June 9-13, 2017; San Diego, CA; Full Report – Insulin Therapy – Draft

Executive Highlights

This document contains our coverage of Insulin Therapy at ADA 2017. Immediately below, we enclose our themes on the category, followed by detailed discussion and commentary. Talk titles highlighted in yellow were among our favorites from ADA 2017; those highlighted in blue are new full report additions from our daily coverage.

For comprehensiveness, we have included some talks in this report that also overlap with our ADA 2017 GLP-1 Agonist and Policy and Reimbursement reports.

Themes

Devote CVOT for Tresiba: Hypoglycemia Benefit, Opportunities for Future Trials

• The big headliner from DEVOTE is the demonstrated superior reduction in severe and nocturnal severe hypoglycemia with Tresiba vs. Lantus in long-term, randomized, double-blinded, large outcomes trial. Tresiba was associated with a very significant 40% relative risk reduction in the overall rate of severe hypoglycemia compared to Lantus (HR=0.60, 95% CI 0.48-0.76, p<0.001 for superiority) and a whopping 53% reduced risk for nocturnal severe hypoglycemia (HR=0.47, 95% CI: 0.31-0.73, p<0.001). Overall, a participant taking Tresiba was 27% less likely to experience one or more episodes of severe hypoglycemia (HR=0.73, 95% CI:0.60-0.89, p<0.001). Very impressively, this reduction in hypoglycemia occurred in the context of non-inferior A1c and superior fasting plasma glucose reductions for Tresiba compared to Lantus. These results further substantiate the hypoglycemia reduction findings in the SWITCH 1 and SWITCH 2 trials - these trials also demonstrated impressive hypoglycemia risk reduction with Tresiba therapy compared to Lantus, though this was demonstrated in a much smaller and shorter blinded crossover study (in which participants served as their own controls). Data from multiple trials confirming risk reduction for hypoglycemia will likely prove convincing and compelling as patients, providers, and even payers consider the “validity” of benefit – we’re curious if we might even see these findings discussed in future iterations of diabetes treatment guidelines.
  
  • That said, there are several limitations to the findings from the current study. For example, only information on severe hypoglycemia was collected and adjudicated, so it’s difficult to assess the impact of Tresiba on “mild-to-moderate” hypoglycemia, though the SWITCH 2 trial showed a 30% reduction in overall symptomatic hypoglycemia. This does not affect “health outcomes” as much as severe hypoglycemia does, but this is still clearly an area of interest to clinicians and patients as it certainly affects adherence, productivity, etc. As we understand it, there was no systematic collection of blood glucose levels or to insulin titration or mandated laboratory fasting blood glucose; as a result, Novo Nordisk says it could not have assessed incidence of blood glucose under 70 mg/dl because it didn’t have the full dataset. It’s unclear what data on this front would show – we certainly hope Tresiba would reduce incidence of blood sugars ≤70 mg/dl, as “less-severe” levels of hypoglycemia still have enormous quality of life and engagement and adherence and productivity implications for patients. We very much hope that inclusion of such data will be considered going forward. Overall, we continue to believe that CGM studies would be enormously helpful in characterizing the benefit of next-generation insulin products especially (but other drugs as well) and we wish that CGM data could have been gathered for this large and long-term study. We recognize, of course, that this study initiated many years ago and CGM accuracy improved significantly with the advent of Dexcom’s G4 approved in 2012, just before the 2013 study start date for DEVOTE and well after the DEVOTE clinical trial design was finalized.
• With the DEVOTE results we can certainly rest assured that Tresiba is at the very least safe from a CV standpoint. Tresiba demonstrated non-inferiority compared to standard of care insulin glargine (Sanofi’s Lantus) for the primary 3-point MACE composite endpoint, as well as each of its individual components (non-fatal MI, non-fatal stroke, and CV death). Many of these hazard ratios trended in the “right direction” – more on this below – though we cannot draw any definitive conclusions about potential cardioprotective benefit. That said, non-inferiority in and of itself is reassuring given Tresiba’s long and complicated regulatory history. As a reminder, the product’s first regulatory submission in the US received a Complete Response Letter (CRL) from the FDA, requesting a CVOT to further investigate a signal for increase expanded MACE risk observed in the phase 3 trials. The FDA’s eventual approval based on firewalled interim data was certainly reassuring on this front and we’re pleased to get our hands on full CVOT data that suggests not even a whiff of increased risk for Tresiba.

Outcomes Beyond A1c: Cardiovascular, Renal, Hypoglycemia, Patient-Reported

• Outcomes beyond A1c were front and center in many clinical trial findings presented at ADA 2017. Each year at the Scientific Sessions, the ADA selects a number of particularly high-profile clinical trial results to highlight in dedicated symposia sessions, rather than in oral presentations. Of the six such dedicated symposia highlighted on the ADA 2017 meeting webpage, five were focused on trials investigating cardiovascular endpoints in diabetes.  In two back-to-back sessions, we saw primary results from two cardiovascular outcomes trials (CVOTs): the CANVAS trial for J&J’s SGLT-2 inhibitor Invokana (canagliflozin) and the DEVOTE trial for Novo Nordisk’s Tresiba (insulin degludec). We also were treated to additional analyses from the LEADER trial of Novo Nordisk’s GLP-1 agonist Victoza (liraglutide, first presented at ADA 2016). Further, we saw results from the ODYSSEY DM program, evaluating the LDL cholesterol reduction efficacy of Sanofi’s PCSK9 inhibitor Praluent (alirocumab) in patients with diabetes). And finally, within the type 1 diabetes realm, the long-awaited results from the JDRF-sponsored REMOVAL trial of metformin in type 1 diabetes – which featured a primary endpoint of carotid intima media thickness (cIMT), a surrogate marker for CV risk – were a source of great interest as well. Beyond these highly-anticipated clinical trial findings, a separate symposium dedicated to discussing the role and future of CVOTs in diabetes care (including commentary from the highly-respected Dr. Lawrence Leiter) was a major highlight of the very first day of ADA – and this symposium, too, featured new data from the SUSTAIN 6 CVOT of Novo Nordisk’s once-weekly GLP-1 agonist semaglutide, delving into the retinopathy and weight loss findings further.
• While CVOTs were designed to demonstrate safety in CV endpoints, the long-term and largescale nature of these trials has yielded a bounty of data on other findings, including renal outcomes and hypoglycemia. The 2017 ADA meeting offered an equal focus on these exciting additional findings from CVOTs. The major headliner of the DEVOTE trial, rather than the CV safety of Tresiba, was the evidence that Tresiba substantially reduces severe hypoglycemia risk by 40% and nocturnal severe hypoglycemia risk by 53% compared to Sanofi’s Lantus (insulin glargine). The LEADER trial has also previously suggested a hypoglycemia benefit for Victoza and two separate sessions at ADA delved into the possible connection between hypoglycemia risk reduction and cardioprotection in the trial (a symposium featuring Dr. Stephen Bain and an oral presentation by Dr. Bernard Zinman) – spoiler alert, hypoglycemia was not a mediating factor of the CV benefit observed in the trial, though it is an important independent risk factor for CV events. We certainly had not expected to learn about amputations, and the fact that we did reinforces further the value of CVOTs.
  
  • Renal endpoints were of major interest both in CVOTs and in shorter trials. One of the other big headliners of the CANVAS data was the impressive renal benefit that corroborated the benefit observed for Jardiance in EMPA-REG OUTCOME – in CANVAS, Invokana therapy was associated with a 40% risk reduction for a composite renal endpoint (renal death, renal replacement therapy, or 40% reduction in eGFR). While the trials and endpoints are not really comparable, the EMPA-REG OUTCOME trial demonstrated a 39% risk reduction for a composite endpoint of progression to macroalbuminuria or doubling of serum creatinine accompanied by eGFR ≤45 ml/min/1.73 m2 or renal replacement therapy or death due to renal disease. Outside of CVOTs, we saw intriguing data from the AWARD-7 trial, which compared Lilly’s GLP-1 agonist Trulicity (dulaglutide) head-to-head with insulin glargine, both on top of insulin lispro therapy. While the primary glycemic endpoint results were comparable, Trulicity was very intriguingly associated with a potential preservation of eGFR throughout the trial. We’re certainly looking forward to the REWIND outcomes trial for Trulicity to further investigate the impact of this therapy on renal outcomes.
• We were also pleased to see an increasing focus on patient-reported outcomes in diabetes clinical trials. The very well-attended symposium highlighting new data from the LEADER trial featured patient-reported outcomes results as well – liraglutide demonstrated superiority in both the European Quality of Life (EQ-5D) index score (p=0.020) and the EQ-5D visual analog scale (VAS) score (p=0.019) and we were extremely pleased to see the inclusion of patient-reported outcome measures in one of the largest trials of a GLP-1 agonist to date. Novo Nordisk certainly appears to be becoming a leader (no pun intended) in this field – also at ADA, the company featured two posters highlighting patient-reported outcome data for Xultophy (insulin degludec/liraglutide) and Tresiba (insulin degludec). We think patient-reported outcomes and other measures beyond A1c are especially crucial to demonstrate the value of next-generation diabetes therapies like these and we’re so glad that Novo Nordisk is already incorporating this into its trials. We would like to see far more standardization on this front and hope that this is coming soon. 

Combination Therapy Data Galore

• Several exciting trials further characterized the clinical benefits of GLP-1 agonist/basal insulin combinations. This was the first ADA meeting with two such fixed-ratio combinations on the market, as both Sanofi’s Soliqua (lixisenatide/insulin glargine) and Novo Nordisk’s Xultophy (liraglutide/insulin degludec) were approved in November 2016 (on the same day, in fact). Full results from DUAL VII made headlines on Saturday, with Xultophy showing superiority to basal-bolus therapy (insulin glargine/insulin aspart) on critical outcomes beyond A1c, from hypoglycemia, to daily insulin dose, to weight loss. Xultophy was associated with an 83% risk reduction for hypoglycemia (p<0.0001), a mean 40-unit daily insulin dose vs. 84 units on a basal-bolus regimen (p<0.001), and a mean ~2 lbs weight loss over 26 weeks vs. ~6 lbs weight gain on basal-bolus treatment (p<0.001). A separate, late-breaking poster highlighted the patient-reported outcomes from DUAL VII as well – we were very pleased to see patient-reported outcomes highlighted in this way! Looking to co-administration (rather than fixed-ratio combinations), AZ shared promising efficacy data from DURATION-7, which compared GLP-1 agonist Bydureon (exenatide once-weekly) vs. placebo added to background insulin therapy. After 28 weeks, Bydureon demonstrated greater A1c-lowering efficacy (-1.0% vs. -0.3% from a baseline 8.5%; p<0.01) as well as greater weight loss efficacy (-3.3 lbs relative to placebo; p<0.001). Notably, 20% more participants randomized to Bydureon vs. placebo achieved the composite endpoint of A1c <7% with no weight gain or severe hypoglycemia.
• Notably, in all these data-heavy presentations on combination therapy, there was a distinct emphasis on outcomes beyond A1c. Most of these diabetes drugs were, or will be approved based on superior A1c-lowering vs. placebo. Once these products are on the market, however, we’d love to see them used optimally, which more often than not involves combination with another, complementary agent as well as advice on diet, exercise, mental health, etc. Patients with diabetes care about so much more than A1c: they want to experience weight loss, they want smaller postprandial glucose excursions, they want lower cholesterol and blood pressure, they want to live without fear of hypoglycemia. Combination therapy is one way to achieve better outcomes across the board, as this collection of data from ADA 2017 seems to show (results from the VERTIS program, DUAL VII, DURATION-7 and -8, etc.). Insulin will be necessary for type 1 patients, and for type 2 patients in later stages of the disease, but co-administration of a GLP-1 agonist could lower daily insulin dose, could bring down hypoglycemia risk, and could at least neutralize weight effects without sacrificing glycemic control. Formulations of two drugs in one – either fixed-ratio injectable combos or fixed-dose oral combos – come with the additional benefit of patient convenience (lower injection/pill burden) and a single co-pay. We were pleased to see so much new data on combination therapy packed into the ADA 2017 agenda, and were happier still to note how scientists, researchers, and thought leaders are promoting combination approaches in terms of outcomes beyond A1c. It has been distressing, however, to see commercial uptake so low – this is the fault of the payers as we understand it (not to be too reductive).
• Repeatedly, thought leaders – including Dr. James Gavin during a Monday-morning symposium dedicated to combination therapy and Drs. Julio Rosenstock and Melanie Davies during an AZ-sponsored symposium – framed combination treatment as a solution to therapeutic inertia in diabetes care. We should listen to these leaders more! It makes perfect sense – if patients and healthcare providers struggle to add or intensify medications, treatment guidelines should encourage earlier use of combination therapy to circumvent the problem entirely. Step one, according to Dr. Gavin, is abolishing the treat-to-fail paradigm in diabetes management, and we couldn’t be happier to see it go – how great would this be! Dr. Gavin explained how a chronic disease as complicated as diabetes, which implicates the ominous octet as well as the microbiome, immune system, and glucose absorption in the stomach/small intestine, cannot possibly be managed by a single agent. He generated a sense of urgency around the need to move up combination therapy in algorithms, and drew a fascinating parallel to hypertension, a therapeutic area in which guidelines recommend initial combination treatment for 75% of patients. Drs. Rosenstock and Davies gave a joint presentation during an AZ-sponsored dinner symposium, highlighting the multifaceted benefits of a product that combines two agents with complementary mechanisms of action. For healthcare providers who see patients coming in with very high A1c at first visit, they suggested that the path forward is clear: Why try medications in a stepwise fashion, when we have combination agents in our therapeutic arsenal with demonstrated efficiency? We’re hearing an increasing number of expert opinions in support of earlier intervention with combination therapy, and all in all, we left San Diego with a lot of optimism on this front. We hope to see continued focus on the advantages of combination treatment at other diabetes conferences and at future ADA Scientific Sessions.

Innovation in Rapid-Acting Insulin

• For the second year in a row, ADA 2017 featured more new, exciting data for rapid-acting insulins than for basal insulins. ADA 2016 was one of the first Scientific Sessions in recent history when this was the case, following several years of spotlight on new basal insulins (especially as next-generation Tresiba and Toujeo were getting approved). In the poster hall this year, Lilly’s rather secretive, internally-developed phase 2 ultra-rapid-acting insulin formulation drew much attention. The candidate LY900014, which contains citrate and trepostinil to speed insulin lispro absorption (and to make the analogue more physiologic), showed a superior PK profile (with faster onset/offset) and smaller postprandial glucose excursions vs. Humalog (insulin lispro) in both type 1 and type 2 diabetes. In the type 1 trial (n=30), the ultra-rapid formulation reduced time to half-maximal drug concentration by 36.5% (p<0.0001) and reduced total glucose excursion over a five-hour meal test by 44% (p<0.0001). In the type 2 trial (n=29), the phase 2 candidate reduced time to half-maximal drug concentration by 23% (p<0.0001) and reduced total glucose excursion over a five-hour meal test by 105% (p<0.0001). LY900014 could enter phase 3 by the end of 2017, and we’ll be eagerly following its clinical progress. Adocia also put up two posters on ultra-rapid BioChaperone Lispro, each sharing data from a 14-day study in type 1 or type 2 diabetes. The phase 3-ready candidate significantly improved postprandial glucose excursions vs. Humalog in both trials. In a surprise move, Lilly terminated its licensing partnership for BioChaperone Lispro in January, and it remains to be seen who will swoop in to carry the candidate forward through clinical (and hopefully commercial) development. Novo Nordisk’s Fiasp (faster-acting insulin aspart) is the first next-generation prandial insulin on the market in Europe, though we still await an FDA decision. We were pleased to see positive one-year efficacy data from the Onset 1 trial, in which Fiasp showed superior A1c-lowering (treatment difference of 0.1%) and one-hour postprandial glucose excursions (treatment difference of ~16 mg/dl) vs. insulin aspart – of course, not to be a broken record, but what we really want to see is time in zone, particularly given how strong the reception has been to Fiasp from patients (including Kelly, who loves the pens that she received). Lastly, we saw two posters from Sanofi on what could potentially become the first biosimilar rapid-acting insulin on the market – Insulin lispro Sanofi. Results from SORELLA 1 and SORELLA 2 (in type 1 and type 2 diabetes patients, respectively) support the phase 3 candidate’s similar PK profile compared to Humalog, and also demonstrate non-inferiority vs. Humalog on A1c.
• Clearly, rapid-acting insulin is a therapy area with substantial room for improvement. To that end, we’re happy to see ongoing innovation. While skeptics have claimed that Fiasp’s benefits over NovoRapid (insulin aspart) and other exiting prandial products are “incremental” rather than truly groundbreaking, we maintain that what we have right now is simply not good enough – so we’ll “more than” take incremental improvements, which for many patients appear to be quite meaningful. The faster onset/offset of Fiasp, Lilly’s phase 2 ultra-rapid candidate, and Adocia’s BioChaperone Lispro means lower risk of hypoglycemia and greater flexibility in bolusing, both of which are key variables in patient quality of life. Biosimilars are also promising in this era of skyrocketing insulin prices, so we look forward to the market potential of Insulin lispro Sanofi. That said, biosimilar basal insulin hasn’t been as cost-saving in the real world as initially anticipated (for many reasons, including unfamiliarity among providers), so our enthusiasm for Insulin lispro Sanofi is somewhat measured – though it’s possible we’ll seeing greater discounting with biosimilars once multiple biosimilar options are available. In either case, this will be a very interesting story to watch as it unfolds – Sanofi’s candidate received a positive CHMP opinion in May, recommending EMA approval, though there has been no word on plans for US submission.

Clinical vs. Commercial Enthusiasm

• As thought leaders sounded off on the latest and greatest in diabetes care at ADA 2017, we couldn’t help but notice some discrepancies between what scientists/researchers are most excited about and what’s being adopted by real-world patients/providers. A glaring example of this is combination therapy. We heard an abundance of enthusiasm on this front from diabetes experts, including Dr. John Buse, who advocated for greater uptake of fixed-dose and fixed-ratio combination products, and Dr. James Gavin, who advocated for earlier intervention with multiple agents (simultaneous as opposed to sequential treatment). On the other hand, patients/providers in the real world show a certain reluctance to combination therapy. In a separate call with our team, Dr. Sam Engel, Associate VP of clinical research in diabetes at Merck, attributed this hesitation to two factors: (i) HCPs feel obligated to up-titrate drugs to maximum dosage before trying something new, even though the majority of an agent’s efficacy will show at low- to mid-range doses. (ii) HCPs fear that it’ll be difficult to parse out the cause of adverse events if they start patients on more than one drug at a time, even though the side-effect profile of an agent is usually well-characterized prior to approval. Moreover, one of the distinct advantages to combo pills or injections is that each component comes at a lower dose, and the combination thus comes with a milder side-effect profile vs. either monotherapy. Guidelines are starting to evolve, and are recommending earlier co-administration of drugs for patients with A1c >9%, but it’ll take dedicated, concerted effort to educate diabetes care providers far-and-wide on the benefits to combination therapy. We see great potential for pharmaceutical companies to play a leading role in this education. Merck, for example, is already positioning its SGLT-2/DPP-4 fixed-dose combination (ertugliflozin/sitagliptin) high on the priority list within the ertugliflozin franchise – oral presentations on VERTIS FACTORIAL and VERTIS SITA2 both emphasized the convenience of a single, oral tablet that combines two agents with complementary mechanisms of action. AZ is also investing strategically in Qtern (dapagliflozin/saxagliptin) and hosted a corporate symposium at this meeting with lots of discussion on combination therapy as a means to circumvent therapeutic inertia. We’d love to see additional patient/provider education efforts outside the context of scientific meetings, from these and other companies with combo products in their diabetes portfolios.

Insulin Pricing

• Insulin pricing continued to be a major focus at the ADA, where – for the third year in a row – a headlining symposium was dedicated to the topic at the Scientific Sessions. The symposium was chaired by Dr. Irl Hirsch (one of the first to sound the alarm bells on the insulin pricing controversy) and featured experts from all perspectives on the topic, including former ADA Chief Medical and Scientific Officer Dr. Robert Ratner, Yale’s Dr. Kasia Lipska, University of Kansas’ Dr. David Robbins, and pharmacist Dr. Alan Carter. Every speaker in the session acknowledged the complexity of the healthcare and drug pricing system and emphasized that no one stakeholder is the sole driver of increased prices. That said, there were varying degrees to which the presenters highlighted the role of pharmacy benefits managers (PBMs) and pointed the finger at pharmaceutical companies. Dr. Ratner, in particular, noted that rebates to PBMs rose substantially from $67 billion in 2013 to a whopping $106 billion in 2015 – leading him to suggest that we should get rid of these “middlemen with no added value increasing expenditures.” We aren’t sure they add no value, but we agree that we’d like to see more transparency. On the other hand, Dr. Lipska briefly acknowledged the role of PBMs in insulin pricing during Q&A, but largely described the role of what she termed “incremental innovation” and new patents from pharmaceutical companies in increasing the price of insulin. In terms of solutions, all speakers emphasized that “it takes a village” to substantially improve the financial burden of insulin for patients. Dr. Robbins in particular highlighted several things that individual healthcare providers, patients, regulatory agencies, pharmaceutical companies, and the FDA can do to improve this issue. For the field as a whole, Dr. Robbins asked all the various stakeholders to stop oversimplifying the issue of drug pricing and to share the blame, rather than point fingers. Further, the formation of partnerships to tackle this problem are crucial. He also emphasized the need to healthy, educated, and fair critics, while recognizing that we are all subject to bias. To that end, he emphasized that “new” is not always better. And finally, he called upon attendees to always advocate for their patients. Dr. Ratner looked at specific ongoing or proposed events and policies and their potential impact on insulin costs, including the arrival of more biosimilar competition, the proliferation of direct-to-consumer discount programs, lawsuits that force pricing transparency as part of discovery, and several proposed policy and legislative changes. All in all, it’s clear that the furor over insulin pricing has not abated, and we’re glad to see continued discussion of concrete solutions to help patients on this front.

ADA Pathway to Stop Diabetes Symposium

• As always, the ADA Pathway to Stop Diabetes symposium offered an inspiring glimpse into the future of diabetes management. Most notably, UNC’s Dr. Zhen Gu, co-founder of Zenomics, a startup recently awarded $5.8 million from MicroPort Scientific Corporation, discussed a variety of smart insulin delivery approaches currently being investigated in his lab. In his view, the main challenges facing the smart insulin field today are (i) achieving a fast response comparable to normal beta cell activity; (ii) avoiding hypoglycemia; (iii) achieving ease of administration; and (iv) ensuring biocompatibility. Overall, beyond Dr. Gu’s star power, the symposium boasted an impressive range of ongoing projects, from Dr. Daniel Ceradini’s work (NYU Langone Medical Center) investigating accelerated diabetic wound closure to Dr. Kathleen Page’s results (USC) on central adiposity in childhood as an early indicator of intrauterine exposure to gestational diabetes and maternal adiposity. Other highlights included Cornell’s Dr. Praveen Sethupathy, who discussed recent findings demonstrating how a high-fat diet contributes to small intestinal morphology and physiology, and UW’s Dr. Joshua Thaler, who remarked on astrocycte and microglial inflammatory signaling as it pertains to obesity susceptibility.

Detailed Discussion and Commentary

Symposium: Cardiovascular Safety of Insulin Degludec vs. Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) Trial Results

Introduction and Trial Design

Steven Marso, MD (University of Missouri, Kansas City, MO)

Dr. Steven Marso set the stage by presenting the trial design for DEVOTE. This randomized, double-blind, treat-to-target trial (n=7,637) enrolled people with type 2 diabetes on at least one diabetes therapy and an A1c >7% or <7% with basal insulin treatment at least 20 units/day. The study population had a high-risk cardiovascular profile; enrollment criteria included cardiovascular or chronic kidney disease for people over the age of 50 and the presence of cardiovascular risk factors for people over the age of 60. This global population included participants from five continents, 20 countries, and 438 trial sites. As is typical for CVOTs, the primary endpoint was time from randomization to first occurrence of a three-point MACE (non-fatal MI, non-fatal stroke, or CV death). Secondary endpoints included rate and incidence of severe hypoglycemia episodes.

Cardiovascular Outcomes

Darren McGuire, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Darren McGuire took the stage to discuss the primary cardiovascular outcomes from DEVOTE. Novo Nordisk’s next-generation basal insulin Tresiba (insulin degludec) met its primary endpoint by demonstrating non-inferiority compared to standard of care insulin glargine (Sanofi’s Lantus) for three-point MACE (non-fatal MI, non-fatal stroke, and CV death). The hazard ratio (HR) point estimate was in the “right direction” at 0.91, but did not achieve statistical significant for superiority (95% CI:0.78-1.06, p<0.001 for non-inferiority, p=0.21 for superiority). Expanded MACE (including hospitalization for unstable angina) was non-inferior as well (HR=0.91, 95% CI:0.80-1.05, p=0.22), and Tresiba additionally demonstrated non-inferiority for each component of the MACE endpoint, with point estimates to the “left of unity” (meaning <1.0) in each case, including non-fatal MI (HR=0.85, 95% CI: 0.68-1.06, p=0.15), non-fatal stroke (HR=0.90, 95% CI: 0.65-1.23, p=0.50), and hospitalization for unstable angina (HR=0.95, 95% CI:0.68-1.31, p=0.74). Similarly, point estimates for all reported mortality endpoints were in the “right direction,” though not statistically significant for superiority, including CV death (HR=0.96, 95% CI: 0.0.76-1.21), all-cause mortality (HR=0.91, 95%CI:0.76-1.11), CV death excluding undetermined cause of death (HR=0.91, 95% CI: 0.69-1.20), and non-CV death (HR=0.84, 95% CI: 0.60- 1.16). 

Source: NEJM

• All in all, we can certainly rest assured that Tresiba is at the very least safe from a CV standpoint (though we cannot draw any definitive conclusions about potential benefit). That said, non-inferiority in and of itself is reassuring given Tresiba’s long and complicated regulatory history. As a reminder, the product’s first regulatory submission in the US received a Complete Response Letter (CRL) from the FDA, requesting a CVOT to further investigate a signal for increase expanded MACE risk observed in the phase 3 trials. The FDA’s eventual approval based on firewalled interim data was certainly reassuring on this front and we’re pleased to get our hands on full CVOT data that suggests not even a whiff of increased risk for Tresiba.
• The robustness of these results are underscored by the fact that the DEVOTE study population was selected to reflect the global population of people with type 2 diabetes. Between the Tresiba (n=3,818) and insulin glargine (n=3,819) arms, participants aged 65 years, an average diabetes duration of 16 years, a BMI of 33.6 kg/m3, and an A1c of 8.4%. Respectively, 86% and 85% of participants had established cardiovascular disease or chronic kidney disease and the remaining 14% and 15% had cardiovascular risk factors.

Glycemic Efficacy and Hypoglycemia

Bernard Zinman, MD (University of Toronto, Canada)

The great Dr. Bernard Zinman presented the very impressive hypoglycemia and glycemic efficacy findings from the DEVOTE trial. In many ways, while these were all secondary endpoints, these findings were the real headliners of the study – indeed, the independent commentary from hypoglycemia expert Dr. Elizabeth Seaquist focused almost entirely on the hypoglycemia results. The results are a big win to be sure: Tresiba was associated with a very significant 40% relative risk reduction in the overall rate of severe hypoglycemia compared to Lantus (HR=0.60, 95% CI 0.48-0.76, p<0.001 for superiority) and a whopping 53% reduced risk for nocturnal severe hypoglycemia (HR=0.47, 95% CI: 0.31-0.73, p<0.001). (Amazing confidence intervals.) Severe hypoglycemia was adjudicated in the study and defined as low blood glucose requiring the assistance of another person – in total, 1,005 events were sent for adjudication and the independent confirmed 752 events as severe hypoglycemia for the analysis. 4.9% of participants in the Tresiba group experienced one or more episodes of severe hypoglycemia, compared to 6.6% of participants in the Lantus group (odds ratio: 0.73; 95% CI: 0.60-0.89; p<0.001 for superiority). Overall, a participant taking Tresiba was 27% less likely to experience one or more episodes of severe hypoglycemia (HR=0.73, 95% CI:0.60-0.89, p<0.001).

Source: NEJM

• Notably, these reductions in hypoglycemia occurred in the context of virtually identical low mean A1cs at the end of the trial and lower fasting plasma glucose. Mean A1c was 7.55% in the Tresiba group and 7.5% in the Lantus group (baseline A1c=8.4%).  The end-of-trial A1c difference between the two arms was estimated at 0.01% (p=0.78). On the other hand, mean fasting plasma glucose (FPG) was 7.2 mg/dl lower in the Tresiba group compared to the Lantus group at the end of the trial (128 mg/dl vs. 136 mg/dl, p<0.001). This was driven by a larger reduction in FPG in the Tresiba group – 40 mg/dl vs. 35 mg/dl. The end-of-trial average basal insulin dose was slightly but significantly higher in the Tresiba group (2 units higher than average in Lantus group, p=0.04).
• Based on a subgroup analysis, it appears that the severe hypoglycemia benefit of Tresiba is more pronounced in those with established CV disease than in those without. There is a very clear 48% rate reduction for severe hypoglycemia in those with established CV disease at baseline (HR=0.52, 95% CI: 0.40-0.66). On the other hand, the point estimate among those with risk factors for CV disease – but no established CV disease – actually trended slightly toward increased risk at 1.24, though the confidence intervals were very wide and crossed the line of unity (95% CI: 0.65-2.38). Very notably, the p-value for interaction was 0.014. We’ve seen some previous analyses (based on the very large TECOS dataset) suggesting that those with a history of a previous CV event are more likely to experience subsequent severe hypoglycemia – suggesting that those with established CV disease at baseline are more vulnerable to hypoglycemia. While of course this subgroup analysis is only exploratory and hypothesis-generating, we’re intrigued by the implication that Tresiba therapy could perhaps offer hypoglycemia benefit to those who are most vulnerable and most at risk. We’ve increasingly heard some suggest that older patients, more frail patients (many of whom have had a previously hypoglycemic event) should be treated to higher A1c targets due to concerns about hypoglycemia. At the same time, some of these same thought leaders advocate for the use of human insulins in patients who are unable to afford newer analogs (including older patients in the Medicare Part D “donut hole”) and argue that insulin analogs – including next-generation analogs like Tresiba – offer only “incremental benefits”. We hope that long-term, compelling data like these findings from DEVOTE can help improve reimbursement and access to these drugs and allow older patients achieve lower A1c targets safely. We also hope that providers and others in the community who are concerned about both hypoglycemia and cost do more to advocate for the inclusion of these next-generation agents on formularies, etc.
  
  • There was no heterogeneity in effect for differences in sex, age, BMI, renal function, diabetes duration, baseline insulin regimen, or region.

• The full results offered a very exciting and impressive – but limited – look into the impact of Tresiba on outcomes beyond A1c. The data released thus far does not mention impact on weight – we hope to see this and other outcomes beyond A1c in future analyses. “Mild-to-moderate” blood glucose-confirmed hypoglycemia was not adjudicated in this trial and it’s unclear if any data on this front was collected – we certainly hope so as “less-severe” levels of hypoglycemia still have enormous quality of life and productivity implications for patients. We continue to believe that CGM studies would be enormously helpful in characterizing the benefit of next-generation insulin products especially (but other drugs as well) and we wish that CGM data could have been gathered for this large and long-term study (though, of course, we recognize that this study initiated many years ago and CGM accuracy has only relatively recently tremendously improved – at least relatively speaking).

Safety

Richard Pratley, MD (Florida Hospital Diabetes Institute, Orlando, FL)

Dr. Richard Pratley reviewed safety outcomes from DEVOTE, which were largely similar between Tresiba- and Lantus-treated participants, indicating that insulin degludec is safe and well-tolerated. There were 1,473 serious adverse events in the Tresiba arm of the trial, affecting 39% of patients vs. 1,517 serious adverse events in the Lantus arm, affecting 40% of patients. Severe adverse events occurred in 25% of both the Tresiba and Lantus groups (945 and 962 events, respectively). Adverse events leading to treatment discontinuation occurred in 5% of the Tresiba group vs. 6% of the Lantus group (200 and 222 events, respectively) – 24 of these events were reported by investigators as probably/possibly related to insulin degludec, while 31 were probably/possibly related to insulin glargine. He called special attention to neoplasms, likely because of age-old concerns that insulin, as a growth factor, heightens cancer risk (though these worries have dissipated with additional studies, including ORIGIN). In DEVOTE, neoplasms were classified by one chairman and two independent oncologists, who sorted events into categories for malignant, benign, and unclassifiable. The hazard ratio for benign neoplasm was 1.37 in favor of Lantus, though this did not reach statistical significance (95% CI: 0.76-2.47). The hazard ratio for malignant neoplasm was 0.94 in favor of Tresiba, but there was no statistically significant signal for risk reduction (95% CI: 0.71-1.24). All in all, there were 45 benign neoplasms observed during the course of the trial (26 in the degludec group and 19 in the glargine group) and 192 malignant neoplasms (93 in the degludec group and 99 in the glargine group). These safety findings underscore Tresiba’s non-inferior profile vs. Lantus, which holds true not only for CV effects, but for all adverse events as well.

• Dr. Pratley listed 16 adverse events occurring at a frequency ≥1% in DEVOTE, but emphasized that they were all equally likely to happen whether a patient was randomized to insulin degludec or insulin glargine. Hypoglycemia reported as an SAE was more common with Tresiba then glargine (see table), but adjudicated events (actually numerically higher in number as they were captured on a special form) were lower. This likely an effect of the reporting structure.  The adjudicated events are the most accurate representation of the difference in hypoglycemia risk. Other adverse events included atrial fibrillation, acute MI, angina pectoris, angina unstable, coronary artery disease, MI, congestive cardiac failure, non-cardiac chest pain, cellulitis, pneumonia, fall, hypoglycemia, ischemic stroke, transient ischemic attack, acute kidney injury, and chronic obstructive pulmonary disease. Frequency on each of these is displayed in the table below.

Conclusion and Clinical Implications

John Buse, MD (University of North Carolina, Chapel Hill, NC)

Dr. John Buse delivered concluding remarks on the DEVOTE full results, putting this trial into context with BEGIN, SWITCH 1 and SWITCH  2, and our knowledge to-date of how hypoglycemia affects CV risk and patient quality of life. One of the most important takeaways, in his view and ours, is that the significant 40% risk reduction for severe hypoglycemia at a similar A1c level and the 53% risk reduction for severe hypoglycemia overnight corroborate Tresiba’s hypoglycemia benefit as reported in BEGIN, SWITCH 1, and SWITCH 2. Novo Nordisk has submitted SWITCH 1 and SWITCH 2 data to the FDA for inclusion on the Tresiba label (decision expected in July), and this label update was recently EMA-approved. Novo Nordisk has also submitted the DEVOTE data to both the FDA and the EMA. Busy patients/providers deserve ready access to information on empirically-grounded benefits, such as lower risk for hypoglycemia, particularly significant hypoglcyemia, a key outcome beyond A1c metric. Fear of hypoglycemia affects patients and providers alike, with 79% of type 1 patients and 58% of type 2 patients who experience a severe episode opting to decrease their insulin dose (leading to suboptimal glycemic control). Similarly, 72% of PCPs and 79% of diabetes care specialists endorse that they would treat patients more aggressively if hypoglycemia was not a concern. Dr. Buse also shared findings from a large, systematic metaanalysis that linked hypoglycemia to a significantly increased risk for all-cause mortality (HR=1.8, 95% CI: 1.5-2.2), CV mortality (HR=2.2, 95% CI: 2.0-2.4), and major CV events (HR=2.3, 95% CI: 1.1-5.0). While the decrease in hypoglycemia seen in DEVOTE wasn’t sufficient to significantly lower CV events and CV death for people on Tresiba vs. Lantus, Dr. Buse emphasized that reducing the severity and frequency of hypoglycemia could have an independent positive impact on a patient’s cardiovascular health. What’s more, helping patients avoid hypoglycemia allows for best practice diabetes management and substantially improves quality of life for people living with this chronic disease. Although cost wasn’t explicitly mentioned during Dr. Buse’s presentation, we know hypoglycemia incurs major avoidable costs on the healthcare system due to hospitalizations, emergency care, productivity loss, and more. We imagine the profound hypoglycemia benefit in DEVOTE could come into play for Tresiba in formulary negotiations – we’d surely love to see a health economic analysis predicting cost-savings. Dr. Buse announced that further analysis from DEVOTE, focused on the associations between glycemic control, glycemic variability, and outcomes, will be presented at EASD 2017 in Lisbon, Portugal. We can’t wait.

Independent Commentary

Elizabeth Seaquist, MD (University of Minnesota, Minneapolis, MN)

University of Minnesota and the International Hypoglycemia Study Group’s Dr. Elizabeth Seaquist provided a thoughtful and balanced independent commentary on the DEVOTE results. She praised the strengths of the trial design, including the randomized, double-blinded, event-driven, and treat-to-target design with well-defined endpoints. She highlighted the large size of the trial as well (n=7,637 at 434 sites on five continents), commenting that the study’s “generalizability to patients with type 2 diabetes is assured.” The very low dropout rate (2%), standardized titration protocol, rigorous adjudication of severe hypoglycemia, and systematic collection of adverse events also improved Dr. Seaquist’s confidence in the findings and conclusions. That said, Dr. Seaquist also pointed out several weaknesses in the data that was collected – one was directed more at the design of the trial while the other two were directed at the limited clinical information provided by the trial. On the first, Dr. Seaquist noted investigators in the trial could modify the titration protocol based on clinical judgement and it’s unclear if these modifications were applied in a standardized way between the two arms of the trial. In terms of the information included in the endpoints, Dr. Seaquist underscored that data on moderate symptomatic hypoglycemia and on hypoglycemic events with blood glucose levels ≤54 mg/dl were not collected. The former is the most common kind of hypoglycemia experienced by patients and the lack of inclusion of this endpoint makes it difficult to assess the impact of Tresiba on more common forms of hypoglycemia. The latter information would be important and useful to have since it’s known that impaired awareness of hypoglycemia is more likely to develop with recurrent episodes of hypoglycemia with blood glucose ≤54 mg/dl. Dr. Seaquist also highlighted additional questions that should be addressed using the DEVOTE data, including (i) Was the reduction in severe hypoglycemia in the Tresiba arm associated with a reduction in healthcare costs?; and (ii) Was the reduction in severe hypoglycemia in the Tresiba arm associated with improved quality of life/sleep and reduced fear of hypoglycemia (this is yet another question that would have been aided by greater collection of hypoglycemia data in our view)? Furthermore, she highlighted several questions that DEVOTE leaves unanswered: (i) Does Tresiba reduce hypoglycemia more relative to Lantus in patients with severe renal impairment?; (ii) What is the relative impact of Tresiba vs. Lantus on severe hypoglycemia in insulin-naïve patients?; and (iii) How do the effects of Tresiba on glycemic control and hypoglycemia in type 2 diabetes compare to Toujeo (U300 insulin glargine)?

Oral Presentations: Landscape of Therapeutic Trials in Type 2 Diabetes

Efficacy and Safety of Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus (BB) Therapy in Patients with Type 2 Diabetes (T2D): DUAL VII Trial

Liana Billings, MD (North Shore University Health System, Skokie, IL)

To numerous rounds of thunderous applause, Dr. Liana Billings (North Shore University Health System, Skokie, IL) presented the impressive results of the DUAL VII trial comparing the safety and efficacy of Novo Nordisk’s Xultophy (insulin degludec/liraglutide) versus traditional basal-bolus therapy in type 2 diabetes. People with type 2 diabetes on insulin glargine (n=506) were randomized in an open-label setting to once-daily Xultophy for 26 weeks or to basal-bolus regimen with insulin glargine and insulin aspart. The trial met its primary endpoint by demonstrating that treatment with Xultophy is non-inferior to basal-bolus therapy with respect to A1c lowering (-1.48% vs. -1.46%, baseline A1c 8.2%) and furthermore demonstrated superiority for a host of secondary outcomes. Compared to basal-bolus therapy, average total daily insulin dose among those taking Xultophy was less than half that of those on basal-bolus therapy (40 vs. 84 units; p<0.001). The end-of-trial body weight difference was also substantially in favor Xultophy (-0.93 kg [2.1 lbs] vs. +2.64 kg [5.8 lbs], p<0.001). Very notably, Xultophy additionally proved superior in terms of hypoglycemia: only 20% of participants in the Xultophy arm experienced blood glucose-confirmed symptomatic or severe hypoglycemia during the study period, versus a whopping 53% of participants in the basal-bolus therapy arm, an extremely impressive 89% risk reduction (HR= 0.11; 95% CI: 0.08-0.17; p<0.0001). Xultophy’s safety profile remained consistent with previous findings; unsurprisingly, nausea was the most frequently-reported adverse event (28 patients in the treatment arm vs. 4 in the basal-bolus arm), but Dr. Billings pointed out that only <3% of the participants in the IDegLira arm experienced nausea at any given time. Indeed, as we understand it, the basal insulin component of these combinations can mitigate the GI side effects typically associated with GLP-1 agonists. During Q&A, the esteemed Dr. Julio Rosenstock deemed this the "most robust, most impressive piece of data I've seen in years." We are equally impressed with these clinical advantages for Xultophy over traditional basal-bolus treatment regimen – especially in terms of the crucial outcome of hypoglycemia risk reduction – and hope these findings help to advance the uptake of the emerging class of GLP-1 agonist/basal insulin co-formulations. We expect to continue to see increasing preference for GLP-1 agonists over prandial insulin as a basal intensification option, and DUAL VII lends strong clinical evidence for this choice. We’ll be back with more on DUAL VII with our take on additional analyses, presented in two posters: one on the cost effectiveness of Xultophy (981-P) and another detailing patient-reported outcomes from DUAL VII (124-LB). While we are happy to see this research, it is our sense that it is extremely challenging for patients to actually gain access to this therapy, despite now years of robust praise.

Efficacy and Safety of Exenatide QW vs. Placebo Added to Insulin Glargine in Uncontrolled Basal-Insulin Treated Type 2 Diabetes: DURATION-7 Trial

Juan Frias, MD (National Research Institute, Los Angeles, CA)

In a packed oral session, Dr. Juan Frias (National Research Institute, Los Angeles, CA) presented the results from the DURATION-7 study, demonstrating clinical glycemic and weight benefits for AZ’s GLP-1 agonist Bydureon (exenatide once-weekly) as an add-on to insulin therapy in people with type 2 diabetes. Participants already on insulin therapy (n=461) were randomized to once-weekly Bydureon or placebo in combination with their existing insulin regimen. With Bydureon, participants experienced a significantly greater mean reduction in A1c (-1.0% vs. -0.3%, baseline A1c=8.5%, p<0.01) after 28 weeks, and 25% more patients in the Bydureon treatment arm achieved an A1c of <7% by the end of the study. Therapeutic intensification with Bydureon furthermore reduced fasting plasma glucose and 2-hour postprandial glucose by an average of 9 mg/dl (p=0.028) and 27 mg/dl (p<0.001) versus placebo, respectively. Notably, participants in the Bydureon arm additionally lost an average of 1.5 kg (3.3 lbs) relative to placebo (p<0.001), and 20% more participants using Bydureon achieved the composite endpoint of an A1c <7% with no weight gain or major hypoglycemia. Participants taking add-on Bydureon also experienced a 2 unit/day decrease in daily insulin requirements, but this did not achieve statistical significance (p=0.07). Adverse events were not significantly different between the treatment and placebo arms (125 vs. 133 events); gastrointestinal complaints were numerically higher in the exenatide group (35 vs. 25 events), as expected with a GLP-1 agonist, and no severe hypoglycemia events occurred in either treatment arm. Together these results underscore the superiority of exenatide once-weekly in combination with basal insulin over basal insulin therapy alone.

Oral Presentations: ADA Presidents Oral Session

Efficacy and Safety of Oral Basal Insulin: Eight-Week Feasibility Study in People with Type 2 Diabetes (T2DM)

Leona Plum-Mörschel, PhD (Profil, Mainz, Germany)

In the very last presentation of ADA 2017, Dr. Leona Plum-Mörschel (Profil, Neuss, Germany) shared phase 2a data for Novo Nordisk’s recently discontinued oral insulin candidate. The oral formulation paired longer-acting insulin analog insulin 338 with an absorption enhancer – Dr. Plum-Mörchel emphasized that oral delivery allows for insulin absorption via the portal vein, which could potentially translate into more physiologic action and less hypoglycemia. The eight-week trial randomized 50 insulin-naïve patients with type 2 diabetes to once daily oral insulin 338 or once daily insulin glargine injection (Sanofi’s Lantus). The trial was conducted in a double-blind, double-dummy manner – participants either took active oral insulin 338 and injectable placebo or injectable insulin glargine and oral placebo. All other diabetes medications except metformin and DPP-4 inhibitors were discontinued during the two-week washout period. At baseline, participants had a mean A1c of 8.1% in the oral insulin 338 arm and 8.2% in the insulin glargine arm. Insulin dose over the eight-week period rose comparably in both treatment groups and the end-of-trial treatment ratio was 347 nmol of oral insulin 338 to one unit of insulin glargine. Oral insulin 338 was found to be non-inferior to insulin glargine on a number of glycemic endpoints, including the primary endpoint of fasting plasma glucose (5.2 mg/dl higher with oral insulin, p=0.46), 10-point plasma glucose profile, A1c (0.3% higher with oral insulin, p=0.077), fructosamine (9.6 umol/l higher with oral insulin, p=0.37), and fasting C-peptide (0.02 nmol/l lower with oral insulin, =0.68). Notably, the only statistically significant finding was an increase in variability in fasting plasma glucose profiles over time with oral insulin 338 compared to insulin glargine (p=0.0060). That said, despite the increase in variability, fewer hypoglycemic events occurred in the oral insulin 338 arm (seven events in six patients) than in the insulin glargine arm (11 events in six patients) – fortunately, there were no reported episodes of severe hypoglycemia. The rate of other adverse events in the trial were similar across the two arms of the study, with no treatment-emergent serious adverse events, no severe adverse events, and no medical events of special interest. Further, Dr. Plum-Mörschel shared that there were no clinically significant findings in vital signs, ECG, physical examination (including fundoscopy), or safety laboratory data. Overall, the trial demonstrates the feasibility of glycemic management via oral insulin delivery, though it’s not clear that this candidate offers any substantial benefit over current insulin formulations, other than the convenience of oral dosing. That said, dose titration for oral insulin remains a complex prospect and, given the increasing popularity of non-insulin alternatives for type 2 diabetes (including GLP-1 agonists – which will soon be offered in oral and implantable formulations – and SGLT-2 inhibitors) that may delay the need for insulin initiation altogether. Given the increasingly high bar for new diabetes drugs, Novo Nordisk’s robust clinical development pipeline, and the company’s recent shift in its R&D priorities to focus on truly disruptive diabetes therapies and diabetes-adjacent indications, we’re not surprised by the decision not to pursue this candidate further given this data.

Oral Presentations: Hospital-Based Care and Diabetes – Adherence to Diabetic Care Strategies

How Much Does Adherence to Insulin Influence Glycemic Control?

Julie Lauffenburger, PhD (Harvard University, Boston, MA)

Dr. Julie Lauffenburger presented results from an analysis of insurance claims data designed to identify independent predictors of good glycemic control and quantify the extent of each factor’s predictive value. The analysis involved 690 patients with good glycemic control (A1c <8%) and 733 patients with poor control (A1c >8%). Investigators found that independent predictors of good control included age, mail order use, rapid-acting insulin use, insulin lispro use, insulin persistence, number of fills for insulin testing supplies, endocrinologist visits, and number of different pharmacies used. Of these factors, those considered potentially modifiable yielded a Net Reclassification Index (NRI) value of 0.38, meaning that modifying those variables could move 38% of the patients in the poor control group to the good control group or vice versa. Individual factors with the highest NRI were insulin therapy (0.28), lifestyle (21%), and provider and pharmacy (30%). A chi square analysis found that 76% of the variation in glycemic control was attributable to modifiable factors. Individual factors that explained most of the variation were provider and pharmacy (35%), insulin therapy (31%), lifestyle (12%), and insulin persistence (4%). Dr. Lauffenburger concluded that factors related to insulin therapy seem to be the most influential in predicting glycemic control, emphasizing that persistence is a fairly strong factor in itself. This underscores the need to empower patients to be more engaged in their medication regimen and other aspects to diabetes management, given that persistence itself could move so many individuals into the favorable category of good glycemic control (which, importantly, could translate to better health outcomes overall).

Questions and Answers

Q: I would think defining adherence to insulin would be more challenging than adherence to a once-daily pill. The number of units prescribed is not necessarily what the person takes or what the physician instructs them to take. What was your definition of insulin persistence?

A: The challenge with insulin in particular is that it’s about the days’ supply. When you calculate medication adherence or persistence, that’s what the pharmacist inputs. The persistence measure we used was published in Endocrine Practice. We looked at the first time they filled the prescription and the second time and divided patients into percentiles based on the time between the first and second fill. If the time between the first and second fill was longer than the 90th percentile, they were labeled non-adherent. If they didn’t fill it for 30-60 days after we thought they should, they were non-adherent.

Q: I’m fascinated by the results showing that payment for use of testing supplies was related. A lot of that is a function of the health insurer. Was there any variability that this insurer had in co-payments? Was it a large enough variability to examine?

A: The co-pays were fairly right-skewed. There was a decent degree of variation, largely associated with which insulin products patients were receiving.

Posters

A Novel Formulation of Insulin Lispro Containing Citrate and Treprostinil Shows Faster Absorption and Improved Postprandial Glucose Excursions vs. Humalog in Patients with T1DM (959P)

C Kazda, J Leohr, R Liu, S Reddy, MA Dellva, ST Lim, MT Loh, MP Knadler, T Hardy, L Plum-Moerschel

Lilly presented new data on its novel ultra-rapid insulin formulation LY900014, demonstrating that the candidate shows faster absorption and improved postprandial glucose excursions vs. Lilly’s Humalog (insulin lispro) in type 1 diabetes. Type 1 diabetes patients (n=30) were randomized to either LY900014 or Humalog. Results demonstrated that the LY900014 group had accelerated early insulin lispro absorption compared to the Humalog group: LY900014 reduced the time to early half-maximal drug concentration by 36.5% (p<0.0001) and the insulin lispro area under the concentration curve vs. time from 0 to 30 min post dose increased by 123% (p<0.0001) compared to Humalog. Additionally, the total glucose excursion over the 5-hour test-meal was significantly reduced by 44% for LY900014 vs. Humalog. We will have more information to follow on how long the insulin “lasts” etc. Regarding tolerability and adverse events, the type 1 patient population demonstrated no differences in local tolerability and the number or severity of hypoglycemic events. As a reminder, LY900014 is Lilly’s internally-developed candidate that could begin phase 3 trials by the end of 2017. This ultra-rapid insulin has recently received more attention after the disappointing termination of Lilly’s partnership with Adocia on the phase 3-ready ultra-rapid insulin BioChaperone Lispro (see its data from ADA 2016). For more on Lilly’s discussion around the new candidate, please see our 4Q16 update.

• LY900014’s formulation contains locally-acting excipients, citrate and trepostinil, to help accelerate insulin lispro absorption with the goal of providing ultra-rapid prandial insulin. Specifically, citrate increases vascular permeability at the injection site and treprostinil accelerates insulin lispro absorption by local vasodilation with no measurable systemic exposure. With this formulation, the goal is that LY900014 will more closely mimic physiologic prandial insulin secretion, improving postprandial glucose control and allowing greater flexibility in insulin administration timing.

Superior Glycemic Control with a Glucose-Responsive Insulin (GRI) (961P)

M Moore, D Kelley, M Smith, P Zafian, T Ye, S Lin, N Kaarsholm, R Nargund, M Van Heek, B Farmer, P Williams, A Cherrington

Findings from a preclinical study of Merck’s glucose-responsive insulin candidate MK-2640 (a lectin-bound insulin analog – it’s unclear if this is the same phase 1 MK-2640 GRI candidate) were presented in a poster. The study investigated the insulin in a dog model (n=8) vs. canine or human insulin, with each animal receiving both treatments in random order. Infusion of the insulin was adjusted in a low-glycemic condition to match canine/human insulin levels to bioequivalence. In a condition of hyperglycemia, the liver then reduced extraction of the insulin from the blood, allowing more of the glucose-responsive insulin to remain in active circulation. Greater plasma levels of the drug were correlated with increased hepatic glucose uptake (p<0.05 vs. control), non-hepatic glucose uptake (p<0.05 vs. control), and overall glucose disappearance (p<0.001 vs. control). Tracer-determined glucose levels declined in the presence of the insulin analog (p<0.05 vs. control). These results – which are extremely early-stage – support the potential of a lectin-bound molecule for smart insulin delivery, and the poster concludes that this is an approach to glucose-responsive insulin worth further consideration. That said, this very early-stage study was limited in that there’s no indication (yet) of how sensitive this lectin-bound analog will be in humans or whether it will prove clinical utility. Glucose-responsive insulin is one of the most challenging areas of diabetes research, given insulin’s narrow therapeutic range, the complexity of insulin dosing/titration, and the safety concerns that stem from releasing insulin into the bloodstream but expecting it to turn “on” and “off” automatically. We’re not giving up hope, and we’re so glad that Merck’s continued research interest in this area. Merck also has a glucose-responsive insulin candidate – MK-2640 – that finally completed its phase 1 trial in August 2016 (per its ClinicalTrials.gov page) after being delayed several times.   Whether or not the company decides to move forward with this preclinical candidate or with a phase 2 program for MK-2640 (and at this point, we’re not sure, at least in the near-term), these results will be incredibly informative to the community of researchers working on smart insulin. This includes Dr. Zhen Gu’s lab at the University of North Carolina (which recently published positive preclinical results on a smart insulin patch and was highlighted today during the ADA Pathways symposium) and many other preclinical candidates outlined in our insulin competitive landscape. Merck’s MK-2640 remains the most advanced pipeline candidate in this area, and we would of course love to see ongoing clinical development, but we’ll have to wait-and-see. Dr. Gu continues to offer big inspiration to us!

A Novel Formulation of Insulin Lispro Containing Citrate and Treprostinil Shows Significantly Faster Absorption and an Improvement in Postprandial Glucose Excursions vs. Humalog in Patients with T2DM (978P)

C Kapitza, J Leohr, R Lu, S Reddy, MA Dellva, M Matzopoulos, MP Knadler, MT Loh, T Hardy, C Kazda

In this poster, Lilly shared new data on its novel ultra-rapid insulin formulation LY900014, demonstrating that the candidate shows faster absorption and improved postprandial glucose excursions vs. Lilly’s Humalog (insulin lispro) in type 2 diabetes. Patients (n=29) were similarly randomized to either LY900014 or Humalog. LY900014 reduced the time to early half-maximal drug concentration by 23% (p<0.0001) and increased the insulin lispro area under the concentration curve vs. time from 0 to 30 min by 117% (p<0.0001) compared to Humalog. As for postprandial glucose excursions, the total excursion over the 5-hour test-meal was reduced by 105% (p<0.0001) for LY900014 vs. Humalog. Regarding tolerability and adverse events, the type 2 patient population demonstrated no differences in local tolerability and the number or severity of hypoglycemic events. As a reminder, LY900014 is Lilly’s internally-developed candidate that could begin phase 3 trials by the end of 2017. This ultra-rapid insulin has recently received more attention after the disappointing termination of Lilly’s partnership with Adocia on the phase 3-ready ultra-rapid insulin BioChaperone Lispro (see its data from ADA 2016). For more on Lilly’s discussion around the new candidate, please see our 4Q16 update.

Older Adults with Type 2 Diabetes (T2D) Experience Less Hypoglycemia when Switching to Insulin Glargine 300 U/mL (Glargine-300) vs. Other Basal Insulins (DELIVER 3 Study) (986P)

FL Zhou, F Ye, V Gupta, R Gupta, J Sung, P Berhanu, L Blonde

Sanofi presented data from the DELIVER 3 study demonstrating that switching to Toujeo (insulin glargine U300) vs. other basal insulins was associated with significantly less hypoglycemia and similar glycemic control among older patients (≥65 years) with type 2 diabetes. DELIVER 3 was a retrospective cohort analysis of de-identified patient-level EMR data in the US. The analysis included patients who switched to either Toujeo (n=468) or another basal insulin (n=1,142) between March 1, 2015 and March 31, 2016. Mean age was 71.8 years in the Toujeo group and 73.1 years in the comparator group; baseline A1c was 8.5% and 8.3% in the respective groups (both statistically significant differences). After six months, both cohorts achieved similar A1c reductions and a similar percentage of patients with A1c <7% and <8%. However, patients in the Toujeo cohort were 50% less likely to experience hypoglycemia during the follow-up period compared to the comparator cohort after adjustment for confounders (p=0.0002). The authors highlighted the fact that these results reflect Toujeo’s performance in real clinical practice, without the constraints of a randomized controlled trial. They also identified a number of limitations: the potential for selection bias, underreporting of hypoglycemia, coding errors, lack of adherence, and a lack of data on insulin dose, reasons for switching, duration of disease, and discontinuation rates. With these substantial limitations as caveats (the lack of dosing information seems particularly problematic), these results should help Sanofi build its case that Toujeo offers clinically relevant benefits over other basal insulins.

Patient-Reported Outcomes (PROs) in Insulin Degludec/Liraglutide (IDegLira) vs. Basal-Bolus (BB) Therapy in Patients (Pts) with Type 2 Diabetes (T2D): DUAL VII Trial (124-LB)

LK Billings, A Doshi, D Gouet, A Oviedo, HW Rodbard, N Tentolouris, AK Busk, A Basse, and E Jodar

This poster overviewed patient-reported outcomes (PROs) from the DUAL VII trial, demonstrating that treatment with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) resulted in greater improvements related to diabetes management, treatment burden, and adherence than treatment with basal-bolus therapy. People with type 2 diabetes on insulin glargine (n=506) were randomized in an open-label setting to once-daily Xultophy for 26 weeks or to basal-bolus regimen with insulin glargine and insulin aspart. In assessing PROs, the Treatment-Related Impact Measure for Diabetes (TRIM-D) questionnaire, which consists of 28 questions across five domains, showed significant moderate significant improvements for patients on Xultophy versus basal bolus therapy in all domains, including diabetes management, treatment burden, compliance, daily life, and psychological health. After 26 weeks, total score change from baseline was +9.2 for the Xultophy group, versus +3.5 for basal bolus therapy (p<0.0001). Furthermore, the Short Form-36 version 2 questionnaire (SF-36), which consists of 36 items across eight domains, showed small improvements in all domains with Xultophy, with a significant benefit for Xultophy over basal bolus therapy in the mental health component of the survey (+2.5 vs. -0.2, p=0.0074). Additionally, after 26 treatment weeks, 85% of participants in the Xultophy arm were “very” or “extremely” willing to continue their treatment, versus only 68% of participants in the basal-bolus therapy arm. These results demonstrate that in addition to the glycemic and weight loss benefits for Xultophy demonstrated in the main DUAL VII results, this drug may have additional benefits for perception of outcomes by the patient – a major win in our eyes in terms of outcomes beyond A1c. We imagine that this improved perception of treatment outcomes with Xultophy could be influenced by better glycemic control, fewer injections, weight loss, or lower rates of hypoglycemia. However, it should be noted that this was an open-label trial, and these results could be influenced as such.

Comparable Glycemic Control, Greater Weight Loss, and Lower Hypoglycemia with Once Weekly Dulaglutide Versus Insulin Glargine, Both COmbined with Lispro, in Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7) (138-LB)

KR Tuttle, MC Lakshmanan, JL Gross, B Rayner, RS Busch, B Woodward, AG Zimmermann, FT Botros

The 52-week AWARD-7 trial evaluated GLP-1 agonist dulaglutide (Lilly’s Trulicity) in a head-to-head comparison with insulin glargine (Sanofi’s Lantus), both in combination with insulin lispro (Lilly’s Humalog) in patients with chronic kidney disease. Primary endpoint results of A1c change at 26 weeks were reported in this poster, as were safety findings. The trial randomized 576 patients with eGFR between 15 and 60 ml/min/1.73m² to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. AWARD-7 met its primary endpoint by demonstrating non-inferiority to insulin glargine in terms of A1c reduction: mean A1c reduction was 1.19% in the dulaglutide 1.5 mg group, 1.12% in the dulaglutide 0.75 mg group, and 1.13% in the insulin glargine group (baseline A1c=8.6%, p<0.001 for all comparisons to baseline). This similarity in A1c occurred in the context of increases in fasting plasma glucose (FPG) in the dulaglutide groups (+23.1 mg/dl in the dulaglutide 1.5 mg group and +17.7 mg/dl in the dulaglutide 0.75 mg group), compared to a reduction in FPG in the insulin glargine group (-19.1 mg/dl; p<0.001 compared to both dulaglutide arms). This suggests that dulaglutide has a greater effect on postprandial glucose lowering, as is expected for a GLP-1 agonist.  Similar proportions of participants achieved A1c<8% and A1c<7% in each group.

• Very notably, dulaglutide was associated with substantial weight loss and hypoglycemia benefits compared to insulin glargine. The 0.75 mg and 1.5 mg doses of dulaglutide produced mean body weight reductions of ~2 kg (~4.4 lbs) and ~3 kg (~6.6 lbs), respectively, compared to a weight increase of ~1 kg (2.2 lbs) in the insulin glargine group. Compared to insulin glargine, dulaglutide was also associated with a significantly lower rate of total hypoglycemia (p<0.001), documented symptomatic hypoglycemia (p<0.001), and nocturnal hypoglycemia (p<0.001). In addition, the higher 1.5 mg dose was associated with a lower rate of severe hypoglycemia as well (p<0.05). Participants did not wear CGM during this study, so it’s possible that these results underestimate the rate of documented symptomatic and nocturnal hypoglycemia – we would love to see greater use of CGM in these types of studies to better characterize potential hypoglycemia benefits – particularly given how easy CGM use in trials has become! Notably, these improvements in hypoglycemia occurred in the context of slightly greater increases in insulin lispro dose in the dulaglutide group compared to the insulin glargine group. From a baseline insulin lispro dose of about 0.25 U/kg, lispro dose increased to ~0.4 U/kg in the glargine group, while lispro dose increased to ~0.45 U/kg in the dulaglutide 1.5 mg group and to ~0.5 U/kg in the dulaglutide 0.75 mg group.
• Adverse events were as expected, with a higher rate of nausea, vomiting, and diarrhea in the dulaglutide-treated group. All other adverse event rates were comparable between the two groups.
• Even more intriguingly, secondary endpoint data demonstrating a potential renal-protective effect of dulaglutide on eGFR compared to insulin glargine was presented in a separate late-breaking poster (142-LB). See below for our coverage.

Dulaglutide versus Glargine, Both Combined with Lispro, Mitigated eGFR Decline in People with Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7) (142-LB)

KR Tuttle, MC Lakshmanan, JL Gross, B Rayner, RS Busch, AG Zimmermann, A Haupt, DB Woodward, FT Botros

This poster detailed results for a pre-specified secondary endpoint of impact on eGFR and albuminuria in the AWARD-7 trial. The AWARD-7 study team, led by Dr. Katherine Tuttle, evaluated the effect of dulaglutide (Lilly’s Trulicity) vs. insulin glargine (Sanofi’s Lantus), both in combination with insulin lispro (Lilly’s Humalog), in patients with type 2 diabetes and moderate to severe chronic kidney disease. The 52-week trial randomized 576 patients with eGFR between 15 and 60 ml/min/1.73m² to either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or titrated insulin glargine. Very impressively, dulaglutide treatment appeared to mitigate further eGFR decline throughout the trial. While eGFR declined by an average of 1.9 in the insulin glargine group at 26 weeks, eGFR only declined by 0.1 and 0.4 in the 1.5 mg and 0.75 mg groups, respectively. Baseline eGFR was around 38 in all three treatment arms. The treatment difference in eGFR decline for the 1.5 mg and 0.75 mg groups was thus, respectively, 1.8 and 1.6 (p<0.05 for both comparisons to insulin glargine). By percent change from baseline, those in the insulin glargine group experienced a 7.7% decline in eGFR, while those in the dulaglutide 1.5 mg arm experienced a 0.8% decline in eGFR (p<0.05 vs. insulin glargine), and those in the dulaglutide 0.75 mg arm experienced a 3.3% decline in eGFR (p<0.05 vs. insulin glargine). Furthermore, the percent decline in eGFR in both of the dulaglutide arms was not statistically significant compared to baseline, while the decline in the insulin glargine arm was highly statistically significant (p<0.001). These differences in eGFR were driven by an apparent protective effect in patients with macroalbuminuria at baseline. On the other hand, UACR was reduced in all three treatment arms and the between-treatment difference was non-significant for this endpoint. From a safety standpoint, there were no significant differences between dulaglutide and insulin glargine for renal events of interest. Overall, these results – while only hypothesis-generating – are certainly extremely intriguing. At the very least, we can largely rest assured that dulaglutide does not increase renal risk compared to insulin glargine. Further, there appears to be a suggestion of renal benefit that we would love to see characterized further when the REWIND trial for Trulicity reports in July 2018. The LEADER and SUSTAIN 6 trials for Novo Nordisk’s GLP-1 agonists Victoza (liraglutide) and semaglutide both demonstrated a potential beneficial effect for these agents on hard renal endpoints and it would be amazing to see that corroborated in REWIND.

• Primary endpoint and safety results were presented in poster 138-LB (see above).

Qualitative Assessment of the Imapct of Insulin Degludec on Quality of Life in Patients with Type 2 Diabetes (823-P)

W Polonsky, S Lanar, N Knoble, J Weatherall, J Hakan-Bloch, E Constam, A Philis-Tsimikas, and A Marrel

This poster presented results from a prospective, non-interventional, qualitative research study demonstrating substantial quality of life (QoL) benefits following initiation of insulin degludec therapy in patients with type 2 diabetes. Twenty adults with type 2 diabetes from two sites in the US and one in Switzerland who had switched to insulin degludec from another insulin were interviewed about their experience after at least three months of use. The mean age for these patients was 66 and the mean most recent A1c was 7.8%. After qualitative analysis, four major effects of insulin degludec were identified: (i) improved physical wellbeing; (ii) increased sense of adaptability and freedom; (iii) more security, especially regarding hypoglycemia; and (4) reduced sense of burden from diabetes. Interestingly, American patients placed more weight on medical outcomes such as A1c as markers of success, whereas Swiss patients more frequently identified overall quality of life measures. Limitations of this study include the small and homogenous study population, which was mostly white, unemployed or retired, and more than 60 years old. This study may help to drive future qualitative and quantitative research to identify unique QoL benefits of diabetes medications. We feel that the benefits of next-generation therapies like Tresiba are most acutely observed on outcomes beyond A1c, such as patient-reported quality of life outcomes, and we’re glad to see Novo Nordisk take a leadership role in formally characterizing these benefits.

Ultra-Rapid Biochaperone Lispro Improves Post-Prandial Glucose Excursions Versus Insulin Lispro in a 14-day Treatment Study in Subjects with Type 1 Diabetes (964-P)

G Andersen, G Meiffren, D Lamers, A Ranson, B Alluis, M Gaudier, O Soula, T Heise, and S Bruce

Adocia’s ultra-rapid BioChaperone Lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose excursions compared with insulin lispro (Lilly’s Humalog) in people with type 1 diabetes. The randomized, monocentric, double-blind, comparator-controlled 14-day phase 1 crossover trial enrolled 36 participants (mean age 45 ± 12 years) with type 1 diabetes. Patients were randomized to receive bolus doses of either BCLIS or insulin lispro for 14 days. While in the inpatient setting for days 1-3 and 14 of the study, patients received the insulin they had been assigned to 15 minutes before, immediately before, or 15 minutes after an individualized mixed-meal, with blood samples and lispro concentrations subsequently measured. Patients continued the insulin regimens to which they had been randomized in the outpatient setting on days 4-13, and additionally self-measured plasma glucose (SMPG) levels four times daily.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS dosing additionally resulted in significantly lower post-meal glycemic excursions as compared to insulin lispro  if the insulin was dosed immediately before the meal’s start or 15 minutes thereafter. Notably, postprandial glycemic excursion profiles were similar between BCLIS injected fifteen minutes after a meal’s start and insulin lispro injected immediately before a meal’s start. Mean outpatient SMPG values didn’t differ significantly BCLIS and insulin lispro. Safety profiles were also similar between the treatment groups.

Real-World Use of IDegLira Significantly Improves Glycemic Control in Patients with T2D (988-P)

H Price, B Schultes, R Prager, T Phan, B Thorsted, M Bluher

Drawing on dataset from the multi-center, retrospective EXTRA study, this poster demonstrated improvements in glycemic control, body weight, and hypoglycemia risk associated with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) in a real-world setting. The EXTRA study included data (from EMRs) for 611 adult patients with type 2 diabetes in five European countries. All participant had been taking Xultophy for at least six months at time of analysis. Meeting its primary endpoint, the study found a mean A1c reduction of 0.9% six months after initiation of Xultophy (p<0.0001); similar results were observed at 3 and 12 months. A1c reductions were observed regardless of baseline therapy at time of initiation (e.g. basal insulin, oral antidiabetic drugs, GLP-1 agonists, etc.) Fasting plasma glucose also decreased by an average of 45.8 mg/dl at six months (p<0.0001). This reduction was sustained at 12 months as well (mean reduction of 44.5 mg/dl, p<0.05). Adding to these benefits, investigators also found a 0.7 kg (1.5 lbs) reduction in body weight at 6 months (p<0.05), though this varied depending on pre-study treatment regimens (weight expectedly increased with Xultophy therapy in those on just GLP-1 agonists and oral agents at baseline, for instance). The MDI at baseline subgroup was the only one that experienced significant weight loss following Xultophy initiation in this subgroup analysis – of course, subgroup analyses are notorious finicky with small sample sizes, so it’s quite likely that the weight benefits of Xultophy apply to the other subgroups as well. On the safety side of things, hypoglycemia events per patient-year decreased from 0.28 to 0.06 after Xultophy initiation — a very impressive 81% reduction (p=0.0001). Ultimately, this study shows that Xultophy is effective at improving glycemic control and reducing risk of hypoglycemia in routine clinical practice, outside of an interventional study.

Ultra-Rapid Biochaperone Lispro Improves Postprandial Blood Glucose Control versus Humalog in a 14-day Treatment Study in Subjects with Type 2 Diabetes (994-P)

T. Heise, G. Meiffren, D. Lamers, B. Kronshage, A. Ranson, B. Alluis, M. Gaudier, E. Anastassiadis, O. Soula, S. Bruce

Adocia’s ultra-rapid BioChaperone lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose control versus insulin lispro (Lilly’s Humalog) in people with type 2 diabetes. The randomized, monocentric, double-blind, comparator controlled 14-day crossover phase 1 trial enrolled 51 participants (mean age 62 ± 9 years) with type 2 diabetes. Participants were randomized to receive either individualized BCLIS or insulin lispro bolus doses with meals. On inpatient days 1-2 and 13-14, patients received the insulin to which they had been randomized with an individualized mixed-meal, after which blood samples and lispro concentrations were assessed. In the outpatient setting on days 3-12, patients continued their assigned insulin regimens and measured their plasma glucose (SMPG) levels.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS additionally resulted in significant reductions in post-prandial glucose exposure for up to three hours after dosing as compared with insulin lispro.  Differences in glycemic excursions between treatments were most pronounced on days 13-14. Mean outpatient SMPG values didn’t differ significantly between BCLIS and insulin lispro, but notably, similar values were achieved with 10% lower BCLIS doses. Treatment with BCLIS was safe and well tolerated. 

SORELLA-1: Similar One-Year Efficacy and Safety in People with T1DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100) (1003P)

S Garg, K Wernicke-Panten, M Rojeski, S Pierre, K Jedynasty

This poster featured one year data from the phase 3 SORELLA 1 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 1 diabetes, reinforcing the 26-week findings presented at ADA 2016. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 507 people with type 1 diabetes were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 52 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of 0.06% (95% CI: -0.084% to 0.197%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all categories of hypoglycemia: severe (13.5% vs. 13.4%), documented symptomatic <70 mg/dl (87.3% vs. 89.8%), and asymptomatic <70 mg/dl (97.2% vs. 97.6%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (62.5% vs. 63.1% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 54.4% of SAR-treated and 55.5% of insulin lispro-treated participants reported any adverse event. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 1 diabetes.

Similar Glucose Control, Postprandial Glucose Excursions, and Safety in People with T2DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100): SORELLA 2 Study (1004P)

KM Derwahl, T Bailey, K Wernicke-Panten, L Ping, and S Pierre

This poster featured initial phase 3 data from the SORELLA 2 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 2 diabetes. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 505 people with type 2 diabetes (mean age 62 years; mean BMI 32 kg/m3; mean A1c 8%) were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 26 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of -0.07% (95% CI: -0.215% to 0.067%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all prespecified categories of hypoglycemia: severe (2.4% vs. 1.6%), documented symptomatic <70 mg/dl (60.1% vs. 66.3%), and asymptomatic <70 mg/dl (35.2% vs. 37.3%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (38.4% vs. 36.7% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 46.6% of SAR-treated and 42.9% of insulin lispro-treated participants reported any adverse event. There was one death in the SAR arm and two deaths in the insulin lispro arm, but these were unrelated to the study drug. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 2 diabetes.

Switching to Insulin Degludec Improves Glycemic Control in Patients with T2D in a Real-World Setting (1010-P)

B Schultes, N Tentolouris, S Knudsen, A Lapolla, M Eidenmueller, R Prager, T Phan, M Wolden, T Siegmund

This poster featured results from the EU-TREAT study, evaluating the real-world impact of switching to Novo Nordisk’s next-generation Tresiba (insulin degludec) on glycemic control and safety in patients with type 2 diabetes. Based on EMR records from 833 adults with type 2 diabetes, switching to insulin degludec  from other basal insulins produced improved glycemic control maintained over 12 months, as measured by A1c and fasting plasma glucose. Primary endpoint results demonstrated a moderate decline in A1c with switches to insulin degludec, from 8.4% to 7.9% (p<0.001), maintained at 12 months. Fasting plasma glucose also decreased from 178.9 mg/dl to 155.2 mg/dl (p<0.001), maintained at 12 months. Switching to insulin degludec also significantly lowered basal, prandial, and total insulin requirements. A 3.2% reduction in daily insulin requirements (p=0.006) was seen at 6 and 12 months. Body weight did not change from baseline to 6 or 12 months. Perhaps most notably, the rate ratios of overall, non-severe nocturnal, and severe hypoglycemic episodes were all significantly lower at both 6 and 12 months post-switch. At six months, switching to insulin degludec was associated with a 61% reduction in overall hypoglycemia (p<0.001), a 60% reduction in non-severe overall hypoglycemia (p<0.001), a whopping 90% reduction in non-severe nocturnal hypoglycemia (p<0.001), and a very, very impressive 92% reduction in severe hypoglycemia (p=0.004). 9% of patients discontinued insulin degludec use by 6 months, mostly due to cost, insufficient efficacy, and “other reasons.” Ultimately, this study shows that insulin degludec is effective at improving glycemic control and reducing risk of hypoglycemia in patients with type 2 diabetes in routine clinical practice, outside of an randomized, controlled trial. We applaud Novo Nordisk for undertaking these kinds of studies to better characterize the benefits of Tresiba in real-world clinical practice – at first glance, it appears that the hypoglycemia results here are even more impressive that that seen in the randomized, controlled DEVOTE and SWITCH 2 trials. While of course these types of studies will not replace RCTs, we do think they provide valuable clinical decision-making information for providers.

Switching to Insulin Degludec Reduces the Risk of Hypoglycemia in Patients with T1D in a Real-World Setting (1014-P)

T Siegmund, N Tentolouris, S Knudsen, A Lapolla, M Eidenmueller, R Prager, T Phan, M Wolden, B Schultes

Very notably, this poster highlighted results from a real-world study – using the EU-TREAT dataset – demonstrating that patients with type 1 diabetes switching to Novo Nordisk’s next-generation Tresiba (insulin degludec) from other basal insulins achieved improved glycemic control maintained over 12 months, as measured by A1c and fasting plasma glucose. What’s more, switching to insulin degludec significantly lowered basal, prandial, and total insulin requirements, while also reducing overall, severe, and non-severe nocturnal hypoglycemic episodes in the same sample. The study drew on EMR data from 1,717 adult patients with type 1 diabetes collected during the multicenter, retrospective EU-TREAT study of patients who switched to insulin degludec from another basal insulin. Results showed a small but significant decline in the primary endpoint of A1c at six months with insulin degludec, from 8.0% to 7.8% (p<0.001). Notably, this reduction was maintained at 12 months. Fasting plasma glucose also decreased from 63.4 mg/dl to 144.6 mg/dl (p<0.001), maintained at 12 months. A 10.6% reduction in daily insulin requirements (p<0.001) was observed at 6 months among those who switched to insulin degludec and the difference increased to 11.4% at 12 months. However, there was a small weight increase of +0.6 kg (1.3 lbs, p<0.001), which was stable at +0.5 kg (1.1 lbs) at 12 months. Perhaps most notably, the rate ratios of overall, non-severe nocturnal, and severe hypoglycemic episodes were all significantly lower at both six and 12 months post-switch. The six months, insulin degludec was associated with a 21% reduction in overall hypoglycemia (p<0.001), a 19% reduction in non-severe overall hypoglycemia (p=0.001), a very impressive 46% reduction in non-severe nocturnal hypoglycemia (p<0.001), and a whopping 85% reduction in severe hypoglycemia (p<0.001). These risk reductions were very similar at 12 months. In terms of safety, 5.6% of patients discontinued insulin degludec use by six months, mostly due to insufficient efficacy, cost, and “other reasons.” Ultimately, this study shows that insulin degludec is effective at improving glycemic control and reducing risk of hypoglycemia in routine clinical practice, outside of an interventional study.

Efficacy and Safety of MYL-1501D (Mylan’s Insulin Glargine) Compared with Lantus (Sanofi’s Insulin Glargine) in Patients with Type 2 Diabetes After 24 Weeks: The INSTRIDE 2 Study (1017-P)

T Blevins, A Barve, A Jacob, B Sun, and M Ankersen

Mylan’s biosimilar insulin glargine candidate, MYL-1501D, demonstrated similar efficacy and safety to Sanofi’s Lantus (insulin glargine) in people with type 2 diabetes over 24 weeks. MYL-1501D has the same amino acid sequence and formulation as Lantus. The phase 3 INSTRIDE 2 study enrolled 560 people with type 2 diabetes with A1c <9.5% who were either insulin-naïve or on once-daily Lantus and ≥two oral antidiabetic drugs (OADs) for three months before screening. Patients were randomized to either once-daily MYL-1501D (n=277) or Lantus (n=283) for 24 weeks while maintaining other OADs. After 24 weeks, MYL-1501D met its primary endpoint for non-inferiority: From a baseline A1c of 8.1%, participants in the biosimilar arm experienced a mean A1c reduction of 0.6% while those in the Lantus arm experienced a mean A1c reduction of 0.66% (A1c treatment difference of 0.06%, 95% CI: -0.10%-0.22% which crosses the line of unity). Secondary endpoints also supported the candidate’s non-inferiority vs. Lantus. There was no significant difference between groups on change in fasting plasma glucose, for example (p=0.51). On safety, both groups had similar rates of adverse events, with hypoglycemia being the most common and occurring in 27% and 23% of biosimilar-treated and Lantus-treated patients, respectively. Mylan/Biocon are expected to submit the drug candidate to the FDA “shortly,” although the date has been pushed back repeatedly according to Mylan’s 1Q17 earnings call. The candidate was submitted to the EMA in 3Q16.

Efficacy and Safety of MYL-1501D (Mylan’s Insulin Glargine) Compared with Lantus (Sanofi’s Insulin Glargine) in Patients with Type 1 Diabetes After 52 Weeks: The INSTRIDE 1 Study (1018-P)

T Blevins, A Barve, A Jacob, B Sun, and M Ankersen

This analysis of Mylan’s Biocon-partnered biosimilar insulin glargine candidate, MYL-1501D, demonstrated non-inferiority to Sanofi’s Lantus (insulin glargine) in people with type 1 diabetes (n=558). This poster presented 52-week results from INSTRIDE 1, an open-label, randomized, phase 3 study. After a six-week run-in period on Lantus, patients were randomized to either once-daily MYL-1501D (n=280) or to continue on Lantus (n=278) in addition to mealtime insulin lispro (Lilly’s Humalog). After 52 weeks, the mean change in A1c from baseline (~7.4%) was 0.21% and 0.25% for the MYL-1501D and Lantus groups, respectively, such that MYL-1501D met criteria for non-inferiority vs. Lantus (A1c treatment difference of 0.05%, 95% CI: -0.15%-0.06% which crosses the line of unity). Rates of hypoglycemia were comparable between groups, at 55% vs. 61% in the biosimilar and Lantus arms, respectively, as were rates of other adverse events. The poster concludes that Mylan’s biosimilar insulin candidate met its primary endpoint in the INSTRIDE 1 trial extension. Mylan/Biocon are expected to submit the drug candidate to the FDA “shortly,” although the date has been pushed back repeatedly according to Mylan’s 1Q17 earnings call. The candidate was submitted to the EMA in 3Q16.

Symposium: Combination Therapy in Type 2 Diabetes—Promise Delivered?

The Future of Combination Therapy in the Treatment of Type 2 Diabetes—Which Classes, Why, and When?

John Buse, MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC)

Dr. John Buse, a vocal advocate for basal insulin/GLP-1 agonist combinations from the start, suggested that these products (Novo Nordisk’s Xultophy and Sanofi’s Soliqua) should supplant insulin monotherapy as second-line treatment for type 2 diabetes. He highlighted the superior A1c-lowering efficacy, impressive weight loss, and “stunning” reductions in postprandial glucose shown across several clinical studies of Xultophy (insulin degludec/liraglutide) and Soliqua (insulin glargine/lixisenatide). What’s more, these agents are able to get a sizeable proportion of patients to A1c <7% (and ~40% of patients to A1c <6.5%) without inducing hypoglycemia – as Dr. Buse put it, in this danger zone of 0.7%-0.8% A1c-lowering below recommended targets, you’d expect to see an “exploding” increase in hypoglycemia and severe hypoglycemia, but the GLP-1 component of these compounds sidesteps the issue entirely. To further support his position on this particular combo class, Dr. Buse pointed out that the great promise of GLP-1 agonism has always been on a background of insulin. The first paper on GLP-1 in man, published in the NEJM in 1992, investigated the effects of a GLP-1 agonist on top of optimized insulin therapy. In the LEADER trial demonstrating a substantial CV benefit to liraglutide (Novo Nordisk’s Victoza), most patients were taking insulin at baseline. We echo Dr. Buse’s enthusiasm for basal insulin/GLP-1 agonist fixed-ratio combinations, and we’re eager to see greater uptake of Xultophy and Soliqua, which were only FDA-approved seven months ago (coincidentally, on the same afternoon). Pooled sales from these two products totaled $19 million in 1Q17, and we hope to see steep growth for this highly-anticipated and advanced class. We’d also love to see numbers on prescription volume, and will be keeping our fingers crossed for improved reimbursement (since we can’t expect a wide patient population to benefit from these effective new drugs if they aren’t affordable and accessible). To ADA’s credit, basal insulin/GLP-1 combos were swiftly incorporated into the 2017 Standards of Care, which were published <one month after FDA-approval of Xultophy and Soliqua. That said, particularly US-based clinicians as well as payers globally seem to be slow to move to combinations first regardless of the data showing they would benefit from this.

• “I do think there’s a role for SGLT-2 inhibitors in combination with insulin.” Dr. Buse spent part of his talk discussing this potential future direction for combination approaches in type 2 diabetes. He underscored that a majority of patients in EMPA-REG OUTCOME (Lilly/BI’s CVOT for empagliflozin, branded as Jardiance) were taking insulin at baseline, which is suggestive that these two agents can be efficacious and synergistic (though, on the other hand, only about half of participants in the CANVAS program were taking insulin at baseline). There is little guidance for patients/providers right now on how to maximize clinical benefit from a medication regimen incorporating both an SGLT-2 inhibitor and an insulin product, but Dr. Buse hopes for more language on this in upcoming iterations of professional guidelines, and so do we.
• Dr. Buse expressed early excitement for multivalent peptides, including triple combinations of GLP-1/GIP/glucagon. Preclinical investigations in animal models have produced highly-promising data so far, and Dr. Buse especially emphasized how these compounds can optimize weight loss without sacrificing glycemic control (definitely a key consideration in type 2 diabetes care). He characterized this as an up-and-coming area of combination therapy to look out for.
• Moreover, Dr. Buse called attention to a “huge opportunity” for combining a diabetes drug with a weight loss agent – he focused on canagliflozin/phentermine as an example. Phase 2 results from J&J (which markets canagliflozin as SGLT-2 inhibitor Invokana) were presented as a late-breaking poster at ADA 2016, and additional analyses were presented at this meeting. Unlike benefits to A1c, which for a combination therapy are typically less than the sum of reductions from each component monotherapy, Dr. Buse explained that benefits to weight loss can be very close to additive. Indeed, we saw additive weight loss effects for GLP-1 agonist/SGLT-2 inhibitor co-administration in DURATION-8 –  though Dr. Buse was less positive about the glycemic effects of the combination (see below). It’s unclear at the moment whether J&J will move forward with phase 3 studies of canagliflozin/ phentermine, but with such unequivocal support from a thought leader like Dr. Buse, we see a strong case for further clinical development.
• Lastly, Dr. Buse shared some skepticism on GLP-1 agonist/SGLT-2 inhibitor combination approaches. While results from DURATION-8 investigating AZ’s Bydureon (exenatide once-weekly) alongside Farxiga (dapagliflozin) were positive, Dr. Buse emphasized the sub-additive benefits to A1c – “I had hoped for more.” He mentioned the differential effects on glucagon from SGLT-2 inhibitors vs. GLP-1 agonists as one potential concern. On the other hand, Dr. Buse acknowledged that this area of combination treatment holds possibility for aggregate CV benefits. While topline results from the EXSCEL CVOT for exenatide were neutral, other GLP-1 agonists like liraglutide and semaglutide have shown significant cardioprotection, and we’ve now seen CV superiority vs. placebo for two SGLT-2 inhibitors as well – empagliflozin and canagliflozin. Dr. Buse concluded: “Before rushing off and building up GLP-1/SGLT-2 as the clear savior of all patients with diabetes and CV disease, we need to be cautious about understanding this combination better.”

Symposium: Dealing with the Rising Costs of Insulin – An Active Dialogue

The Rising Costs of Insulin – Introduction and Historical Perspective

Kasia Lipska, MD (Yale School of Medicine, New Haven, CT)

Dr. Kasia Lipska opened this highly-anticipated symposium on insulin costs with a look at the history of insulin development and pricing. Unsurprisingly, given her somewhat controversial previous commentary on insulin pricing, Dr. Lipska took a relatively critical stance on the value of modern insulin analogs, describing what she termed “the paradox of incremental innovation.” While the benefits are of course incremental for some, they are quite striking for others, and it was disappointing to hear this dismissive, one-size-fits-all language. She acknowledged that substantial and important advances have been made in insulin therapy – making insulin much safer and “more convenient” – since its discovery in 1922, but pointed out that these improvements have occurred in a stepwise manner, with new patents accompanying each advance. (She didn’t give another view on how she would suggest advances take place.) Further, she noted that, with the arrival of newer insulin, older insulins often largely became obsolete and disappeared from the market in high-income countries like US in particular. She highlighted this as the “paradox,” as generally older products create a market for generics, which largely has not happened in the insulin field – though this may be changing with the arrival of Lilly/BI’s biosimilar insulin glargine Basaglar (and upcoming biosimilars from Merck and Mylan/Biocon). All in all, she posed the question, “Was each incremental innovation worth the price that we pay today?” While we certainly sympathize with the point that insulin pricing is a major problem for many patients (as, we would add, prices for heart attacks, strokes, dialysis etc), it is not our sense that innovation in insulin is the main driver of increasing costs (compared to the complex PBM/rebate negotiation system, etc.) and we certainly would not term substantial benefits in hypoglycemia and ease-of-dosing an “incremental” improvement in quality of life for many patients. That said, we recognize that insulin analogs may be out of reach for some patients in the current healthcare system and, to that end, we appreciated Dr. Lipska highlighting her recent JAMA viewpoint (co-authored with Drs. Irl Hirsch and Matthew Riddle) on practical tips for physicians on human insulin therapy in patients with type 2 diabetes. We also appreciated Dr. Lipska’s acknowledgement that human insulin certainly is not a solution for everyone and that modern insulins are “definitely better” than older versions from a pure clinical standpoint (which presumably she would acknowledge is important – the clinical viewpoint). Finally, Dr. Lipska concluded her presentation by acknowledging the complexity of contributors to insulin pricing and highlighted several remaining questions: (i) Who are the other players contributing to rising insulin prices?; (ii) What else can clinicians do to keep costs down?; and (iii) What are the potential policy solutions? She didn’t say what part of her work would be addressing this, but we look forward to her solutions.

Questions and Answers

Q: The average wholesale price (AWP) shown in that diagram – why is there so little transparency in that?

A: Some say “AWP” also stands for “Ain’t What’s Paid.” It’s not the real price of the insulin. Pharma companies tell us that the actual net price of insulin has either stayed the same or hasn’t increased as well. The gap between the two has risen, and part of that is because of rebating and discounts for insurers and PBMs in this process. You’re right, we need more transparency to see if we can judge it as far as it’s not clear where money changes hands in this system (Editor’s note – it’s not clear if Dr. Lipska has looked at annual reports for these organizations – for the last several years, this information has been publicly report by Novo Nordisk and Lilly and others) .

Understanding the Players in the Rising Costs of Insulin

Alan Carter, PharmD (MRIGlobal, Kansas City, MO)

Pharmacist Dr. Alan Carter emphasized the complex “cast” of players in the issue of insulin pricing, including suppliers of raw materials, manufacturers pharmaceutical wholesalers, pharmacies, prescribers, and people with diabetes. Overall, however, he underscored in great detail that insulin is an extremely complex process, with safety and quality assurance standards largely in the court of individual manufacturers. As a result, trust in insulin manufacturers is paramount and quality assurance trumps price. He suggested that new policies like Medicare Part D and the ACA had the unintended consequences of increasing PBM leverage, which is one of the main drivers of increasing costs. At the same time, Dr. Carter argued that it will take all stakeholders – “a village” – to safety and effectively lower insulin costs without sacrificing safety and quality.

Clinical Decision-Making in a Cost-Conscious Era

David Robbins, MD (University of Kansas, Kansas City, KS)

Dr. David Robbins outlined several opportunities for healthcare providers, patients, the ADA, the government, pharmaceutical companies, and all of us to impact insulin, drug, and healthcare pricing. For the field as a whole, Dr. Robbins asked all the various stakeholders to stop oversimplifying the issue of drug pricing and to share the blame, rather than point fingers. Further, the formation of partnerships to tackle this problem are crucial. He also emphasized the need to healthy, educated, and fair critics, while recognizing that we are all subject to bias. To that end, he emphasized that “new” is not always better. And finally, he called upon attendees to always advocate for their patients – hear hear!

• For healthcare providers, Dr. Robbins emphasized the need to be a “tough, but fair, critic.” He suggested that conflicts of interest and bias is rampant in among prescribers. Underscoring his point, he cited a study that found every additional $13 payment or gift from a pharmaceutical company to a prescriber was associated keeping a patient on a particular drug for an additional 107 days (p<0.001). He emphasized that the healthcare field has a whole has to take a hard look at conflicts of interest and be honest with themselves about how this may bias clinical care. To help make better decisions on which diabetes drugs to actually prescribe, Dr. Robbins highlighted the importance of healthcare providers asking patients about their individual resources. Dr. Robbins also called upon healthcare providers to demand better guidelines and rigorous comparisons of new vs. old medications and tools. Additionally, more emphasis on the prevention and early reversal of type 2 diabetes is needed. Finally, Dr. Robbins suggested that healthcare providers have an obligation to spend time volunteering care in free clinics.
• For patients, Dr. Robbins highlighted the benefits of being an informed consumer. Dr. Robbins asked patients to understand the benefits of drugs and ask their providers if the branded medications are really better than lower-cost generics. Further, in cases where insurance coverage may be denied, Dr. Robbins called on patients to doggedly ask the insurance companies for the reason behind the denial, rather than just accepting it.
• For the ADA, Dr. Robbins wished for greater transparency on the organization’s funding sources and the inclusion of such disclosures on the widely-used ADA diabetes guidelines. Dr. Robbins acknowledged that pharmaceutical funding is critical to support the wide breadth of programs that the ADA is engaged in, but he suggested that separating ADA guideline and opinion statements from such funding. He also asked the ADA to support comparative effectiveness studies of different medications – including both branded and generic options – to help providers with difficult clinical decision-making. Finally, Dr. Robbins argued that the ADA should not taking advertising from pharmaceutical companies on its website or other materials.
• From a regulatory standpoint, Dr. Robbins argued that the FDA and other government agencies should set a higher bar for new diabetes drugs, demonstrating improvements over standard of care rather than just demonstrating efficacy compared to placebo. As he put it, the government has dual obligations of protecting and also guiding the consumer.
• Dr. Robbins also highlighted several opportunities for pharmaceutical companies. In particular, he asked manufacturers to demonstrate that new drugs are cost-effective and to expand and simply safety net programs for expensive and critical drugs. He also suggested that companies stop fighting Medicare’s efforts to employ competitive bidding (though, in our view, competitive bidding processes must also be accompanied by rigorous quality assurance standards). Finally, Dr. Robbins emphasized that pharmaceutical companies need to do a better job of communicating their narrative and “what they do right.” For instance, he emphasized that these companies employ truly dedicated people, the USA leads the world in discovery and innovation, and these companies often return reasonable profit margins (which the exception of predatory companies like Turing and Valeant). All in all, Dr. Robbins suggested that manufacturers need to do a better job of communicating the high cost of drug R&D.

Paving the Way Forward

Robert Ratner, MD (Georgetown University School of Medicine, Washington, DC)

Answering the question “What’s the solution to high insulin prices?,” former ADA Chief Scientific and Medical Officer Dr. Robert Ratner stated that there is only one real solution: “Someone has to make less money.” He emphasized that the system of insulin pricing/coverage/rebating is extremely complicated and that a lack of transparency makes it difficult to understand where the bulk of the money is going. That said, Dr. Ratner noted that rebates to pharmacy benefits managers (PBMs) rose substantially from $67 billion in 2013 to a whopping $106 billion in 2015. While acknowledging that an appropriate level of profit from insulin supports R&D and prices in the US subsidize insulin in low- and middle-income countries, Dr. Ratner stated to great applause, “The issue of middlemen with no added value increasing expenditures is something we can get rid of without having any downward pressure on insulin pricing elsewhere” – hear hear! Dr. Ratner views free market competition mechanisms as the most likely to be successful in driving insulin pricing reform. He acknowledged that the very first biosimilar insulin glargine – Lilly/BI’s Basaglar – has not been discounted quite as much as some had hoped (in the US, the follow-on biologic is discounted about 15% relative to originator Lantus). On the other hand, he underscored that we typically must wait for two or more generics to see price driven down, and Dr. Ratner was fairly optimistic on the future launch of additional biosimilars given that new FDA commissioner Dr. Scott Gottlieb has publicly highlighted simplification of the biosimilar regulatory process as one of his goals. Even with the current, rather complicated process, Merck has already submitted a biosimilar insulin glargine formulation and Mylan/Biocon are planning to submit their own formulation shortly. Dr. Ratner also sees greater proliferation of direct-to-consumer programs as promising – he highlighted Walmart’s $26/vial human insulin as an excellent example of how the complex insurance/PBM/rebate system can be bypassed entirely to bring insulin directly to patients at a lower cost. We think that the Blink Health and InsideRx direct discount programs are a good example of this principle as well, though the prices for medications through these programs are admittedly still much higher than that of Walmart insulin. Most promising in Dr. Ratner’s view, however, are the recent proliferation of lawsuits accusing insulin manufacturers, payers, and PBMs of price-fixing in insulin. While he reserved judgement on whether any of these lawsuits had merit, he pointed out that they will force transparency in this opaque field by forcing various stakeholders to disclose their contractual agreements as part of discovery. We think it’s highly unlikely that any actual price-fixing is occurring and, while we wholeheartedly agree with the need for transparency, we wish it wouldn’t take several high-profile lawsuits to encourage companies to disclose their financial agreements. We certainly believe voluntary disclosures would generate more goodwill, while these lawsuits that only further exacerbating the public furor over drug pricing. The “story” has spun out of control in many ways and we continue to hope that manufacturers and other stakeholders will take the initiative to address these concerns head-on – without being pushed by external forces. Some progress has been made in recent months, but there is still much more room to help relieve the financial burden of diabetes care for patients.

• On the other hand, Dr. Ratner was less optimistic about the potential for legislative or regulatory controls to offer near-term relief on insulin pricing. He noted that there has been significant discussion among politicians and in legislature (both at the state and the national level) on potential policy solutions to the issue of high drug costs. He highlighted proposals to allow Medicare Part D to negotiate with manufacturers, government-imposed price controls, and challenges to “pay for delay” tactics, but ultimately emphasized that the legislative process can be incredibly slow. On the regulatory front, he suggested that some of the proposals floating around could have unintended, negative consequences from a global perspective. For instance, he noted that calls to allow the importation of drugs from other counties have become popular in some circles and that this would actually be possible within the current purview of the FDA, without need for legislative change. That said, Dr. Ratner pointed out that the last four FDA commissioners (including Dr. Gottlieb) has come out “categorically against” this idea. Further, Dr. Ratner suggested that cross-border importation of insulin would actually incentivize companies to only sell insulin in companies that can command a higher price, like the US, and potentially create insulin shortages in other countries.

Symposium: ADA Pathway to Stop Diabetes Symposium

Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery

Zhen Gu, PhD (University of North Carolina, Chapel Hill, NC)

Echoing his talk at the JDRF Mission Summit in January, Dr. Zhen Gu discussed several approaches to glucose-responsive insulin delivery that his iMedication lab is researching. Two projects – the microgel and nano-network approaches – use the enzyme glucose oxidase to convert glucose to gluconic acid and create an acidic environment that activates the release of insulin. While these approaches have shown some positive effects in preclinical models, Dr. Gu explained that response speed has been a challenge, as the body’s buffering ability makes it difficult to immediately generate an acidic environment. Therefore, the lab is also exploring a hypoxia-sensitive insulin patch that releases insulin when oxygen levels fall (both glucose and oxygen are consumed in the glucose oxidase reaction). Finally, Dr. Gu mentioned his lab’s preliminary efforts to use red blood cells for smart insulin delivery: the cells are coated with modified insulin that detaches in response to high glucose. In addition to speed, other key challenges that Dr. Gu cited include the risk of hypoglycemia, ease of administration, and biocompatibility.

Symposium: What’s New in Insulin-Related Therapy?

Old Problems, New Solutions – Insulin Management Through Innovation

Lori Berard (WRHA Health Sciences Centre Diabetes Research Group, Winnipeg, CA)

Ms. Lori Berard’s talk on non-pharmacological innovations in insulin initiation and titration centered on a singular theme: “We’ve had 100 years of insulin, but there are still a LOT of problems we deal with on a day-to-day basis.” Ms. Berard set the stage for this topic by reviewing the classic barriers to insulin therapy (e.g., fear of needles, hypoglycemia, complications, weight gain, etc.), noting that while the field has addressed many of these limitations, there is still much left to do. She acknowledged that we’ve done a fairly good job at ‘figuring out’ insulin therapy in people with type 1 diabetes, attributing this to the fact that these patients are often seen by specialists accustomed to prescribing insulin. Meanwhile, she argued that primary care physicians are left with the responsibility of treating a growing type 2 population and that it is here that we are failing our patients (especially in terms of initiation). In particular, Ms. Berard shared her assessment that many PCPs lack confidence in prescribing insulin to type 2s (leading to delayed starts) and that even when we do give insulin, “we’re not good at supporting patients beyond the initial prescription.” More broadly, she pointed out that this is a population in which perceived disease severity is often lacking and in which there is a very strong perception of failure. She argued that these factors are all the more reason to focus future innovation on our prescribers and equipping them with better tools to prescribe/titrate insulin and communicate with their patients – e.g., automated insulin titration, shared decision-making systems. As she summarized playfully at the end, “If we could just help the people who help patients get to goal, then we’d be in a better place.” Agreed!

Corporate Symposium: The Physiologic and Mechanistic Rationale for Achieving HbA1c Target Goals with Basal Insulin in Vulnerable Patients with Type 2 Diabetes (Sponsored by Sanofi)

The Physiologic Rationale for Optimizing HbA1c Target Goal Attainment with Basal Insulin

Vivian Fonseca, MD (Tulane University School of Medicine, New Orleans, LA)

There are currently 29 million people with diabetes and 1.9 million new cases per year, and approximately 50% of these individuals are unable to achieve glycemic targets (A1c ≤7%). Dr. Vivian Fonseca opened his presentation with these hard-to-stomach stats, and continued on to outline multiple reasons that keep patients from getting to goal: Namely, the complex pathophysiology of type 2 diabetes and the progressive decline in beta cell function. Insulin therapy is necessary in type 2 diabetes because it is sometimes the sole therapeutic agent that can help patients achieve glycemic goals. Furthermore, insulin is safe when properly administered, and has proven effectiveness. Patients are often reluctant at first to start insulin, but delaying insulin therapy can be harmful later on. Dr. Fonseca argued that it’s important to start insulin at a lower A1c, because it is more effective at reducing A1c ≤7% when the baseline level is lower. In order to find an insulin that works best for each individual, important factors to consider include the absolute A1c reduction rate, amount of hypoglycemia, level of complexity, and insulin titration and doses. Dr. Fonseca concluded by re-emphasizing the importance of using basal insulin as a therapeutic option early on in individuals with type 2 diabetes.

Optimizing Glycemic Control While Mitigating Hypoglycemic Risk in Challenging Patients with T2D

Pablo Mora, MD (Dallas Diabetes Research Center, Dallas, TX)

Dr. Pablo Mora discussed the role of basal insulin and walked attendees through the barriers to insulin use in real-world clinical practice. He opened by appreciating patient/provider concerns related to hypoglycemia, weight gain, and the stigma associated with insulin use. That said, Dr. Mora emphasized that intensive glucose lowering is safe and carries the greatest lifetime benefit when initiated early in the course of diabetes. He turned to data on the most advanced basal insulin products on the market, including Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300). Specifically, Dr. Mora discussed the molecular nature of the degludec and glargine insulin analogues and reviewed positive results from the SWITCH studies and the EDITION clinical program. He highlighted that these newer basal insulins offer less variability, longer duration of action, easy and safe titration methods, and improved safety outcomes (on the hypoglycemia front, on the CV front). Dr. Mora concluded that the PK/PD profiles of new insulin therapies and the advanced features of new insulin delivery devices have made insulin therapy significantly more user-friendly.

All Basal Insulins Are Not Created Equal: Comparative PK/PD, Efficacy, Side-Effect (Hypoglycemia), and Safety Profiles for Established and New Longer-Acting Basal Insulins

Guillermo Umpierrez, MD (Emory University, Atlanta, GA)

For type 2 diabetes, Dr. Guillermo Umpierrez advocated that insulin should be started in patients with hyperglycemic emergencies, high baseline A1c, or when combination oral or injectable agents are no longer effective. For these patients, there are many different basal insulin products available, at different doses and different dosing frequencies. Many of these products have similar effectiveness, but Dr. Umpierrez described how patients will make their choice based on personal preferences: It comes down to how they relatively weigh injection frequency, lifestyle factors, flexibility of regimen, level of support available, and cost. Moreover, when basal insulin is no longer sufficient, patients may add bolus insulin in order to improve glycemic control, which comes with its own set of options. Regardless of the type of insulin used, the addition basal insulin to a diabetes treatment regimen helps between 40-50% of patients reach A1c goals, and adding mealtime insulin helps between 50-60% of patients achieve A1c goals, according to Dr. Umpierrez. Combination therapy using insulin and incretin agents is especially effective in helping individuals with type 2 diabetes improve glycemic control and reduce hypoglycemia. We loved this mention of fixed-ratio GLP-1/basal insulin combos, including Sanofi’s Soliqua (lixisenatide/insulin glargine) and Novo Nordisk’s Xultophy (liraglutide/insulin degludec).

Modifying Insulin Therapy in Complex and Vulnerable Patients: Practical Approaches for Switching to a Physiologic, Basal Insulin Formulation

Juan Frias, MD (National Research Institute, Los Angeles, CA)

Dr. Juan Frias delivered a clinician-focused presentation on practical considerations for the use of basal insulin. Acknowledging the many barriers that lead to the delay of insulin therapy, Dr. Frias highlighted the advantages of newer insulin delivery devices. Specifically, he noted that insulin pens are associated with greater accuracy, reduced hypoglycemia, and improved patient adherence. He also gave high praise to insulin glargine U300 (Sanofi’s Toujeo), sharing that compared to the U100 formulation of insulin glargine (Sanofi’s Lantus), Toujeo has a more constant and prolonged PK/PD profile, lower glycemic variability, and lower hypoglycemia risk. In discussing practical approaches for Toujeo use, Dr. Frias suggested titrating doses based on self-monitored fasting plasma glucose results, no more frequently than every three-four days. In addition, he shared insights on the clinical use of insulin degludec (Novo Nordisk’s Tresiba), advising attendees on recommended starting dose, dose increases, and patient education on missed doses. In conclusion, Dr. Frias positioned basal insulin as the gold standard of injectable therapy.

Questions and Answers

Q: In what populations do you use Sanofi’s Lantus (insulin glargine U100)?

Dr. Umpierrez: I very seldom use glargine U100, except in type 1 diabetes at very low doses. In general, this is once-daily.

Q: How do you overcome socioeconomic barriers?

Dr. Frias: I hear about this a lot from my patients – 90% are Latino. They’ve seen their relatives have severe problems with diabetes and they associate that with insulin. A lot of this can be solved through education. It helps to show them the needle and say we can always stop if needed.

Dr. Mora: The Hispanic population gets really worried when we talk about multiple injections a day. So giving the story that insulin is good and safe and only needs to be injected once per day can help.

Dr. Fonseca: And giving the first injection sometimes helps. They realize that it doesn’t hurt so bad.

Dr. Frias: Also, sometimes adding a GLP-1 agonist to basal-bolus therapy is nice.

Dr. Mora: In my experience, the level of comfort to initiate GLP-1 therapy is not quite there yet. For both the clinician and the patient.

Q: What are the options for GLP-1 agonists in patients with an eGFR of 48 ml/min/1.73m²?

Dr. Fonseca: There isn’t much of a concern. These agents are not toxic to the kidney. There may be some nausea, vomiting, and dehydration. These side-effects can be more problematic for people with lower eGFR. But in general, I don’t think that’s much of a concern.

Dr. Umpierrez: The study with liraglutide showed that the GLP-1 agonist agent can be used safely on eGFRs as low as 30 ml/min/1.73m².

Q: Thoughts on the hypoglycemic profile of ultra-concentrated, U500 insulin compared to other formulations of insulin glargine?

Dr. Umpierrez: I have very little experience with U500. I don’t believe in it a lot, so I don’t use it.

Dr. Fonseca: I use it a fair amount in these people who have severe insulin resistance. So you don’t get much hypoglycemia. But when you get them under better control, it could be a problem. I can get by without using basal. I give it three times/day, sometimes with a GLP-1 agonist.

Dr. Mora: I would have a bit of caution with U500 in that it accumulates at the end of the day, so it’s good to back off at the end of the day.

Corporate Symposium: Optimizing Comprehensive Glycemic Management in Challenging Patients with Type 2 Diabetes (Sponsored by Sanofi)

Vanita Aroda, MD (Georgetown University School of Medicine, Hyattsville, MD), Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Vivian Fonseca, MD (Tulane University Health Sciences Center, New Orleans, LA), and Juan Frias, MD (UCLA, Los Angeles, CA)

This Sanofi-sponsored corporate symposium highlighted the potential of basal insulin/GLP-1 agonist fixed-dose combinations as an optimal therapeutic options for patients not achieving their goals on basal insulin alone. Dr. Vivian Fonseca kicked off the symposium with an overview of current treatment options, the need for therapies that help patients achieve glycemic goals with minimal hypoglycemia and weight gain, and the importance of the patient-oriented perspective on minimizing injections and daily burdens of therapies. Dr. Vanita Aroda then discussed the importance of addressing postprandial glucose (PPG) as an integral part of treatment to lower A1c. PPG may also be tied to cardiovascular risk, although trial data has been mixed. She examined both short- and long-acting GLP-1 agonists and their differing effects on PPG, finding that short-acting GLP-1 agonists like exenatide and lixisenatide flattened PPG glucose levels significantly while long-acting liraglutide only showed some suppression of PPG. Dr. Blonde then led a review of the treatment options in type 2 diabetes and the use of basal insulin as the initial insulin therapy recommended by the ADA and AACE. Interestingly, in a series of five studies investigating basal insulin as the first injectable, GLP-1 agonists were found to be more effective in A1c reduction and additionally helped with weight loss. Dr. Blonde also reviewed the impact of hypoglycemia in insulin use, which is a key challenge for patients and a common reason cited for patients who choose to discontinue insulin. Newer insulins like Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Toujeo (insulin glargine U300) are associated with similar A1c and weight reductions as older insulins but also have the additional benefits of lowering the risk for both nocturnal and severe hypoglycemia, as demonstrated  in trials like SWITCH 2 and EDITION 1, 2, and 3. However, Dr. Blonde pointed out that many patients will not attain or maintain target glycemia with basal insulin alone, and there are further strategies for intensification including combination injectable therapy with a basal insulin analog and a GLP-1 receptor agonist. To conclude the symposium, Dr. Juan Frias knitted everything together with a broad overview of the complementary mechanisms of action between basal insulin and GLP-1 agonists on insulin release, glucose uptake, glucose production, glucagon secretion, and gastric emptying. The two major fixed-dose combinations – Sanofi’s Soliqua (insulin glargine/lixisenatide) and Novo Nordisk’s Xultophy (insulin degludec/liraglutide) - are approved in the US for patients suboptimally controlled on any basal insulin or lixisenatide and/or liraglutide in combination with any oral medication. However, in Europe these agents have more expansive labels approved as the first injectable agent. The benefits of a fixed-ratio combination compared to individual components is compelling – improved glycemic control, a body weight benefit, no increase hypoglycemia, and reduced GI side effects.

Questions and Answers

Q: Some patients stop responding to GLP-1 agonists. Can you explain why this happens and how to address it?

Dr. Fonseca: Some people just stop taking the medication and you need to have a frank discussion about that. Secondly, you wonder about the development of antibodies, particularly with exenatide. Neutralizing antibodies are not that common in GLP-1 agonists except in exenatide. In that case, you can stop the drug and switch to another GLP-1 agonist and see what happens. Thirdly, it is possible to use GLP-1 agonists inappropriately because the patient lacks insulin. If you’re insulin deficient, nothing is going to work.

Dr. Frias: Secondary failure is the nature of type 2 diabetes management. At some point you reach an equilibrium or your diabetes progresses.

Q: It seems like we are giving our patients all of these drugs, but not reaching our goals. What else can you do?

Dr. Aroda: We keep treating to failure and we need to prevent that.

Dr. Blonde: There are studies that show earlier treatment with combinations of agents may produce more durable reductions in A1c. It would be interesting to do a study in coformulations that looks at simultaneous versus sequential therapy. There are studies that suggest simultaneous is better than sequential.

Q: You use U500, the maximal amount of insulin. What do you do when someone needs more than that?

Dr. Aroda: Well you’ve got to treat the patient. If they need more insulin then give it to them, but you should also be asking why the maximum amount of basal is not working. And maybe you should consider bariatric surgery or something of the like to handle this.

Q:  The ideal combo would be U300 and lixisenatide for a lot of patients. Why wouldn’t you use this?

Dr. Fonseca: Well the simple answer is that you can’t give test two experimental agents at the same time and these two drugs were in the experimental process at the same time so you can’t do that right now. The FDA won’t let you do that. But in the future you may see that there are trials around this and while I don’t like to predict the future often, you could see this coming sometime soon. 

Product Theaters

Diabetes – Treatment and Management (Presented by Sanofi)

Bruce Bode, MD (Emory University, Atlanta, GA)

Dr. Bruce Bode presented a product theater focused on Sanofi’s Toujeo (U300 insulin glargine), highlighting its gradual and stable insulin release, A1c reductions, and safety profile. Dr. Bode first opened by stressing the complexity of type 2 diabetes treatment and the ADA 2017 guidelines’ various therapeutic options. He also stressed the importance of discussing insulin early in people with diabetes, highlighting the progressive nature of the disease and the need to dispel negative myths of the progression to insulin as an indicator of failure. Moving to present Toujeo, Dr. Bode emphasized its reduced injection volume, smaller precipitate, and gradual insulin release. He shared much of the clinical data from the EDITION study program, dosing recommendations, safety information, and warnings and precautions. Closing the product theater, Dr. Bode additionally mentioned the accompanying COACH support program and Sanofi’s co-pay card.

Questions and Answers

Q: Any differences between hypoglycemia for Lantus vs. Toujeo?

A: I was a researcher in several of these trials. EDITION 1 and 2 showed significant reductions in hypo. In EDITION 3 and 4, there was a trend toward hypoglycemia but it was not significant.

Q: What’s your experience of Toujeo in practice?

A: It’s very easy to get. I rarely get denials up until the launch of the new insulin from Lilly. Basaglar and Tresiba are covered. And coupons can be used for Part D.

Q: What’s the accuracy and variability of the pen device?

A: It’s more precise than giving a syringe. That’s been true since pens have been developed. Pens’ accuracy is quite accurate.

Q: What would you do with other oral agents?

A: Always stop SFUs – it impairs the ability to titrate insulin without causing hypoglycemia. Always keep metformin, if the patient can tolerate it. I’ll also generally keep GLP-1s and SGLT-2s.

Q: When should I change Lantus to Toujeo?

A: Based on the label, when you are not getting control at night, especially for type 1 diabetes. If you’re not yet at goal, Toujeo’s a good choice.

Clinical Data Review – Comparing the Safety and Efficacy of Two Once-Daily Basal Insulins in Patients with Type 1 and Type 2 Diabetes

Carol Wysham, MD (University of Washington, Spokane, WA)

In this Novo Nordisk-sponsored product theater, Dr. Carol Wysham reviewed the data from the SWITCH 1 and SWITCH 2 trials demonstrating significant reductions in hypoglycemia with Novo Nordisk’s Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine). In SWITCH 1, Tresiba was associated with 11% less severe and symptomatic hypoglycemia, 36% less nocturnal hypoglycemia, and 35% less severe hypoglycemia than Lantus in patients with type 1 diabetes. In SWITCH 2, Tresiba was associated with 30% less severe and symptomatic hypoglycemia and 42% less nocturnal hypoglycemia than Lantus in patients with type 2 diabetes. Novo Nordisk announced in its 1Q17 update in May that the EMA has approved a label update for Tresiba based on the SWITCH results; a corresponding FDA decision is expected by September 2017. Novo Nordisk has also submitted data from DEVOTE (which demonstrated an impressive 40% reduction in severe hypoglycemia and 53% reduction in nocturnal severe hypoglycemia with Tresiba compared to Lantus) to the FDA and the EMA.  Novo Nordisk is clearly hoping that these label additions will help give Tresiba an edge over its most direct competitor, Sanofi’s Toujeo (U300 insulin glargine), which has no hypoglycemia claim in its label.

Questions and Answers

Q: Why is Tresiba not recommended in pediatric patients needing less than five units?

A: It wasn’t studied and I assume you couldn’t use that pen for that amount of insulin.

Q: Why was the fasting plasma glucose goal so low?

A: Those were the goals used in several other basal insulin studies and they found that it was a safe goal. Almost all the trials that targeted a glucose <100 mg/dl never achieved a level below 115-120 mg/dl, so the goal was to get fasting glucose more consistent.

Q: Why were the results taken at the end of the maintenance period?

A: We were looking not at what might happen during the time when we were rapidly changing the dose but assuming that during the maintenance period the dose would be fairly consistent, so the groups would be most comparable.

Q: What was the conversion for patients with type 2 diabetes on BID basal insulin?

A: Patients already on once-daily basal insulin were converted unit per unit. If they were on twice-daily insulin, the recommendation was to decrease it, although it was individualized by A1c and frequency of hypoglycemia.

Q: Why did the Tresiba trials not show A1c superiority to glargine?

A: Remember that the original trials of glargine against NPH didn’t show superiority either. The investigators had guidelines and were told to titrate to get to goal. They made the decision on whether to titrate based on strict criteria, so this result was expected. In order for hypoglycemia rates to be compared, you had to have equivalent A1c reductions. Otherwise you couldn’t really meet the FDA requirements for understanding hypoglycemia rates.

Q: Was there any difference in the types of oral medications in SWITCH 2?

A: No, the patients were pretty well balanced.

Q: In SWITCH 1, was there any difference in the timing of injections?

A: The recommendation was to give it at the same time every day but the investigators were given some leeway. Because they were comparing Tresiba to glargine, they were asked to give it at the same time every day.

Q: Was there a difference in dosage?

A: In SWITCH 1, in order to achieve the same A1c, a 3% lower dose of Tresiba was required. In SWITCH 2 it was a 4% lower dose.

-- by Melissa An, Ann Carracher, Abigail Dove, Helen Gao, Divya Gopisetty, Varun Iyengar, Stephanie Kahn, Nancy Liu, Payal Marathe, Emily Regier, Yrenly Yuan, and Kelly Close