March 23-26, 2019; New Orleans, LA; Days #1-2 Highlights – Draft

Hello from New Orleans! ENDO 2019 kept our team busy all weekend, and we’re delighted to bring you our very top highlights from the first few days of the meeting. Below, you’ll find key data for AZ’s Farxiga in type 1 and Novo Nordisk’s oral semaglutide, important guideline news and discussion, and so much more. Check back soon for more coverage (see our preview for a sneak peek at what’s coming).

Top Eight Highlights

1. DEPICT Post Hoc of BMI ≥27 kg/m² Shows Meaningfully Lower DKA Risk with Farxiga Compared to Overall Cohort: 1.7% on Farxiga vs. 1.0% on Placebo Experienced DKA

A risk/benefit analysis of DEPICT-1 and DEPICT-2 demonstrated that patients with a BMI ≥27 kg/m² experienced less DKA than the overall, pooled population, while efficacy and CGM-based outcomes were similar between the ≥27 kg/m² subgroup and the entire cohort. In the entire pooled population from both DEPICT studies over 52 weeks, 4.0% of participants on Farxiga and 1.1% on placebo experienced DKA (4.6 and 1.3 events per 100 patient years; definite DKA events only). However, in the subgroup of patients with BMI ≥27 kg/m², only 1.7% on Farxiga and 1.0% on placebo experienced DKA (1.9 and 1.2 events per 100 patient years) – wow! Of note, this analysis includes 51% of the total Farxiga group (n=272) and 54% of the total placebo group (n=289), with similar baseline characteristics and demographics between the treatment groups. We find it particularly encouraging that >half of total DEPICT participants comprise this analysis, both (i) supporting the notion that this trend is real and (ii) reflecting that a truly substantial proportion of type 1s stand to qualify for use of the therapy if and when restricted to those ≥27 kg/m².

Among the authors of this poster are Drs. Chantal Mathieu, Paresh Dandona, and Moshe Philip, and we’re thrilled that the DEPICT team got this analysis out so quickly following a February 1 opinion from EMA’s CHMP that recommended approval of the type 1 adjunct for adults with a BMI ≥27 kg/m² with drug initiation and supervision by physicians experienced in type 1. CHMP has put forth an equivalent opinion for Sanofi/Lexicon’s sotagliflozin (this came a month later), and EMA is expected to grant final approval to both SGLTs for type 1 within 1H19. The BMI requirement came as a surprise to many given a lack of previous emphasis on BMI as a mediator of DKA risk, and it was also a point of critique at ATTD 2019. However, these data show that there is, indeed, substantial merit to the restriction recommended by CHMP – bravo to the agency for zeroing in on a salient and clinically useful selection criterion. Farxiga for type 1 remains under review at FDA, and we’ll be extremely curious to see how this data might impact discussion at a possible Advisory Committee meeting (and FDA’s final decision). FDA just issued a CRL for sotagliflozin for type 1.

• Participants with BMI ≥27 kg/m² saw efficacy with Farxiga similar to the entire pooled cohort. Placebo-adjusted A1c reduction with Farxiga was 0.43% at 24 weeks (95% CI: -0.55, -0.31) and 0.34% at 52 weeks (95% CI: -0.48, -0.19). Body weight loss was 3.1 kg (~6.8 lbs) at 24 weeks and 3.6 kg (~7.9 lbs) at 52 weeks with Farxiga (placebo adjusted). Placebo-adjusted difference in mean time in range was 9.7% at 24 weeks, translating to an additional 2.3 hours in range on Farxiga, with no increase in time <70 mg/dl. And on the composite endpoint of ≥0.5% A1c reduction without severe hypoglycemia, the odds ratio with Farxiga vs. placebo was 3.52 (95% CI: 2.39-5.21) at 24 weeks and 2.63 (95% CI: 1.78-3.88) at 52 weeks. There was also a trend toward less hypoglycemia with Farxiga in the ≥27 kg/m² subgroup: The exposure-adjusted incidence rate for severe hypoglycemia was ~16 events per 100 patient years with Farxiga, compared to ~24 on placebo.

• On average (mean), participants in the BMI ≥27 kg/m² groups (Farxiga and placebo) were 45 years old, 42%-50% male, and had a BMI of ~32 kg/m² – we’re curious how this relatively high BMI impacted results. Are those with a BMI of 27 at greater risk of DKA compared to those with a BMI of 32 kg/m²? We doubt DEPICT had enough DKA events to be sensitive to a continuum of risk, but we do think this is an important clinical question and we’ll be interested to see how else researchers can parse out DKA risk. Average total daily insulin dose was 71-72 units, duration of diabetes 21-22 years, and A1c 8.4%; 42%-44% were on pump therapy and 28%-32% used CGM. 

2. Poster Displays Full PIONEER 3 Results: 14 mg Oral Semaglutide Shows Significant A1c and Weight Loss Benefits vs. DPP-4 Sitagliptin; ~12% of Patients on 14 mg Discontinue Therapy Following AEs

Novo Nordisk presented full results from PIONEER 3 (oral semaglutide vs. sitagliptin) on a poster, adding more granularity to the topline data released last June (JAMA publication and editorial from Dr. Irl Hirsch). The company just submitted its first-in-class oral GLP-1 agonist to FDA, and given the use of a priority review voucher, a decision is expected in six months, by September 2019. Notably, this poster shared specific numbers from the trial’s primary intent-to-treat (ITT) analysis, whereas the topline release focused more so on the secondary on-treatment analysis. FDA will use the ITT in its evaluations (this follows all participants, even if they discontinued medication or needed rescue therapy); key efficacy data is summarized in the table below. Baseline A1c was ~8.4%. The higher doses of oral semaglutide (7 mg and 14 mg) showed significantly superior A1c-lowering after 26 weeks, with estimated treatment differences vs. sitagliptin (Merck’s DPP-4 inhibitor Januvia) of 0.2% and 0.5%, respectively (both p<0.001). Only the 14 mg dose demonstrated significant A1c benefit after 78 weeks (1.5 years), with an estimated treatment difference of 0.4% (p<0.001). A1c reduction was significantly inferior with 3 mg oral sema vs. sitagliptin after 26 weeks, which highlights dose-dependent potency of Novo Nordisk’s newest GLP-1 candidate. Management has mentioned to us in the past that they’ll submit 14 mg oral semaglutide to FDA, but there was no confirmation in the company’s NDA announcement of which dose(s) were filed. Even weight loss proved to be dose-dependent in PIONEER 3 (and other PIONEER trials): After 26 weeks, the highest dose of oral semaglutide gave ~2 lbs more weight loss vs. the 7 mg dose, and after 78 weeks, it still gave ~1 lb additional weight loss. The injectable formulation of semaglutide is currently under investigation for obesity (the phase 3 STEP trials and SELECT CVOT), and we’ll be curious to see how oral semaglutide is leveraged for its pronounced weight loss benefits as well. Despite some concerns over the tolerability of oral semaglutide (more on this below), we are very confident that this treatment will be approved for type 2 diabetes, and we’re terribly excited.

PIONEER 3 Summary of Results (Intent-to-Treat Analysis)

*p<0.001 favoring oral semaglutide. **p<0.05 favoring sitagliptin. ***p<0.05 favoring oral semaglutide.

• Unsurprisingly, GI symptoms were more common with the GLP-1 vs. DPP-4 and were also dose-dependent, affecting 32%, 35%, and 42% of participants on 3 mg, 7 mg, and 14 mg oral semaglutide, respectively, vs. 32% of those on sitagliptin. Moreover, 12% of patients randomized to 14 mg oral sema discontinued the medication due to adverse side-effects, compared to only ~6% of patients taking the lower doses and only 5% of patients on Januvia. The main criticism of on-treatment analysis is that it excludes data from participants who dropped off therapy, thereby inflating efficacy results by ignoring adherence challenges. It was reassuring to see that the ITT findings from PIONEER 3 were largely similar to the on-treatment findings. That said, adherence will only be more difficult in the real world compared to an RCT setting, and to this end, we wonder if having multiple doses of oral semaglutide on the market would ease patients through the GI side-effects and allow for smooth up-titration. The PIONEER 3 poster emphasized that the most common GI symptom was mild/moderate nausea, and that this nausea was transient.

• Overall adverse events were balanced across all treatment arms in PIONEER 3. Severe AEs occurred in 10% of patients on 3 mg oral sema, 8% of patients on 7 mg oral sema, 9% of patients on 14 mg oral sema, and 11% of patients on Januvia. Hypoglycemia was numerically more common with sitagliptin vs. any dose of semaglutide (8% vs. 5%-8%), though the difference was not statistically significant (and we’d add that both DPP-4s and GLP-1s come with low hypo risk due to their mechanism of action).

• PIONEER 3 enrolled 1,864 patients with type 2 diabetes and ran for 83 weeks total. Week 78 marked the end of the treatment period, with a low, medium, or high dose of oral semaglutide, or with sitagliptin. All pills were taken once-daily in the morning.

3. Real-World Observational Study (n=93) of MiniMed 670G in Children/Adolescents Finds 38% Discontinuation Rate; For Those Who Continued, A1c Reductions (~0.3%) at Six Months Not Maintained at 12 and 24 Months

Boston Children’s Hospital’s Dr. Gregory Goodwin presented results from a real-world observational study (n=93) of Medtronic’s MiniMed 670G in children and adolescents (average age: 17.2 years) showing high rates of discontinuation (nearly 40%). All participants were on pumps prior to the study and received dedicated 670G training, consisting of a two-hour initial clinic visit, a two-week follow-up visit, during which Auto Mode was initiated, a 4-6-week follow-up visit with a diabetes nurse educator, and quarterly follow-ups thereafter. Despite the large degree of support, ten patients (11%) never initiated Auto Mode, with the predominant issue being sensor difficulties. Of those who continued into Auto Mode, an additional 25 participants (27%) withdrew from the study, amounting to a total discontinuation rate of 38%. As Dr. Goodwin noted, this rate stands in significant contrast to clinical trials finding withdrawal rates closer to 5% – we wonder if the nearly 8x rate of discontinuation in this study had more to do with demographics, degree of follow-up/support in previous trials vs. this study, or something else. Average time to withdrawal from the study was 2.5 months, and participants mostly commonly cited frequent alarms, forced exits, and calibration requirements as reasons for discontinuation. Withdrawals were more common in older patients, as the mean age of those who stopped using the system was 18.4 years (just over the threshold of college age, unsurprisingly) vs. 16.6 years for those who stuck with it. Dr. Goodwin concluded that “more user-friendly technology” is needed for widespread, effective use of hybrid closed loop systems in type 1 diabetes. While we fully agree that more user-friendly tech will benefit greater swathes of the population, it’s hard to ignore the fact that 670G is a first-generation system that FDA approved in ~three months based on a single-arm study; perfect first-to-market systems are rarely expected to be perfect. Medtronic has a rich closed loop pipeline which promises to push its offerings in the direction of user-friendliness one year out and beyond (and has already enhanced the Guardian Sensor 3 transmitter so that it doesn’t require as much user interaction). Nearer term, Tandem’s Control-IQ, slated for a US launch between “summer and end of Q3 (September),” will provide the first FDA-approved hybrid closed loop in the US that leverages the factory-calibrated Dexcom G6 and TypeZero’s (Dexcom) algorithm with automatic boluses. Future systems promise to make meaningful gains along the adoption curve.

• Patients who did remain on the 670G (n=58) saw modest outcomes. While A1c significantly declined by 0.27 percentage points (baseline: 8.0%) at six months, statistical significance was not maintained at 12 or 24 months. Still, Dr. Goodwin pointed out a significant association was shown between lower A1c and greater time in Auto Mode. Average 670G duration of use was 9.6 months, making this study the “longest longitudinal follow-up” of the system to Dr. Goodwin’s knowledge.

  • Dr. Goodwin also pointed out the “very wide range” for time in Auto Mode, which averaged 50% but spanned from 5%-90%.

4. Drs. Buse and Wilt Debate ADA vs. ACP Guidelines for A1c: Is there a Benefit to Targeting <7%?; Considering RCT Evidence, Target vs. Achievement, Cost Effectiveness, and Practical Implications

Drs. John Buse and Timothy Wilt debated the resolution, “A reasonable A1c goal for many nonpregnant adults is <7%.” While Dr. Wilt sought to construct an argument that an A1c <7% has not been associated with any meaningful, long-term outcomes benefit, Dr. Buse aimed more to illustrate the practical function and implications of an A1c target – and why it’s beneficial for many to target <7%. Importantly, this debate was focused on type 2 diabetes. As Dr. Marie McDonnell pointed out in moderating the debate, virtually all professional guidelines leave room for patient-tailored targets. In his rebuttal, Dr. Buse said, “There’s no dichotomy between the major statements of both organizations. For many, <7% is reasonable. For most, 7%-8% is good.” Indeed, Dr. McDonnell closed by asking whether the question is one of semantics: “It occurs to me that when we set up a target, we often don’t arrive at it. If it’s <7% in a trial, we might get to 7.5%. Could you discuss target vs. achievement?” In response, Dr. Buse said that this was actually the root issue, quipping that “clearly I didn’t make that point strong enough” (for reference, an audience vote that began at an ~80/20 split in favor of <7% and ended at ~60/40). Below, we outline each presenter’s argument:

Dr. Buse concluded that the crux of achieving optimal diabetes outcomes is the attained A1c and how it is approached – an A1c goal of <7% is “fundamentally a tactic” aimed at achieving lower average A1c: “I do think a target of <7% is a tactic to get to 7%-8%, which I do think is a reasonable A1c. One of the slides I didn’t show is data from Scandinavia showing that if average A1c achieved over 20 years is 7.5% or less, there are almost no clinically meaningful microvascular complications. The fear is that the average A1c is going to be 7.8% or 7.9%, not the 7.4% it’s at now,” and that will lead to more complications and poorer quality of life for patients. This is precisely the reaction we had when these guidelines were released: The ACP statement gives little guidance for personalization (or use of CGM or newer therapy classes), making it easy to apply a 7%-8% target to all type 2s and allowing population-level rises in A1c. Evidence aside, we appreciated one of Dr. Buse’s closing remarks: “Would you as an individual aim for an A1c target of <7% if you had diabetes?” We suspect most in the room would have answered yes.

• Dr. Buse demonstrated that the statement is question is self-evidently true: There are many individuals for whom an A1c <7% is reasonable. He presented data from the Carolina Data Warehouse (~12 hospitals and 200 practices in NC, n>70,000). Overall, 50% were already achieving an A1c <7%. Among three key groups – (i) those who already have an A1c <7% without adverse events and >10 year life expectancy (~20% of total population), (ii) women of childbearing potential (~10% of total population), and (iii) people with CVD or CKD (~50% of total population) – 39%, 42%, and 50% were already achieving an A1c <7%, and many more could get there safely (not on insulin or SUs).

• Dr. Buse also explained that changing the A1c target to <8% could dramatically reduce clinician ability to prescribe lifesaving drugs for patients. He showed that many current prior authorization forms require that a patient has an A1c ≥6.5%, based on the ≤7% target from ADA/EASD. If a shift toward higher recommended A1c took place, and that translated to prior authorizations, it would disqualify many patients already “doing well” from being able to use newer, better therapies – including those used for CV risk reduction in addition to glucose lowering (GLP-1s and SGLT-2s).

Dr. Timothy Wilt, who helped author the ACP’s contentious 2018 guidelines, argued that a target of 7%-8% for most people with type 2 diabetes incorporates both clinical and patient values, but he also left room for personalization based on patient discussion, preferences, health, and life expectancy plus costs of care and treatment burden. Interestingly, he commented, “My primary care colleagues and a large majority of the patients I treat were thankful and receptive of the recommendation.” One key issue emerged later in his presentation: With pay for performance measures, HCPs are currently asked to target an A1c of 7% in a 65 year old on three drugs with an A1c of 7.5% – and we certainty agree with Dr. Wilt that rigidity of these guidelines is a huge problem. But should we be more flexible with all type 2s? In evaluating the benefits vs. harms of specific A1c targets, Dr. Wilt ran through ACCORD, ADVANCE, UKPDS, and VADT: By his characterization, two of these showed no benefit (ADVANCE, VADT), one mixed or small benefit (UKPDS – insulin/SU and metformin arms), and the last showed harm (ACCORD). To be fair, as Dr. Buse pointed out, the early stopping of ACCORD for harm taught us not to blindly lower A1c with reckless ambition; we also feel that all of these trials would be designed very differently if conducted with modern medicine and technology, and many question whether they created a big enough glycemic divide to show any difference: Is there no benefit simply because it has not been demonstrated in type 2 diabetes? Nevertheless, Dr. Wilt did aptly point to a fairly large gap in the RCT evidence, and he further cited the harm that lower A1c targets can cause – namely, higher healthcare burden, costs, and increased adverse events.

• Dr. Wilt strongly emphasized the importance of cost-effective and cost-conscious care, and this is where the two speakers seemed to diverge most strongly: Is it more cost-effective to lower glucose to <7% with a pricier GLP-1 agonist (potentially causing weight loss, preventing CV events, avoiding hypoglycemia and hospitalizations) or to target 7%-8% with NPH or premix insulin (a cheaper medication but one associated with more hypoglycemia – which is not necessarily A1c dependent – and weight gain)? To be sure, this hypothetical vastly over-simplifies a complex debate, but it seemed to us that Drs. Buse and Wilt were taking disparate stances on this question. We certainly agree with Dr. Wilt’s assertion that diabetes medications cost a lot, US healthcare is poor value, and high list prices are contributing to sky-high healthcare costs – he specifically questioned the near-ubiquitous use of insulin pens, “how much are we willing to pay for convenience?” But while Dr. Buse asserted using newer, pricier therapies like GLP-1s and SGLT-2s up-front prevents costly complications down the line, Dr. Wilt directly questioned the data supporting their cost-effectiveness and whether they would meet ICER’s $150,000/QALY threshold.

5. Endocrine Society Guidelines for Older Adults Recommend Individualized Glycemic Targets (Deprioritizing A1c) and Hypoglycemia Minimization

The Endocrine Society just published a Clinical Practice Guideline on Treatment of Diabetes in Older Adults (press release); following an overview of the guidelines from Dr. Derek LaRoith, Dr. Anne Peters moderated a series of case-based discussions between three members of the writing committee – Drs. LeRoith, Marie McDonnell, and Mark Molitch – designed to elucidate key takeaways from the new guideline. Epidemiologically, the guidelines emphasize that prediabetes is particularly prevalent in older people, but, positively, interventions aimed at diabetes prevention are very effective in this group. Similarly, type 2 prevalence increases with age, driving microvascular and macrovascular complications. As such, regular screening for prediabetes and diabetes is important. The guidelines emphasize shared decision-making and individualization as key, given heterogeneity in the health of older individuals. They also note the unique issues affecting older individuals with diabetes: sarcopenia, frailty, and cognitive dysfunction, all of which can contribute to lower treatment adherence, hypoglycemia risk, falls, and loss of independence. As the overall and diabetes populations age, the ability of endocrinologists and PCPs to effectively and safely treat older individuals with diabetes and prediabetes is only going to become more important, and we’re glad to see this focus from The Endocrine Society. Read on below for key takeaways from the five cases presented.

• Screening: In what Dr. Peters characterized as the most surprising recommendation, the guidelines advocate for a 2-hour, 75 g oral glucose tolerance test (OGTT) as the best test of diabetes in older individuals. While the panelists were sympathetic to the challenge such a test poses to many patients – both in terms of comfort and time – Dr. McDonnell explained that the literature is very clear that the diagnostic specificity and sensitivity of A1c declines with age. Using A1c (or FPG) alone runs the risk of missing diabetes diagnoses in older adults, and this is most relevant to those at highest risk of diabetes. Dr. McDonnell explained that clinical judgement is also important – in an individual with metabolic syndrome, high triglycerides, low HDL, and an A1c of 6.2%, an OGTT is highly recommended. On balance, however, Dr. Molitch commented that both accuracy and convenience are important: ADA moved to include A1c in its diagnostic criteria because it’s easy. And while not all clinicians will move to use the OGTT commonly, he said it’s important to recognize that A1c is not as accurate in older adults. Dr. Peters added that how much information the patient wants is also important – in this case, a highly-functional and engaged 78 year old woman was presented, and Dr. Peters commented that a diabetes diagnosis would change how she would treat the patient. After all, as Dr. LaRoith explained, a precise diagnosis will have a meaningful impact on both treatment and what medications can be prescribed.

• Glycemic Targets: Blood glucose targets are prioritized over A1c (particularly in light of lower accuracy, above), and glycemic targets should be chosen via shared-decision making based on assessment of the patient’s overall health. The panelists endorsed the established concept of “bucketing”  or “grouping” patients into good, intermediate, and poor health to help determine A1c targets. The idea of an “A1c floor” was keenly addressed, particularly for patients on hypoglycemia-causing medications – if an older adult has an A1c of 6.5% on nothing that can cause hypoglycemia (SUs or insulin), that’s great. Dr. LeRoith explained that targets can also move: Particularly when starting at a higher A1c, it’s best to lower gradually and proceed carefully.

• Medication Selection and Hypoglycemia: In those over 65 years old, outpatient diabetes regimens should be specifically designed to minimize hypoglycemia risk. Glycemic targets should be tailored to overall health and management strategy, regardless of medication used. The panel considered an 80 year old woman (BMI 24.3 kg/m², eGFR from 60 to 30 in past two years) with 20+ years of type 2 diabetes who is careful about food, medications, and exercise; she’s been on basal-bolus for 10 years but has decreased appetite, is alone most of the day, and is having mild hypoglycemia several times a week. While the audience poll suggested switching to basal insulin plus a DPP-4 inhibitor, Dr. Molitch did question whether a DPP-4 would be effective after 20 years of diabetes, explaining that a post-meal reduced dose of prandial insulin could also be an option. Due to decreased appetite and normal BMI, he warned against a GLP-1 (and did the same for metformin due to GFR) and emphasized that serious consideration should be given to raising glucose targets. Dr. McDonnell highlighted the value of CGM for figuring out exactly what’s happening. One danger, the panel said, is that patients can be seriously insulin deficient – and taking them off insulin can do more harm than good. Per Dr. McDonnell, insulin production in older adults is often not just low, but late and inefficient (C-peptide can be useful if “insulin therapy doesn’t necessarily match the natural history of the disease”). Dr. Peters noted value in caregivers for insulin dosing but also in simplified insulin regimens (e.g. 2x daily dosing).

• Lipids: In those 65 years and older, statin therapy and an annual lipid profile are recommended for reducing CV and mortality risk. No specific LDL-C targets are recommended in this guideline, though the authors do recommend generally less strict LDL-C targets for those ≥80 years old with short life expectancy. See diabetes-specific cholesterol guidelines from AHA/ACC.

• Blood pressure: In those 65 years and older, an ACE inhibitor or ARB should be used as first-line therapy. For those 65-85 years old, a target of 140/90 mmHg is recommended to decrease CV and renal risk. Higher-risk groups (previous stroke, progressing CKD, albuminuria) can be considered for a lower, 130/80 mmHg target, at which point monitoring and screening for orthostatic hypotension is important. Conversely, a higher target may be considered for those with high disease complexity and poor health (145-160/90 mmHg), and shared decision making is always important. Dr. McDonnell praised ADA and other organization for not applying the SPRINT trial and a 130/80 mmHg target to diabetes universally, noting that autonomic neuropathy common in patients with diabetes can lead to negative side effects when blood pressure is too low.

6. Dr. Paresh Dandona Presents New Topline 26-Week Data on Liraglutide for Type 1, Teases Triple Therapy Study of Insulin/Semaglutide/Dapagliflozin (n=114) Funded by JDRF

Following presentation at ADA 2018 of a promising year-long study of liraglutide in type 1, Dr. Paresh Dandona detailed similarly inspiring results from a separate 26-week study in type 1s with overweight and obesity. This JDRF-supported study randomized 64 type 1s with overweight and obesity to either liraglutide (n=37) or placebo (n=27). Significant improvements with liraglutide vs. placebo were seen on A1c (~0.4% treatment difference), time in range, time in hyperglycemia, weight loss, total fat percentage by body composition, systolic blood pressure, fasting and postprandial endogenous GLP-1 levels, and several biomarkers of inflammation, favoring liraglutide. Please note that hard numbers were not provided for much of this data.

• A trend toward an increase in time in hypoglycemia was seen with liraglutide treatment, but this difference was not significant. We note that hypoglycemia events were balanced across all groups in data presented by Dr. Dandona at ADA 2018; however, this only included CGM data from four weeks compared to 26 weeks in this study. During Q&A, Dr. Cecilia Low-Wang pressed on this issue, and Dr. Dandona highlighted that “we have not had one patient leave this drug because of a hypoglycemia effect.” Dr. Low-Wang also asked about the insulin titration protocol that Dr. Dandona uses with these type 1s on liraglutide, and he detailed that while both basal and prandial insulin doses fall, he tries to stick to mainly minimizing prandial insulin doses, since this is where liraglutide exerts most of its effect (i.e., postprandial glucose lowering).  

• Weight loss with liraglutide was entirely via body fat composition and not in lean body mass. Dr. Dandona noted that this was one of the most exciting results of the study. Total fat mass significantly declined in the liraglutide group compared to placebo, while lean body mass was unchanged in both groups. Visceral adipose tissue (VAT) also significantly fell in the treatment group. Dr. Dandona explained that this finding of VAT decline is actually the first clinical evidence of the phenomenon, as similar data has not been shown in type 2 studies yet. Mechanistically, it was also seen that levels of UCP2 – a protein associated with increasing the metabolic state of fat cells – was also increased in the treatment group. This increase was associated with an elevation in CPT1 level, which is an enzyme that transfers free fatty acids across the mitochondrial membrane to the mitochondrial matrix and causes increases in fat burn.

• Dr. Dandona highlighted the increase in endogenous GLP-1 level with liraglutide treatment as a “very remarkable effect.” Significant increases in fasting and postprandial endogenous GLP-1 levels were associated with liraglutide treatment. Dr. Dandona hypothesized that there “must be some positive feedback regulator” responsible for this effect and pointed toward preliminary data from in vitro studies that show incubating islets with GLP-1 increases GLP-1 secretion. Interestingly, this data also implies that there may be local GLP-1 secretion from islets as well – this point got a murmur of surprise from the audience.

• Very excitingly, Dr. Dandona divulged that JDRF has just funded his group to complete a triple therapy study of insulin/semaglutide/dapagliflozin in type 1 diabetes. He also noted that this is the largest grant the JDRF has ever given for a study – wow! The trial will be 52 weeks long and will enroll 114 people with type 1 diabetes. A 2:1 randomization protocol will be used, with a control group of 38 patients using standard of care insulin therapy. In the treatment arm, 76 patients will be assigned to an insulin therapy + semaglutide (Novo Nordisk’s Ozempic) arm for the first 26 weeks of the study, which is notable in and of itself. After 26 weeks, half of this arm will also have dapagliflozin added, while maintaining insulin and semaglutide. No further detail on endpoints or expected completion date were shared, but we’re extremely excited nonetheless. Dr. Dandona expressed the hope that “we can get 60-70% of type 1s under 7.0% A1c” with triple therapy – this would surely be a smashing success! On balance, however, we imagine that using triple therapy in type 1 takes a tremendous amount of care and expertise from both patient and provider (as does using just one adjunct therapy). Questions abound: How effective will semaglutide – a much longer-acting GLP-1 than liraglutide – be on glucose and weight in type 1? How will semaglutide and dapagliflozin interact in type 1, particularly on insulin requirements and DKA and hypoglycemia risk? Is there a specific reason semaglutide and dapagliflozin were chosen amongst the wide variety of GLP-1s and SGLT-2s available?

• Dr. Dandona noted that he has “the world’s largest number of type 1s on liraglutide” and that they like the drug so much that they refuse to leave it. Dr. Dandona joked that these patients “are addicted to liraglutide” because of the drug’s efficacy and impact on glycemic variability. We’re glad to see this sustained excitement and use of liraglutide in type 1, even after Novo Nordisk has declined to further pursue the therapy in this population following middling results in the ADJUNCT ONE and ADJUNCT TWO trials. Just last week at ENDO Fellows 2019, we heard similar enthusiasm from Dr. David Harlan on GLP-1s for type 1 – Dr. Harlan detailed that he uses this therapy in almost all of his patients with diabetes who show measurable C-peptide. Considering this enthusiasm from patients and providers, we really do hope to see larger scale studies of GLP-1s in type 1 diabetes. At the very least, we imagine that positive data like this from Dr. Dandona’s group will help liraglutide become a more popular adjunct therapy in type 1, especially with a generic version set to hit the market in 2023.

7. Endocrine Society Commissions Task Force to Develop Innovative Models of Care; Dr. Robert Gabbay Address HCP Burnout; 1.4% A1c Reduction Just From co-PCP/Pharmacist Diabetes Management?

In a session chaired by Joslin’s Dr. Robert Gabbay, we learned that the Endocrine Society has commissioned a task force to examine innovative models of care. As Dr. Gabbay asserted, such innovation can help to tackle the concerning amount of physician burnout in the US by “reconnecting to the joy and work that had us follow this career in the first place.” The impact of burnout, Dr. Gabbay explained, is widespread, affecting physicians both professionally and personally – he reiterated that, every day in the US, a physician commits suicide. Dr. Gabbay identified five major themes that can help to mitigate burnout: (i) finding meaning; (ii) having a sense of autonomy; (iii) comradery; (iv) equity; and (v) co-creating solutions. Interestingly, the degree to which these themes must be fulfilled is fairly small: evidence suggests that physicians who spend at least 20% of their professional effort focused on work they find “most meaningful” are at a “dramatically” lower risk for burnout. In fact, a ceiling effect at 20% is observed, meaning that physicians who spend even 50% of their time on meaningful pursuits are no less at risk of burnout than those who spends 30% of their time. How can physicians get to that 20%? Dr. Gabbay outlined four (easier-said-than-done) steps: (i) identify a passion; (ii) make a business case; (iii) speak to administration; and (iv) seek out funding if needed. The need to make a business case was particularly emphasized during the session. We were intrigued by a question from an audience member positing whether medical education should be revamped to help future physicians acquire business acumen. Dr. Gabbay responded: “Absolutely. If we’re going to take back our practice, we have to have some knowledge.” See below for examples of innovative models of care presented by members of the Endocrine Society taskforce.

• Vanderbilt University Medical Center’s Dr. Michelle Griffith described how her health system is using direct-to-patient telemedicine to improve patient outcomes while also enhancing physicians’ experiences. A nationwide survey (n=4,345) on attitudes surrounding telemedicine in primary care indicated that 52% of respondents would like to see their own provider via telemedicine. 15% would consider leaving their current provider to see one who offered telemedicine. For endocrinologists, telemedicine improves space utilization, increased efficiency for certain types of visits, allowed for greater practice variety, and served as a practice differentiator. After initiating telemedicine at Vanderbilt, 91% of patients felt satisfied overall and 81% indicating feeling a connection with their provider equivalent to an in-person visit. We think telemedicine will play a major role in diabetes management given the need for high-touch care. Moreover, endocrinologists are at high-demand – we were shocked to hear that there are “zero or one” endocrinologists in the state of California between Sacramento and the Oregon border. For patients living in this area, having access to an endocrinologist via telemedicine could literally be life-changing. The big hurdle for telemedicine today – according to a Rock Health survey and JAMA letter – is moving adoption beyond young, urban-dwellers toward less mobile populations in more remote locations.

• Parkview Health’s Dr. Jeffrey Boord advocated for co-management of diabetes between primary care physicians and pharmacists. This solution has been implemented at Parkview Health, and according to Dr. Boord, “patients really like having another person helping,” and “the primary care physicians love it.” In this model, clinical pharmacists focus on patients’ diabetes management, developing individual care plans, providing education, initiating therapy, and monitoring patient adherence. As Dr. Boord put it, pharmacists are “masters of barrier removal,” as they are uniquely equipped to navigate the complex web of formularies and prior-authorizations, as well as consider and respond to factors like reluctance and affordability. Outcomes at Parkview have been very strong: at just three months, patients saw an A1c reduction of 1.4% (baseline A1c: 9.8%). We think this is a great model – it allows primary care physicians to focus on the myriad other healthcare concerns that arise in a general doctor visit, while still providing patients with access to high-quality diabetes care.

• Other examples of innovative models that were presented included team-based care, a transfer summary for pediatric to adult transitions in care, and electronic consults (eConsult). The eConsult essentially formalizes the work that many specialists already do for primary care physicians. PCPs routinely will ask for specialists’ advice via email. With eConsult, the process is recorded and, more importantly, can be billed. UCSF’s Dr. Elizabeth Murphy noted that at San Francisco General Hospital, there are over 50,000 eConsults annually, substantially saving time. 50% of endocrine referrals were handled by eConsults and never made it to the clinic. While the proportion is smaller for diabetes (20%-25%), it’s clear that this solution is able to cut down on unnecessary clinic visits.

8. Ms. Davida Kruger Presents Dr. Bergenstal’s Nine Steps to Interpreting CGM; Plans to Bring Direct-To-Consumer CGM Study in Primary Care to Large Health Systems

In a session sponsored by Abbott, Henry Ford Health System’s Ms. Davida Kruger described the nine steps she takes to instigate better patient communication surrounding the AGP CGM data display. [This procedure was first outlined by Dr. Rich Bergenstal at ADA 2018.] Ms. Kruger first recommends checking for adequate data (14-days of readings are ideal). Next, she marks up the AGP with her patients, noting factors that may affect a patient’s individual management plan, such as wakeup, meal, and insulin dosing times. Importantly, prior to offering her own analysis, Ms. Kruger asks patients what they see. She underscored that simply asking is not enough – to reap the full benefits of this step, physicians actually have to listen to the response! Following this brief discussion, Ms. Kruger identifies patterns of hypoglycemia with her patients, ensuring that she is “treating the cloud.” To this end, Ms. Kruger cautioned clinicians against only looking at the darker trace on the AGP, which reflects just 50% of a patient’s glucose readings. Hypoglycemia trends are identified next followed by areas depicting wide glucose variability. In working to mitigate this variability, Ms. Kruger explained that clinicians tend to jump directly to an insulin dose adjustment. However, she underscored that there are many factors that could contribute to such activity. We love Ms. Kruger’s suggestion to then compare the current AGP to past AGPs and reinforce successful strategies. Focusing on what is working, rather than only chastising patients for their mistakes, is a crucial component to Adam’s Bright Spots mentality. Lastly, Ms. Kruger agrees on an action plan with her patients, and then makes copies of the AGP for the patient and EMR. While we recognize that many clinicians new to CGM may find the data overwhelming at first, having a simple nine-step plan will hopefully prove helpful in standardizing their approach.

• During Q&A, Ms. Kruger referenced an ongoing project to introduce CGMs in primary care. We assume she was referring to the Helmsley-funded study conducted by the Jaeb Center in collaboration with Cecilia Health and Wisconsin Research and Education Network, first described at ATTD. As Ms. Kruger explained, the study allows patients to choose their device (Dexcom G6 or Abbott FreeStyle Libre) and initiate the CGM outside the clinic with remote education provided by a CDE. She noted that when the pilot wraps up, the team “hopes to do a huge study.” Large systems including Geisinger and Blue Cross have already “been approached.” At ATTD, Dr. Roy Beck expected to also incorporate decision support tools and mental health support/coaching as the study expands. We’re very excited about the study, which we see as an important stepping stone towards acquiring CGM without a prescription.

Technology Exhibit Hall

Abbott

Abbott’s booth advertised the 14-day FreeStyle Libre, approved by the FDA last July. A screen boasted Abbott’s impressive real-world database, which was featured in an awesome poster at ATTD (see our report). With four years of data from over 470,000 readers, Abbott has amassed 4.8 billion glucose measurements. As the display noted, FreeStyle Libre 14-day users have averaged 12 scans/day, well above the ADA recommendation of 6-10 glucose checks per day for patients on MDI or insulin pump therapy. Affordability was emphasized both at the booth and during the company’s product theater. Indeed, the 14-day FreeStyle Libre still has the lowest startup cost on the US market, as users can purchase one sensor in-pharmacy for ~$60 cash and use the free FreeStyle LibreLink smartphone app, meaning that purchasing a reader is not required. As Dr. Ernest Asamoah (Marian University Osteopathic School of Medicine, Indianapolis, IN) claimed during the product theater, “I’ve used all the CGMs and they’re all great. The difference is the FreeStyle Libre is affordable and a lot of patients are paying out of pocket. This is why the FreeStyle Libre is the gamechanger in diabetes going forward.”

Companion Medical

At the Companion Medical booth, we learned that the InPen has officially launched in retail pharmacies as of March 8. Those with commercial insurance can expect to pay “no more” than $99, and Medicare copays “vary.” Overall, median copays are <$50 – similar to the estimate at JPM, where we heard that this figure was $50. While the representative could not provide a user base update from the 2,000 patients shared at JPM, he mentioned that it is “significantly growing” – we expect that with the added convenience of the recent pharmacy launch, these number will only continue to rise. Companion Medical has also “significantly” expanded its sales team to match the greater anticipated demand. As for the company’s plans for a study of InPen vs. traditional MDI using FreeStyle Libre, the representative shared that it has “already begun enrollment.” The trial will assess time-in-range as the primary endpoint at three and six months.

Dexcom

At the Dexcom booth, we learned that G6 Medicare shipping is estimated to begin this September. This is potentially a delay from timing shared on the company’s 4Q18 call in February, which estimated shipping in the “near-term.” As the booth representative pointed out, it is a responsible decision to delay shipping until supplies are sufficiently robust to support the Medicare population over time. In fact, the representative shared that Dexcom is doubling its manufacturing capacity to meet overall demand. No updates were provided on the lower-cost G6 transmitter, slated to launch in 2H19, or the G7 (Dexcom/Verily Gen 2), for which an initial launch is expected in late 2020.

Glooko

Glooko representatives were excited to discuss the company’s recent decision to make its mobile app free for anyone with diabetes. Previously, there was an annual $59.95 subscription fee for individuals not sponsored through their provider, health plan, employer, or device company. This is an obvious and long-needed strategic move for Glooko. According to the representatives, providers have been “enthusiastic” to speak with their patients about downloading the app. Glooko is rated a strong 4.0/5 star rating on Google Play (913 ratings) and 3.1/5 stars on the App Store (64 ratings). Google Play notes 50,000+ installs.

Insulet

An Insulet booth representative shared that the new Bluetooth-enabled Dash PDM is set to roll out in a matter of weeks, likely aligning with 4Q18 expectations to launch Dash at no upfront cost by the end of 1Q19. Later, management shared that Dash was launched in the pharmacy channel in select areas as part of the ongoing limited market release. Separately, brochure at the booth highlighted the impressive amount of data collected from the Omnipod Horizon hybrid closed loop trials. To date, the clinical program has involved 7,720 cumulative hours of hybrid closed loop from 132 participants. The booth representative confirmed that the pivotal trial is expected to be complete by the end of this year. As of the company’s 4Q18 call, Omnipod Horizon is expected to launch in 2H20 with direct smartphone control on Samsung Galaxy phones. We were also excited to see the brochure describe Insulet’s partnership with Tidepool to develop an automated insulin delivery system using the DIY Loop algorithm. Insulet remains the first and only pump company to partner with Tidepool, although we would not be surprised to see others join. Per the brochure, the Loop algorithm will run on the user’s smartphone and will “activate, control, and deactivate” the pod.

Medtronic

In an update on the specifics of the OUS 670G launch, we learned that the 670G has rolled out to Australia, Austria, Belgium, Canada, Chile, Denmark, Finland, Ireland, Italy, Netherlands, Norway, Slovenia, Spain, Sweden, Switzerland, and the UK, hitting all the countries (and then some) expected for the initial launch as of EASD. According to the booth representative, other areas in South America are slated for a launch “soon,” but as of now no calendar date has been shared. The booth representative noted that Colombia already has approval for the 670G. There were no updates on Medtronic’s exciting slew of pipeline efforts, which include four product launches expected in the April 2019-April 2020 (FY20) window as of JPM: (i) the next-gen “advanced hybrid closed-loop system,” now called the MiniMed “780G,” with automated correction boluses, Bluetooth, and remote software updating; (ii) non-adjunctive CGM claim and iCGM indication for what looked like Guardian Sensor 3 (enabling Medicare coverage); (iii) Guardian Connect on Android (previously expected by this coming April); and (iv) Sugar.IQ “Gen 2” with meal handling and carb counting advice (Nutrino acquisition) and predictive insights going beyond 60 minutes (partly launched last week for hypoglycemia).

• As a side note, we stumbled upon the below graphic on Medtronic Diabetes’ Australia site. For the record, that’s 13,259 cumulative years in range!

Senseonics

The Senseonics booth included a section dedicated to the newly launched Eversense Bridge Program, offering the 90-day Eversense for $99 to eligible patients. A brochure highlighted the easy enrollment process: physicians need only add their interested patients to the Eversense Ordering System portal and check a box indicating that the patient wants to apply for the program. After that, Senseonics takes care of the rest, including confirming available insurance coverage via pre-authorization and appeal services and working with clinics to schedule sensor placements. One clinician visiting the booth commented that while she has done a few insertions, she believes that the 180-day Eversense XL will be the real gamechanger in adoption. While we are inclined to agree, the 90-day version should be sufficiently attractive to garner reasonable uptake. With cash dwindling (Senseonics does not believe it has enough remaining to fund operations through March 2020) establishing a strong user base in the US is more essential than ever. Still, we’re pleased to see Senseonics forging ahead on its rigorous pipeline efforts. A booth representative confirmed that the 180-day US clinical trial for Eversense XL is still enrolling, aligning with 4Q18 comments anticipating enrollment to wrap up in 3Q19. The booth representative expects to see FDA approval and launch for the Eversense XL in the next 18-24 months – the far end being a bit later than we might have anticipated, given the study is estimated for completion in December 2019. The booth representative also touted Eversense’s recently launched integration with Glooko, announced earlier this month.

Tandem

At the Tandem booth, we learned that the t:slim X2 is now available in 11 countries outside the US plus Canada (i.e., 13 countries total). Per the company’s 4Q18 call in February, the Basal-IQ with G6 integration will begin launching internationally this year, but timing will vary country-to-country. The booth representative explained that a key step in this process is acquiring regulatory approval for the Tandem Device Updater (TDU). Booth representatives confirmed expectations to launch a t:slim X2 mobile app for Apple and Android in 2Q19 – towards the end of 4Q18 timing anticipating a broader 1H19 launch. The app will initially offer wireless data uploads from the t:slim X2 pump to t:connect, but wireless smartphone control of the pump remains the ultimate goal for the app. The booth representatives confirmed that the app will be free and will be enabled with a remote software upgrade. While representatives could not comment on the potential for Tandem to launch the Control-IQ/G6 hybrid closed loop with a pediatric indication (6+ years), they confirmed that the pivotal trial in 14+ years is fully enrolled (n=168). Per the 4Q18 call, the study is expected to complete in April and will report data at ADA in June.  As a reminder, Tandem now expects Control-IQ to launch in the US between “summer and end of Q3 (September),” as a brand-new study in 6+ years could enable a pediatric launch out of the gate.

--by Ann Carracher, Martin Kurian, Payal Marathe, Maeve Serino, Brian Levine, and Kelly Close