June 7-11, 2019; San Francisco, CA; Day #2 Highlights – Draft

Hello from San Francisco with our top highlights in therapy and technology from day #2 of ADA 2019! After you peruse our coverage below, don’t forget to check out our ADA 2019 Resource Hub and Conference Preview for a look at what’s to come – including tomorrow’s readout of the REWIND CVOT for Lilly’s GLP-1 Trulicity.

Diabetes Therapy Highlights

1. Oral Semaglutide vs. SGLT-2: PIONEER 2 Shows Significant Glycemic Benefit, Uncertain Weight Loss Benefit to Novo Nordisk’s Oral GLP-1

Barcelona’s Dr. Eduard Montanya shared detailed results from PIONEER 2 (oral semaglutide 14 mg vs. empagliflozin 25 mg), expanding on the topline data that Novo Nordisk released last year. From a baseline 8.1%, mean A1c declined to 6.8% for those on the oral GLP-1 agonist (n=411) and to 7.2% for those on Lilly/BI’s SGLT-2 inhibitor Jardiance (n=410) over 26 weeks (p<0.05). This glycemic benefit was sustained at 52 weeks (p<0.05), and appears even greater when considering only those participants who finished the trial on-treatment without rescue therapy (1.3% A1c drop with oral sema vs. 0.8% with empagliflozin, p<0.05). A higher proportion of patients taking semaglutide achieved a target A1c below 7% (66% at week 52 vs. 43% taking Jardiance, p<0.05). Weight loss was similar in both groups, looking at the primary analysis of all participants randomized. From a baseline 202 lbs, mean body weight fell by 8 lbs with both molecules (non-significant p-value) – a majority of this weight loss occurred in the first 26 weeks and was maintained through the full year. Dr. Montanya highlighted that there wasa significant weight loss benefit to oral semaglutide when looking at the secondary on-treatment analysis: After 52 weeks, weight loss amounted to 10 lbs for patients who adhered to their oral semaglutide regimen vs. 8 lbs for those who adhered to their Jardiance regimen (p<0.05). In a conversation with our team, Novo Nordisk CMO for North America Dr. Todd Hobbs argued that this on-treatment finding gives a more accurate sense of oral sema’s weight loss efficacy, because patients who stopped taking Jardiance were eligible for injectable GLP-1 agonists as rescue therapy, and weight loss may have been inflated for some in the trial’s comparator arm. The discussion over weight loss data continued during Q&A, with one audience member differentiating between fluid loss and loss of adipose tissue: SGLT-2 inhibitors lead to a negative fluid balance which results in apparent weight loss, but the more important outcome is reduced adipose tissue mass, and GLP-1 agonists including oral semaglutide may be better at this. Dr. Montanya agreed that oral semaglutide may demonstrate a significant benefit over empagliflozin on weight loss through adipose tissue specifically; to support this hypothesis, he pointed out that waist circumference was significantly reduced with oral semaglutide but not Jardiance in PIONEER 2.

• Of note, discontinuation was more common in the semaglutide group compared to the empagliflozin group: 75% of patients randomized to the GLP-1 remained on-treatment without rescue medication (n=310) vs. 79% of those randomized to the SGLT-2 (n=322). There are some concerns circulating about tolerability of oral semaglutide and whether this will translate to suboptimal adherence in the real world, but Dr. Montanya emphasized that the GI side-effects seen in the PIONEER program largely match what’s expected of any GLP-1 agonist, oral or injectable. In PIONEER 2, nausea affected 20% of patients on oral semaglutide and 2% of those on Jardiance; 7% and 2% experienced vomiting, respectively. Decreased appetite occurred in 5% of semaglutide patients and <1% of empagliflozin patients (although this was listed as an adverse event, we note that suppressing appetite is one component of a GLP-1 agonist’s mechanism of stimulating weight loss). GI symptoms led 8% of study participants on oral semaglutide to discontinue therapy, vs. <1% of people taking Jardiance.
• Results from the entire PIONEER program have been submitted to FDA to support approval of the first-ever oral GLP-1 agonist. Dr. Hobbs told us that he’s “very optimistic about approval this year.” Novo Nordisk filed its oral semaglutide NDA in March with a priority review voucher, meaning a regulatory decision is expected by September 2019. Despite ongoing discussion in the diabetes community about intent-to-treat vs. on-treatment analyses of the PIONEER trials, we ultimately believe that both sets of results contain valuable knowledge. We’re excited about oral semaglutide and its potential to get more patients on a GLP-1. To this end, we were interested to learn from Dr. Hobbs that oral semaglutide marketing will be targeted toward primary care physicians, who have previously shied away from prescribing injectable GLP-1s. This is a great idea from our view – we’d love to see the suggestion as soon as possible. 
• As for how oral semaglutide will compete with oral SGLT-2 inhibitors? That remains an open question. Much will depend on how Novo Nordisk prices oral sema (nothing has been disclosed on this front), and on how payers interpret PIONEER 2. We view oral semaglutide as a fantastic addition to the diabetes treatment toolkit, a new therapy that should improve diabetes care overall rather than compete with existing oral drugs per se. We suspect that different patients may do better on an oral GLP-1 agonist vs. an injectable GLP-1 agonist vs. an SGLT-2 inhibitor, and we’re curious to see how oral sema could be used in combination with an SGLT-2 to achieve even better outcomes.

2. PIONEER 4 Demonstrates Oral Semaglutide’s Superiority to Victoza on Weight Loss and Possibly Glycemic Control

Following PIONEER 2, Dr. Richard Pratley presented full results from PIONEER 4 (n=711), Novo Nordisk’s phase 3 study comparing GLP-1 agonists oral semaglutide 14 mg and injectable liraglutide 1.8 mg (Victoza). As described in the full results below, oral semaglutide was noninferior on A1c lowering and superior on weight loss vs. Victoza at the primary timepoint of 26 weeks. By the end of the full 52-week treatment period, oral semaglutide was also superior to Victoza on weight loss. Results were simultaneously published in The Lancet, expanding on topline results shared last June. Importantly, Novo Nordisk continues to present both an intention-to-treat (“treatment policy estimand”) and on-treatment (“trial product estimand”) analysis for the PIONEER program. In our view, superiority to the market-leading Victoza on weight loss at both time points is particularly notable. During an interview with our team, Dr. Todd Hobbs (North American CMO for Novo Nordisk) described how, as early as Ozempic’s phase 2 program, the semaglutide molecule itself displayed an outsized impact on weight vs. Victoza – a feature that has driven further investment in semaglutide for obesity and NASH. For his part, Dr. Pratley suggested that achieved plasma level, which is more stable with the oral form, could also be a key factor. Moreover, the gain of superiority on A1c lowering between 26 and 52 weeks is encouraging: The A1c curve for the pill doesn’t “drift” upward as with Victoza, perhaps indicating that patients better adhered to oral semaglutide dosing.

A1c Results

Weight Loss Results

* = p<0.05 vs. placebo

⁺ = p<0.05 vs. Victoza

• The safety and tolerability profile of oral semaglutide aligns with the known profile of liraglutide. In the oral semaglutide arm, 11% of participants discontinued study drug due to any adverse event, compared to 9% on Victoza and 4% on placebo. There does seem to be a slightly higher prevalence of GI side effects with oral semaglutide: 44% of participants experienced any GI side effect on the oral, compared to 34% on Victoza and 24% on placebo. Dr. Pratley highlighted that nausea, rather than diarrhea or vomiting, is the primary driver of GI side effects (see below), impacting 20% of those on oral semaglutide and 18% on Victoza. Very importantly, he showed that 47 of 70 (67%) of nausea events with the oral and 51 of 67 (76%) with the injectable were mild, and events were concentrated in the early weeks of the trial. Interestingly, it seems that nausea with oral semaglutide may take longer to taper off than with Victoza. 

• In addition to these results, Dr. Pratley presented data on (i) percent achieving A1c <7.0%; and (ii) FPG. The former was achieved by 68% on oral semaglutide, 62% on Victoza, and 14% on placebo at 26 weeks in the ITT analysis; at 52 weeks, these numbers decreased similarly across the two treatment groups, to 61%, 55%, and 15%. In the on-treatment analysis, the percent achieving A1c <7.0% was 72%, 65%, and 16% at 26 weeks and 69%, 63%, and 18% at 52 weeks, respectively. FPG results align with the A1c findings: Oral semaglutide gave a 36 mg/dl reduction, Victoza 34 mg/dl, and placebo 7 mg/dl at 26 weeks, slightly attenuated to 34 mg/dl, 27 mg/dl, and 13 mg/dl by 52 weeks – at which point oral semaglutide gained superiority over Victoza.
• PIONEER 4 randomized people with type 2 diabetes on metformin, with or without an SGLT-2 inhibitor and in need of additional glycemic control in a 2:2:1 ratio to 14 mg oral semaglutide, 1.8 mg liraglutide, or placebo. Titration for oral semaglutide took place over eight weeks (four weeks on 3 mg, then four weeks on 7 mg), and titration for liraglutide took place over four weeks (two on 0.6 mg and two on 1.2 mg). 97% of participants in the oral semaglutide and liraglutide groups completed the trial, with 85% and 87% completing treatment overall and 78% and 81% completing treatment without rescue medication. Baseline A1c was 7.9%-8.0%, age 56-57 years old, diabetes duration 7-8 years, and BMI 33 kg/m².

Select Q&A

Q: Do you think there’s potential for beta cell protection?

A: If there is a chance for beta cell protection, I think you’re more likely to see it with a drug like this than one like liraglutide where there are more daily ups and downs.

3. Drs. Bruce Perkins and David Nathan Spar Over SGLTs in Type 1, Giving a Master Class on the Risk/Benefit Balance; Audience Support for SGLT Adjunct Therapy Drops from ~80% to ~50% After Debate

Drs. Bruce Perkins (Mount Sinai) and David Nathan (Harvard University) engaged in a lively debate on one of the hottest topics over the past couple of years: Do the benefits of adjunct SGLT inhibitor therapy in type 1 outweigh the risks? Dr. Perkins argued in favor of SGLTs for type 1, while Dr. Nathan took the opposite stance. Dr. Jeremy Pettus moderated the debate and polled the audience at the start of the very well-attended session: ~80% of the room’s hands went up in favor of SGLT adjunct therapy, while the remaining ~20% said no or were unsure. At the end of the session, after both speakers had their turn to argue and rebut, Dr. Pettus once again posed the same question – finding that the room was split roughly half-and-half on the issue. Read below for the key arguments from both speakers to see what so heavily influenced the audience. We viewed this session as a tremendous compilation of key points that we’ve heard from thought leaders over the past many months on this very contentious topic. Ultimately, the interpretation of the data is partly subjective – just as the decision to use an adjunct in type 1 should be highly personal and personalized. We salute both of these esteemed KOLs for a stimulating, informative, entertaining, and passionate debate, highlighted by a rigorous analysis of existing data to support their positions. 

Are SGLTs as an Adjunct Therapy in Type 1 Diabetes Worth It?

Quotable Quotes

• “I think that the FDA got it right.” – Dr. Nathan in regard to FDA’s 8-8 split Ad Comm and subsequent CRL for sotagliflozin in type 1.
• “Clinical trials are the BEST we are going to do [in terms of DKA rates]. Rates of DKA in clinical practice will only be higher.” – Dr. Nathan on how DKA rates will probably be even higher in the real world when compared to those seen in clinical trials because of (i) pre-selection in clinical trials of patients with low baseline DKA risk; and (ii) more intensive monitoring and education in trials than might be performed in everyday practice. 
• “For those of you that think this drug will dampen fluctuations and lead to a decrease in severe hypoglycemia, the data show a clear NO.” – Dr. Nathan on how although improvement with time in range are seen with SGLT treatment, there is no reduction in time in hypoglycemia or severe hypoglycemia. 
• “It’s important to keep in mind that these modest A1c reductions seen are ON TOP of intensive insulin management.” – Dr. Julio Rosenstock, chiming in during Q&A. (Although type 1s in the trial may have had intensive insulin management, we point out that those in the “real world” who would take it would not necessarily have this). 
• “There is no evidence that these drugs reduce CVD and renal risk in type 1 patients. It’s true that in a subset of those with type 2 diabetes and established CVD they do show benefit. But it’s a slippery slope to apply those findings to type 1s.” – Dr. Nathan on the generalizability of positive CVOT findings of SGLT inhibitors in type 2 diabetes to type 1 populations. We totally agree with his point here and look to see stakeholders generate long-terms outcomes data in this area. 
• “There’s really no right or wrong answer to this debate, but I can say that the wrong answer is to take a complex disease like type 1 diabetes and withhold one set of options that might work for some patients.” – Dr. Perkins on the need for patient choice
• “It’s not about us selecting the patient, it’s about the patient selecting the therapy, with full knowledge of the benefits and risks. Not everyone goes on pumps, for example, but we need to make that choice available.” – Dr. Perkins on the important distinction between patient selection vs. patient choice. 
• “People living with type 1 want options, and this is an option.” - Dr. Perkins
• “It’s not a therapy for all, but it would be a crime to not make this available for some.” – Dr. Perkins

4. New DiRECT Data Demonstrates Full Functional Recovery of Beta Cells during Diabetes Remission

Newcastle’s Prof. Roy Taylor unveiled an exciting new cut of the two-year DiRECT (diabetes remission) data demonstrating that the impairments in beta cell function seen in type 2 diabetes can be reversed if excess fat is removed from the pancreas with intensive weight management early in the progression of the disease. In addition to the usual intervention (~800 calories/day for three-five months with stepped food reintroduction and structured long-term weight maintenance support), a subgroup of DiRECT participants were subjected to the Stepped Insulin Secretion Test with Arginine (SISTA) at baseline and at 24-months follow-up to measure insulin secretory response during three sequential hyperglycemia challenges. At baseline, DiRECT participants showed an impaired first-phase insulin secretory response of ~0.5 nmol/min/m² (vs. 1.02 nmol/min/m² for age- and sex-matched controls with no diabetes). However, responders who ultimately achieved diabetes remission through year two of the study (n=38) showed recovery of first-phase insulin secretory response of the beta cells sufficient to allow return to a non-diabetes level of function. This became apparent as soon as 4 months into the trial. In contrast, the beta cell maximal capacity (response to arginine during hyperglycemia) was around 50 % of normal at baseline. It improved gradually 0.94 nmol/min/m², during the SISTA hyperglycemia challenges at 12 and 24 months to reach levels indistinguishable from non-diabetes controls.  The non-responders (n=18) experienced no change in either first-phase or maximal insulin secretory response throughout the 24 months. Though early, these results are extremely hopeful and shed light on precisely how this diabetes remission comes about. In a sentence, Prof. Taylor summarized the results as “good news for people with diabetes” and we couldn’t agree more.

• A previous study by Prof. Taylor sheds light on the potential mechanism for this phenomenon: Modifications in liver and pancreatic fat. In this study, after a DiRECT-like weight loss intervention, participants experienced a dramatic reduction in liver fat (leading to normalization of liver insulin sensitivity within one week) as well as a decrease in intra-pancreatic fat levels over the course of eight weeks (as assessed by MRI).

• Characteristics of the responder and non-responder populations were nearly identical at baseline, with the exception of diabetes duration: 2.7 years for responders vs. 3.8 years for non-responders. Responders and non-responders had no meaningful differences in mean age (53 years), sex (42% vs. 50% female), body weight (100.6 kg [221.7 lbs] vs. 102.1 kg [225.0 lbs]), or BMI (34.9 kg/m² vs. 35.7 kg/m²). Responders and non-responders even experienced the same weight loss over the two year trial (11.6 kg [25.5 lbs] vs. 11.8 kg [26.0 lbs]), indicating that diabetes remission is not dependent on weight loss writ large. All together, this data intriguingly suggests that intervention time is the major determiner of a person’s likelihood to achieve diabetes remission, though this would need to be substantiated in future, larger studies. When the issue of genetic differences between responders and non-responders arose during Q&A, Prof. Taylor explained that this is an active area of follow-up, though the small study population may make it impossible to draw a strong conclusion.

• As a reminder, full two-year data from the DiRECT study demonstrated impressive 36% diabetes remission following the intensive weight loss program. For those who lost >10 kg (22 lbs), diabetes remission rates rose to 64%. From where we stand, it’s hard to over-emphasize the significance of these results: Not only does DiRECT achieve an impressive rate of diabetes remission, but it shows that can be done in the primary care setting through nurses and dieticians with fairly minimal training. We are thrilled to think about this moving to standard of care and all the people that could do so much better with appropriate investment in this intervention – and further investigations into the mechanisms underlying its effectiveness.

5. PREVIEW Study Reduces Diabetes Incidence to Just 4% Over 3 Years with High/Med Protein Diet + High/Med Intensity Activity in Prediabetes (21% Incidence Predicted Without Intervention); No Difference Between Diet/Activity Groups, but >50% Attrition Rate

In a jam-packed session, Dr. Ian MacDonald presented results from the highly-anticipated PREVIEW study (n=2,223 adults with prediabetes) – the largest multinational RCT to date on the prevention of type 2 diabetes in adults with prediabetes through diet and exercise. In the 2x2 factorial design, permutations of high protein/moderate protein diets and high-intensity physical activity (75 min/wk)/moderate-intensity physical activity (150 min/wk) were tested over three years following an 8-week, low-calorie diet run-in. After 3 years, just 4% of the population that remained in the study (see more on attrition below) had been diagnosed with type 2 diabetes, and there were no differences between diets or exercise regimes. A placebo arm for the study was deemed unethical based on unequivocal evidence that lifestyle programs reduce type 2 diabetes incidence, though researchers estimated that the incidence rate over three years in this population would have been 21% without the interventions, 16% with the medium protein diet, and 11% with the high protein diet prior to the study. For reference, the US DPP program (n=3,234) achieved type 2 incidence rates of ~9% with lifestyle changes alone, ~16% with metformin alone, and ~23% with placebo at 3 years, suggesting PREVIEW’s program to be an irrefutable success (though the patient populations may also have differed to some extent) relative to other prevention strategies. Dr. MacDonald attributed PREVIEW’s success, and the equality across the study groups, to the large initial and mostly sustained weight loss throughout the trial. During the low-calorie diet run-in period, 79% of all eligible subjects achieved ≥8% weight loss (from a mean starting weight of 100 kg), with the average weight loss coming to 10.7 kg. After the 3 years, 737 of the 945 completers (78%) still had weight loss from baseline: 31% between 0%-5%, 26% between 5%-10%, and 21% ≥10%.

• After the calorie-restricted run-in, at least 35% of participants no longer had prediabetes, but this dropped to ~19% of completing participants (175 of 945) after the 3-year weight maintenance phase. The former result was based on fasting plasma glucose only, while the latter was based on both fasting and 2-hour glucose. Intriguingly, the average fasting plasma glucose values and A1c’s of each group rebounded nearly to their starting points at the end of the 3-years, which Dr. MacDonald called a “cause for concern”. However, 2-hour glucose and insulin levels rebounded only marginally, similar to weight.

• Only 43% of participants completed the 3-year program, demonstrating how difficult it can be to sustain these significant lifestyle changes. Attrition rates were similar across the four groups, suggesting no perceived difference in difficulty between the different arms. Physical activity rates were consistent for all groups across the three years (for completers), suggesting strong internal validity on this variable. Protein intakes were different between the two diets in the first 12-18 months, suggesting good adherence to the dietary advice early on, but in the second 18 months, the intake became similar (though they remained above pre-study levels). In the future, Dr. MacDonald believes adherence to these programs will prove a key barrier, and one that is deserving of more research. Personally, we’d be interested to see if long-term attrition rates improve with a coach – similar to Virta’s low-carb + continuous remote care program – as we’ve heard multiple people attribute the success of such programs to the support system rather than the diet. According to Dr. MacDonald, the support system for participants was extensive in the first 12 months, with cognitive behavioral therapy and motivational interviewing major parts, but these visits were intentionally reduced in years 2 and 3 to mimic clinical practice.

6. Liraglutide in New-Onset Type 1 Improves C-Peptide vs. Placebo Over One Year in NewLira Trial (n=68); Novo Nordisk’s Study of Liraglutide + anti-IL21 to Bring Clarity

A small (n=68) but intriguing study of liraglutide (Novo Nordisk’s Victoza) in new-onset type 1 diabetes indicates a possible role for the GLP-1 agonist in beta cell protection. Dr. Thomas Dejgaard presented results from NewLira; After one year of treatment with either liraglutide 1.8 mg and insulin or placebo and insulin, those randomized to liraglutide had a 44% higher AUC C-peptide than the placebo group (the study’s primary endpoint), meeting significance at p=0.04. After 52 weeks, both groups returned to insulin therapy alone, and by week 58 of follow-up, there was no significant difference between the two groups though the liraglutide group still had numerically higher C-peptide levels (see below). As would be expected, liraglutide also had a variety of positive metabolic effects reflected in the study’s secondary endpoints: At 52 weeks, the liraglutide group had reduced its total daily insulin use by six units/day from baseline, while the placebo group increased TDD by 12 units/day (p<0.001 for comparison). At week 58, however, that difference was almost entirely gone. The liraglutide group also had a significantly lower A1c at the 12 and 36-week timepoints, though not at 24 or 52 weeks, and lost 1.1 kg of weight over the year compared to 1.6 kg of gain in the placebo group (NS). Very positively, liraglutide conferred a 13% relative risk reduction for mild hypoglycemia <70 mg/dl (IRR=0.87, 95% CI: 0.82-0.93, p<0.05). By far, the most common adverse event was nausea, reported by nearly 50% of participants in the liraglutide group (and ~20% in the placebo group). While our sense was that the room was not overwhelmed with the positivity of these results – Dr. Julio Rosenstock asked Dr. Deigaard (inappropriately from our view) if he was ready to give up on the concept – we do think GLP-1s in type 1 warrant further investigation – more on that below. 

• NewLira randomized people 18-40 years old with a type 1 diabetes diagnosis within the last 6 weeks and postprandial C-peptide >200 pM. At baseline, participants were 29-30 years old, had a fasting C-peptide of ~110 pM, diabetes duration of 4 weeks, BMI of 23-24 kg/m², and A1c of 8.3%-8.6%. Additionally, 94%-97% were positive for antibodies ICA, GAD, or IA2. Only three participants discontinued liraglutide and only two discontinued placebo.
• A larger (n=308) phase 2 Novo Nordisk-sponsored study of liraglutide in new-onset type 1 completed in February. Critically, however, that study tests an anti-IL21 therapy in combination with liraglutide (on top of insulin) – meaning it aims to both protect beta cells directly with a GLP-1 while also dampening the autoimmune attack against them, which could prove a critical partnership. The primary endpoint is C-peptide at 54 weeks. Novo Nordisk has previously slated the first readout for 2Q19, but this may prove an ambitious timeline. This treatment holds Orphan Drug Designation from FDA.

7. Dr. James Gavin Highlights Fournier’s Gangrene Risk with SGLT-2s: Providers Must Be Extra Vigilant and Focus on Prevention; Recent Review Finds Increased Number of SGLT-Associated Cases

In a Lilly/BI-sponsored product theater focusing on SGLT-2 inhibitor Jardiance (empagliflozin), Dr. James Gavin III (Emory University) urged potential prescribers to take the risk of Fournier’s gangrene seriously and to engage in earlier interventions for prevention of this complication. Reviewing the usual side effects that could accompany Jardiance treatment (genital mycotic infections, putative DKA risk, dehydration, and more), Dr. Gavin paused when discussing the risk of Fournier’s gangrene (necrotizing fasciitis of the perineum), apparently going off script to emphasize the seriousness of this complication and measures that providers should take to mitigate risk. Dr. Gavin noted that “this is a very serious adverse event that can lead to serious surgery-requiring interventions” and we further add that mortality rates with the complication are alarmingly high (~7.5%). Dr. Gavin emphasized that there are currently no standardized procedures for the evaluation of Fournier’s gangrene, and as a result, providers must be increasingly vigilant when prescribing SGLT inhibitors and engage in extra precautionary measures: “What we really have to do is be vigilant. If [our patients] complain about pains, we have to do what we don’t do normally – we have to pull pants down and pull skirts up and see what’s happening in the perineum and do earlier interventions so that this doesn’t happen.” We salute Dr. Gavin for using this platform to advocate for better vigilance of this complication and for educating providers about the seriousness of Fournier’s gangrene – to our knowledge, it’s the first we’ve heard of a KOL on the conference circuit directly discussing how to mitigate the risk. Nonetheless, we’d be remiss if we didn’t mention that the absolute risk on a population level appears to be small: FDA as of August 2018 has received reports of only 12 cases over five years of monitoring, compared to 1.7 million US users in 2017 (more on this below). 

• As a reminder, FDA began requiring a new safety warning for all approved SGLT-2 inhibitor and SGLT-2 inhibitor combination labels in August 2018 following 12 identified cases of the infection among those taking an SGLT-2 inhibitor between March 2013 (when the first member of the class was approved) and May 2018. A signal for Fournier’s gangrene was not observed in any of the clinical trials for SGLT-2 inhibitors but was observed in FDA’s real-world monitoring. Despite the low rates of Fournier’s gangrene seen, FDA’s swift action in requiring an additional safety warning was of high interest to the broader diabetes community – we note that our initial coverage of the news was one of our top 10 most read diabetes-therapy related pieces of 2018. 
• On this front, a review was just published this week in the Annals of Internal Medicine detailing the reported cases of Fournier’s gangrene associated with SGLT-2 inhibitors. Interestingly, the authors reported an updated number of cases identified by FDA: 55 cases between March 2013 and January 2019, a significant increase from the 12 initially reported by the FDA last August for the time period of March 2013 to May 2018. It’s unclear if the 43 new cases occurred between May 2018 and January 2019 alone or if additional past cases were identified in the study. Of the 55 cases, all required surgical debridement, eight had fecal diversion surgery, two required lower extremity amputations, and three patients died. The study also notes 19 cases of Fournier’s gangrene associated with other diabetes drugs between 1984 and January 2019 (a much wider timeline): 8 with metformin, 6 with insulin glargine, 2 with mealtime insulins, 2 with sitagliptin/metformin combos, and 1 with dulaglutide. We note that diabetes is the most common comorbidity and a known risk factor for Fournier’s gangrene, reported to be present in 20%-70% of patients with the infection. 

8. Gretchen Youssef Argues “Access is Everything” in Outstanding Educator in Diabetes Award Lecture

CDE extraordinaire Ms. Gretchen Youssef received this year’s Outstanding Educator in Diabetes Award, focusing her award lecture on the ongoing policy battles for improved access to diabetes care. Starting with her childhood best friend, who tragically passed away in her early 30s due to complications of type 1 diabetes, Ms. Youssef has worked with countless people with diabetes. From all this experience, she surmised that in diabetes “access is everything” – specifically access to prevention services, prescription medications, programs for diabetes education, and providers. To this end, Ms. Youssef highlighted two of the ADA’s biggest policy battles to improve healthcare access for people with diabetes: Insulin affordability and expanding the availability of diabetes self-management training (DSMT). 

• On insulin affordability, Ms. Youssef championed the efforts of ADA’s Insulin Access and Affordability working group. Lobbying from this organization and others has spurred 12 federal hearings on insulin affordability to date, including stakeholders ranging from diabetes thought leaders to PBMs and manufacturers. The importance of this issue is difficult to overstate. Ms. Youssef contextualized that this is an issue that affects 7.4 million Americans using insulin – 24% of whom fall below the federal poverty level and are particularly susceptible to rising prices for this essential medication. While transparency in the insulin pricing process and permanent solutions for affordability are not yet a reality, 2019 has seen great strides in the right direction. 

• On DSMT, Ms. Youssef highlighted the newly-introduced Expanding Access to DSMT Act – a bill submitted to Congress in March 2019 that would remove co-pay costs and deductibles associated with DSME services, allow such services to be provided in a community-based location, allow a wider range of healthcare providers to refer patients to DSMT services, and pave the way for future Medicare coverage of virtual DSMT programs. At present diabetes education programs are “grossly underutilized”, with only 7% of people on commercial insurance and 5% of Medicare beneficiaries taking part. This stands in stark contrast to Ms. Youssef’s vision that people be referred for diabetes education at diagnosis, annually, when new complicating factors arise, and when new transitions in care occur. 

Diabetes Technology Highlights

Automated Insulin Delivery

1. Medtronic Initiates Two Pivotal Trials: MiniMed 780G Advanced HCL (Automatic Bolus, Bluetooth) and Next-Gen CGM with Day-1-Only Calibration

Today, Medtronic announced it has begun enrolling participants in two major pivotal studies: (i) the MiniMed 780G advanced hybrid closed loop with automatic correction boluses, Bluetooth, remote software updating, an >80% time-in-range goal, and an adjustable target down to 100 mg/dl; and (ii) a next-gen Guardian CGM with fingerstick calibration only on day one and seven-day wear. Both trials are up on ClinicalTrials.gov (here and here), and both were announced in company press releases (here and here). These are large studies – up to n=350 for the 780G and n=460 for the next-gen CGM – with primary completion of both expected in early 2020 (January-February). Given the size of the CGM study and primary endpoints (% within 20/20, % within 15 mg/dl for <70 mg/dl), we’d guess it will be used to support an iCGM filing for the next-gen Guardian CGM. The 780G study is enrolling users 7+ years, while the CGM study has a broader enrollment of 2+ years; this implies both products could also launch with pediatric labeling. Like the precursor 670G, the 780G pivotal will be tested in a three-month safety evaluation (home study), with co-primary end points – change in A1c and change in time-in-range (70-180 mg/dl) from baseline. That should enable a fast study and time to market, piggybacking off all the 670G experience and moving much faster than Tandem’s six-month Control-IQ pivotal (reporting data tomorrow). Medtronic has recently forecasted a launch of the MiniMed 780G by April 2020 (see 1Q19 call), which seems doable with this pivotal trial now starting enrollment. We expect the 780G will use a version of the currentGuardian Sensor 3 requiring at least two daily fingersticks. The on-body form factor does not look different with the next-gen Guardian CGM (that will wait until the next-next-gen Synergy sensor), though we will hear more tomorrow and presumably launch timing in Medtronic’s Analyst Briefing at 11am PT. 

• These are key pipeline moves for Medtronic as Control-IQ looks to launch in 4Q19,leapfrogging the 670G with automatic boluses, the no-fingersticks G6 CGM, remote software updates, Bluetooth, and a simpler user experience. Assuming Medtronic hits the April 2020 timing, it may come out with a competitive product only a few months behind Control-IQ. It’s been a very exciting pipeline meeting for Medtronic, as it announced plans yesterday to integrate with Tidepool Loop as an interoperable ACE pump and iCGM. See below for summary of study details, a picture of the 780G from Medtronic’s booth video, and 780G poster highlights.

• Only two sites are currently listed for the 780G study (SoCal Diabetes and Ranier), and none are yet listed for the CGM study; this will obviously expand as the year progresses.

• The press release gave an early look at two MiniMed 780G posters (1040-P and 1041-P), which we’ll be covering in a later report. Notably, 100% of participants in a feasibility study rated the MiniMed 780G system as the best therapy they have ever used, reporting overall satisfaction as extremely satisfied or very satisfied. All participants stated that they trusted the system to take care of their glucose and that it significantly increased their flexibility and confidence in taking care of their diabetes. The 780G was safe, improved glycemia, and simplified diabetes management, even when users forgot to administer a bolus of insulin at mealtime or carb counting was inaccurate. Hypoglycemia (<70mg/dL) dropped by 27% and hyperglycemia (>180 mg/dL) was reduced by 14% with no serious adverse events reported; the baseline comparator was not given in the press release, but we’ll be back to report what the posters say. 

2. 46% of 670G Users at Stanford Discontinued by One Year (40% by Six Months); Predictors of Success? Older Age, Greater Use of Guardian Sensor 3 in One-Week Pre-Auto Mode Period

Stanford’s Dr. Rayhan Lal presented results from a one-year, prospective observational study of type 1s who initiated the MiniMed 670G (n=79), finding that 46% were no longer using Auto Mode at 12 months. The significant predictors of the individuals who were using Auto Mode >0% of the time – a very low bar – were age (continuers mean age was 32 years vs. discontinuers at 22 years) and percent time using the Guardian Sensor 3 in the week prior to Auto Mode initiation (84% in continuers vs. 61% in discontinuers). 84 patients received a 670G at the outset of the study, and five were lost to follow-up; the remainder used the PLGS feature for one week, started Auto Mode, had weekly calls and CareLink downloads with Stanford providers for the first four weeks, and then follow-up visits at three, six, nine, and twelve months. That is quite a lot of hand-holding, and we have to imagine there is a higher discontinuation rate at a lower-resource clinic with less bandwidth for outreach. The population’s mean age was 27 years (33% were under 18 years-old), average diabetes duration was 15 years, baseline A1c was 7.9%, baseline time-in-range was 60%, and the mean percent time using the Guardian Sensor 3 in the one-week prior to Auto Mode was 77%. The figure below shows percent time in Auto Mode over time, with the mean dropping from >70% at one week, to ~50% by three months, ~40% at six months, and ~35% at nine and twelve months. The effect was clearly driven by those who stopped Auto Mode altogether: one person was not using it at all at one week, 31% at three months, 40% at six months, 44% at nine months, and 46% at twelve months, suggesting that those who make it six months on Auto Mode are highly likely to make it the full year. Not surprisingly, the lower an individual’s baseline A1c, the more time they spent in range at all time points (example at one week below). Dr. Lal concluded that education and adequate preparation is crucial in setting realistic expectations for closed loop systems, a focus on usability and human factors is necessary to ensure patients stay on treatment, and next-generation technology will hopefully balance safety with simplified device operation (sure to come with future AID systems from the likes of Tandem, Medtronic, Insulet, Beta Bionics, Bigfoot, etc.).

• Dr. Lal reported that those who continued to use Auto Mode did so because they wanted to stay in range, though they realized that it wouldn’t necessarily come with less work. On the other hand, those who stopped using Auto Mode did so because of sensor issues (60% of respondents), problems obtaining supplies (17%), fear of hypoglycemia (10%), MDI preference (7%), and sports (7%). 
  
  • There were two significant product developments during the course of the study: (i) Dexcom’s G6 launched in the US. Dr. Lal noted that some switched to G6 and stopped using Guardian Sensor 3 entirely, while others wore G6 and fed that information into 670G, so they were still in Auto Mode; and (ii) Medtronic updated its Guardian Sensor 3 transmitter to reduce unnecessary blood glucose calibration requests. Dr. Lal and team are looking at whether fewer requests increases those who use Auto Mode – based on the number who stopped due to sensor issues, this improvement should be beneficial.  
• At ENDO 2019, Boston Children’s Hospital’s Dr. Gregory Goodwin presented similar results, albeit from an exclusively pediatric/adolescent (n=93). In this cohort, nearly 40% of users had ceased to use the 670G, with an average time at withdrawal of 2.5 months.     

Selected Questions and Answers

Dr. Jen Sherr (Yale): Do you have information about the number of boluses per day between groups? I wonder if those who stopped were non-compliant bolusers.

A: That’s a great question. The problem was, we felt that doing those metrics may make it difficult because we didn’t have CareLink access for the people who discontinued Auto Mode.

Dr. Andrew Ahmann (OHSU): Take people that had the Dexcom sensor first, then changed sensors to Medtronic’s. Did you do that analysis? 

A: Yes, there’s no difference.

Q: Did cost have anything to do with people dropping off the sensor?

A: This population actually had pretty good coverage. There was probably only one publicly-insured patient in the group. That’s another limitation of the study. But most were fairly well reimbursed.

Dr. Ahmann: Are you tracking going forward with new Medtronic transmitter to see if it makes a difference?

A: Absolutely, that’s part of the plan.

Dr. Roman Hovorka (Cambridge): Based on these results, are you changing your education strategy – who you’re putting on the system?

A: As we gained experience with some of the issues, that trickled down to CDEs and ourselves, so when we had conversations with folks going forward, we knew these were some of the challenges people experienced and tried to share that with patients so they know the pros and cons.

Q: Do you recall how many patients, if they were unhappy with the control level, specifically commented that they couldn’t get their fasting blood glucoses below 130?

A: We didn’t collect direct data on that. Empirically, folks were pretty happy with their overnight control, that’s one of the things they did like.

3. Beta Bionics iLet Insulin-Only Home Study: TIR of 70% (+1.9 hours/day), with successful use in MDI and integrating Dexcom G5 and Senseonics Eversense

Beta Bionics’ integrated Gen 3 iLet touchscreen device performed very well in its first human study (n=34),running in insulin-only mode for seven days with either Dexcom’s G5 or Senseonics’ Eversense CGM. Compared to usual care, time-in-range (70-180 mg/dl) improved by 1.9 hours per day on the iLet (70% vs. 62%; p=0.01), while mean glucose improved by 7 mg/dl (155 vs. 162 mg/dl; p=0.09) with no difference in hypoglycemia <54 mg/dl (0.6% in both arms). The random-order, crossover, home study compared seven days of usual care to seven days of insulin-only automation with the custom-built, dual-chambered iLet pump device (embedded Bionic Pancreas control algorithm); n=17 participants used the G5 CGM at Stanford and n=17 used Senseonics 90-day Eversense CGM at MGH. The study enrolled bothMDI (n=12) and pump users (n=22), only used body weight to initialize the algorithm, and compared CGM outcomes on days 3-7 of the iLet vs. days 3-7 of usual care. (Days 1-2 were excluded for two key reasons: the algorithm takes one day to adapt to the person, and investigators wanted to exclude any residual basal insulin from MDI users.) Overall CGM outcomes were nearly identical to the previous iPhone-based research platform (Tandem pumps), and the ball-and-stick plot (see below) again showed a nice tightening in the population’s range of average glucose while reducing hypoglycemia – a testament to how automation can level the playing field regardless of therapy or baseline outcomes. Dr. Jafri concluded that the insulin-only iLet was safe and effective in both pump and MDI users, with no need for a run-in or lengthy training – a big advantage of using body weight alone for initialization. MDI users did not have any more hypoglycemia – impressively fast algorithm adaptation! – and the study showed two different CGMs can successfully power the Beta Bionics system. The results also led to design improvements for the next-gen iLet Gen 4, which we first saw at FFL 2018 and will be used in the pivotal trials: an insulin-only pivotal is expected to start in 1Q20, with bihormonal expected in 1H20 (using Zealand dasiglucagon). 

• The G5 and Eversense CGMs performed similarly with the iLet: time-in-range was 72% with G5 vs. 68% on Eversense; mean glucose was 154 mg/dl with G5 vs. 155 mg/dl with Eversense; time <54 mg/dl was 0.3% with G5 vs. 0.8% with Eversense. Sensor accuracy was measured relative to the Contour Next BGM, which came in surprisingly high: 22% for G5 and 18% for Eversense. (For comparison, MARD is ~9% on both systems vs. YSI.) 
• This data nicely complements the iLet bihormonal vs. insulin-only home-use study shared just before ADA (n=10): In bi-hormonal mode, participants spent 79% time in range (70-180 mg/dl), nearly two hours more per day than the 71% time-in-range with insulin only (p<0.01). Time in hypoglycemia (<70 mg/dl) was 2.4% during the bi-hormonal period and 3.6% during the insulin-only period – a difference of ~17 minutes. Time <54 mg/dl was 0.3% during the bi-hormonal period and 0.6% during the insulin-only period. Participants achieved a mean glucose of 139 mg/dL during days 2-7 of bi-hormonal mode, compared to 149 mg/dL during days 2-7 of insulin-only mode (p<0.01).

4. IV Insulin+Dextrose Inpatient Closed Loop System: 94%-98% Time-in-Range in Type 1 & 2; No Severe Hypoglycemia Recorded

MGH’s Dr. Jordan Sherwood presented data on an inpatient configuration of an insulin+dextrose closed loop system, which can be used to achieve normal glycemia without severe hypoglycemia for type 1 and type 2 adults in the ICU. This configuration of the Bionic Pancreas was adjusted to use Abbott’s Navigator CGM and insulin and dextrose administered intravenously via a hospital Symbiq pump. The control algorithm was located on a laptop, and the system, which did not require meal announcements, was initialized solely with body weight. Adults with type 1 diabetes (n=6) and type 2 diabetes (n=6) participated in an eight-hour study period, including an unrestricted meal and a simulated two-hour tube feeding with an abrupt stop to mimic real-world inpatient conditions. Time-in-range (70-180 mg/dl) was 98% in type 1 diabetes and 94% in type 2 diabetes, with 0%-0.5% spent <70 mg/dl. Dr. Sherwood explained that the lowest glucose reading was 66 mg/dl, occurring just when the system was initiated. Mean blood glucose was maintained from 106 mg/dl to 107 mg/dl in type 1s and decreased from 175 mg/dl to 125 mg/dl in type 2s. Dr. Sherwood noted that there was a “wide degree of glucose variability” at the study’s start, but as the algorithm adapted, variability decreased. We’re thrilled to see such strong results and are excited by the ongoing work in this area. Prior to this study, the Cambridge group was the main academic team researching closed loop for the inpatient setting; Admetsys is trying to build a commercial version, though we haven’t heard an update in some time. We would be fascinated to see how the glycemic control afforded by closed loop impacts patients’ long-term hospital outcomes. 

• Dr. Sherwood highlighted that that type 2 patients had a nearly ten-fold higher insulin requirement as compared to type 1s. Conversely, patients with type 1 diabetes required roughly three-times as much dextrose as those with type 2 diabetes.

5. Cambridge Group Finds Fully Closed Loop to Be Feasible and Efficacious Regardless of Fiasp vs. Novolog in Type 2 Adults

University of Bern’s Dr. Lia Bally presented results from the Cambridge group’s double-blind, randomized crossover study (n=15) of Fiasp vs. Novolog in a fully closed loop system for type 2 diabetes. The system consisted of a Dana pump, Navigator II CGM, and the Cambridge MPC control algorithm, which modulated insulin delivery every 10 minutes. Over the 10-hour study period, participants received a standard breakfast and lunch and took a 20-minute walk. There were no significant differences observed for time-in-range (100-180 mg/dl), time <100 mg/dl, time <70 mg/dl, time >180 mg/dl, mean glucose, or glycemic variability. Participants spent 68% time-in-range (100-180 mg/dl) with Fiasp and 71% time-in-range (100-180 mg/dl) with Novolog, amounting to 16-17 hours. There was one hypoglycemia event (<63 mg/dl) reported with Fiasp and two with Novolog. Postprandial glucose was also equivalent for the two insulin types. Dr. Bally concluded that a fully closed loop system in type 2 patients is feasible and efficacious regardless of insulin type; however, she noted that larger and longer studies are needed to elucidate Fiasp in different target populations. We wonder what the difference would look like in type 2 diabetes closing the loop with regular insulin vs. Novolog (for cost purposes).

• Dr. Bally emphasized that ~10% more insulin was required with Fiasp than with Novolog. In line with the higher insulin requirements, she explained that higher insulin exposure was observed with Fiasp as compared to Novolog.

6. Capillary Biomedical Receives NIH Grant to Perform 7-Day Crossover Study of “Kink-Proof” SteadiSet Infusion Set vs. Commercial Teflon set in Type 1s; CGM and PK/PD Outcomes

TJU’s Dr. Jeffrey Joseph shared that Capillary Biomedical has received an NIH SBIR grant for additional study of the “kink-proof” SteadiSet infusion set with a soft, multi-port, flexible cannula. The group is currently planning a prospective, crossover trial comparing use of the SteadiSet for seven days vs. use of a commercial Teflon set for seven days in type 1s. Outcomes will be gauged by CGM (“safety and efficacy”), as well as by glucose clamp to assess PK/PK on days one, three, five, and seven. Per ATTD, Capillary is eyeing a 2020 launch for the seven-day-wear set. Based on the slew of preclinical swine data that Dr. Joseph et al. have accrued demonstrating less tissue damage and more consistent insulin absorption vs. current commercial sets, we have to imagine that these properties will carry over to humans. Through a hard-hitting slide (below), Dr. Joseph emphasized the important take-home message that delivery of insulin from commercially-available infusion sets is highly variable from day to day and dose to dose. The top row demonstrates progressive tissue damage – bleeding, collagen deposition – with the Teflon cannula inserted at 90 degrees, variable bolus distributions (as depicted in micro-CT images in the second row), and higher pressure in the tubing/catheter (“up to several thousand mmHg,” especially on days two and four). “This is why we’re getting variable PK/PD in the real world,” Dr. Joseph concluded. Compare this figure to a similar study of the investigational SteadiSet: There is still some inflammation around the cannula beginning on day two, but the multiple orifices on the catheter allows the insulin to get into the tissue; there is higher pressure initially on days two and four, but this quickly comes down; and importantly, the full bolus is effectively delivered on every day. Below these two figures, we also include a striking image showing the SteadiSet delivering insulin into swine subcutaneous tissue on day six and histology showing a significantly thicker layer of inflammatory tissue around the commercial Teflon set (right) vs. SteadiSet (left). 

• Dr. Bruce Buckingham told an audience at CarbDM (April) that his Stanford group will study Capillary Biomedical’s SteadiSet “in the near future.” The group has also studied Convatec’s Coated Lantern Infusion Set out to 10 day-wear. As of April, 18 of 24 subjects had completed the study: 90% of subjects had worn the set for seven days, with an average duration of 8.6 days. We’ll see coated Lantern data in a poster here at ADA.

Questions and Answers

Q: Do you have any idea how the increased surface area might affect the blood insulin level?

A: We’re doing that work as we move forward. It’s preliminary work. If you do the calculations, greater surface area means faster absorption, more consistent deliver, but that needs to be proven.

Dr. Steve Russell (MGH): What is the material of the catheter?

A: It’s a soft, flexible polymer currently used in FDA-approved products for anesthesia. It’s in the body for 5-7 days, but we haven’t disclosed what the material is. 

Q: I didn’t see data comparing the SteadiSet to a rigid steel cannula. Have you looked at that?

A: I removed the slide, but we did six swine comparing Teflon to stainless steel catheters, and it’s scary how much damage there is to the subcutaneous tissue with steel. It turns dark brown from the bleeding and the hemoglobin degrades. Keep in mind that it’s swine, they lay on the cannula, it’s not a person with diabetes, but it’s scary how much damage there is under the skin. Steel causes the most damage, Teflon at 90-degree-angle next, Teflon at 30-degree angle next, and then SteadiSet.

Dr. Ed Damiano (Beta Bionics): One thought I’ve been knocking around for a while is that you have retrograde flow around the catheter that could wet the adhesive on the infusion set, which could affect plausibility of 7-day wear, especially with a port closer to the surface like you have. Anything you’ve looked at there?

A: We have not seen that as a problem. The cannula is angled and 13.5-mm in length. It has a distal hole, and each hole is 2 mm above that. The proximal-most hole is at least 4 mm away from dermis, and we haven’t seen leakage as a problem.

CGM

1. Three-Year COMISAIR Data (n=94) Show CGM Drives Similar Glycemic Outcomes Regardless of Insulin Delivery Method in Type 1s; Five-Hour Increase in Time-in-Range

In an early morning Dexcom-sponsored symposium, Charles University’s Dr. Jan Šoupal presented three-year results from the COMISAIR study (n=94 type 1 adults) comparing four combinations of diabetes treatments. The prospective, real-world, investigator-initiated study is the longest CGM trial ever conducted, evaluating: (i) SMBG + MDI (n=21); (ii) SMBG + pump (n=25); (iii) CGM + MDI (n=22); and (iv) CGM + pump (n=26). The main takeaway from the study supported preliminary one-year results (Šoupal et al., 2016) presented at EASD 2016: adding CGM to MDI drove similar glycemic outcomes as adding CGM and a pump. Participants were naïve to both CGMs and pump therapy upon enrollment and were asked to select their preference for treatment modality – the investigators agreed with the patients’ choice in 94% of all cases. For time-in-range, time <70 mg/dl, and A1c, participants in the CGM groups achieved significant improvements over the SMBG groups. Time-in-range increased from 49% to 69% in the CGM + MDI group and increased from 51% to 72% in the CGM + pump group – impressive improvements of ~5 hours/day. There were no significant differences observed in the SMBG groups. Similarly, time <70 mg/dl decreased from 9.4% to 5.5% in the CGM + MDI group and 9.0% to 5.3% in the CGM + pump group – declines of nearly one hour. Once again, no significant differences were observed in the MDI group. A1c decreased by 1.3% and 1.2% for the CGM + pump and CGM + MDI groups, respectively (baseline A1c: 8.2%). There were no significant changes in A1c observed for the pump groups. Dr. Šoupal concluded that improvements with CGM were stable after three years and emphasized that insulin delivery modality is “not so important” – CGM + MDI reduced A1c more than SMBG + pump (-0.8% in favor of CGM). Dr. Šoupal positioned CGM + MDI as a “suitable alternative” for patients unwilling or unable to try sensor-augmented pump therapy. Given the high cost of pump therapy, this study is a major win for CGM, adding to evidence from DiaMonD and GOLD. Full results will be presented at EASD 2019.

• Dr. Šoupal noted “really nice adherence” over the three-year study: out of the 94 participants enrolled, 88 completed all study visits (94%). Mean sensor use at three-years was quite strong, with the CGM + MDI group and CGM + pump group showing 88% and 87% sensor wear-time, respectively. Impressively, 100% of participants in the CGM groups wore their sensor >70% of the time over the three years. Dr. Šoupal attributed the strong adherence to allowing participants to choose their own therapy group.
• Glycemic variability as measured by standard deviation (SD) significantly improved in both CGM groups, as well as the SMBG + pump group. Once again, there was no significant difference observed between the CGM groups by insulin delivery method. There were seven severe hypoglycemia episodes spread across the four groups, and three ketoacidosis episodes spread equally across both SMBG groups and the CGM + pump group.

• The average number of fingersticks per day changed only in the CGM + MDI group, which saw a significant decline from 3.7/day to 2.7/day. There were also significant decreases in the number of insulin boluses per day in all but the SMBG + MDI group. The CGM +MDI group increased from 3.9/day to 6.6/day; CGM + pump increased from 3.8/day to 7.1/day, and SMBG + pump increased from 3.8/day to 4.9/day. Dr. Šoupal noted that in order to be successful with CGM, patients should be willing to use more boluses. He also prefers rapid-acting insulin over human to avoid stacking, and advised the consideration of half-unit pens for leaner patients.

2. First US Eversense Real-World Data: 11.2% MARD, ~75% Patients Re-Inserted; Potential for Flash CGM Version of Eversense without Transmitter; 180 HCPs Trained to Perform Insertions/Removals in US

In her first public appearance as Senseonics CMO, Dr. Fran Kaufman presented data on the first 205 US patients to have completed 90 days of Eversense wear. Roughly one-third of patients were CGM naïve, 80% were type 1, and there was an equal gender split. MARD based on 27,705 paired readings was 11.2%. While this is a notable increase from the MARD vs. YSI of 8.5% reported in Senseonics’ US clinical trials, such declines in accuracy are typical in real-world use. Promisingly, ~75% of these patients have been re-inserted with their second Eversense sensor. Patients spent 62% time-in-range (~15 hours), just 4% time <70 mg/dl (~1 hour) and 34% time >180 mg/dl (~8 hours). Mean sensor glucose was 162 mg/dl, corresponding to a mean GMI of 7.2%. Importantly, Dr. Kaufman highlighted that there have been “minimal safety issues” reported: 10 (5%) patients experienced transient skin irritation; 4 (2%) experienced mild infection at the insertion site; 4 (2%) failed to remove the sensor on the first attempt; and 5 (2.5%) experienced irritation to the transmitter patch/adhesive. We’re hopeful that continued collection of such positive real-world outcomes will help convince payers that Eversense is another valuable CGM option. Dr. Kaufman highlighted Eversense’s non-adjunctive dosing indication approval just before ADA, moving towards Medicare reimbursement as the ultimate goal.

• Dr. Kaufman shared details on the 180-day US Eversense XL PROMISE trial, last slated in May to complete enrollment in 3Q19. Participants (n=180) will engage in nine study visits over the six-month trial, totaling 1,440 total visits. Accuracy vs. YSI will be assessed in hyperglycemia and hypoglycemia, amounting to >55,000 CGM-YSI pairs. During Q&A, Dr. Kaufman confirmed plans to use the first 90-days of data from the trial to support an iCGM indication for the 90-day Eversense. She expects to see iCGM categorization in “a little less than a year.” At the same time, Senseonics is collecting accuracy, efficacy, and safety data as part of its ongoing post-approval study for the 90-day Eversense in the US.
• Dr.Kaufman briefly described pipeline efforts for Senseonics: Extending sensor life to 365 days as an eventual goal, though more immediate priorities include reducing calibrations to one fingerstick/day for the 180-day Eversense XL in the US. She also would like to expand the patient population to pediatrics and believes an iCGM categorization would make “a big, meaningful impact.” As we’ve heard in the past, she shared the idea of enabling a “flash CGM opportunity,” allowing users to scan their sensor with a smartphone for readings when not wearing the transmitter. This would be an excellent move for Senseonics, as it would make the system deliver on the fully implantable, nothing-on-the-body promise. It could also open up another segment of the market for those who don’t want anything showing on the body – something Abbott, Dexcom, and Medtronic still have.
• There are ~180 trained healthcare providers who can perform Eversense insertion/removal procedures in the US. Aligning with comments on the company’s 1Q19 call, Dr. Kaufman noted ~400 clinicians have prescribed Eversense in the US to date. Dr. Kaufman also shared that in Europe, there are 1,000 trained healthcare providers, and Eversense is available in 700 clinics across 15 countries. 
• Dr. Kaufman reviewed Senseonics’ poster (976-P) depicting the long-term safety of Eversense in its post-market safety registry in Europe. Two-year data from 3,066 subjects across 15 countries revealed no severe adverse events and just a 3.3% occurrence rate of adverse events, the most common being sensor location site infection (n= 28, 0.91%), unable to remove sensor at first attempt (n=24, 0.78%), and adhesive patch location site irritation (n=18, 0.59%).

3. Dexcom G6 Pro launch delayed to early 2020; G7 to reduce warmup time; Companion InPen Data in Clarity

In a Dexcom product theater, CTO Jake Leach shared that the G6 Professional CGM is now slated to launch in early 2020, a delay from the JPM plan to launch in 2019. On one hand, this isn’t too surprising, given the demand for G6 and ongoing capacity expansion. It’s also possible the G6 Pro disposable transmitter will need to leverage the lower-cost G6 personal transmitter manufacturing, which will begin production in 3Q19. (We've confirmed with Dexcom that G6 Pro is not yet FDA cleared, as it is different from the "Pro-Q" retrospective-only product that was FDA cleared in November 2018.) As a reminder, G6 Pro includes the same 10-day sensor (factory calibrated), a one-time-use disposable transmitter, an ability to run in blinded or real-time mode, a reader to download the data in clinic after 10 days, and the ability for users to get real-time CGM data through the same G6 app. (Based on the Pro transmitter, the G6 will run in a simplified mode.) It will be a big upgrade from the current G4 professional CGM and help Dexcom catch up to Abbott’s FreeStyle Libre Pro.

• In a new update on G7, Mr. Leach said the next-gen CGM will have a faster warm-up time, implying a move down to a one-hour startup – this would put it on par with FreeStyle Libre 14-Day and halve the current two-hour warmup in G6. We cannot recall ever hearing this before, alongside the other compelling features: a fully-disposable, single-piece sensor-transmitter with a smaller on-body footprint, a “significant cost reduction,” iCGM accuracy without calibration, extended wear (14-15 days), direct Bluetooth to the phone, and simple application. It remains on track for a late 2020 limited launch, with broader international rollout in 2021. Mr. Leach highlighted the same new markets slide shown in Dexcom’s 1Q19 call, calling out the especially strong potential for CGM in type 2 diabetes to optimize medications (dose and timing) and encourage healthy behavior.
• Mr. Leach showed some brand-new screenshots of the Companion Medical InPen partnership, with insulin pen data flowing directly into Dexcom Clarity.Seeing the purple strikes for boluses (under the CGM trace) adds a whole new dimension – this additional data source is going to be very illuminating for understanding what is happening day to day. 

• In line with 1Q19and ATTD, Direct-to-Apple Watch remains “under development” and Dexcom hopes to “bring it to market as soon as possible.” Per ATTD, this has “taken a while” because Dexcom “really wants to get the user experience right.” It was previously expectedto launch in 2019.
• Dexcom is working on an API to share real-time CGM data with partners “for use cases that make sense for real-time data” – we assume decision support, bolus calculation, and forward-looking CGM prediction would fall in that category. Currently, the Dexcom API shares CGM data with a three-hour delay, limiting partners to retrospective use cases (e.g., CGM analysis, patterns, stats). 
• Also on the data partner front, we noticed Onduo shown on the partner slide for the first time. Dexcom CGM data is used in Onduo’s program and app, and Dexcom became the preferred CGM in Onduo as part of the restructured Verily agreement.

4. Consensus on Time-in-Range Goals Published in Diabetes Care; Davida Kruger’s Nine-Step CGM Analysis Plan

In a talk covering the basics of Dexcom Clarity, time-in-range, and CGM stats, we snagged two updates from Henry Ford Health System’s Ms. Davida Kruger: (i) the international consensus on time-in-range has been published in Diabetes Care (Battelino et al.), in tandem with its presentation as poster 2-LB (key tables from the paper are below; we’ll be back with the details in a later report); and (ii) Ms. Kruger’s valuable nine-step plan for analyzing CGM data in-clinic.

5. New (and Recent) FreeStyle Libre Studies Underscoring Efficacy in T2D, RWD, Accuracy of New Algorithm, etc. Called Out by Drs. Gavin & Ajjan During Abbott-Sponsored Symposium

At an Abbott-sponsored dinner CME event, University of Leeds’ Prof. Ramzi Ajjan and Emory’s Dr. Jim Gavin reviewed a slew of new data – much of it presented for the first time at this year’s ADA – on the FreeStyle Libre. We have listed all of them, in the order in which they were presented, in the following table:

• Dr. Gavin suggested that CGM has potential to meet many unmet patient (“targeted population”) needs, specifically pointing to: 
  
  • Use during pregnancy planning and during gestation
  • Hypoglycemia avoidance, dose/timing of therapies in both type 1 and type 2 diabetes
  • Effects of activities of daily living, illness, and treatment intensification for both type 1 and type 2 diabetes
  • Broader employment in type 1 diabetes
  • In type 2 diabetes, we can use CGM to better understand time of onset, evidence of progression, treatment response timing
  • Use in prediabetes to understand individualized natural history, progression, and response to treatment
  • Use in clinical trials to better understand the scope/timing of response, glycemic variability, and “diabetogenic effects of various interventions”
  • Facilitation of patient empowerment, self-management, and risk avoidance.
  • (In other words, anyone touched by glucose intolerance – type 1, type 2, prediabetes, gestational – can benefit from CGM!)
• Dr. Gavin highlighted NHS’ Forward Plan to offer all pregnant women with type 1 diabetes CGM to help improve neonatal outcomes. This was seemingly a direct outcome of the JDRF-funded CONCEPTT trial, which was followed by a health economic analysis showing savings of ~$2,800 per conception. It is great to see such fast action by NHS!
• Dr. Bergenstal took four rapid-fire questions at the end of the symposium, which he adequately summed up as “Dr. Bergenstal, you’ve gone off the deep end.” He replied, “Come on in, the water’s fine.” He then proceeded to answer the questions one-by-one: (i) Time-in-range shouldreplace A1c for daily management, but not altogether – A1c is necessary but not sufficient currently, as we understand it; (ii) We are not going to condense the time-in-range bins from five to three; (iii) No, we don’t want to go after A1c if a patient’s time in-range and time-in-hypo improve, but we do want to continue to strive to improve time-in-range and time-in-hypo; and (iv) If the SMBG and CGM don’t agree, take a deep breath and just use the CGM.

6. Dr. Dan Einhorn on the Joy of Using FreeStyle Libre 14-Day in Clinic

Scripps’ Dr. Dan Einhorn provided an enthusiastic overview of FreeStyle Libre 14-Day in a standing-room-only product theater. He used the word “fun” repeatedly in describing clinic visits with FreeStyle Libre, noting the data from CGM gives him “something meaningful to talk about” with patients. He highlighted the advantage of seeing patterns related to food choices, some of which can be “uncomfortable” for a provider to make (e.g., ethnic foods). With CGM, instead of advising someone to “stop eating rice,” you just see the objective pattern and can talk about it; we had not appreciated this kind of benefit for HCPs, but it is a lovely point and a reminder of the tough behavioral change they must propel. Dr. Einhorn emphasized the simplicity of FreeStyle Libre many times, comparing it to the iPhone and harkening to Steve Jobs’ initial introduction of the technology here in Moscone Center. “Living with [FreeStyle Libre] has proven to be easy and compelling. You don’t need a big manual with instructions.” Dr. Einhorn shared three compelling FreeStyle Libre cases from his clinic (one in type 1, two in type 2) bolstered by video interviews taken from a smartphone – very authentic. The type 1 user called FreeStyle Libre a “life-changer” at least three times in a two-minute video (he used it in hospital after a recent surgery), while the others showed the benefits in type 2 users having a difficult time (one had a baseline A1c of 13%). 

• In Q&A, Dr. Einhorn said he tries to use CGM in all of his patients at least once: “Even if patients are not on something that might cause hypoglycemia, even if A1c is in-range, I try to use CGM in all my patients at least once. You get a surprise almost every time. What happens at breakfast when you have a boxed cereal? I tell my patients, ‘What kind of food can live at room temperature forever and not spoil?’ Rice is the other classic one. It makes it real – seeing the pattern. Do I do CGM continuously in stable patients? No; I use it intermittently. But why do you do an A1c? It’s the same thing. CGM is not just for people on insulin.”

The diaTribe Foundation’s Fourth Annual Musings Under the Moon: Easier, Better, Cheaper: Where are We in Diabetes?

The diaTribe Foundation hosted its fourth annual Musings Under the Moon event, kicking ADA 2019 off on Thursday night with two powerhouse panels of diabetes industry leaders. Our own Adam Brown and Kelly Close served as moderators of two discussions focused on improving diabetes care, achieving better outcomes, and lowering cost. Below, you’ll find the most Quotable Quotes from the night, followed by a complete transcript of both panels. 

On the first panel, “Supercharging Design and Delivery,” were BrightInsights’ Dr. Kal Patel (President), Dexcom’s Ms. Claudia Graham (Former Senior Vice President), Bigfoot’s Ms. Jennifer Block (Vice President of Clinical and Medical Affairs), and Abbott’s Dr. Marc Taub, PhD (Divisional Vice President, for Abbott's diabetes care business).

Up next – on “The Future of Evidence Generation” – were AZ’s Dr. Elisabeth Bjork (Senior VP, Head of Late CVRM, R&D Biopharmaceuticals), Insulet’s Dr. Trang Ly (Senior VP and Medical Director), Novo Nordisk’s Dr. Todd Hobbs (Diabetes Chief Medical Officer), Lilly’s Dr. Sherry Martin (VP of Global Medical Affairs), and Sanofi’s Dr. Christopher Sorli (VP of Medical Affairs). 

Quotable Quotes

On Physician and Patient Burnout

• “Providers are buried by prior authorizations. For each full-time endo, 32 hours per week are spent on prior authorizations.” – Ms. Jennifer Block
• “[PCPs] spend about 6 hours per day out of a 10 hour workday in the EMR. And when you ask what gives job satisfaction, 80% of it comes from the feeling that they’re doing something good for people. So people are going into medicine with the desire to help people and then feel like they’re a slave to technology, and they’re leaving in droves. Primary care is so underserved – it’s devastating to think of the consequences.” – Dr. Christopher Sorli
• “I have a son who is a surgical resident. Right now, we have a generation of physicians, myself included: I did not use a computer to do work until I was almost 30 years old and in fellowship. The technology that has come along has far outpaced the learning agility curve of trained physicians from 30 years ago. At the same time, they’re trying to master the body of information and multiple new drug therapies, the technology has been hitting them. I ask my son, how does your day go? He doesn’t feel, at 29 years old, the same burden around technology that I see when I talk to a 50 year old. He’s lived with it from a young age. I think we’re at the cusp of breaking through – in the trough of burnout.” -Dr. Sherry Martin
• “In my experiences working with patients, you can have very engaged people with type 2 diabetes. The type of diabetes does not define the engagement. Diabetes is challenging for everyone who deals with it, and we have a responsibility as a community to support.” – Ms. Block

On Real-world Evidence

• “The FDA is struggling because RWE is not homogeneous. I remember having conversations in the Trulicity development program, and they wouldn’t even come to the table then. Can we do things in the label? They said it’s interesting data, but no. It behooves us to be able to accurately explain the different types of data we have access to. Some types of data you can’t look at until the product is in the market, so RCTs are still important. It’s a dialogue now, and it’s going to evolve. Payers are going to be doing these analytics regardless.” – Dr. Martin
• “I don’t know what you guys are doing, but we have gotten things approved with RWE. We made improvements to cannula design by slightly changing the angle of insertion. When we presented this to FDA, we needed to do a safety study with 30+ patients over 6 weeks collecting occlusion data – they said, well, you might now be infusing in the subdermal tissues, or by changing the insertion angle it slips out and causes higher rates of hyperglycemia. The new design was submitted to Health Canada and cleared. We said to FDA, “Instead of doing the study with 30 patients over 6 weeks, why don’t we run the new cannula design in Canada in randomized pods – one with the old design and one with the new? Then track rates of hyperglycemia.” When we got that back, the rates of hyperglycemia and hypoglycemia were unchanged. We saw a greater than 75% reduction in occlusion rates. And the FDA cleared that! That was in lieu of a controlled study that would be expensive. If we do this, we direct so much more data into the real world.” – Dr. Trang Ly
• “We would love for the FDA drug and device divisions to talk more to each other. We’re encouraged by the fact that CDRH is encouraging things. CDER is more conservative, but we’re talking to them about it.” – Dr. Martin
• “You need to have both RWE and RCTs to assess effectiveness. What I look forward to is if it’s possible to randomize into the real world set and collect the data. Even if you use the analytics, it’s not as good as randomization. We can get to a place where we can randomize and then stay and collect the data.” – Dr. Elisabeth Bjork

On Product Design

• “At Abbott, we believe that innovation without access is meaningless. When we started working on the FreeStyle Libre, we knew it had to be accurate but also affordable to benefit everyone. We knew we’d have to design it from the beginning to scalable; we knew that it had to be made at low cost. We knew that it had to have a 14-day sensor to drive price down and pass benefit on to the patients. We knew that we had to introduce the first factory calibrated system in order to remove cost of test strips from the device. That led us to develop Libre as we did. It had to be simple, scalable, and easy.” – Dr. Marc Taub
• “For us at Bigfoot, one of the challenges is thinking about the environment that we will deliver our devices too: The HCPs and the patients. This is an environment that is taxed. It’s amazing to have CGM data and see how that can improve outcomes, but so many don’t know what to do with that data or don’t know how much insulin to take. Providers want to help but also may not have a solid understanding of insulin. So for us, the challenge is in architecting a system to meet people where they are and drive outcomes.” – Ms. Block
• “When you’re designing and developing you need to make sure it’s solving a problem. Just think about all of the things that have been designed and developed that don’t actually help the patient. They haven’t solved a problem. If you begin with the premise of solving a problem, we will all be better off. Because a company may have a lot of money, they can convince you their product has helped people, but it might not have.” – Ms. Graham
• “I think the reason we can even talk about user-driven research and ecosystems in diabetes is because companies have already tackled the core fundamental digital innovations. 10 years ago, we would be hypothesizing about what Bigfoot, Abbott, and Dexcom have already done. Now that the groundwork is set, we can think about optimizing around the user.” – Dr. Kal Patel 
• “Don’t launch before it’s your time – that has been the biggest mistake that many companies do. In doing so, you take the patient along a tortuous route of failures and bad experiences as well. It’s difficult for patients and companies to overcome.” – Ms. Graham

On Innovation in Research and Digital Health

• “The primary care physician has become a gatekeeper. For example, renal insufficiency, refer to nephrologist – PCP’s hate that and want to own the patient. Technology is changing into a system that provides info that’s actionable and empathetic and allows that connection to start taking place.” – Dr. Sorli
• “I would love clinical research sites to look at someone with albuminuria, retinopathy, andrenal insufficiency – can we do something with an RCT where I can look at my database and actually find 100,00 of these people? We’re headed that way. There are issues with transparency and consistency, but we’re getting there.” – Dr. Sorli
• “One other aspect that holds promise is, as we are going beyond glucose, if there are other biomarkers that we can more easily recognize early as signs of a positive outcome, versus having to follow people for 5-6 years to understand what the outcomes may be. The new guidelines around time-in-range are such that we’ve got biomarkers that we can assess more quickly and understand what those population responses are.” – Dr. Martin
• “I’d like to see trials with wearables and virtual elements so that patients don’t have to come into the clinic for all visits. Also, downloading sensors at home and expanding the number of patients at a lower cost, with caveat that FDA accepts the data generated. A little more reality – incorporating patient virtual elements into the RCTs so we can get a greater wealth of data.” – Dr. Hobbs
• “I’ve had type 1 for 31 years, and for so many I thought about how glucose sensing was never going to make it here. To think I can look in my pocket and see not only by blood sugar, but my son’s a thousand miles away – I don’t want us to take that for granted.” – Dr. Hobbs

More to come on the panel! 

-- by Adam Brown, Ann Carracher, Abigail Dove, Martin Kurian, Brian Levine, Payal Marathe, Peter Rentzepis, Maeve Serino, and Kelly Close