March 20-23, 2021; Virtual; Day #1 Highlights – Draft

ENDO 2021 is now officially underway. See here for our coverage from the meeting’s pre-conference session on COVID-19 and diabetes and read our top highlights from day #1 below.

Top Omnipod 5 Highlights

With three notable Omnipod 5 study results read out today, we summarize the results from all three in the table below. Below the table, we recap the important product features and anticipated launch timing for Insulet’s hybrid closed loop system. Effectively, what illuminated about the studies was the efficacy, the ease of use, and the safety, shown by better A1c/TIR, the qualitative comments by so many who have used the systems, and the safety record shown by the very low “time in hypoglycemia.” Detailed coverage of each study is given below; Insulet’s investor meeting was also truly special – see the very compelling patient presentation here by a mother/son duo, Dr. Trang Ly’s presentation here, which covers an interview with PI Dr. Bruce Bode from Atlanta – Dr. Ly was smart-as-a-whip in how she characterized the data and plainly radiant – here is the audio which reviewed what had been given at ENDO moments earlier and in a little less detail.

The Omnipod 5 system is the first tubeless, patch-based AID system and will be the first AID system to offer full smartphone control. As a reminder, the system includes the Omnipod insulin patch pump, Dexcom G6, and the Omnipod 5 algorithm, which is built into the patch. When it launches in a few months, patients who have Android smartphones will be able to access their data and control their insulin delivery via the Omnipod 5 app. For now, those who use iOS devices will use a locked Android phone as a controller until the iOS version of the Omnipod 5 app is fully developed and cleared by the FDA - in the analyst meeting Q&A, SVP of Innovation and Strategy went through the reasoning behind this. Outside of smartphone control, the system has several notable features: (i) customizable glucose targets from 110 mg/dl to 150 mg/dl that can be adjusted by time of day – this shows the benefit of being the third system to market, when the field (and FDA) can see this is a better approach; (ii) a HypoProtect feature that allows users to temporarily set their glucose target at 150 mg/dl and restricts insulin delivery while switched on; and (iii) a built-in smart bolus calculator in the app and controller that is informed by CGM values and trends.

Omnipod 5 has already been submitted to the FDA and is expected to receive clearance in the coming weeks with a limited launch still “in the first half of this year.” It does have “breakthrough device” status, after all, and we can see why after this presentation. Insulet CEO Shacey Petrovic has reiterated on multiple occasions that a limited launch for Omnipod 5 in 1H21 will be followed by a broader rollout by the end of 2021 or early 2022 at the latest.

1. Omnipod 5 pivotal trial for adults and adolescents (ages 14-70): TIR +2.2 hour/day to 74%; A1c improves from 7.2% to 6.8%; patient satisfaction data to be shared at ADA 2021

In a very highly anticipation session, Dr. Sue Brown (University of Virginia) presented results from the adolescent and adult (ages 14-70) subgroup of Insulet’s Omnipod 5 pivotal trial. The 3-month, single-arm study took place across 17 centers across the US and enrolled 241 total participants with type 1 diabetes (129 adolescents and adults and 112 children). Participants went through a 14-day baseline phase, wearing Dexcom G6 and performing their usual insulin regimen. After three months of Omnipod 5 use, Time in Range in adults and adolescents (n=128) improved from 65% to 74%, or 2.2 hours/day. While most of this improvement came from reducing time in hyperglycemia, the pivotal trial also showed significant improvements in time in hypoglycemia. After three months of Omnipod 5 use, mean A1c fell from 7.2% to 6.8%; by the end of the study, two-thirds of participants had A1cs below 7%. Finally, the system was safe to use, with two incidences of severe hypoglycemia and no cases of DKA during the study (both event rates below that of the T1D Exchange registry).

To start, the hypoglycemia results are spectacular. While the “aim” has been less than 4% of time < 70 mg/dl for some time, to see the group start at 2% and then cut that in half (nearly) to 1.1% is outstanding. While we understand the goal of 4% or less, that is nearly an hour a day in hypoglycemia! We are glad that this group started off at 2%, which is still 28 minutes a day, and could get to 14 minutes a day!

At the other end of the spectrum, while the result of the change from Omnipod 5 to give pateints an additional 2.2 hours per day “in range” are definitely positive, we are also curious to see what else will move patients’ mean glucose further down. The mean glucose did not change too much, from 161 mg/dl to 154 mg/dl – we may have expected more given the extra 2.2 hours a day! We know lots of HCPs who follow TIR closely who like to see the mid 130s rather than the mid 150s.

While the results are very strong, the guidelines do want PWD to have no more than 25% of their “time in diabetes” as “time above 180 mg/dL” – the group here hits 25% exactly! Given the “mean” is still fairly high, we wonder what the HCPs would advise the patients to try to get the mean down, given that the “TIR” is a success.

The results are summarized in the table below with further discussion in the bullets below. As a reminder, these results are for the 128 adult and adolescent participants in the study.

• Time in Range improved from 65% to 74% (+2.2 hours/day) using Omnipod 5. Importantly, this significant Time in Range improvement was seen across all age groups. That this includes so many people who are at very challenging periods of their lives, like adolescents (see chart below, this group’s starting TIR was the most challenging at 57%), and that the COVID-19 period was likely particularly stressful for so many people with diabetes, that two-thirds of the people in this large group (n=128) had had A1cs under 7% is very impressive. We would love to see other segments like what percentage of patients got to A1C < 6.5%. As we’ve seen in other AID studies (see MiniMed 780G and Control-IQ), overnight Time in Range saw even bigger improvements. During the overnight period (midnight – 6 AM), Time in Range with Omnipod 5 was 78%, compared to 64% at baseline (+50 minutes/night). That is the time, of course, with “no disturbances” or at least fewer disturbances (meals with carbs, stress from work or other elements of life, even exercise, which can throw off glucose).

• Not surprisingly, given that most groups had a relatively low “time in hypoglycemia” to start, most of the Time in Range improvement was driven by reduced time in hyperglycemia. Time spent >180 mg/dl was reduced from 32% to 25%, representing a reduction of 1.8 hours/day and hitting the recommendation spot on (of course, less than 25% is even better but this is a very hard one to hit for the average person with diabetes). Strikingly, time >250 mg/dl was reduced from 10% to 6% (-1 hour/day). This is even more impressive from our view given that it’s a 40% reduction in the time period that most clinicians want to see as close to 0% of time as possible, even though the guidelines technically state that “below 5%” is the goal. On the hypoglycemia side, Omnipod 5 also drove improvements, from a very impressive baseline. Time <70 mg/dl was cut in half from 2% to 1%. Time <54 mg/dl fell slightly from a low baseline (0.22% to 0.17%). Since the goal is <4% time below 70 mg/dl, and <1% time below 54, we felt the outcomes were very strong – that the hypoglycemia outcome actually improved significantly given that it could’ve technically “gotten worse” and still been “in goal” was great.

• With Omnipod 5, mean A1c fell from 7.2% to 6.8%. Viewed differently, the percentage of participants meeting the A1c goal <7% rose from 45% at baseline to two-thirds (66%). Importantly, the A1c improvement was seen regardless of baseline A1c. As would be expected (unless one believes those with higher baseline A1cs are far harder to help), those with higher A1cs at baseline (≥8%) saw a bigger A1c improvement – from 8.5% to 7.6% - than those with lower A1cs at baseline (<8%; improvement from 6.9% to 6.6%). That makes sense to us because if you are starting at a relatively lower baseline, we think that is harder to change. We were struck that on the analyst call, we heard that one person who entered the trial had an A1c of 5.2% - we are wondering what the outcomes changes were for that person. While a 0.3 change may not sound like a massive change, we know that the time in range change was still more significant.

• While Omnipod 5 offers five glucose set point options (110, 120, 130, 140, and 150 mg/dl), participants spent the vast majority of time at the most aggressive setting. Collectively, 81% of the study time was spent at the 110 mg/dl set point. Compared to overall study results, outcomes with the 110 mg/dl were even more impressive. Mean Time in Range with the 110 mg/dl setting was 76%, compared to 74% for all settings and 65% at baseline. Notably, using the 110 mg/dl set point was not associated with more time in hypoglycemia. While this is positive overall, the low time in hypoglycemia even in the standard treatment group makes us wonder slightly about how generalizable this group is – on that front, however, if the average person going on Omnipod 5 struggles more with diabetes on average than those in the trial, they are more likely to show even greater outcomes. Outcomes from this trial as well as other outcomes trials makes us wonder how recommendations might change in the future; while the trial ended, on average, with participants having a 74% TIR, it’s great to see a 76% TIR outcome for those with a 110 mg/dL target. We imagine there could be specific targets for “set points” given to patients depending on their approach to their diabetes and their overall setting. 

• Following a software anomaly, the Omnipod 5 pivotal trial was paused in early March 2020 and resumed in June 2020. We are impressed that all went well during this time and that not too much time was lost, particularly given the vagaries of COVID-19. Though not intentional, Insulet’s SVP and Medical Director Dr. Trang Ly noted during a separate Insulet webinar event, also today (the analyst meeting explaining this data!) that this turned the pivotal in some respects, into a pseudo-crossover trial. The median participant spent 44 days on Omnipod 5 before the study pause, and 49 days on Omnipod 5 after the study pause. During the pause, participants could use the Omnipod + Dexcom system in open loop or another form of therapy. During both AID phases (before and after the pause), mean Time in Range was 74%-75%, significantly higher than non-AID phases (baseline and during the pause). We’d guess that in a “non-COVID” time as well as a time without the benefit of a closed loop system, the TIR would be even lower in the non-AID times. This is also a good (if inadvertent) example of how TIR shows far more than A1c; for at least 60 of the people with four A1cs taken at that time, the A1c wasn’t that different even though the TIR was worse during the pause – 67% vs 74%-75%.

• As background, at baseline, most study participants had pretty well-controlled glycemia with a mean A1c of 7.2%. Mean age was 37 years old and the study skewed slightly female (61%). At baseline, 18% of users were using MDI, something Insulet management highlighted during the company’s investor webinar – this does highlight the relative sophistication in the trial, since 82% were already on a pump, unlike most people with type 1. We don’t think this matters too much overall.  

• Participants spent an impressive 95% of time in closed loop. We do note that while we think this metric is valuable, it will never bring significant positivity to a trial for us; we’d only really notice it if the metric were not high. All this means is that 95% of the time, the Omnipod 5 was in use. While this is good, this is about an hour a day on average that the Omnipod 5 wasn’t in use, which we wouldn’t want to see any higher, given the safety and reliability of the system has been so established. The Omnipod 5 system was safe to use with two severe hypoglycemia events and no DKA events. According to Dr. Brown, both severe hypo events (presumably in the treated groups) were preceded by a user-directed insulin bolus.

• The vast majority (92%) of adult and adolescent participants opted to continue into the 12-month extension phase of the trial. In total, 124 out of 128 participants completed the trial, suggesting high rates of participant satisfaction. (No reason was given for those who discontinued – while we are curious what those are and while we will ask, it’s certainly a low baseline number.) During Q&A, we asked about patient satisfaction data. According to Dr. Brown, data on that topic will be presented at ADA 2021, but “anecdotally, no one wanted to stop [using Omnipod 5].” We were very glad to hear there will be further unpacking of this data.

2. Omnipod 5 pivotal for children (ages 6-<14): TIR +3.7 hours/day to 68%; A1c improves from 7.7% to 7%; massive reductions in hyperglycemia (-3.6 hours/day >180 mg/dl)

In the second part of Omnipod 5’s pivotal trial results, the renowned Dr. Bruce Buckingham (Stanford University) presented results from the 112 pediatric participants (ages 6-<14 years). The pediatric participants followed the same protocol as the adolescent and adults (see above), wearing Omnipod 5 for three months. This group was not in nearly as strong shape as the adults as adolescents on average, who began with a baseline 65% TIR, compared to a 52% for this group. Again, we summarize results in the following table and discuss notable results in the bullets below. We note that the mean glucose improvement here was 23 mg/dl, compared to just 7 mg/dL above.

• Time in Range improved by an extremely significant 3.7 hours/day in the pediatric group, from 52% to 68%. That is over a day a week – truly nirvana to any parent! Achieving 68% Time in Range in this age group is extremely impressive since so often in pediatrics, patients are far below levels even approaching this and heterogeneity reigns, largely driven by other factors relating to puberty, other health factors, socioeconomic status of family, attention of doctor, how close the family is to a healthcare provider who has time for them, even whether or not there is a pediatric endo nearby or in the state. Nearly all of the improvement seen with the Omnipod 5 system came from reducing time in hyperglycemia, as time >180 mg/dl was reduced from 45% to 30% (-3.6 hours/day) – this is a big deal in our view since in other trials, time in hyperglycemia did not move too much. While spending 30% of the day in hyperglycemia is not ideal, and still, in fact, massive, at nearly eight hours a day (!), it’s a massive improvement from nearly half of the day. Omnipod 5 did not affect time in hypoglycemia, which was already low at baseline for study participants – in the “real world,” we would imagine that far more hypoglycemia would be seen at baseline.  

• Mean A1c was reduced from 7.7% to 7%. By the end of study, over half (53%) of participants had an A1c below 7%, compared to just 23% at baseline. This is also very significant. As with adults (as with virtually anyone in any diabetes trial), those with higher A1cs at baseline saw a larger improvement in A1c. For those with baseline A1c ≥8%, mean A1c fell from 8.7% to 7.6%, a very strong change of over 1 percentage points. For those with baselines <8%, mean A1c fell from 7.1% to 6.7%, a smaller change, though as a reminder, even this smaller difference still results in over an hour more time in range for the person, and over an hour’s more productivity per day.

• Compared to the adolescents and adults, pediatric participants spent more time with higher glucose set points. As noted above, adults spent 81% of the study time with the most aggressive 110 mg/dl set point. Pediatric participants spent 61% of the cumulative study time at the 110 mg/dl set point. While some may imagine that many pediatric participants opted for higher set points to avoid hypoglycemia when away from their parents/guardians, such as when they were at school, we would imagine that ultimately, once more patients are on closed loop, and it is established as proven and standard of care and not associated with hypoglycemia, they will be more likely to have the most aggressive goal. That said, for now, the world is not used to this, and there is still likely fear around hypoglycemia – old habits die hard. Indeed, Dr. Buckingham shared that 71% of pediatric participants used more than one set point a day during the course of the study – we also imagine they may be higher around dinner when hyperglycemia may be harder to avoid for some.

• As with adults, pediatric participants spent 95% of time in closed loop and the system was safe to use. During the study, there was one incident of severe hypoglycemia and one incident of DKA. According to Dr. Buckingham, the severe hypoglycemia occurred when the user delayed eating after delivering a meal bolus and the DKA occurred due to infusion site failure (this is rare with Omnipod since they use traditional sets). Overall, 99% of participants continued on Omnipod 5 into the 12-month extension study, a very high percentage that reinforces how the much children and young teens and families must have liked the system.

3. Early Omnipod 5 in type 2s feasibility study results (n=4): TIR from 27% to 59% (+7.7 hours/day); baseline A1c of 9.3% to GMI of 7.5%; no adverse events

In the other very exciting Omnipod 5 trial results of the day, Dr. Bruce Bode (Atlanta Diabetes Associates) presented the first data from a small feasibility study using AID in people with type 2 diabetes. The study is still enrolling, and we had not expected to see this data – although it was small, it was thrilling to see these results and to see how committed Insulet is to helping people with type 2 diabetes. Results from the first four participants were presented today – admittedly, while this is a very small number, we were extremely interested to see how the group was faring. The small study eventually aims to enroll 24 participants (across four sites) with type 2 diabetes and A1c between 8%-12%. The participants wear Dexcom G6 for two weeks on standard therapy (either MDI basal-bolus or basal-only insulin therapy), then wear Omnipod 5 for eight weeks. Participants will continue on any previous glucose-lowering drugs (e.g., metformin, GLP-1s). We think it’s interesting and a reflection of care for people with T2D that “basal only” insulin therapy is even an approach that is used with any of the people in the trial, since 9.3% A1c is the base!

To-date, “more than 177 person-days” of data on AID has been gathered across four participants. Mean Time in Range increased from 27% at baseline to 59% after eight weeks on AID (+7.7 hours/day). This is radical improvement and displays (although, again, in a small study) just how poorly people with T2D are often doing, even those on insulin. Interestingly, some improvements in Time in Range appeared by week 2 (27% at baseline to 34% during weeks 1-2), but the most meaningful increase appeared during weeks 3-4 (to Time in Range of 51%). At baseline, the participants were spending a significant amount of time in hyperglycemia, with a whopping 40% of time ≥250 mg/dl – here, it is clear that they are either not taking insulin doses (at work, etc. – not hard to imagine that they would not be engaged) or that they are not titrating insulin up as we believe all patients are taught to do – and probably aren’t, even in these impressive centers. By weeks 7-8, the percentage of time ≥250 mg/dl had been nearly quartered to 11% - a major result, although this does still reflect, as we saw in the trial above, social norms that are probably not consistent with good diabetes health – 11% time over 250 mg/dl is still over 2.5 hours a day (but much better than ten hours a day!). In addition to demonstrating feasibility of using AID in people with type 2 diabetes (it’s feasible all right), the study also demonstrates the hugely significant improvements in glycemia that can be achieved for people with poor glycemic control at baseline, a group that’s sometimes underrepresented in clinical AID trials, which tend to not include or even consider people with type 2 diabetes as we’ve seen so far. We’d be very interested in seeing from the four people in the trial, who had the best numbers and what else is happening – we know the system has to be tested “without” other interventions, we’re very interested in what else Dr. Ly would like to see after used as a more multi-disciplinary intervention, including a collective focus on food and exercise, for example.   

• For the three participants who first completed the trial, mean baseline A1c was 9.3%, compared to a CGM-measured GMI of 7.5% during week eight. Notably, this GMI of 7.5% was achieved with almost no time spent in hypoglycemia – just 0.1% of time was spent <70 mg/dl during weeks 7-8 of AID use. Given that the “upside” associated with those with T1D using a closed loop is often associated with the upside of “staying out of severe hypo,” we wonder from a cost-effectiveness perspective, how the return on investment would be seen for a group with T2D. We imagine it would be positive due to the difference in A1C that will presumably emerge; on the other hand, we know that criticisms will come about the costs of the system. We wish it were possible to predict future costs for various populations; stay tuned on this for some learning from Dr. Atul Butte from UCSF.

• No severe adverse events have been reported so far. One participant in the study was diagnosed with COVID-19 during the study, but safely continued on their AID therapy. During the study, time in closed loop was high at 93%, meaning the participants were not using the system or the system wasn’t working well about 90 minutes a day.

4. Insulet stays busy with Analyst meeting directly following ENDO – the case is made for closed loop for a very large population of PWD

Just as the Insulet ENDO talks were most compelling, so were discussions with investors starting just after the scientific presentations. We’re not sure who was at more, but all were certainly well-received. We’re not sure we’ve ever seen as illuminating and persuasive discussion about three very different groups of people with diabetes as Dr. Trang Ly gave, through putting patients at the center of all the discussions – down to a recorded message from one of the trial participants!  

Dr. Bruce Bode made what was for some a surprise appearance from our view both at ENDO and at the analyst meeting – the data from his trial with people with T2D wasn’t one we had known we would see results on. It was great to see from our view for several reasons:

• It’s great to remind people, particularly investors, of the massive unmet needs for people with T2D, such as those with a Time in Range of 20%;

• Although this wasn’t mentioned today, from COVID-19, it’s never been so clear that so many people with type 2 diabetes are in need – we believe that showing the massive changes that can take place is positive, to help increased visibility; and

• The Omnipod 5 system clearly works well with all groups – while this group of people with T2D is small, we’d be surprised to see different outcomes for other groups of people with diabetes.

• There is so much stigma around taking insulin, giving shots, etc and we believe this approach would help address some of this.

The algorithms seem compelling for all groups of people with diabetes who are testing them.

The discussion at the analyst meeting about the teens and children reflected success in the trials that we believe stems from “easy” and “low hassle” – for the adults with T2D it would seem that ease of use may be even more important for the healthcare system.

All in all, Dr. Ly was a complete star for the day – she clearly knew the data cold and could discuss her perspective and Dr. Bode’s perspective broadly about how positive it would be for the field, especially given the ease of use not just associated with using it but also getting it (no $5,000 “down payment” for the traditional pump, etc.) We’ll be eager to see how the apps work, how long IOS takes to develop, etc. but so far, based on learnings from today, we believe Omnipod 5 will both expand the universe as well as give MDIs other ways to better manage their diabetes.

How to work against the 20-25% of the time in hyperglycemia remains a challenge for the entire field, that is addressed seemingly only in small part by algorithms; more focus on the behavioral diabetes front, we imagine, would be useful, including how to include a holistic look at food, exercise, etc.

The win of the day, in our view, was imagining so many more people with T1D and T2D managing diabetes and “in range,” – we’ll look forward to hearing more about all trials moving ahead. We’d love to see larger trials as well, and would like to know how much less insulin is used in all groups (another cost-saver) and to get a better sense of what’s happening on the concentrated insulin front. Lots to look forward to hearing more about, and we salute Insulet for getting people with T2D firmly in the conversation. We’re staying tuned …. 

Top Diabetes Drugs and Big Picture Highlights

1. Debate on SGLT-2s in Type 1 Persists: Hope for Continuous Ketone Monitoring, Ongoing Unmet CKD Need, and More

Discussion on the use of SGLT-2 inhibitors in patients with type 1 diabetes was alive and well amongst audience members during the afternoon debate between Dr. Anne Peters (Director, USC Clinical Diabetes Program; Professor of Medicine, Keck School of Medicine at USC), representing the ‘pro’ side, and Dr. Andrew Ahmann (Director, Harold Schnitzer Diabetes Health Center; Professor of Medicine, Oregon Health & Science University), supporting ‘con.’ Although the FDA has consistently ruled against the use of the drug class as an adjunct to insulin (three times in fact – see FDA CRLs for (i) Lexicon’s sotagliflozin in March 2019; (ii) AZ’s dapagliflozin in July 2019; and (iii) Lilly/BI’s empagliflozin in March 2020), it’s clear that select HCPs continue to use the therapy whether as approved in Europe or ‘off label’ in the US and beyond, and interest has been further spurred by overwhelmingly positive results in recent heart failure with reduced ejection fraction and chronic kidney disease trials.

• Although Dr. Peters herself is one of said clinicians who continues to prescribe SGLT-2 inhibitors to select patients (though she paused during much of the COVID-19 pandemic to avoid potential DKA), today, she represented the ‘con’ side of the coin. On top of the standard arguments – increased risk of diabetic ketoacidosis (DKA), euglycemic DKA, relatively moderate A1c and weight loss reductions, no reduction in hypoglycemia, etc. – Dr. Peters homed in on her concern of whether or not clinicians will be able to accurately decide which patients can safely use an SGLT-2 inhibitor. This is why, in our view, the field needs to get to CKM – the main question is which patients are chosen, not whether CKM would enable them to use this compelling treatment well.  Using her own experiences treating patients from both the “Westside” (the wealthy side of LA, including Beverly Hills) and “Eastside” of LA (populations with far lower SES), Dr. Peters emphasized (in case any hadn’t realized this) that even the most well-educated and wealthy patients cannot completely eliminate DKA risk, particularly since it’s even hard to know which ER’s will recognize it. Furthermore, she worries that because patients with a lower SES often have higher A1cs (upwards of 9%), less informed clinicians may mistakenly believe that these patients are the optimal candidates for an SGLT-2 inhibitor, not taking into account the patient’s potential lack of ability to test ketones, limited access to healthcare, etc. In terms of DKA risk mitigation protocols, Dr. Peters ruled that sufficient data is lacking. Indeed, the phase 3 trials which investigated the aforementioned SGLT-2 inhibitors in type 1 diabetes utilized what Dr. Peters called “very odd” and inconsistent trial-to-trial protocols for treating ketones, so whether or not a standardized process could alleviate DKA concerns remains undetermined. As such, unless an individual has the skills, education, and access to use SGLT-2 inhibitors as safely as possible, Dr. Peters generally prefers using hybrid closed loop technology when available (although this doesn’t get rid of all hyperglycemia – many might think the two approaches would work well together despite the cost), or a GLP-1 for patients with weight or CVD concerns. Importantly, Dr. Peters referenced continuous ketone monitoring technology – of which development efforts are being worked on by companies like Indigo Diabetes and PercuSense and Abbott and multiple others – as a potential gamechanger for the drug class in the future, and we saw several questions regarding when the technology would become available during Q&A. We believe that the strides in closed loop are very likely to make closed loop therapy Standard of Care for at least those with T1D – this will also heighten the remote risk of failed sets, which would make CKD even more useful as a tool, assuming it can be cost-effective.

• On the ‘pro’ side, Dr. Ahmann began by giving a compelling overview of the current state of affairs for type 1 diabetes complications. In particular, Dr. Ahmann highlighted the often-overlooked fact that very little progress has been made to prevent end stage renal disease (ESRD). Citing a 2014 study published in the NEJM, Dr. Ahmann noted that of the major diabetes complications – including MI, stroke, etc. – the field has made the least progress on reducing rates of ESRD with diabetes, and, based on data from 1990-2010, individuals with diabetes have a 6x higher chance of developing ESRD compared to those without diabetes. Of course, CVD continues to be a major concern as well. Although careful to not make any assumptions, Dr. Ahmann shared that there is “no reason to believe that there wouldn’t be a similar benefit in type 1 diabetes” for SGLT-2 inhibitors on renal/CV outcomes vs. type 2 diabetes. Indeed, SGLT-2 inhibitors are known to address several of the most important predictors for mortality and cardiovascular complications in type 1 diabetes (albuminuria/eGFR, A1c, systolic BP, etc.), and post-hoc analyses of trials like dapagliflozin’s DEPICT have revealed strong early evidence of a potential renal benefit in type 1 diabetes (via improvements in albuminuria). Dr. Ahmann also made the promising point that while DKA rates in the US are on the rise, related mortality rates are actually decreasing, suggesting that patients and clinicians are becoming ‘better’ at treating DKA. Altogether, these potential benefits make SGLT-2 inhibitors worthy of continued pursuit as an adjuvant to insulin therapy. When asked which patients Dr. Ahmann would personally feel comfortable prescribing to during Q&A, he listed “willingness to be educated” and “early CKD” as his two top considerations.

2. Abstracts on STEP 1 Show Improved Body Composition with Semaglutide in Obesity and Efficacy Irrespective of Race, Age, or Glycemic Status

Two ENDO 2021 abstracts provided us with a more nuanced perspective on the STEP 1 trial for Novo Nordisk’s GLP-1 semaglutide 2.4 mg in obesity – currently under review by FDA. Thus far, results from all four STEP trials – STEP 1 for semaglutide and lifestyle intervention in adults with obesity; STEP 2 for semaglutide and lifestyle intervention in adults with type 2 diabetes and obesity; STEP 3 for semaglutide and intensive behavioral therapy in adults with obesity; and STEP 4, assessing the importance of continued semaglutide usage – have been very positive. As a refresher on STEP 1, semaglutide met both primary endpoints in the trial, driving weight loss of 14.9% from a baseline of 232 lbs compared to 2.4% for the placebo group after 68 weeks; moreover, 86% of participants on semaglutide achieved weight loss of at least 5% compared to 32% with placebo.

• First, an exploratory analysis by Dr. John Wilding (University of Liverpool) revealed promising improvements in body composition for those on semaglutide. As body composition impacts cardiometabolic disease risk and energy expenditure/physical functioning, changes in composition can significantly impact patient quality of life. Of the 1,961 adults enrolled in STEP 1, 140 participants with BMIs ≤40 kg/m² at baseline qualified for the substudy (mean weight of 98.4 kg, BMI of 34.8 kg/m², and 76% female). Substudy participants experienced a mean 15.0% decrease in bodyweight from baseline with semaglutide vs. 3.6% with placebo. These weight reductions were composed of 3.5% and 2.0% reductions in the proportion of total fat mass and visceral fat mass, respectively, as determined by dual energy X-ray absorptiometry (DEXA). Notably, total lean body mass also decreased by nearly 10% in individuals on semaglutide – which could a potential concern for some smaller group of patients – though the overall lean body mass:fat mass ratio increased due to fat loss. Ultimately, this ratio increased by 0.23% (95% CI: 0.14 to 0.32) in individuals treated with semaglutide over the 68 weeks, and no major changes in body composition were observed for those on placebo.

• Next, an abstract by Dr. Robert Kushner (Northwestern University Feinberg School of Medicine) et al. showed consistent reductions in body weight with semaglutide irrespective of baseline characteristics outside of sex and baseline body weight. Abstract authors performed an evaluation of categorical weight loss with semaglutide from baseline to week 68 (≥20% vs. 15 to 20% vs. 10 to 15% vs. 5 to 10%) by baseline characteristics age, sex, race (White, Asian, Black, “Other”), body weight, BMI, weight circumference, and glycemic status (normo-glycemia vs. pre-diabetes). Intriguingly, the distribution of participants across categorical weight loss groups did not appear to be affected by any of the aforementioned baseline characteristics, barring sex and baseline body weight – mean percent weight loss was greater among female participants, and those with a lower body weight at baseline vs. higher (p<0.001 for association with weight loss). Further studies comparing participants from STEP 1 (individuals with overweight or obesity) and STEP 2 (individuals with overweight or obesity and type 2 diabetes) may provide greater detail on any glycemia-related differences. 

3. Global Study Shows Children with Type 1 Diabetes Have Increased Risk of Complications due to COVID-19

Dr. Manish Raisingani (Pediatric Endocrinology, University of Arkansas for Medical Sciences) walked through sobering results of a study which compared rates of complications in children (ages 0–18) with and without diabetes with significant findings for mortality, intubation, and sepsis. This study consolidated medical records from over 60 healthcare organizations in 31 countries.

• Overall, children with type 1 diabetes (n=3047) had a significantly greater risk of death, intubation and sepsis compared to children without type 1 diabetes (n=502,655). In terms of relative risk (compared to the risk for children without type 1 as the baseline), there was a 7.04 times greater risk (p<0.0001) of death, a 11.65 times greater risk (p<0.0001) of intubation, and 4.32 times greater risk (p<0.0001) of sepsis.

  • 10 of the 3047 children (0.328%) with type 1 diabetes died, compared to 235 of the 502655 (0.047%) children without type 1 diabetes.

  • 15 of the 3047 children (0.492%) with type 1 diabetes developed sepsis, compared to 575 of the 502655 (0.114%) children without type 1 diabetes.

  • 10 of the 3047 children (0.328%) with type 1 diabetes were intubated, compared to 142 of the 502655 (0.028%) children without type 1 diabetes.

• However, it is important to note that the success of diabetes management has implications for complication risk. Within the cohort of children with type 1 diabetes, 482 were identified to have an A1c ≤ 7%, indicating well-controlled diabetes. No patient with an A1c ≤ 7% died, developed sepsis, or was intubated, indicating that there is little difference in complication risk between the group without type 1 diabetes and with well-controlled type 1 diabetes.

4. Obesity Associated with ICU Admission and Increased Duration of Stay due to COVID-19; Relationship with Mortality Less Clear

In a study analyzing data from patients (n=3246) hospitalized with COVID-19 (positive PCR test) between March 10 and September 1, 2020 in the Yale-New Haven Health System, researchers found significant associations between BMI and ICU admission, as well as duration of ICU stay. In a talk under the theme of “the Relationship Between COVID-19 and Endocrinology,” Dr. Yu Mi Kang (Internal Medicine, Yale New Haven Health) presented observational data and results from the study.

• Obesity has been identified as a common comorbidity of COVID-19 since early on in the COVID-19 pandemic. Although mechanisms behind this comorbidity are not yet well-understood, there are several proposed mechanisms linking cardiometabolic diseases to an increased risk for complications due to COVID-19 through risk factors like high LDL cholesterol, high HDL cholesterol, and high triglycerides.

• Approximately 43.2% (n=1403) of patients in the study were obese, 30.5% (n=990) were overweight, 23.5% (n=763) were at a normal weight, and 2.8% (n=90) were underweight when classified using WHO standards. The median age for the underweight hospitalized group was highest, at 78.5 years, decreasing steadily to 59 years for those with obesity. Approximately 41.2% of all patients had diabetes.

• Significantly more cases were admitted to the ICU from the population with obesity vs. other groups, and slightly more patients died or were transferred to hospice care. Patients from the group with obesity made up 45.9% (compared to 21.2% of the “normal weight” group) of all ICU admissions, and 33.7% (compared to 32.3% of the normal weight group) of all deaths or hospice transfers.

• When organized by incidence (%), the differences in incidence between all BMI classes and the normal weight group in death or hospice transfer rates were statistically significant (p<0.05). There were also differences, albeit less significant, between the incidence in ICU admission between BMI groups – 26.5% of the “all obesity” group were admitted to the ICU, compared to 22.6% of the “normal weight” group, and within the “all obesity” group, Class III obesity patients had a significantly higher incidence of ICU admission at 32.4% than Class I and Class II obesity at 23.0% and 27.6%, respectively.

• There were also significant differences in length of ICU stay between patients in the “normal weight” and “all obesity” classifications. On average, “normal weight” patients were in the ICU for 6.6 days, compared to 9.5 days for patients with obesity. This trend was also seen within the “all obesity” group, with stays averaging at 9.1 days, 9.3 days, and 10.2 days for Class I, II, and III, respectively.

Q: Could you talk a little bit about obesity and diabetes? Did you notice any differences related to diabetes or A1c levels?

A: Diabetes definitely plays a role here. An A1c level of 6% or greater was seen more in patients with obesity compared patients with normal weight, and we took that into account while doing the multivariate adjustment. We will conduct further analysis on this.

5. Dr. Atul Butte of UCSF wows the crowds with discussions of big data.

Dr. Atul Butte of UCSF has given several striking presentations historically that big data can transform medical care. Today, at ENDO, Dr. Butte made prescient points on ZIP codes and diabetes, and on how moving into slightly better neighborhoods was associated with better diabetes outcomes. He discussed using predictive assessments to decide how to treat newly diagnosed patients – we look forward to getting his slides so we can discuss his approach at greater length. Metformin only as a strategy “works” rarely, he said; he’s like clinicians to choose other strategies by examining what patients have in common with other patients in which UCSF (or other clinics) already have experience. He made the point in chat that Time in Range data is still only taken down in “notes” in the EMR – it sounds like there would be much more use for this if it could be truly part of the EMRs. Technology and records can absolutely predict who will be helped by various interventions – he referenced a UCSF poster at ENDO that we’ll be back to write more on. For our updated coverage, see here. 

6. Nearly 100,000 with T1D experience DKA that sends them to the hospital; 20% are re-admitted within 30 days and over 200 fail to recover

Meanwhile, the poster “Rates and Predictors of 30‐Day Readmission in Adults with Type 1 Diabetes Hospitalized for Diabetic Ketoacidosis in the US: A Nationwide Study” by Chicago’s Dr. Ikechukwu Achebe and Hazeef Shaka was illuminating and most depressing. National databases show that 91,625 people with type 1 diabetes entered the hospital with DKA each year. In 2017, 225 people with T1D died, never to leave the hospital, and fully 20% were readmitted within 30 days. We’ll be back with more details on this one as well; we’re working to reach the authors and wanted to take time at this stage, following day #1, to alert readers to the high numbers of DKA alone, of mortality related to DKA, and of early approaches that we are seeing in the field now. For a more detailed report, see here. 

Exhibit Hall

Diabetes Technology

Abbott

The Abbott booth’s videos and materials highlighted the FreeStyle Libre 2’s optional threshold alarms (which FreeStyle Libre “1” did not have), accuracy in the low glucose range (which was a critique of FreeStyle Libre “1”), affordability, and pediatric indication (ages 4+ compared to 18+ for Libre “1”). The booth also provided resources on Abbott’s myFreeStyle two-week free trial program, which is similar to Dexcom’s Hello Dexcom program that launched in December 2020. We also popped into a Zoom room and chatted with very smart representatives. As we understand it, a FreeStyle Libre 2 app is under review with the FDA currently; we also hope that they are making progress toward removing the contraindication against AID use. In particular, we believe that securing approval for the app will be important to user satisfaction and system simplicity, as many FreeStyle Libre “1” users may have been using an app and likely, are less interested in carrying around an additional device to monitor their glucose levels.

Dexcom

While we missed Dexcom’s lime green virtual booth set up, Dexcom’s webpage in the ENDO exhibit hall provided attendees with links to learn more about Hello Dexcom, Dexcom Clarity, and Dexcom’s telehealth resources during the COVID-19 pandemic. Attendees could also watch two short videos on Hello Dexcom and Dexcom’s G6 Pro, both part of Dexcom’s larger campaign to drive CGM adoption in primary care and with non-intensive type 2s. Dexcom also included two info sheets in its exhibit page: the first focused the company’s partnership with Lilly advancing the use of G6 and Lilly’s Lyumjev rapid acting insulin to prevent post-prandial hyperglycemia and the second provided information about the Dexcom Follow app (Google Play, App Store) which allows up to 10 people G6 users to share their glucose data with up to 10 followers including family and caregivers.

Insulet

The Omnipod 5 pivotal readout was front and center in Insulet’s virtual booth with multiple pages and countdown clocks counting the days, hours, and minutes to the readout. In addition to drawing attention to the pivotal readout, the virtual booth directed attendees to two Omnipod posters, one on three months of Omnipod use in children with type 1 and the other a feasibility study with adults with type 2 (see our coverage above). The booth included videos on the Omnipod and Omnipod DASH systems, which emphasize the system’s simplification of diabetes management and diabetes care. In particular, it draws attention to the Omnipod Virtual Care system, including automatic data upload via Insulet Provided Glooko, remote monitoring with the Omnipod DISPLAY and VIEW apps and Omnipod DASH’s availability through the pharmacy channel, which makes for “easier prescribing,” “less paperwork,” and a “faster start to therapy.” As of February, “over 35%” of US volume was running through the pharmacy channel, a figure which continues to increase (~30% in 3Q20; almost 30% in 1Q20; over 25% in 4Q19). The videos also draw attention to integrated “CalorieKing” database, which provides users with nutrition facts for 80,000+ foods on their PDM or Omnipod app to support bolus dosing for pump users, the new Spanish language option and the highly anticipated full smartphone control that will launch with Omnipod 5.

Medtronic

InPen headlined Medtronic’s exhibit page with a ten-minute tutorial on InPen from Dr. Diana Isaacs (Cleveland Clinic). Dr. Isaac’s tutorial covered the various options for insulin delivery including pens, pumps, and smart pens and highlighted the ability of InPen to help track insulin doses, timing, and integrate with Guardian Connect CGM data in real time. Dr. Isaacs also walked attendees through the InPen app which provides patients with reminders for meal-time insulin, long-acting insulin, and bedtime and post-meal glucose checks. The InPen app also offers three “modes” for the InPen insulin dose calculator: carb counting, meal estimation, and fixed dose allowing patients to choose the option that best fits their insulin needs.

Diabetes Therapy

Novo Nordisk

Novo Nordisk started its “Virtual Experience” by redirecting visitors to a separate website with visuals of floating through clouds. Visitors then excitingly (we felt) “parachuted” into the exhibit halls and watched an introductory message from Novo Nordisk’s US president Mr. Doug Langa about the company’s priority areas of diabetes, obesity, hemophilia, and growth disorders. We thought it was particularly great that Mr. Langa himself was connecting with the HCPs and researchers. Not that it’s a competition, but we believe he has the most challenging job at Novo Nordisk as the person that runs the high-pressure and closely-watched US division of the GLP-1 giant. Next, visitors have the choice to explore two interactive booths: one tailored to diabetes and one tailored to medical information. We’ve noticed that multiple pieces of ENDO are particularly patient-friendly; the diabetes area actually specifically caters to patients, while the medical information area caters to licensed healthcare professionals.

The diabetes exhibit enables visitors to explore booths on GLP-1s Ozempic (once weekly injection) and Rybelsus (once daily tablets), as well as “next-gen” basal and fast-acting insulins Tresiba and Fiasp. Each booth shares affordability resources, resource libraries, and other topic-specific brochures focusing on things like physical activity, drug-specific affordability programs, and drug-specific commercials. Notably, visitors (presumably authorized subscribers) can also request free samples of Fiasp at the Fiasp booth, though no samples are available at the other diabetes product booths.

As has become standard for the virtual exhibit hall, visitors can also chat with Novo Nordisk representatives at each booth. The medical information section was slightly more straightforward with only one booth that lets visitors learn about metabolic adaptation or hypoglycemia with PDF info-documents, as well as the possibility of live video chatting with a Novo Nordisk medical information professional. This live chat option is part of “Novo Now,” which seems like the company’s venture into digital marketing, touting “anytime, anywhere information for healthcare providers.”

Lilly

Lilly’s ENDO 2021 offering was split into two sections – one a link to Lilly’s “100 years of insulin” website, and the other redirecting conference-goers to a virtual Lilly-themed conference venue. In the venue, attendees could navigate toward a room on “Approved Products” or “Lilly History and Resources.” Within the very impressive 360 degree Approved Products room, there was lots to see – this is as expected for the manufacturer with the broadest product portfolio of any diabetes company around. Notably, the three centrally featured products were best-sellers GLP-1 Trulicity and SGLT-2 inhibitor Jardiance along with recently-approved rapid-acting insulin Lyumjev. As well, visitors could zoom in on booths for each of Lilly’s diabetes products including basal and human and rapid acting insulins Basaglar, humulin, and Humalog and next-gen glucagon Baqsimi, Walking to the “Lilly History and Resources” area, guests could view either a three-minute video entitled “Make Life Better” on the company’s founding by Colonel Eli Lilly and the company’s commitment to “trusted quality medicines” or an interactive timeline on insulin development similar to the one on Lilly’s website here. Despite the undoubtedly stunning visuals, our team missed the opportunity to “live chat” with representatives (we tried at many different hours) and we hope person-to-person interaction will once again be a part of Lilly’s booth moving forward as it was at other booths. That being said, we were thrilled by Lilly’s highlight of ‘100 years of insulin,’ considering the company’s release of phase 2 data on once-weekly basal insulin-FC right here at ENDO 2021. 

Zealand

Instead of a virtual booth, Zealand opted for a collection of educational resources dedicated to patch pump V-Go, highlighting it as the “only once-daily self-contained basal plus bolus insulin option.” Resources included a video on “How V-Go Works” – detailing the engineering behind the device’s pre-set basal and on-demand bolus dosing – and “The Clinical Outcomes of V-Go” – sharing a story on a patient struggling to keep up with his current MDI insulin regimen who transitioned to V-Go. In the latter, we were particularly struck by the statistic that 72% of patients with type 2 diabetes prescribed ≥3 shots per day do not inject insulin away from home. In addition, 92% of HCPs reported increased engagement (they called it “compliance”) in their patients who switched from MDI to V-Go. While the majority of materials were very helpfully geared towards patients, Zealand also linked to its clinical data summary for HCPs.

Pfizer

Pfizer’s booth did not show any diabetes products, and instead, focused on the Somavert and Genotropin franchises for treatment of growth disorders. We had hoped that we would see the SGLT-2 Steglatro, particularly since we suspect that HCPs will be visiting Pfizer more and more post-2025. See more on Pfizer’s pipeline here that is relevant to diabetes, last updated in early February, namely GLP-1R danuglipron in phase 2 and PF-07081532 in phase 1 for diabetes and obesity (see page 7 and 8 that is the internal medicine pipeline in particular). At the booth, visitors can learn more about each therapy’s treatment indications for those featured at the booth, as well as learn about Pfizer’s rare disease offerings in Medical Affairs. Clicking on the rare disease medical affairs button opens up several informational PDFs and videos, focusing on Pfizer’s research in endocrine disorders, the company’s rare disease pipeline, and information on gene therapies. While there is a contact button at the booth, there is no option to communicate with a Pfizer representative live. There was also no mention of Pfizer’s BioNTech-partnered COVID-19 vaccine at the booth – this would be a big opportunity at upcoming meetings including the ADA Scientific Sessions given that by that point, we imagine that all people with diabetes over 16 will be eligible for the COVID-19 vaccine and that people with T2D and people with obesity will continue to be among the many that still need to learn about the vaccine and who remain high-risk without it compared to those that do not have these conditions.

Xeris

Xeris’ interactive ENDO 2021 booth was fully dedicated to the Gvoke HypoPen, launched for severe hypoglycemia rescue in 2Q20. Virtual attendees moved like Sims through the booth and clicking on various e-resources zoomed conference-goers further in, giving it one of the most realistic feels of the entire conference. Resources covered information from dosing to safety and efficacy of the HypoPen. In addition, the Webinar section contained several in-depth video offerings – a 20-minute talk by Dr. David Domek, giving general background on Gvoke, and a copy of Xeris’ hour-long Community Launch Event with CEO Mr. Paul Edick, Dr. Steven Edelman, and Beyond Type 1 patient advocate Neil Greathouse. Our hats off to Xeris for one of the most interactive virtual experiences! Good for the company to work overtime to gain visibility for what we call, along with Lilly’s Baqsimi, “next generation glucagon” – we wonder how long traditional glucagon will be offered by Lilly and Novo Nordisk as the experiences associated with taking Gvoke and Baqsimi are undoubtedly less work and better than the traditional glucagons.

--by Ursula Biba, Rhea Teng, Gerol Fang, Hanna Gutow, Katie Mahoney, Albert Cai, and Kelly Close