediately after treatment initiation. Of note, Novo Nordisk management has characterized semaglutide as highly tolerable across all doses in phase 2, which led to their decision to use once-weekly 2.4 mg injections in phase 3. We wonder how the higher concentration coupled with less frequent dosing will affect nausea patterns.
- Study design: Dr. O’Neil specified that all treatment was adjunct to a lifestyle intervention, including encouragement to increase physical activity and a recommended diet designed to produce a 500 calorie/day deficit. This will be important in translating results into the real world, since all obesity pharmacotherapy works best when supported by lifestyle modification strategies, and we’ll be curious to see what lifestyle counseling is provided to patients in the phase 3 STEP trials. The 957 participants came from eight different countries, with mean age of 47, mean baseline body weight of 244 lbs, BMI of 39 kg/m2, and waist circumference of 118 cm; 35% were male and 73% were white. After 52 weeks, 777 patients (81% of the starting pool) were still on drug, and were thus included in the on-treatment analysis. Weight assessment was available for 93% of all participants at week 52. The trial design also included a follow-up visit after another seven weeks – these results weren’t available for Dr. O’Neil’s ENDO presentation, but he stated that they will be covered in the published manuscript, addressing the important question of whether or not there’s rebound weight gain after people stop taking semaglutide for obesity management.
In a talk on the CV effects of metformin, we learned from Dr. Gregory Schwartz that the new VA-IMPACT CVOT will begin later this year, enrolling nearly 8,000 participants across 37 sites to evaluate metformin vs. placebo in people with prediabetes and atherosclerotic CV disease. This could be another “landmark” CVOT when it completes, expected in 2024-2025, for a number of reasons: (i) there’s growing interest in prediabetes as a CV risk marker, (ii) there have been suggestions that we should intervene even earlier in the course of hyperglycemia development to reduce CV risk, and (iii) metformin has exciting implications for population-level diabetes prevention, particularly given its generic status/low cost. For all these reasons, we’re so excited that the VA Office of Research and Development has sponsored this trial – kudos! According to ClinicalTrials.gov, VA-IMPACT will investigate a primary endpoint of five-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or symptom-driven coronary revascularization). Secondary endpoints include new-onset diabetes, new-onset cancer, and the individual components of the primary composite. Median follow-up time is expected to be 4.5 years. Dr. Schwartz characterized VA-IMPACT as a “large, simple trial,” as national VA electronic health records will be used to identify patients, follow-up will be via telephone, labs won’t be blinded, non-serious adverse event reporting will be limited, and drug dispensing will be centralized and direct-to-patient. Metformin will be titrated to a target dose of 2,000 mg/day, assuming tolerability. He explained how investigators noticed that no clinical trial has rigorously assessed CV outcomes with metformin, and there’s even less data on the agent’s CV effects in prediabetes. The 342-person metformin subgroup in UKPDS (a “miniscule” sample, as Dr. Schwartz put it) did benefit on all-cause death (p=0.01, 119 events) and MI (p=0.01, 112 events) compared to conventional dietary treatment (n=411), but the number of events was small and Dr. Schwartz called these data “hypothesis-generating” at best. He also cited observational data from the international REACH registry (n=19,691) showing a lower cumulative incidence of all-cause death at two years in patients taking metformin vs. patients not taking metformin (p<0.001). Combined with UKPDS, there’s certainly evidence supporting further investigation of metformin on CV parameters. On the choice to investigate metformin in prediabetes specifically, Dr. Schwartz explained, “we can’t be too cavalier about just telling people to take metformin. There are some tolerability issues, some risk, and some cost, and prediabetes affects a huge segment of the population (84 million adults in the US).” Though we do wish metformin were more utilized for diabetes prevention in the real world, we understand that it can’t be broadly implemented as a population-level solution without a very convincing dataset – a CVOT could provide just that. During Q&A, one audience member asked why the trial doesn’t just investigate metformin in the general population, and Dr. Schwartz explained that, while data show that benefit could exist independent of glycemic/metabolic status, “we have one shot here, and prediabetes does give a higher CV event rate.” Moreover, the glucose-lowering effects of metformin might also reduce CV risk among those with prediabetes, and the largest group of people with atherosclerotic CV disease exists within the prediabetes population. All in all, we’re incredibly excited that this trial is being conducted; it holds significant implications for both the treatment and recognition of prediabetes as a disease, and positive results could improve outcomes for millions of people. The main downside we see is that it wasn’t done sooner, and we’ll have to wait six or seven years for results. Given these major implications, we think “IMPACT” is an apt name for this study.
During a debate on LDL targets (how low should you go?), Dr. Steven Nissen shared a critical perspective on the ODYSSEY Outcomes CVOT for Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab). This highly-anticipated trial just read out at ACC 2018, and all eyes were on a subgroup analysis that suggested the greatest CV benefit in patients with baseline LDL ≥100 mg/dl (24% risk reduction vs. placebo for the primary composite endpoint, 29% risk reduction for all-cause death). But Dr. Nissen pointed out dose confounding. He explained how trial protocol included back-titrating, meaning patients on alirocumab were scaled back to a lower dose once they reached LDL ≤25 mg/dl, while alirocumab treatment was stopped entirely once LDL fell ≤15 mg/dl. Thus, the participants who started with LDL above 100 mg/dl (the highest bracket) were more likely to receive maximum doses of the PCSK9 inhibitor – Dr. Nissen considers this a flaw in study design, limiting the new knowledge we can glean from ODYSSEY Outcomes. Were investigators allowed to aggressively lower LDL (How low should you go? The lower the better), Dr. Nissen implied that alirocumab could very well have conferred a greater margin of CV risk reduction across the entire study population. He argued that the field should look to FOURIER, rather than ODYSSEY Outcomes, for clinical practice advice, due to the dose confounding issue in the latter. He reviewed a pre-specified FOURIER analysis that found significant cardioprotection across all baseline LDL subgroups, and he emphasized that Amgen’s Repatha (evolocumab) demonstrated CV efficacy by decreasing LDL to a median 30 mg/dl; that means half the patients had LDL even lower than that. Ultimately, this served as a solid argument for Dr. Nissen’s side of the debate, as he advocated for even lower LDL goals in patients facing CV risk.
- With both FOURIER and ODYSSEY on the books, we hope providers are convinced of the efficacy/safety of the PCSK9 class – of course, our sense is that it’s not the HCP community that needs convincing, but payers. To-date, poor reimbursement has been the primary obstacle to uptake of Praluent and Repatha, and we’re very interested to see how payers respond to this combination of CVOT data. We suspect Dr. Nissen believes these agents should be covered for patients regardless of starting LDL level, because the drugs are going to prevent adverse CV outcomes across the spectrum. We agree that there are so many people who could benefit from more aggressive lipid-lowering with PCSK9s, and eventually, we do believe Repatha and Praluent should bring cost-savings. That said, risk stratification should be a practical tool in convincing payers of the cost-savings – step #1 would be securing stronger reimbursement for hyperlipidemia patients with very high LDL, and subsequently, PCSK9 inhibitor coverage would extend to more and more patients. This sets up a dangerous dilemma, where people have to be “more sick” to gain access to more advanced treatment, but perhaps it’s the best way to get the ball rolling on reimbursement? The current coverage situation for PCSK9s is quite bleak, and we do have to start somewhere.
We attended our first product theater on Ozempic (once-weekly semaglutide) at ENDO, since Novo Nordisk’s highly-anticipated GLP-1 agonist was just FDA-approved in December, launched in February. Dr. Carol Wysham (University of Washington, Spokane, WA) led the discussion, highlighting superior A1c-lowering with Ozempic vs. other approved diabetes drugs, including DPP-4 inhibitor Januvia (Merck’s sitagliptin), GLP-1 agonist Bydureon (AZ’s once-weekly exenatide), and GLP-1 agonist Trulicity (Lilly’s once-weekly dulaglutide). She summarized SUSTAIN 7 results, published recently in Lancet Diabetes & Endocrinology: In this head-to-head vs. Trulicity, semaglutide was associated with ~0.4% more A1c-lowering and with approximately double weight loss (7 lbs with high-dose dulaglutide vs. 14 lbs with high-dose semaglutide) after 40 weeks. These effects were statistically significant, and are another indication of semaglutide’s potency and efficacy, since dulaglutide is also considered to be an extremely efficacious molecule. Indeed, Dr. John Buse called the ~0.4% A1c difference a “thrashing” benefit in the head-to-head trial business, “half a drug’s worth.” Dr. Wysham also emphasized the impressive weight loss seen with semaglutide, though she clarified that Ozempic is not yet approved for obesity. To this end, Novo Nordisk has a robust phase 3 program planned for once-weekly semaglutide in obesity; four STEP studies and the SELECT CVOT (the first-ever obesity CVOT!) are all slated to begin in 2018. In our view, weight loss is one of the most meaningful advantages of Ozempic (and of GLP-1 therapy more generally), given rising global rates of obesity. Moreover, weight loss has positive downstream effects on a patient’s treatment satisfaction, medication adherence, and quality of life, not to mention the additional CV risk reduction and improved clinical outcomes.
- Dr. Wysham addressed the SUSTAIN 6 retinopathy signal right off the bat, but expressed minimal concerns, at least not to the extent that they would stand in the way of her prescribing Ozempic. She alluded to early worsening phenomenon, wherein rapid A1c decline in patients who were previously poorly controlled leads to a transient increase in adverse eye events. Notably, she reminded everyone that the diabetes field has known about early worsening for ~three decades, since the DCCT (the intensive control group also experienced early worsening phenomenon, but better glucose control still had a protective effect on microvascular complications in the long term). Dr. Wysham pointed to “pretty dramatic” A1c reductions in SUSTAIN 6 (again, semaglutide is a very potent molecule). We’d add that insulin therapy has been associated with some early worsening of retinopathy as well, and indeed, the US Ozempic label features warning language similar to that on insulin labels for this temporary risk. As part of the terms for EMA approval, Novo Nordisk will conduct a long-term retinopathy outcomes study with semaglutide. We look forward to these results, as they could mimic DCCT findings by illustrating that early worsening is in fact transient, and that better glucose control actually reduces retinopathy risk with longer follow-up.
- In line with the US product label, Dr. Wysham characterized SUSTAIN 6 as a CV safety trial for Ozempic. Although the CVOT reported a 26% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, or CV death) with semaglutide vs. placebo (HR=0.74, 95% CI: 0.58-0.95, p=0.02 for superiority), Dr. Wysham explained that this was a secondary analysis because the study was designed/powered to show non-inferiority (and p<0.001 for non-inferiority). We understand that speakers at these provider-facing product theaters must stay “on-label” in their discussion – there was some pushback during Q&A, and Dr. Wysham maintained that “it’s a little bit of a technicality, but that’s what FDA has mandated, another separate CV superiority trial if the company wants a CV label claim.” Novo Nordisk announced recently that this post-market CVOT for Ozempic will be named “SOUL,” will enroll ~13,000 type 2s facing high CV risk, and will begin mid-2018 with results anticipated in 2023. We do hope that Ozempic is eventually indicated for cardioprotection, because getting this CV benefit into product information helps spread awareness among real-world HCPs/patients. Novo Nordisk’s Victoza (liraglutide) received this indication from FDA based on LEADER data in August 2017. Moreover, Ozempic’s product label in the EU acknowledges significant CV benefit, and we’ll be curious to see how this affects the company’s promotional materials as well as early uptake of the second-gen drug in Europe vs. the US.
In a Salix-sponsored product theater for Cycloset (bromocriptine-QR) – an insulin sensitizer that acts through the central nervous system – Dr. James Gavin highlighted a 42% reduction in the composite CV endpoint in a 52-week study, calling this “rather intriguing and encouraging.” This data isn’t new (it was published in 2010), but speaking to the company after the session, we learned that a CVOT is in the works. The rep was cryptic, only telling us that it will start in “more than half a year” and the molecule will be evaluated as an add-on to metformin, but probably not sulfonylureas. Given that the oral drug appears to have a rather tame side-effect profile for most people, improves A1c, and is potentially cardioprotective, we wonder why it isn’t more frequently discussed (or used?) in clinical practice. While the RCT (n=3,000 type 2s) was intended to show safety and non-inferiority to placebo, the hazard ratio for the primary CV endpoint (non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for chronic heart failure, or coronary revascularization) was 0.58 (95% CI: 0.35-0.96), which suggests possible superiority, though with a rather wide confidence interval. By 13 months, there was a notable difference in CV events between the two groups, with cumulative incidence of ~35% in the standard of care + placebo group and ~20% in the standard of care + Cycloset group. There was also a significant reduction in three-point MACE. Dr. Gavin stated that this data is “not unlike the circumstance of the safety study of semaglutide, obtained prior to the CVOT that will be conducted in the post-market setting.” He was referring to SUSTAIN 6, which Novo Nordisk always intended as a pre-market safety trial, even though semaglutide went on to show 26% relative risk reduction for three-point MACE (p=0.02 for superiority). Nevertheless, Dr. Gavin suggested that both SUSTAIN 6 and the Cycloset RCT are considered too short and too small to satisfy superiority requirements of CVOTs. Still, his enthusiasm for the “great promise” of bromocriptine-QR as a cardioprotective agent is notable, and we too look forward to seeing the company progress to a CVOT. In light of bromocriptine-QR’s sympatholytic effects (on top of increased insulin sensitivity and reduced postprandial hyperglycemia), lower CV risk would make sense – as Remme pointed out in 1998, “increased sympathetic adrenergic tone may lead to coronary vasoconstriction and, as myocardial oxygen demand increases concomitantly, myocardial ischemia may ensue.” All biomarkers of CV health measured in the study – including triglycerides, free fatty acids, and blood pressure – improved with Cycloset treatment relative to placebo.
- In the 2010 RCT, adding bromocriptine-QR to standard care had a positive impact on glycemia. Among participants on one-two oral agents as background medication, Cycloset demonstrated 0.5% placebo-adjusted A1c decline over 52 weeks, and a higher proportion of the Cycloset arm achieved target A1c ≤7% compared to the placebo arm (25% vs. 9%). The study drug showed a mild side-effect profile overall; nausea was the most common adverse event, affecting 32% of participants on Cycloset vs. 8% of participants on placebo. However, Dr. Gavin explained that the study used a forced titration scheme, raising the dose quickly and “there’s no need for that the way we use it clinically.” Importantly, hypoglycemia and weight gain were similar between the experimental and placebo arms, though CGM was not used in the study – perhaps there were differences in hypoglycemia in the “dark” times of the SMBG day (e.g., overnight).
- As background, bromocriptine-QR has a neat mechanism in that it enhances dopaminergic signaling in the suprachiasmatic nucleus (SCN; a brain region within the hypothalamus), restoring an important dopamine peak that is often lost due to the western/high fat diet, psychological stress, and sleep deprivation. The SCN, Dr. Gavin explained, produces circadian rhythms of neuroendocrine stimuli, such as cortisol, prolactin, and norepinephrine. By interacting with peripheral tissues, these signaling molecules regulate biochemistry and metabolism, such as modulating insulin sensitivity. Elegant mammal studies showed that when animals are active and foraging for food, there is a surge in dopamine signaling in the early hours post-waking – during this period, the animals are very insulin-sensitive so that they can use the energy from the food they consumed. During the colder months, energy utilization decreases, hepatic glucose production increases, and the loss of the surge of dopamine in the SCN correlates with high insulin resistance. After the correlation was established, another study showed that abolishing dopamine signaling at the SCN boosts insulin resistance. Further, the lack of this dopamine surge leads to what Dr. Gavin called “the entire array of the cardiometabolic risk family” – hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, and visceral adiposity. Bromocriptine-QR, when taken within two hours of waking, restores the morning dopamine surge and thus glucose tolerance.
- In order to work, bromocriptine-QR must be taken within two hours of waking and be in micronized form. If taken outside of this window, it is not biologically effective, and we wonder if it could even be deleterious by confusing other circadian processes. Dr. Gavin also referenced an Iranian study where the authors, he believes, took conventional bromocriptine and tried to convert it into the micronized formula by “simply pulverizing it.” When administered to patients, it didn’t have the expected physiological effects – unless the micronized formulation is used, the molecule doesn’t recreate the dopamine surge.
- Dr. Gavin shared that Dr. Ralph DeFronzo et al. just completed a study showing that max efficacy is achieved with four tablets of Cycloset per day (3.2 mg total). The recommended max dose of 4.8 mg, which likely carries with it a greater array and incidence of unpleasant side-effects, is apparently unnecessary.
7. In-Patient Glycemic Outcomes Worse with U500 than Non-U500 Insulins in UVA Retrospective Study
In retrospective data from UVA Medical Center collected between 2012 and 2015, patients admitted on U500 insulin had significantly worse glycemic outcomes when maintained on U500 (n=52) than those who were switched to a non-U500 insulin (n=43). UVA’s Dr. Samir Panvelker showed that, while in the hospital, mean glucose for patients on U500 and non-U500 insulins were 228 mg/dl and 196 mg/dl, respectively (p<0.001). 7.4% of U500 and 3.1% of non-U500 patient-days saw blood glucose sink <70 mg/dl (p=0.026), while 44.2% of U500 and 54.8% of non-U500 patient-days saw blood glucose rise >180 mg/dl. However, glucose levels climbed above 299 mg/dl nearly twice as frequently in the U500 group: 47.2% of days vs. 26.2% of days (p<0.001). Note that hyperglycemia is defined as blood glucose >180 mg/dl, though we assume it is actually 180-299 mg/dl since the U500 group’s percent of days with severe hypoglycemia is higher than that with hyperglycemia. If that assumption is correct, then the U500 group had blood glucose >180 mg/dl on a shocking 91.4% of inpatient days (81% of days for the non-U500 group). There were no instances in either group of severe hypoglycemia (glucose dropping <40 mg/dl). Since this was a retrospective evaluation, it can’t be ruled out that the reason for hospitalization influenced the outcomes. For example, upon admission, 54.8% of non-U500 patients were “NPO” (instruction to withhold foods and fluids) – possibly an indicator that they were to undergo serious procedures requiring general anesthesia – while only 23.1% of U500 patients were. In addition, the total daily dose decrease upon admission was 75% in the non-U500 group and 36% in the U500 group. More background information would be necessary to determine if the insulin regimen was the root cause of inferior inpatient glycemia, but this data adds another piece to the U500 debate. While the cost-savings associated with U500 are not to be overlooked, they may be canceled out by worse outcomes associated with more inpatient glycemic variability; further, U500 insulins carry a more complicated dosing regimen (for an already difficult-to-titrate therapy), heightened hypoglycemia risk, and weight gain.
- An alarming 18 of the 95 examined admissions had at least one corrected insulin dose. In 17 of these cases, the pharmacy adjusted and prevented the dose from being administered to the patient. Dosing errors are all-too common with U500 in patient hands, particularly when they are not given dedicated 500 syringes, but it is not encouraging that nearly one in five ordered doses in a hospital were faulty. Education of both patients and providers is tantamount with U500.
- Perhaps the most important takeaway from this study is the confirmation that inpatient management of glucose in people with diabetes is very poor, as mean glucose was high in both groups, as were the frequencies of hypoglycemia and hyperglycemia. More and better tools, including CGM and possibly even closed loop, could go a long way to preventing excursions and improving perioperative and general inpatient outcomes.
During a Janssen-sponsored product theater, Albany’s Dr. Robert Busch referred to the combination of SGLT-2 inhibitors with GLP-1 agonists (on top of metformin) as the “hidden secret” of endocrinology. While he didn’t have time to review all the data on this front, we’re inclined to agree with him, and we note two studies that support the efficacy of SGLT-2/GLP-1 combination therapy. AZ’s DURATION-8 compared SGLT-2 Farxiga (dapagliflozin) + GLP-1 Bydureon (exenatide) vs. each drug as monotherapy, and found a 1.8% A1c drop with the combination vs. 1.4% with exenatide alone and 1.2% with dapagliflozin alone (baseline A1c 9.3%, p<0.01 for both comparisons). Lilly’s AWARD 10 was just recently published online. Adding GLP-1 agonist Trulicity (dulaglutide) to any SGLT-2 inhibitor gave 0.7%-0.8% greater A1c reductions than placebo from a baseline 8% (p<0.0001). Weight loss was also significant greater with combination therapy vs. monotherapy in both trials, and the importance of this outcome beyond A1c should not be underestimated for people with type 2 diabetes. As Dr. Busch explained, this impressive efficacy arises from the complementary mechanisms and physiological effects of SGLT-2s and GLP-1s: SGLT-2 inhibitors cause weight loss via urinary glucose excretion, but the weight loss levels off over time as appetite is upregulated in response to a lower threshold for glucose excretion. Meanwhile, GLP-1 agonists suppress appetite, slow gastric emptying, and suppress glucagon. Importantly, while the combination of these classes does give sub-additive effects on A1c and weight loss, the molecules work synergistically, and we’re noticing increased interest in their simultaneous use. On balance, we’ve also heard some skepticism, especially from Dr. John Buse, who voiced concern about potential problems arising from differential effects of SGLT-2s and GLP-1s on glucagon. At a bare minimum, we think more investigation of SGLT-2/GLP-1 combination regimens is certainly warranted, and we appreciate that Dr. Busch called attention to the exciting possibilities here for clinical care. We’d add that we’re also curious about the dual cardioprotection that might come from taking an SGLT-2 inhibitor and a GLP-1 agonist simultaneously, especially since it seems like these two classes have different mechanisms underlying their CV benefit.
- Though he was very positive on SGLT-2s as a class, Dr. Busch warned that these aren’t “open mouth, take pill” agents. That is, they require more diligence and care on the part of both patient and prescriber. When you inhibit glucose reuptake with SGLT-2 inhibitors, you also inhibit salt reuptake, in turn lowering plasma volume. Dr. Busch emphasized the importance of this volume depletion, which he associated with the risk for amputations seen with canagliflozin (J&J’s Invokana). He cautioned against prescribing canagliflozin for any patients with impaired blood flow (low blood pressure, peripheral vascular disease, neuropathy, or those who can’t eat or drink due to surgery or other circumstances). Notably, he emphasized that absolute risk for amputations was very low in CANVAS (six events per 1,000 patient-years with the study drug vs. three events per 1,000 patient-years with placebo). He suggested that if patients are educated on checking their feet regularly, and if providers monitor the feet at every single visit, amputation risk should be manageable in the real world. We absolutely agree with this assessment – amputations can be a very visceral fear for people with diabetes, and this should not be brushed under the rug as a safety concern, nor should it overshadow the remarkable glucose-lowering, weight loss, CV, and renal benefits associated with Invokana (and others in the class).
- Dr. Busch highlighted the renal safety – and potential benefit – of SGLT-2 inhibitors. At an eGFR <45 ml/min/1.73 m2, SGLT-2 inhibitors start to lose their glucose-lowering efficacy, he explained. If you’re not filtering glucose in the kidneys, blocking reuptake of glucose doesn’t help. The 300 mg dose of Invokana is not recommended for patients with eGFR <60 ml/min/1.73 m2. Dr. Busch stressed, however, that these limitations have everything to do with assumed attenuation of efficacy and nothing to do with safety – an important distinction to note. At even lower eGFR, SGLT-2 inhibitors do not seem to be harmful, and they may still confer cardio and renal protection. CANVAS and EMPA-REG OUTCOME found that SGLT-2 agents actually stabilize or protect renal function over time, following an early and expected drop in eGFR; and of course, these were two very positive studies for CV efficacy. Dr. David Fitchett suggested at ESC 2017 that SGLT-2s may demonstrate even greater CV and renal benefits in patients with impaired kidney function (which is so exciting, considering how challenging it still is to treat DKD), and Dr. Busch echoed this view at ENDO. Upcoming studies will elucidate this: J&J’s CREDENCE trial for Invokana in DKD is expected to complete in June 2019, while AZ’s Dapa-CKD for Farxiga in CKD is expected to complete in November 2020, and Lilly/BI will launch an outcomes study of Jardiance in CKD later this year.
- Lastly, Dr. Busch presented a meta-analysis indicating that canagliflozin may be a superior glucose-lowering agent compared to empagliflozin and dapagliflozin. This finding does support anecdotal evidence we’ve heard from thought leaders, including Dr. Anne Peters, who has seen greater A1c reductions and more weight loss in her patients on Invokana vs. Jardiance. In the meta-analysis, canagliflozin 300 mg gave an average 0.86% placebo-adjusted A1c reduction vs. 0.76% with canagliflozin 100 mg, 0.6% with empagliflozin 10 mg, 0.66% with empagliflozin 25 mg, 0.56% with dapagliflozin 5 mg, and 0.66% with dapagliflozin 10 mg. Importantly, this was not a head-to-head trial, so the data should be interpreted with that caveat in mind. This meta-analysis pulled data from CT.gov and journal articles, so publication bias is an inherent risk. Moreover, not all RCTs measure the same outcomes, and there are almost always differences in study population and trial design between any two given studies, so we caution against over-comparison. That said, all signs in the clinical trial literature point to Invokana as an effective diabetes drug, so again, we continue to hope that amputation-related concerns can be mitigated in the real world with stronger patient/provider education. To be sure, J&J may have to play a leading role in this to boost Invokana sales, which fell throughout 2017.
How can we close the gap between RCTs and the real world when it comes to lifestyle intervention? Dr. Donna Ryan tackled this question during a Novo Nordisk-sponsored dinner symposium. While results from the DPP and Look AHEAD were nothing short of remarkable, Dr. Ryan described these RCT interventions as “gold standard,” whereas lifestyle intervention in real-world clinical practice most often manifests as a 15-minute meeting and a simple diet/exercise prescription. In the DPP, intensive lifestyle intervention led to 7% weight loss and a 58% risk reduction for new-onset type 2 diabetes over 2.8 years; participants randomized to the lifestyle arm received training on self-monitoring, stimulus control, reinforcement/shaping, goal-setting, behavioral contracting, meal planning, modification of physical activity, problem solving, and social support. In Look AHEAD, intensive lifestyle intervention was associated with 8.6% initial weight loss, and with 6% weight loss by end of the trial. Dr. Ryan emphasized that participants in the lifestyle arm required fewer anti-hyperglycemic and anti-hypertension medications by study end, while also experiencing A1c decline and scoring higher on quality of life assessments (again, impressive efficacy). That said, the Look AHEAD lifestyle strategy came with even more strategic support for patients, including everything offered in the DPP plus more contact, group settings, and meal replacements. Delivering this lifestyle intervention was both time-consuming and expensive, Dr. Ryan explained, and she acknowledged that this isn’t always realistic in the real world: Hence, more often than not, patients attend quick sessions with their healthcare provider and walk out with a diet/exercise prescription, but none of the rigorous support framework of RCTs. To close the gap, Dr. Ryan stressed that we need to implement specific elements of what worked in the DPP and Look AHEAD, based on what’s most helpful for the individual patient (e.g. maybe one patient benefits the most from meal replacements due to his/her daily demands at work, while another needs guidance in goal-setting and identifying sources of social support). She encouraged HCPs in the room to make the most of their time. In the first 15-minute appointment, consider focusing on self-monitoring; Dr. Ryan underscored that this element of lifestyle intervention is absolutely key, because “if you want to change it, you must measure it.” In the next 15-minute appointment, focus on another aspect of lifestyle modification, prioritizing personalization of treatment plan. Dr. Ryan maintained an optimistic tone. Despite limitations on real-world lifestyle interventions, she argued that there’s a lot HCPs can do: “You can prescribe meal replacements. You can refer patients to Weight Watchers. You can set up group meetings with other staff in your practice.” We certainly appreciated this positive outlook – as diabetes/obesity prevalence continue to climb, it’s becoming increasingly clear that treatment is not enough, that we must also make prevention a reality. What else is standing in the way of good lifestyle interventions in the real world? Dr. Ryan highlighted reimbursement as one of the main hurdles for patients/providers today. Patients aren’t sure that lifestyle modification or behavioral coaching will be covered by their insurance, providers aren’t sure how to get paid for providing these services, and Medicare DPP programs have to be certified in advance. We hope that reimbursement starts to improve for evidence-based lifestyle interventions, but we also understand the difficulty in determining whether any given program is evidence-based or arbitrary; at the bare minimum, this adds administrative hassle for patients, HCPs, and payers, and we wonder how to make this as easy as possible.
- During the panel discussion, Dr. Ryan positioned Novo Nordisk’s upcoming CVOT for once-weekly GLP-1 agonist semaglutide in obesity as a potential
“game-changer for our field.” This first-ever obesity CVOT (named SELECT) was announced during the company’s Capital Markets Day in November 2017, and it’s scheduled to begin sometime this year, with an estimated enrollment of 17,500 people. Very notably, the study design is intended to determine CV superiority, and patients with established diabetes will be excluded. Novo Nordisk management has implied that SELECT will be a landmark study on par with DCCT (for type 1 diabetes) and UKPDS (for type 2 diabetes), confirming that obesity is a biological disease that responds to medical management. Dr. Ryan echoed this view. “If in four years, we have evidence that a lifestyle intervention plus semaglutide produces a reduction in CV events and potentially CV mortality, it would be a game-changer for our field. One of the things that has really held obesity care back is that we don’t have this evidence that weight loss produces a reduction in CV events. It’s been shown with bariatric surgery (through SOS and other studies), but we don’t have this for medical weight loss. We need to show improvements in these hard endpoints to really legitimize our field.” We ourselves can’t wait for SELECT data to possibly revolutionize obesity care, though we’ll have to be patient for now, as this CVOT has yet to officially kick-off and then won’t complete for several years. Dr. Ryan also clarified that this study will evaluate a high-dose (2.4 mg weekly) of semaglutide, meaning it’s a separate drug from the recently-approved Ozempic (semaglutide 0.5 mg or 1.0 mg weekly) for type 2 diabetes, though the lower doses of semaglutide have also stimulated profound weight loss in diabetes clinical trials.
Dr. Scott Kahan quantified provider bias against patients with overweight/obesity, and he showed how this negatively impacts outcomes. He discussed one study that evaluated patient/provider visits (n=40 HCPs and 238 patients): Despite no significant difference in the level of respect reported by HCPs based on a patient’s gender (p=0.82), race (p=0.76), education level (p=0.67), annual income (p=0.77), or health insurance status (p=0.97), HCPs reported significantly less respect for patients with higher BMI (>32.9 kg/m2) vs. those with lower BMI (p=0.009). On his next slide, Dr. Kahan illustrated how this bias adversely and tangibly affects patient outcomes. A 2013 study reported that just 14% of patients who feel judged by HCPs for their body weight achieve clinically-significant weight loss vs. 20% of those who don’t feel judged – a difference of more than 40%. As Dr. Kahan put it, if HCPs unconsciously label people with obesity as “lazy” or “unmotivated,” they are more likely to spend less time with them or care a little less about their outcomes. This translates to poor psychology for patients, and a lower ability to lose weight. Dr. Kahan used this data, in part, to highlight the value of person-first, non-stigmatizing language in obesity care, because patients who sense compassion from their provider team are more engaged, and are ultimately more successful in weight management; he underscored that better language should be adopted by an entire team, because patients often perceive bias from medical assistants or front desk staff. While the language movement has been picking up steam in diabetes, our sense is that it lags behind in obesity, though we’re noticing early momentum from presentations like this one. We’re glad that experts like Dr. Kahan continue to advocate and educate in the fight against weight-based stigma.
Dr. William Dietz delivered powerful words on the need for integrated action (medical professionals + communities) in addressing obesity: “We’re not going to treat our way out of the obesity epidemic. That’s not to discount the importance of medical treatment, but we also need good public health initiatives.” Currently at George Washington University, Dr. Dietz was previously at CDC and played a pivotal role in developing the 10 Provider Competencies for the Prevention and Management of Obesity. Much of his talk focused on lack of adequate medical training and insufficient knowledge among providers on best practices for obesity care. He presented data (in press for the journal Obesity) to show that only 49% of surveyed PCPs (family practitioners, nurse practitioners, internists, and ob/gyn providers) were aware that 150 minutes/week is the recommended level of physical activity necessary for health benefits. Only 16% of those surveyed knew that 12-26 sessions of medical counseling are recommended for adult patients with obesity. We weren’t entirely surprised to see this gap between best practice and reality, given a study of US medical licensing exams: Of 802 total test items reviewed, a mere 36% (289) pertained to obesity in any form or fashion; the same study reported that only 2% of coded items in the US related to obesity care, which spotlights the chronic under-treatment of this chronic disease. Dr. Dietz acknowledged an intensifying burden on primary care providers, as chronic disease – including obesity – outpaces the medical workforce. “How does a busy PCP fit in 26 recommended visits with someone who has obesity? What’s the likelihood that the patient will show up for that many visits?” Dr. Dietz listed these questions as additional examples of the challenges to medical management of obesity. He shared some calculations to drive the point home: Among adults with severe obesity (BMI ≥40 kg/m2), there are 89 patients per available practitioner. For adults with obesity defined as BMI ≥35 kg/m2, this number climbs to 164 patients/practitioner. For children with obesity defined as ≥120% the 95th percentile of BMI, the ratio is 50 patients/practitioner, and we note that managing childhood obesity comes with its own set of intimidating challenges (Dr. Dietz mentioned that best practice for childhood obesity includes 26 contact hours). Clearly, these patient/provider ratios are too high, and with obesity prevalence on the rise, we’re approaching an unsustainable situation in healthcare – if we haven’t reached it already. This was one of the most compelling arguments we’ve heard for the need to focus on prevention efforts (not just treatment) in fighting the obesity epidemic, and we think this extends to diabetes as well. We so appreciated Dr. Dietz’s emphasis on collaboration between healthcare providers and communities, as this is an essential piece of successful public health interventions.
An early morning Amgen symposium gave attendees both good and bad news over breakfast – PCSK9 inhibitors come with very compelling clinical benefits, including efficient lipid-lowering and cardioprotection, but securing reimbursement for these currently pricey products remains a huge challenge. Both PCSK9 inhibitors on the market, Amgen’s Repatha (evolocumab) and Sanofi/Regeneron’s Praluent (alirocumab), offer profound LDL-lowering in addition to CV benefit, as evidenced by FOURIER data for Repatha and hot-off-the-press ODYSSEY Outcomes data for Praluent. And yet, access to these therapies remains painfully low. This was reinforced by remarks from Ms. Mackenzie Ames, a patient advocate with familial hypercholesterolemia (FH). Ms. Ames is perhaps the clearest imaginable example of someone who meets the clinical criteria for PCSK9 therapy: Her untreated LDL was >300 mg/dl at age 5, and it remains above-range at ~150 mg/dl with a maximum intensity statin regimen. She has a long family history of CV events, with several family members experiencing fatal MIs before the age of 30 (some as young as 10 years-old). Despite all this, Ms. Ames’ insurance has repeatedly denied prior authorization for both Repatha and Praluent. Both Amgen and Sanofi/Regeneron have emphasized their efforts to negotiate with payers for better reimbursement, but Ms. Ames’ moving story illustrates that there is still a very long way to go. On that note, Columbia cardiologist Dr. Henry Ginsberg pointed out that a recent health economic analysis, after factoring in quality of life improvements and prevention of costly CV events with PCSK9 inhibitors, places the most cost-effective price for these agents at ~$4,000-$5,000/year – hefty, especially for someone paying out of pocket, but considerably more manageable that the current cost of ~$14,000/year. That said, until payers substantially alter their stance on PCSK9 inhibitors, Dr. Robert Eckel underscored that persistence on the part of the HCP is the best avenue to getting a patient’s insurance to eventually reimburse a PCSK9 prescription: “You have to push this envelope hard. Re-appeal again and again. We can’t ignore who we’re prescribing these medications to.” Notably, a survey conducted by the National Lipid Association found that 97% of providers do follow-up with payers after an initial prior authorization for a PCSK9 is rejected, which is fantastic news, though we note the likelihood of response bias (more engaged HCPs were probably more inclined to take the survey). On the darker side, the same survey reported that 96% of PCSK9 prior authorizations are rejected up front, and even after follow-up from the provider, only 36% are ultimately granted.
- According to Dr. Eckel, the new ODYSSEY Outcomes data on Praluent “may make things interesting” when it comes to payer negotiations for the PCSK9 class. While positive CVOT data from both PCSK9s provides a very compelling suggestion of a cardioprotective class effect, Dr. Eckel pointed out that the majority of the benefit in ODYSSEY Outcomes was driven by the ~one-third of patients with the highest LDL levels at baseline (≥100 mg/dl), raising the possibility that payers could reserve PCSK9 inhibitor coverage for only the highest-risk patients. Dr. Ginsberg also noted that the different study designs between FOURIER (which enrolled people with longstanding atherosclerotic CV disease) and ODYSSEY Outcomes (which enrolled people with atherosclerotic CV disease who had experienced a CV event within the past year) could muddy the waters in payers’ eyes. We’d be remiss not to mention Dr. Steven Nissen’s outright rejection of the ODYSSEY subgroup analysis by baseline LDL; he attributed this finding to dose confounding, which we explain in detail above. Regardless, we don’t think it’s necessarily bad news if payers initially reserve PCSK9 inhibitors for those with very high LDL – people like Ms. Ames. Considering the abysmal state of reimbursement right now, we have to start somewhere in improving coverage for Repatha and Praluent, and risk stratification is a useful strategy to get the ball rolling and convince payers of the potential cost-savings. Eventually, we do hope to see PCSK9 inhibitors reimbursed for everyone who could benefit from a more efficacious lipid-lowering agent, but it will likely be a slow-and-steady climb to “ideal” coverage. Notably, given that diabetes also confers residual CV risk (on top of dyslipidemia), many type 2s may fall into the category of “highest-risk.” We’ve certainly heard thought leaders advocate for more consideration of PCSK9 inhibitor therapy in diabetes care.
Diabetes Tech & Hypoglycemia Highlights
Dr. Judith Fradkin laid out her research agenda for hypoglycemia, emphasizing that CGM will greatly facilitate this work. As she put it: “When we only ascertain hypoglycemia based on ER visits or the assistance of others, I think we’re very much underestimating the burden of hypoglycemia. The use of CGM will be very helpful in that regard.” She listed a number of research topics high on her list: (i) determining the rates and predictors of hypoglycemia not severe enough to require medical intervention; (ii) investigating how a common “frail” phenotype may mediate the relationship between hypoglycemia and cardiovascular outcomes in those susceptible to both, as well as how a precision medicine approach might identify those with such a phenotype warranting extra care; (iii) exploring the existence of racial disparities, as African Americans are disproportionately affected by hypoglycemia, and determining safer approaches to glycemic control in vulnerable populations; and (iv) determining how individuals differ in the degree of hypoglycemia that causes clinical symptoms. The research world clearly has its work cut out! To add to their burden (or opportunity!), we’d add: (i) investigate the round-the-clock risk of hypoglycemia in different populations on certain drugs; (ii) determine how much time spent below 70 mg/dl is “safe and acceptable”; and (iii) better understand the interaction between hypoglycemia and macrovascular outcomes. Clearly, CGM will be a necessary ingredient in most if not all of Dr. Fradkin’s proposed studies (and all of ours). Dr. Fradkin didn’t suggest an “NIDDK Hypoglycemia Initiative,” but it doesn’t seem far out of reach. Imagine how much we could learn with a $500 million allotment to addressing one of the biggest cost drivers in diabetes!?
- The NIH seems to be investing heavily in artificial pancreas research, with Dr. Fradkin proudly stating that six of 17 new funding opportunities released by the NIH/NDDK are within artificial pancreas investigation. These opportunities include projects exploring how closed loop systems affect quality of life, particularly in regard to hypoglycemia. As Dr. Fradkin noted, the extent to which closed loop will be more broadly utilized is still unknown, necessitating further research in diverse populations. She highlighted one project investigating closed loop in older patients more susceptible to hypoglycemia and another using CGM to understand the effect of glycemic excursions on patient wellbeing and cognitive status. We’re especially excited about the potential implications for the second study, though it doesn’t necessarily involve closed loop – the more data that can be collected identifying the clinical relevance of time-in-ranges and glycemic variability, the more likely regulatory institutions may be to consider them in product reviews. Dr. Fradkin was particularly excited about the NIH-funded iDCL trial, particularly the arm using Senseonics’s six-month implantable CGM. Last we heard during Senseonics 4Q17 call, the trial is anticipated to begin in 2H18.
- Dr. Fradkin appreciated the need to remain vigilant of hypoglycemia in older populations but astutely raised the question of whether A1c should be the trigger to pull back care, referencing the highly controversial ACP guidelines released earlier this month. The new ACP guidelines were criticized by the ADA, AACE, and many others for its recommended approach to de-intensify pharmacologic therapy in the elderly with A1c <6.5%. As Dr. Fradkin noted, lower A1c did not predict hypoglycemia in the ACCORD trial, nor in recent analyses from Selvin et al. (Diabetes Care 2017) and Karter et al. (JAMA Int Med 2017). Rather, these papers suggest that deintensification of therapy should depend on risk factors such as age over 77, frailty, previous hypoglycemia, etc. It’s well established that hypoglycemia in older adults with diabetes is linked to increased mortality, but as Dr. Fradkin pointed out, guidelines aiming to mitigate these risks are clearly not being followed: A review of NHANES 2009-2014 data shows that the prevalence of intensive glycemic control increases with age, rather than decreasing. She later added, “While intensive control is appropriate for many healthy seniors, if guidelines linking A1C targets to life expectancy were being followed, on a population basis the proportion with intensive control would be lower in seniors and higher in young adults.”
- Importantly, Dr. Fradkin also detailed the latest consensus on defining levels of hypoglycemia (<54 mg/dl and <70 mg/dl). She noted that such standardization will be very useful when comparing data across future studies. Hear, hear!
Joslin’s Dr. Lori Laffel underscored that if we want to see greater uptake of diabetes technologies like CGM and hybrid closed loop in pediatrics, the field needs to continue to match needs and manage expectations. On hybrid closed loop, Dr. Laffel noted that above all, current systems (i.e., the MiniMed 670G) are far from seamless, requiring significant work and expectation management, and coming with high on-body burden. She was, however, fairly positive on systems that are just on the horizon (Insulet Horizon, Tandem PLGS), and especially “remarkable” DIY closed loop systems. Against the background of a tragic story in which she believes CGM could’ve perhaps saved a young man’s life, Dr. Laffel highlighted recent data demonstrating that CGM performance/accuracy predicts usage, which in turn predicts outcomes. She also briefly commented on Abbott’s FreeStyle Libre (dosing claim limitations) and Dexcom’s G6 (enthusiasm for automatic inserter).
- Said Dr. Laffel on hybrid closed loop technology: “Hybrid closed loop is not seamless. It’s just not. Do you just tell your patients to open the box, and I’ll see you in a year? I don’t think so.” Despite this initial evaluation and high AID expectations and sources of burnout, she was still very positive on systems that seem to be delivering outcomes or have potential to do so. She covered Medtronic’s 670G pivotal data (“remarkable, really remarkable”), the Omnipod Horizon system (pointing to recently-published 36-hour feasibility data), the Tandem PLGS system (pivotal data presented at ATTD, currently under FDA review, with launch planned for summer 2018), and was particularly positive on do-it-yourself (DIY) AID. One of her patients on DIY closed loop (see Dexcom Clarity trace below) had mean glucose of 134 mg/dl, an A1c of 5.5%, and very little hypoglycemia. She commented “This is remarkable – look at this glycemic pattern.” We love to hear providers, especially those of Dr. Laffel’s stature, touting DIY and reminding other providers to support patients who are interested and capable of using such systems. (Adam and Kelly and Dr. Aaron Kowalski have reported similar experiences.) Only a couple of other providers in the room self-identified as having patients on OpenAPS or Loop, and we assume this number will stay fairly modest unless JDRF’s open protocol initiative takes off – Roche is the first company on board, which will hopefully drive to a more interoperable ecosystem for closed loop components.
- Expectation management remains key for closed loop, largely due to the ample sources of AID burden and burnout. Dr. Laffel included on her list: Concerns about accuracy; false alerts/alarms; worries about failures; need for multiple devices/insertions; frequent site changes; tubing (air bubbles); carrying devices and back-up supplies; devices not waterproof; and the need to be discreet, compact, and unobtrusive. Nearing the end, she exclaimed that she was getting exhausted just reading the list! These barriers are also true of DIY systems, and even second-gen closed loop devices will have these issues. We’d guess it will be some time (5+ years) until the field matures to address most/all these barriers in a meaningful way – multiple devices/insertions and infusion set issues are likely to be here for some time.
- Dr. Laffel even pointed to the Cambridge group’s outstanding work automating insulin delivery for type 2s in the inpatient setting – “it’s very nice to know that even in type 2 diabetes patients there’s a glycemic benefit.” As a reminder, this was some of the most compelling data we saw at ADA 2016: closed-loop control significantly improved time-in-target from 38% to 61% for the 100-180 mg/dl range (p<0.001). As a side note, the sub-text of this result was not lost on us at the time: glycemic outcomes in the hospital are all-too-often abysmal. We hope to see CGM and insulin titration move into the hospital in a more meaningful way, perhaps alongside in-hospital closed loop.
- Dr. Laffel, like many others, believes that improved CGM performance likely enhances uptake and therefore outcomes. She pointed to a study from ADA 2016, in which wear time of Dexcom’s newer and improved G4 was higher than the predecessor Seven Plus: At baseline, median wear time per week across users of G4, Seven Plus, and those who eventually switched from Seven Plus to G4 was between ~130-140 hours (77%-83% of the time). However, at 12 months, wear time in the Seven Plus group had fallen to <40 hours per week (24% of the time); the G4 group still wore the sensor ~75 hours per week (45% of the time), and the group that switched from the Seven Plus to the G4, perhaps realizing how lucky they were to have a more accurate sensor, wore their sensors nearly 100 hours per week (60% of the time) even in month 12. (This is not surprising, and something we expect will especially improve as sensors reduce/eliminate fingerstick calibrations, and therefore, perceived and actual error between the meter-CGM.) By the transitive property, Dr. Laffel argued that better performance leads to better outcomes, since previous studies like GuardControl and the JDRF CGM study have shown that increased wear time confers greater glycemic benefit. Acknowledging these conclusions, the Helmsley Charitable Trust is funding the CITY trial (“CGM Intervention in Teens and Young Adults with Type 1 Diabetes”) – “we’re embarking on a study to figure out how to get 14-24 year-olds to wear CGM. We’re going to encourage them to at least try to embrace devices, because they could reduce the burden of care, and possibly prevent adverse events.” The Jaeb Center is coordinating the 15-site study, which kicked off in late January, according to ClinicalTrials.gov. In line with Dr. Laffel’s remarks, the study’s main outcomes are glycemia-based, but it also includes a number of surveys getting at quality of life: CGM Self efficacy questionnaire, problem areas in diabetes (PAID) questionnaire, glucose monitoring satisfaction questionnaire, hypoglycemia confidence questionnaire, diabetes technology attitudes questionnaire, and the Pittsburgh sleep quality index. We’d assume this is using Dexcom’s G5, but the study page does not specify.
- Dr. Laffel sees barriers to sensor use going down even further in the near future, particularly with easier insertion and non-adjunctive (insulin-dosing) claims. For the Dexcom G6, she specifically called out the automatic inserter, calibration-free (unless the user desires to enter one), remote monitoring, and Apple Watch display. Regarding the much improved inserter, she said that in a Joslin study, “nearly every patient enjoyed that feature” – indeed, the new one-button device is a far cry from the more syringe-looking and feeling current version. She also expressed enthusiasm for Dexcom’s and Abbott FreeStyle Libre’s non-adjunctive claims, but cautioned that Libre does have a number of limitations, as blood glucose does need to be checked if blood glucose is low, if there is a single trend arrow up or down, or if the user has recently taken a high dose of vitamin C or aspirin.
- “In the US, we are now limited by the number of pumps. We need to ensure choice among pumps, because if there’s no competition, we will lose the innovation to make them better. All of us should be hopeful that multiple others stay in business, because without competition, innovation will be lost.” Currently, there are only three companies actively selling new pumps in the US – Medtronic, Tandem, and Insulet. It has been a trying year or so for others, as Roche (temporarily?) pulled out of the US and Animas closed its doors for good last fall. Some signs point to this US landscape improving, as Tandem and Insulet and Medtronic all saw record sales in 4Q17, and several new entrants are on the horizon (e.g., Bigfoot, Lilly, Beta Bionics, etc.). New subscription/service business models also hold a lot of promise in our view, as the current four-year model is challenging for patients and payers. See our automated insulin delivery competitive landscape for a rundown of the US and international pipelines – the innovation in this space has serious potential to add greater diversity to the pump market. That said, pricing pressure could rise, and running a pump company remains difficult even for world-class healthcare companies like J&J – delivering strong outcomes, negotiating with payers, and running a world-class software business will become even more important.
FDA’s Dr. Christine Lee detailed the Agency’s Safe Use Initiative, focusing on a recently-developed and validated hypoglycemia risk prediction tool which she believes could lead to improved outcomes. As part of the Initiative, the hypoglycemia risk-stratification tool was developed based on six key risk factors for hypoglycemia, including: (i) patient history of hypoglycemia-related utilization; (ii) insulin use; (iii) sulfonylurea use; (iv) emergency department use; (v) chronic kidney disease; and (vi) age. This tool was published by Karter et al. in JAMA Internal Medicine in August 2017. The internal and external validation took place at Kaiser and Veterans Health Administration/Group Health Cooperative, respectively. In the internal Kaiser sample, those at high risk had approximately a 30-fold greater 12-month hypoglycemia-related utilization rate (6.7%) than patients identified as low risk (0.2%). Implementation of the tool was piloted within the Mayo Clinic in collaboration with Medicare’s Transforming Clinical Practice Initiative (TCPI). According to Dr. Lee, the tool was tested in 90 primary care clinics within the Mayo Clinic Practice Transformation Network, where it identified 52,633 patients at risk of hypoglycemia. These patients were then prospectively observed over the next 12 months, as researchers tracked hypoglycemia-related emergency department or hospital use. We look forward to seeing data from the Mayo Clinic cohort as well to learn more about the generalizability of the tool; or better yet, perhaps the Mayo pilot also includes some intervention in the high-risk group. We are huge believers in risk stratification for diabetes, especially when tools can integrate seamlessly into physician workflow, as it has the potential to greatly improve resource utilization while also improving outcomes. Hypoglycemia is definitely a priority for FDA; according to Dr. Lee, diabetes is one of three disease states whose drugs together are responsible for 60% of all adverse event-related emergency room visits in people over 65.
- Dr. Lee highlighted the FDA’s Social Media Listening project investigating methods to harness unstructured, narrative data. The project is ongoing but she’s already found some pretty cool results – for example, Twitter is the most commonly-utilized social media platform when it comes to talking about diabetes. As part of the project, Dr. Lee is currently conducting a pilot study mining Facebook data to understand peoples’ experiences with diabetes. Preliminary results indicate: (i) reading about others’ experiences with diabetes, particularly regarding diet and exercise, can help patients with self-management; (ii) remaining aware of comorbid conditions is important; (iii) links between the built environment and increased risk of diabetes require further understanding; and (iv) patient support and encouraging community engagement to establish healthier environments should be emphasized.
Over a dinner symposium, Drs. Lori Laffel (Joslin Clinic) and Grazia Aleppo (Northwestern University) reviewed the Endocrine Society’s insulin dosing adjustment recommendations for Dexcom G5 CGM trend arrows. We commend both speakers for crystal-clear presentations, filled with practice examples, comparing the new guidelines to previous methods with helpful visuals. The Journal of the Endocrine Society published recommendations for pediatrics and adults back in November, so this symposium was a public unveiling of sorts. While these recommendations are limited to the G5 – trend arrows are not standardized across CGM manufacturers – we believe they are an improvement over previous methods due to their simplicity and personalization. Specific changes in insulin doses are recommended in absolute units based on the trend arrow shown and a patient’s specific correction factor (CF). In the two slides below, Drs. Aleppo and Laffel compared prior methods to the Endocrine Society’s approach: The DirecNet method was dependent on carb intake and correction factor, and adjustments were given as a percent increase or decrease, demanding higher levels of numeracy; The Scheiner method requires high numeracy and isn’t as easy for MDI (easier with bolus calculator); The Pettus Edelman method is similarly not as easy for MDI; The Klonoff/Kerr method is device-agnostic and provides adjustments in insulin units without calculation, but assumes a maximum insulin sensitivity of 67-75 mg/dl per unit, meaning it excludes people with higher insulin sensitivity (e.g., pediatrics). The awesome graphic in the following slide below shows how Pettus/Edelman, Scheiner, and the Endocrine Society approaches differ across the spectrum of insulin sensitivity; the much more conservative adjustments with the Endocrine Society approach at the lowest levels of insulin sensitivity jump out. With so many methods floating around, it would be great to see a user experience study Ultimately, we imagine one or many of these approaches will be integrated into CGM-based bolus calculators or closed loop algorithms, so the numeracy point may not matter. But outcomes do: perhaps a wide spectrum of patients could use all five dosing strategies sequentially and compare time-in-range, glycemic variability, and satisfaction/ease of use metrics – it may come out that one is superior to the others, though we’re not totally convinced...
- The last portion of the panel featured three patients – a 16-year-old girl on an Omnipod, a 42-year-old man on injections, and a 43-year-old man on a Tandem pump – who spoke highly of the new G5 dosing recommendations. The man on injections finds it easy to simply put the unit adjustments corresponding to different arrows on a sticker that he places on his pen. The Tandem user ( ±1 unit for diagonal arrow, ±2 units for single arrow, and ±3 units for double arrow) and the girl on Omnipod (±0.5 units for diagonal arrow, ±1 unit for single arrow, and ±2 units for double arrow) both said that their adjustments are easy to remember. Though the session was focused on arriving at a regimented, easy-to-follow method of landing in-range after dosing insulin off of CGM, the panelists still spent much of their time discussing the lack of predictability and need to experiment. For example, a headwind or tailwind when doing the same bike ride home from work can mean a blood glucose surge or dip upon arriving home – obviously, the dosing guidelines can’t take that into account. Indeed, these are only recommendations and patients will still have to use common sense and experiential learning to dictate dosing, but another tool belt granting more structure to diabetes is a definite win.
- The workshop provided a number of tools for providers that may be helpful for education purposes: Download the pediatric worksheet, the adult worksheet, and the pocket cards.
Parkview Health’s Dr. Jeffrey Boord took a slightly different tack regarding the ACP guidelines as compared to Dr. Judith Fradkin (see above), urging the audience to avoid allowing the debate to cloud the central issue of improving patient care and reducing the risk of adverse events. To this end, Dr. Boor emphasized the importance of collaborating with primary care clinics to reduce hypoglycemia. He detailed the admirable efforts of the Hypoglycemia Quality Collaborative (HQC), established in 2016, which has since evolved into the Hypoglycemia Prevention Initiative as of 2017. The HQC Strategic Blueprint is published on endocrine.org, identifying six key domains in approaching a framework to address hypoglycemia: (i) define and describe hypoglycemia to help standardize and identify outcomes; (ii) advance hypoglycemia evidence; (iii) measure hypoglycemia quality of care – “a big gap we need to fill”; (iv) advocate for a focus on hypoglycemia by supporting payment and healthcare delivery reform; (v) deliver hypoglycemia education to providers, patients, and health plans; and (vi) recognize hypoglycemia as a public health problem existing on the population level. He identified risk-based contracts and value-based care as excellent theoretical examples of healthcare reform supporting hypoglycemia reduction, though he didn’t show any outcomes to support the assertion that this model actually does reduce hypoglycemia. The HQC is currently involved in implementing an outpatient quality improvement pilot using the blueprint characteristics and is partnering with federal agencies to do so. The pilot feasibility phase is expected to launch in September. Dr. Boord listed 18 organizations participating in HQC – we were proud to see Close Concerns and The diaTribe Foundation among these professional societies, payers, companies, research institutes, and non-profits. For those interested in becoming more involved in the Endocrine Society’s work to reduce hypoglycemia, contact Director of Advocacy & Policy Stephanie Kutler at email@example.com.
UCLA’s Dr. Theodeore Friedman presented results from P.O.W.E.R (Preventing Obesity With Eating Right) medical group visits, showing that the addition of a texting program leads to enhanced weight loss and reductions in A1c. All P.O.W.E.R participants attended exercise classes, individual patient consultations, cooking demonstrations, and nutrition counseling. In collaboration with the non-profit CareMessage, P.O.W.E.R participants (n=355) were given the option of also taking part in a texting program lasting either 12-weeks (offered in 2015-2016; n=80) or 20-weeks (offered in 2016-2017; n=67). Ten patients opted to do both texting programs. The 12-week texting program offered additional nutrition and exercise instruction, while the 20-week program included expanded nutrition and exercise options, educational content, appointment reminders, and motivational texts. Three texts were sent weekly in the 20-week program. Results indicated that those who completed at least one texting program achieved greater weight loss than those who did not (-4 kg vs -2 kg). Those who completed at least one texting program also achieved a significantly greater A1c change (-0.3%) (baseline: 6.7%) as compared to those who did not (+0.1%; baseline: 6.7%). Dr. Friedman emphasized that the results suggest the texting program works synergistically with the clinic yet believes there is promise for such a program to improve outcomes even outside clinical care. These findings are thus particularly relevant for patients unable to access in-person interventions due to limited transportation, hectic schedules, or residing in remote areas. However, Dr. Friedman acknowledged the study is limited as those who chose to participate in the texting program were likely more motivated, computer-savvy, and educated. Still, it’s encouraging to learn that a texting program was successful in a diverse patient population – the majority of the population identified as Hispanic, followed by African-American, with an even split between Spanish and English languages. Participants were also slightly older (mean age 52 years-old), helping to dispel the common and incorrect assumption that technology-enhanced interventions are only effective in younger demographics.
Big Picture Highlights
Medtronic Diabetes CMO Dr. Francine Kaufman delivered a stellar keynote at the annual Women in Endocrinology meeting, addressing the contributions, struggles, and future of women in medicine and endocrinology. Dr. Kaufman was the second-ever woman to serve as ADA President (two others have followed). She entered medical school at a time when only 10% of students were women. Below, we’ve summarized her comments on the current state of medicine and endocrinology for women and how to improve the field going forward.
- By the numbers: While women now comprise 50.7% of medical students, only 33% of currently practicing physicians are women. Disparities across specialties are striking: 80% of ob/gyn specialists are women, compared to only 10% of those trained in vascular and interventional radiology or interventional cardiology. Dr. Kaufman showed that women tend to prioritize work-life balance, patient relationships, and the desire to provide a needed service over the financial considerations that men rank higher, on average: “We’re not the same, nor should we be. When I trained, women were told to man up; I think that was the biggest mistake I ever heard. We should be more like women than we already are.” She continued, offering a personal story, “we’re still a bit more timid than we should be. When I received my first NIH grant in 1980, I couldn’t believe it, so I called to see if they had made a mistake. The secretary said, “what is wrong with you girls? You got the letter? And it has your name on it? Why would you call? No man has ever called!”
- On pay inequity: Among all physicians, women earn 74 cents on the dollar compared to men. Right out of training, women face a $17,000 annual pay gap when adjusted for age, experience, specialty, faculty rank, and measures of research productivity. That gap only gets larger with higher-paying specialties. Female endocrinologists earn 16% less than their male colleagues, translating to a $38,000-$66,000 annual wage gap. What’s more, 50% of female physicians feel they were evaluated using different hiring criteria, and two-thirds feel disadvantaged in negotiating their contracts. This all occurs despite emerging evidence that women provide more evidence-based care, more closely adhere to guidelines, and improve patient experience – at the very least, women do at least as good of a job as men.
- On the future: Women currently make up 44% of practicing endocrinologists, but 72% of those entering training in the field are women. Nevertheless, the future of endocrinology is female, presenting a new challenge. Dr. Kaufman outlined the economic process of “occupational feminization.” As more women enter a field, salaries start to trend down, also impacting men and workers at all skill levels (this is what happened in teaching). With more women entering medicine and endocrinology, salaries will be pushed down as women accept lower pay, leading to even fewer men entering endocrinology and exacerbating drops in pay. In addition to being downright wrong, this “downward spiral” isn’t good for the specialty. Dr. Kaufman emphasized that the time is right for capitalizing on the focus women’s issues are receiving in the media and celebrating the ways women physicians are different. Women (and men) in power need to protect and support their colleagues and enforce zero tolerance policies for sexual harassment, which ~one-third of female clinicians and researchers have experienced. Inequities in pay and promotions should be tracked, exposed, and not tolerated, part of creating a supportive culture for women. Moreover, family-friendly workplaces should be a standard, not an exception. Dr. Kaufman asserted that more emphasis is needed on early mentoring, training, and support – first salary negotiations do matter, and she urged that women with experience should go out of their way to help those coming up the ranks. Finally, she argued that the field needs to start rewarding outcomes (quality measures, PROs) and must transition more swiftly to patient-centered and value-based care: “We’re what the future is going to be about.”
Wharton’s Dr. David Asch provided fascinating examples of using behavioral economics to encourage healthy decisions, relying on the philosophy that the mind is a “high-resistant pathway,” and attempting to go through it is the least efficient way to change behavior. Rather, a better approach is to identify and leverage “behavioral reflexes” to bypass cognition. Dr. Asch described a study in which regret aversion (the tendency for people to hate the feeling of regret) and loss aversion (people are much more likely to avoid a loss than strive for a gain) were harnessed in a “regret lottery” to improve medication adherence. Each participant was provided a two-digit number, and every day a number would be drawn. If a participant’s exact number was selected, he or she would win $100, and if one of the digits was called, $10 would be awarded. The catch is that in order to collect the win, participants had to have taken their medication the day before (tracked by the Informedix Med-eMonitor System) – better still, if they hadn’t taken their medication and their number was called, they received a text informing them of their loss. Volpp et al. found this tactic to improve Warfarin use. In another example demonstrating the importance of framing, a 13-week randomized controlled trial (n=281) found that providing a financial incentive in terms of a loss rather than a gain significantly increased the likelihood of meeting a 7,000-daily step goal. We were also interested to hear that raising copays will decrease adherence, but reducing copays has no effect. This trend makes sense, as only those who are already taking medication will notice the rise in copay, while those not adhering won’t notice a decrease (to us, this seems more like an issue of attention than one of behavioral economics). Still, Dr. Asch emphasized that financial incentives aren’t always legal or appropriate, which is where social incentives come in. In one randomized controlled trial (n=118 African Americans with A1c >8%), social interaction was actually found to be more motivating than financial incentives, as those receiving peer mentorship achieved a significantly greater A1c reduction than those receiving financial compensation at six months (-1.1% from baseline 9.8% vs -0.4% from baseline 9.5%). Given that the peer support consisted only of weekly hour-long calls as compared to the financial incentives, which consisted of $100 if A1c dropped one point and $200 if A1c dropped two points or to 6.5%, these findings can hardly be described as rational. Said Dr. Asch: “we shouldn’t be aiming for rationality, we should be aiming for human.”
- As one audience member importantly pointed out, these same behavioral economic principles can be applied to improving providers’ quality of care. She noticed that in her practice, when physician names were posted next to their corresponding quality metrics like infection rates, performance improved. Dr. Asch chimed in, noting that social pressure is driving these outcomes. In fact, he recently led the largest randomized controlled trial investigating the efficacy of pay-for-performance and found that financial incentives do not serve to be compelling motivators for physicians.
3. ADA President Dr. Jane Reusch and Dr. Jack Leahy: “Lifestyle is Medicine”
In a lively meet-the-professor session, dynamic duo Drs. Jane Reusch and Jack Leahy positioned behavior modification as the cornerstone of type 2 diabetes management. We were pleased to hear Dr. Reusch reference the Fogg Model of Behavior Change, an innovative take on behavioral science from Stanford psychologist Dr. BJ Fogg. The Fogg Model contends that behavior is a composite of motivation, ability, and a trigger. Therefore, if a desired behavior isn’t occurring, you should troubleshoot as follows, in this order: (i) Did we trigger the behavior? (ii) Was it easy enough to do? (iii) Was there motivation to do the behavior? Dr. Reusch underscored that “lifestyle is medicine,” and she emphasized that all of these principles can be redirected to promote diabetes-friendly behaviors like exercising and eating healthy. She advocated that a clinician’s efforts to encourage these healthy behavior modifications should be prioritized on par with encouraging patients to adhere to their medication regimen. Dr. Leahy suggested that while endocrinologists are commonly taught to emphasize behavior modification, they aren’t equipped with the necessary tools to do so effectively. This is a systemic problem within medical education and training, and exacerbating the challenge is a built environment that makes healthy behaviors difficult for patients (e.g. a neighborhood that isn’t conducive to exercise, lack of affordable healthy food, etc.). We continue to hope for a greater emphasis on behavior modification tools like the Fogg framework in clinical training, and we note that this extends also to CDEs who are perhaps best positioned to deliver this kind of care on the front lines.
Neuroscientist Dr. Tamara Hershey provided an overview of the potentially damaging cognitive effects of DKA in youth with type 1 diabetes. She admitted that the literature on this topic is limited, but the early findings point to a concerning relationship between DKA and memory impairment. In one 2015 study, youth who initially presented with type 1 diabetes in DKA demonstrated impaired performance on a spatial memory task ~3.5 months post-diagnosis relative to peers not diagnosed in DKA. Furthermore, higher A1c at diagnosis was correlated with worse performance on the memory task, piquing our curiosity about the relationship between hyperglycemia and memory impairment (we also note growing interest in the overlap between diabetes/Alzheimer’s disease). A follow-up investigation found subtle but nonetheless statistically significant spatial memory deficit in youth with DKA at diagnosis seven years later; the degree of memory impairment was also correlated to the frequency of hyperglycemia. A separate study published in 2010 found a correlation between DKA and impaired performance on associative memory tasks, this time in youth with any lifetime history of DKA (rather than DKA at diagnosis, specifically). Although these findings are concerning, Dr. Hershey underscored that it is unclear whether the DKA-associated memory impairments that arose under these narrow experimental conditions actually translate meaningfully to everyday memory functioning in a real-life setting. Whether these cognitive effects extend to adults with type 1 diabetes and DKA also remains to be seen; to-date, these studies have only been performed in youth. As a potential point of optimism, Dr. Hershey speculated that DKA-associated memory impairment is likely specific to youth with type 1 diabetes (rather than the entire type 1 population), explaining that adolescents are more vulnerable to negative consequences of DKA given that they are in a crucial period of brain development, characterized by complicated dynamics of synaptic pruning, fluctuating ratios of white and grey matter, and shifts in glucose utilization – all factors that ketoacidosis is likely to disrupt. It’s also unclear whether the memory impairments extend beyond the hippocampal forms of memory investigated in these studies, and whether they are generalizable to a wider population than the predominantly white and high socioeconomic status study group. Dr. Hershey acknowledged these as crucial topics for follow-up investigation.
UCLA’s Dr. Vijaya Surampdi presented results from a retrospective chart review of 4,634 patients participating in a weight loss program at the UCLA Weight Management Clinic, showing that caloric restriction can restore normoglycemia. In this large review of the use of caloric restriction for the treatment of impaired fasting glucose, implementing a very-low calorie (VLC) diet was found to be an effective tool to rapidly treat hyperglycemia. As part of the self-paid, university-based outpatient program, personalized meal plans based on individual body composition and basal metabolic rate were designed, with participants placed on a diet of 600-1200 calories/day. Participants were excluded for any history of diabetes and were separated into normal fasting glucose (fasting blood glucose <100 mg/dl) and impaired fasting glucose groups (fasting glucose 100-126 mg/dl). Both groups achieved significant decreases in weight and percent body fat, but there were no significant differences between groups in either metric. As expected, only those in the impaired fasting glucose group saw decreases in fasting glucose, with the most significant drop (107 mg/dl to 102 mg/dl) achieved within the first month despite only moderate declines in weight. By six months, average fasting glucose was 99 mg/dl. While there is some evidence of a link to weight loss, since 50% of those who lost more than 15 lbs saw hyperglycemia remission, remission was still achieved in >30% of those who lost less than five pounds, raising the question – is it caloric restriction or weight loss that drives these improvements? Regardless, Dr. Surampdi finds these results quite exciting, as they suggest VLC diets may be an effective alternative to bariatric surgery. From purely a cost perspective, these findings are incredibly meaningful, as Dr. Surampdi estimates that one month in the weight loss clinic costs $500, while one bariatric surgery clocks in at a whopping $26,000 (and carries a higher risk of complications, we add). She noted that future investigation should explore the mechanisms behind VLC diets, but should also consider the broader healthcare implications. We are curious how true to the diets participants were; perhaps in the out-of-pocket setting, there’s some semblance of “I’m paying a lot of money for this treatment, so I should stick to it,” vs. the “oh boy, my doctor wants me to starve myself,” that may emerge in a reimbursed setting. If adherence was strong, what else did the clinic do to support participants – remote coaching? Telemedicine? Daily emails? Providing them with the foods they were to eat with preparation and timing instructions?
- The DiRECT trial is demonstrating promising diabetes remission results, with one-year data (n=298) presented at IDF showing that 46% of people who received a VLC diet achieved diabetes remission. Aligning with Dr. Surampdi’s findings, the results suggest an association with weight loss – of the 24% who achieved 15 kg (~33 lbs) weight loss, 86% saw diabetes remission. Virta recently published one-year results (n=339) from its RCT investigating a low-carb/high-fat ketogenic diet and tech-enabled remote care. Impressively, 60% of patients in the Virta arm (n=262 type 2s) achieved reversal of diabetes accompanied by a 12% weight loss. Of course, a comparison can’t really be made to Dr. Surampdi’s work for either studies, as Dr. Surampdi was investigating reversal of prediabetes, not diabetes. We’re excited to see the body of literature growing for caloric- and carb-restriction in addressing hyperglycemia. The science has been in textbooks for a long time, but the fact that it is translating to clinical outcomes is remarkable, even if just in trials. The right combination of support – in the form of human interaction and making the healthy thing the easy thing to do – seems to work wonders.
Amgen occupied a commanding booth at the entrance to the exhibit hall, with about half of the square footage dedicated to PCSK9 inhibitor Repatha (evolocumab) and its new CV indication (the first of its kind for a PCSK9 product). In December, FDA approved Repatha for the prevention of heart attack, stroke, and coronary revascularization in patients with established CV disease, and Amgen’s messaging played directly into this. For example, the line “help your patients escape high LDL” was overlaid with imagery of a person escaping a crumbling building to represent MI and stroke. While caffeinating at the popular espresso station, attendees could watch videos discussing Repatha’s mechanism of action and safety/efficacy profile. Also interspersed throughout the booth were large displays detailing vignettes of patients appropriate for PCSK9 inhibitor therapy. A side wall alluded to Amgen’s efforts to improve reimbursement for Repatha, and posters implied that “access is improving.” We’re eager to learn more about the company’s negotiations with payers. Is Amgen collaborating with Sanofi/Regeneron to enhance coverage for the PCSK9 class as a whole? We think this would be an especially smart strategy for all three companies now that there are two positive PCSK9 CVOTs on the books (FOURIER for Repatha and ODYSSEY Outcomes for Praluent, which just reported at ACC).
AZ’s booth was a bit smaller than we’ve come to expect, although we could say this for most of the ENDO exhibit hall. Informational panels promoted SGLT-2 Farxiga and Bydureon BCise (the new autoinjector) in equal turn, sandwiching a smaller piece of real estate for Xigduo (dapagliflozin/metformin fixed-dose combination). AZ seems to have ceased advertising standard Bydureon pens, focusing instead on the new BCise autoinjector, FDA-approved last October; this is a smart strategy in our view. Following the presentation of neutral EXSCEL results at EASD 2017, we’re hopeful that this autoinjector can be a big tailwind for Bydureon, bringing the GLP-1 agonist more in line with Lilly’s once-weekly Trulicity, which also comes in a patient-friendly, IDEO-designed autoinjector. Interestingly, Sanofi has already designed an autoinjector for once-weekly GLP-1 agonist efpeglenatide, even though the candidate just entered phase 3. If autoinjectors aren’t the way of the future for GLP-1 agonists, they’re at least becoming a ubiquitous strategy for competing with Novo Nordisk in the GLP-1 market. Our sense is that most providers view the Bydureon molecule (once-weekly exenatide) as less potent/efficacious than liraglutide (Victoza), dulaglutide (Trulicity), or semaglutide (Ozempic), but we do think Bydureon BCise is a more competitive product than the Bydureon dual chamber pen or single-dose reconstitution kits. We’ll continue to keep a close eye on the franchise, now bolstered by BCise.
J&J – Janssen
Janssen hosted a modest-sized booth in the ENDO exhibit hall, with an eye-catching overhead banner advertising SGLT-2 inhibitor Invokana (canagliflozin), fixed-dose combination Invokamet (canagliflozin/metformin), and fixed-dose Invokamet XR (canagliflozin/metformin extended-release). Reps emphasized that Invokana was first-in-class in the US, and a lot of the company’s promotional materials sent the same message: A recurring slideshow announced that 14 million Invokana prescriptions have been written by US healthcare providers to-date, while 16 million prescriptions have been written in the US for Invokana, Invokamet, and Invokamet XR combined. Another poster mentioned 6.5 years of compelling safety data on canagliflozin (this must include phase 3 clinical trials as well as real-world observations, since Invokana was FDA-approved ~five years ago in March 2013). We imagine real-world safety data will be critical for Janssen in assuaging amputation-related concerns, since canagliflozin was associated with a two-fold risk increase for lower limb amputations in CANVAS; the signal remained significant even after controlling for other known risk factors in a post-hoc analysis. Reps didn’t comment on Invokana/amputations or on the EASEL study, a real-world analysis sponsored by J&J which found significant CV benefit to SGLT-2 inhibitors as a class (compared to other glucose-lowering drugs), but which also reported a ~two-fold risk increase for lower limb amputations (and notably, a majority 58% of SGLT-2 users in EASEL were taking Invokana, while 26% were taking Lilly/BI’s Jardiance and 16% were on AZ’s Farxiga).
Lilly’s booth was very small (the company usually stands out in the exhibit hall, but this time, it was hard to spot). That said, reps were enthusiastic in highlighting that Lilly’s diabetes portfolio includes an offering in every major drug class after metformin: DPP-4 inhibitor Tradjenta (linagliptin), SGLT-2 inhibitor Jardiance (empagliflozin), GLP-1 agonist Trulicity (dulaglutide), basal insulin Basaglar (biosimilar glargine), human insulin Humulin, rapid-acting insulin Humalog (insulin lispro), and glucagon. A glass display case showed off KwikPens for the various insulin products. Reps demonstrated how easy it is to use Trulicity, since the pen (designed by IDEO) comes with a hidden needle and doesn’t require too much force to inject. In fact, they shared data that 99% of patients randomized to Trulicity in clinical trials found the product very easy to use. This confirms what we’ve heard in the name of real-world patient feedback as well.
ENDO 2018 marked the first major diabetes conference featuring Merck/Pfizer’s SGLT-2 inhibitor Steglatro (ertugliflozin), which was FDA-approved in late December 2017, launched in 1Q18. We were so excited to see this debut, as we think a four-product SGLT-2 class is a win for patients (expanding choice); Steglatro joins AZ’s Farxiga (dapagliflozin), Lilly/BI’s Jardiance (empagliflozin), and J&J’s Invokana (canagliflozin). Steglatro material covered ~25% of Merck’s booth, alongside the old standbys DPP-4 inhibitor Januvia (sitagliptin) and fixed-dose Janumet (sitagliptin/metformin). To be fair, the Januvia franchise has made Merck the third largest diabetes drug company in the world, after (i) Novo Nordisk and (ii) Lilly. Januvia/Janumet sales consistently capture nearly two-thirds of the ~$10 billion DPP-4 market. In other words, these are two very important products for Merck and for the diabetes field, justifying their dominant presence in the exhibit hall. Of note, FDA approved three ertugliflozin products in December, also including a fixed-dose combination with sitagliptin (Steglujan) and a fixed-dose combination with metformin (Segluromet). We were slightly disappointed to see that Merck was only promoting standalone Steglatro, though we understand that it’s early in the product’s launch cycle and that building franchise recognition is likely the top priority. That said, we do hope and expect the company quickly transitions to promoting Steglujan in particular. Thought leaders are increasingly enthusiastic about the one-two punch of combining SGLT-2 inhibition with an incretin effect, and having this in a single pill is a huge plus for patients. We’d love to see more effort from manufacturers to overcome resistance to fixed-dose (and fixed-ratio) combinations among both providers and payers, given the significant efficacy and convenience they offer. Moreover, we think Merck is well-positioned to make Steglujan a commercial success, given how familiar diabetes care providers are with the sitagliptin component (branded Januvia on its own).
Merck/Pfizer’s pricing strategy could be key to Steglatro franchise success. At our local CVS in San Francisco, Steglatro is listed at $319 for a 30-day supply (at both the 5 mg and 15 mg doses), which corresponds to a list price of ~$10.63/day. Merck/Pfizer previously announced a list price of $8.94/day, but we understand that price can differ across pharmacies. The average price for other SGLT-2 inhibitors (Lilly/BI’s Jardiance, AZ’s Farxiga, and J&J’s Invokana) is $17/day – significantly higher than $8.94/day or even $10.63/day, which could make Steglatro an attractive option for payers and patients. A 30-day supply of Steglujan costs $620 at our local CVS, which translates to ~$20.67/day. Merck/Pfizer previously announced a list price of $17.45/day, but nevertheless, Steglujan is cheaper than its competitors: Lilly/BI’s Glyxambi (empagliflozin/linagliptin) costs ~$22/day while AZ’s Qtern (dapagliflozin/saxagliptin) costs $24/day.
Conspicuously, there was nothing on Steglatro in Pfizer’s booth on the exhibit hall floor. Compared to Merck, we have sensed somewhat less focus on Steglatro from Pfizer, although we’re not sure of all the details on the commercial side of the partnership and we expect to see more in the future. To our understanding, the original agreement stated that Merck and Pfizer would share manufacturing and commercialization responsibilities, with Merck receiving 60% of revenue, and we haven’t heard any updates to this.
Newly-launched GLP-1 agonist Ozempic (semaglutide once-weekly) was hard to miss around the McCormick Place convention center. Advertisements lined the staircases and escalators, a basketball court was set up at the back of the exhibit hall directing people to Novo Nordisk’s booth, and the booth was then largely focused on Ozempic. Reps highlighted semaglutide’s superiority on A1c and body weight when compared head-to-head vs. other diabetes drugs, including DPP-4 sitagliptin, GLP-1 exenatide, and basal insulin glargine; results from these three studies in particular (SUSTAIN 2, 3, and 4) are included on the US product label. Even though SUSTAIN 7 data is not yet in official product information, reps explained that FDA has given the go ahead to discuss the findings with healthcare providers. This was a head-to-head study of Ozempic vs. Lilly’s Trulicity (dulaglutide once-weekly), published at the end of January in Lancet Diabetes & Endocrinology. Semaglutide was associated with superior A1c-lowering vs. dulaglutide (~0.4% treatment difference, p<0.0001), but reps seemed even more excited by the superior weight loss (5 lbs with low-dose dulaglutide and 7 lbs with high-dose dulaglutide vs. 10 lbs with low-dose semaglutide and 14 lbs with high-dose semaglutide, p<0.0001 for both comparisons). Dr. Carol Wysham also spoke to the implications of SUSTAIN 7 during a product theater on Ozempic (read our coverage above).
Reps at Novo Nordisk’s main booth couldn’t discuss Tresiba’s (basal insulin degludec) hypoglycemia benefit. However, Novo Nordisk also sponsored a separate booth on hypoglycemia education, and there we learned that “some very exciting information about hypoglycemia is coming soon.” Our fingers are crossed that this means the FDA will approve Tresiba’s hypo claim (or has already?). Novo Nordisk is expecting regulatory feedback by end of 1Q18, so a matter of weeks. This label update for hypoglycemia benefit, based on SWITCH and DEVOTE, was approved by EMA in 3Q17.
Novo Nordisk’s first-gen GLP-1 agonist Victoza (liraglutide) was less emphasized vs. Ozempic or Tresiba, though bright, bold posters showed the 13% risk reduction for three-point MACE seen with liraglutide vs. placebo in the LEADER trial (p=0.01 for superiority). In a product theater on LEADER, Dr. Cres Miranda implied that Victoza’s CV indication is “stronger” than the CV indication that FDA gave to Lilly/BI’s SGLT-2 Jardiance (empagliflozin). In August 2017, Victoza was approved for reduced risk of major adverse CV events, including MI, stroke, and death, while Jardiance was approved in December 2016 only for the reduction of CV death (both indications apply to type 2s with established CV disease). Dr. Miranda pointed to homogenous results in LEADER, with data on all three components of MACE trending in favor of liraglutide. On the flip side, he emphasized that the data for non-fatal stroke favored placebo over empagliflozin in EMPA-REG OUTCOME (importantly, this did not reach statistical significance, with p=0.16). We’re not sure it’s worth debating which of these CV indications is “better” or “stronger,” since GLP-1s and SGLT-2s are very distinct drugs (injectable vs. oral, different side-effects, different reimbursement based on payer, etc.), and each is going to be preferred by different patients. What’s amazing is that we now have two different therapy classes showing cardioprotection on top of glucose-lowering and weight loss – even three years ago, it was hard to imagine this day – and a more productive conversation will help HCPs determine which patients should be considered for GLP-1 therapy first or SGLT-2 therapy first for diabetes and CV risk reduction.
Rhythm Pharmaceuticals presented details on the company’s Genetic Obesity Project. Launched in 2016, this initiative supports greater genotyping and diagnosis of genetic forms of obesity, particularly pro-opiomelanocortin (POMC) deficiency obesity and leptin receptor (LEPR) deficiency obesity, which have been responsive to Rhythm’s melanocortin 4 receptor (MC4R) agonist setmelanotide, according to a phase 2 study last year. That said, there was no mention of setmelanotide in the booth. Reps offered handouts describing the Genetic Obesity Project and explaining to HCPs how they can enroll their patients in Rhythm’s Genetic Obesity Genotyping Study, GO-ID, to identify individuals with POMC and LEPR deficiency.
With one of the larger diabetes-related booths on the exhibit hall floor, Sanofi promoted next-gen basal insulin Toujeo (glargine U300), Lantus (glargine U100), mealtime insulin Apidra (glulisine), and fixed-ratio combination Soliqua (insulin glargine/lixisenatide). A section on the side was dedicated to PCSK9 inhibitor Praluent (alirocumab). Sanofi put Lantus front and center with the tagline “no substitute needed,” which we interpreted as a defense against patient switching to Lilly/BI’s biosimilar Basaglar. Apidra was accompanied by the tagline “for when patients need more,” and reps emphasized type 2 diabetes prescriptions. The Toujeo section of the booth focused on SoloStar Max – “coming soon” – but reps weren’t able to offer any specific information on this device (presumably a more advanced product relative to current SoloStar prefilled pens), as it’s still under FDA review. We suspect it offers a higher maximum dose; the current SoloStar pen can dose up to 80 units at once. The trademark on this new device was filed about a year ago, in February 2017, but this is the first we’ve seen on the pen up close. There was no mention throughout the booth of the positive ODYSSEY Outcomes trial, which is understandable, as results were announced just a week ago at ACC 2018 and only became available to the company a week before that. Sanofi continues to highlight Praluent’s lipid-lowering efficacy in patients with prior CV events. Lastly, while we’re still underwhelmed by Soliqua’s sales to-date, we note that Novo Nordisk didn’t have any information on Xultophy (insulin degludec/liraglutide) in its exhibit hall booth, besides listing the product name on its circular overhead banner. Given the incredible efficacy of this drug class, we’re glad to see Sanofi’s continued commitment to Soliqua even against commercial obstacles.
The Abbott booth was buzzing with interest and excitement for FreeStyle Libre, yet one representative noted several pediatric endocrinologists’ frustrations regarding a lack of pediatric indication. In fact, some endocrinologists admitted to prescribing it to their young patients off-label. We also spoke with an endocrinologist from Saudi Arabia, who lamented the severe price discrepancies between countries. According to her, the 14-day sensor costs ~$100 and the reader ~$70-$80 (~$200/month in Saudi Arabia vs. “no more than $75 per month on eligible FreeStyle Libre prescriptions at major retail pharmacies” for most US patients). Because of the high price, many insurance companies are unwilling to provide reimbursement. Abbott representatives were understandably unable to share any updates on a possible FDA pediatric indication for FreeStyle Libre. The company currently has two US FreeStyle Libre trials in peds – a post-approval safety study (n=400 type 1s and 2s) posted on Clinicatrials.gov in late February, plus an accuracy and adverse events trial (n=100 type 1s and 2s) initiated in December.
Companion Medical – whose booth was hopping following the December launch of the durable, smart InPen – is still in its limited launch phase, having sold fewer than 500 devices. The InPen is not yet in retail pharmacies (expected in early 2018, per a December email exchange), meaning Companion and mail order pharmacies continue to fulfill the orders. Six sales reps just came on board on March 1st, suggesting that a ramp could be imminent. On a highly encouraging note, 85% of people who have ordered the InPen are covered commercially, with an average co-pay of just $40! And as an indicator of strong demand, one-third of those who are not covered commercially have paid the full $549 out of pocket. And of the people who have some level of coverage, an impressive 96% have elected to pay their coinsurance or copay – wow, talk about a low walkaway rate. The image below showcases the neat packaging and concise, readable “quick start guide” that patients receive in the mail – we love to see excellent, user-centric design applied in healthcare! If patients require more information, they are directed to the website. Regarding the pipeline, priority number one is launching an Android app. The Android app has not yet been filed with FDA for 510(k) clearance, but reps anticipate a late Q2 launch following a hoped-for review of “no longer than 30 days.” The company is also interested in moving beyond NovoLog and Humalog to accommodate “all insulins” – presumably this would include basal, which could really expand InPen’s potential market. InPen is currently labeled for use in patients 12 years and older, but a pediatric indication is not prioritized at the moment. This makes sense, as the small team certainly has its hands full and providers can prescribe for younger patients off-label if they wanted to anyway. Companion hasn’t posted any studies on ClinicalTrials.gov to date, but it sounds like that could change shortly: it plans to embark on a small six-month trial with three-month results ready by AADE, implying a start date in early May or sooner. Details are still being ironed out, but reps told us a main outcome will be time-in-range. If all goes as planned, this could be the first major study to show the impact of connected pens on glycemic outcomes, which would help for provider awareness and perhaps improve already-encouraging reimbursement!
In line with recent meetings, the Dexcom booth featured G5 mobile with its new (larger) touchscreen receiver, and Apple Watch display, as well as the table-top screens to show providers how to navigate the web-based Clarity data management platform. As expected, there was nothing on the yet-to-be-FDA-approved G6, but reps were very excited about the automatic inserter, echoing Dr. Lori Laffel’s comments earlier in the day (see above). As of the 4Q17 call, one of the big discussion points with FDA is whether the G6 sensor will have a required automatic shut-off at 10 days, like Abbott’s FreeStyle Libre – since it will be factory calibrated, we’d guess it will, but it a final decision was not shared as of the February call. Reps were hopeful that the restriction on remote monitoring in the Medicare population will be remedied within the next six months, in line with comments on the 4Q17 call. The hoped CMS will eventually allow use of the smartphone as a medical device, and then presumably require patients to purchase the receiver – this is how it works for privately insured patients and seems like the very best outcome for Dexcom and other “therapeutic” CGMs (including Abbott’s FreeStyle Libre, once FreeStyle LibreLink is launched in the US).
The Glooko booth featured its new touchscreen transmitter available as of March 15, which representatives characterized as more user-friendly thanks to a stronger, faster connection and displayed download progress (see picture below). The transmitter includes Ethernet, cellular, and NFC connectivity, and takes ~15-20 seconds to download data from most cable devices. Glooko is looking to transfer everyone over to this newer model by the end of the year. Notably, pulling insulin dose data from Apple’s HealthKit is on the roadmap, but no timeline was given – this would enable users to view not only compatible pump data but also that from connected pens, such as the InPen. Representatives were also excited about Glooko’s Mobile Insulin Dosing System (MIDS), which the company plans to pilot in 10 sites already using Glooko in the US – reception at the meeting was reportedly very positive, with many providers volunteering their clinics up as guinea pigs. Business model is still being kicked around internally, though we expect it would wind up with some degree of capitation and perhaps (in a perfect world) some outcomes-based payment. Findings from Glooko’s 14-day feasibility study investigating the basal titration app were positive, revealing significant decreases in average blood glucose levels, as well as increased time-in-range and decreased time in hyperglycemia. As one representative put it, “MIDS is going to change the general practitioner’s world.”
Insulet booth representatives noted that several attendees posed questions regarding the new Omnipod Dash PDM. Many were unaware that it will be fully touchscreen and were particularly excited about this update. Representatives noted that, pending FDA clearance, the Omnipod Dash PDM will be launched in a limited market release. Along with the Omnipod, the booth highlighted a Whitepaper written by Argent Global Services surveying 36 CDEs, who reviewed User Guides for Insulet’s Omnipod, Medtronic’s MiniMed 670G and 630G, Tandem’s t:slim, and MDI, reporting the Omnipod to involve the least number of steps required for basal/bolus insulin therapy. Last we heard, Insulet is in its third IDE trial (five-day hotel study) for the Horizon Automated Glucose Control system. Following this study in pediatrics down to age two years, Insulet will either move to a pre-pivotal later this year or do another study before advancing.
A very simple Medtronic booth showed off the MiniMed 670G hybrid closed loop system on the US side and the just-approved Guardian Connect standalone mobile CGM system on the international side. Given the good news on Guardian last week (and the fact that the 670G side was more swamped), we were drawn to the international half. A single sensor was on display with the clamshell transmitter and an iPhone, all on separate translucent stands. Though the sensor won’t launch until May-July in limited fashion followed by an August-October broader launch, 200 people had filled out an “interest form” in the week since it was put online (pre-orders are not an option at this point since reimbursement isn’t totally solidified). Everyone we spoke to at the booth was under the impression that manufacturing is all up to speed and the company will be able to fulfill all orders, in line with Medtronic’s 4Q17 call. Reps were enthusiastic about the prospect of entering the competitive standalone US CGM market and seeing how the system’s differentiating factors – 10-60 minute predictive alerts, arm wear indication, straight to phone communication without any receiver, and Sugar.IQ app – are perceived by patients. One of the biggest, and least surprising, revelations is that Medtronic pump customers have been asking left and right if they could have access to the Sugar.IQ and remote monitoring feature, to which the answer is “no” at this point because the 670G isn’t equipped with Bluetooth and the Guardian Sensor 3 that talks to the 670G does not have Bluetooth. A Bluetooth-enabled pump is under development, though Medtronic has never shared specific timing on when we might see it. (A Roche webinar last May suggested it could enter the US as early as mid-2018, though that would be an incredible surprise to us at this stage in the year and following JPM 2018 timelines.)
The 670G side was certainly abuzz, in many cases with physicians who came by to show off that they were actually wearing the system. We did not hear any updates on user base (still over 20,000), the under-FDA-review 7-13 year-old pediatric indication, international timing (“working to obtain CE mark” as of February), or the 2-6 year-old pediatric study (which should be wrapping up shortly).
We learned that Science37, a company facilitating “site-less” clinical trials, is currently involved in three new diabetes trials. We’re particularly intrigued by the Diabetes Connected Pen Research study being conducted in partnership with Lilly, in which type 1s and 2s with A1c >8% will use an investigational insulin pen device three times/day over the course of 12 weeks. The booth representative shared that this particular study will only involve ~10 participants. The study’s aim is to help identify how missed insulin doses impact blood sugar levels – presumably, this study is using Lilly’s new connected pen? Lilly has certainly moved quickly since its announcement in November to develop both a smart pen with insulin titration and an automated insulin delivery system with its own pump. Clinical trials were supposed to begin by the end of 2017, but to our knowledge, only the AID system is currently in a phase 1 safety/functionality study. Sanofi is also conducting a Diabetes Diversity study with Science37, comparing the outcomes of Soliqua vs Lantus in a diverse type 2 population comprised of African-Americans, Latinos, and Asians with A1c between 7.5%-10%. Given that minorities are historically underrepresented in clinical trials, diabetes being no exception, we’re thrilled to see a study aimed at exploring outcomes in these groups. Lastly, Whole Biome, a microbiome diagnostics and therapeutics company based in San Francisco, is leveraging Science37’s platform for its Diabetes Probiotic Research study open to type 2 adults treated with diet, exercise, or Metformin with or without sulfonylureas. The study aims to investigate the safety and anti-inflammatory effects of a probiotic in the treatment of diabetes. We also learned that Science37’s recently announced collaboration with Novartis has yet to include a diabetes-specific study, but does involve a NASH study. The “virtual clinical trial” concept is picking up steam as companies recognize the cost-savings and easier enrollment. This is an area to watch…
“t:slim X2: The pump that gets updated, not outdated.” This was one of the catchier taglines we came across in the hall this year, emphasizing Tandem’s unique ability to push software upgrades to patients remotely. Management looks forward to being able to do so (for free!) with Basal-IQ (PLGS) this coming summer, following positive results presented at ATTD and FDA submission prior to February’s 4Q17 call . The t:slim X2 with G5 integration is also with Health Canada and under CE mark review, with launches in both geographies expected in 2H18. Initial launch will consist of G5 integration with no automated insulin delivery, followed by an upgrade to PLGS (or perhaps leap-frogging PLGS to the G6 hybrid closed loop system with automatic correction boluses?). Reps said they couldn’t predict the price of the upgrade overseas at this point due to different reimbursement coding structures. With regards to the PLGS system, it is up in the air whether FDA will require a demonstration that safety and efficacy are maintained with the G6. This should be a no-brainer in our view– if you have a car, it shouldn’t matter if your tires are Michelin or Goodyear – but it’s hard to know how risk-averse the Agency will be in this case. On the one hand, the system almost certainly would perform as well or better than the G5-driven system, and Drs. Courtney Lias and Stayce Beck are huge proponents of open, interoperable ecosystems. Of course, moving to what would be the world’s first AID algorithm driven by a factory-calibrated sensor might require additional scrutiny. However, Tandem quickly expects to file the G6/TypeZero hybrid closed loop system (with automatic correction boluses) in a rolling FDA submission later this year (see 4Q17), so redoing the G6 work for PLGS might not be worth the effort.
-- by Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Maeve Serino, Adam Brown, and Kelly Close