June 22-26, 2018; Orlando, FL; Day #4 Highlights – Draft

Another day of ADA is in the books, following an outstanding day #1, day #2, and day #3. This report covers our top highlights in diabetes therapy and diabetes technology from day #4 (Monday). See a comprehensive list of all our ADA highlights on our Resource Hub. Now, without further ado…

Diabetes Technology + Big Picture Highlights

1. J&J’s One Touch Via Bolus Patch Device Non-Inferior to FlexPen in Large T2D RCT (A1c: -1.6% vs. -1.7%); BUT, Marked Subjective Preference for Via from Patients & Providers

A highly-anticipated trio of posters evaluating J&J’s OneTouch Via (three-day patch insulin bolus delivery device) vs. pen bolus delivery (Novo Nordisk’s FlexPen) in a 62-center, 44-week RCT of type 2s (n=278 with A1c ≥7.5%) ended with mixed results. Both groups experienced similarly robust reductions in A1c (~1.6%-1.7% drops!), but patients and providers alike preferred Via over the pen for implementing basal-bolus therapy, suggesting that the “wearable pen” device, which allows for simplified training and discreet insulin delivery, may drive greater adherence in the real-world setting. Patients were randomized to use either OneTouch Via or the FlexPen when advancing to mealtime insulin, and all used a pattern-based logbook, which combined SMBG values with a simple insulin adjustment algorithm. Initial evaluation lasted for 44 weeks, after which the participants “crossed over” to the opposite therapy for four weeks. During a baseline period and prior to study visits at weeks 4, 12, 24, 36, and 44, participants recorded three days of 7-point SMBG values, and phone calls with subjects were conducted with patients five times during the first eight weeks to assist with self-titration. A CGM sub-study with Dexcom G4 Platinum was performed in 96 of the participants for one week at baseline and for again for a week between weeks 22 to 24. Top-line, 44-week results showed that A1c decreases were significant in both groups, but not significantly different from each other: the FlexPen group saw their A1c drop an average of 1.7% (baseline: 8.7%) while those on Via saw A1c drop an average of 1.6% (baseline: 8.6%). In both groups, all of the improvement in A1c came in the first 24 weeks, then leveled off at ~7.0% (~83% of the reduction came by week 12). Both groups also saw significant reductions in fasting plasma glucose at 44 weeks (roughly -20 mg/dl from baseline of ~160-170 mg/dl), as well as significant reductions in 7-point SMBG (see below). In both groups, mean glucose decreased from ~200 mg/dl to ~140 mg/dl and TDD increased from ~50 units to ~130-140 units in both groups (they were under-insulinized, given the high baseline A1c to start). The only reported SMBG metric that significantly differed between the two study arms was coefficient of variation (CV) of mean daily blood glucose between days (an unconventional metric – not the same as within-day CV on AGP reports); both groups started at ~10.5%, and the Via group’s decreased to 9.4%, while the FlexPen group’s increased to 12% (p=0.02). There were no significant differences in hypoglycemia (defined as blood glucose ≤70 mg/dl), though at night, the pen group reported 74 episodes vs. 60 episodes in the Via group (NS, p=0.09). If anything, the study shows a very robust A1c reduction in both groups, but the edge goes to OneTouch Via in terms of patient and provider preferences (see below). It was remarkable how well the FlexPen group did – far better than we’d see in real-world use.

• For those in the IDC-run CGM sub-study (n=96), the story was the same at week 24: Both groups saw significant decreases in A1c, time in 70-180 mg/dl, alongside a significant increase in time <70 mg/dl, but none of the between group differences were significant. As a preliminary note, we assume that the G4 Platinum was used in its retrospective, blinded mode, but are not 100% sure. Based on the CGM metrics, both groups benefited tremendously by week 24 from just being randomized in the study, as demonstrated in the AGPs below (flatter, narrower, and more in-range!): In the Via group, time 70-180 mg/dl increased by 6.2 hours/day (48%->74%), time >180 mg/dl decreased by 7.2 hours/day (50%->21%), and time >250 mg/dl shrunk by 3 hours/day! Variability, measured by standard deviation, decreased from 53 to 46 mg/dl (though when converted to coefficient of variation, it actually increased from 29% to  33%, which is still very stable). OneTouch Via increased hypoglycemia, as time <70 mg/dl and <54 mg/dl increased by a fairly large 50 minutes/day (1%->5%) and 13 minutes/day (0.2%->1.1%), respectively. The outcomes in the pen group were almost identical: Time 70-180 mg/dl increased by 7.9 hours/day (42%->75%), time >180 mg/dl decreased by 8.9 hours/day (57%->20%), and time >250 mg/dl shrunk by 4.5 hours/day! Variability, measured by standard deviation, decreased from 54 to 45 mg/dl (though again, when converted to coefficient of variation, it increased from 27% to 32%). For hypoglycemia, time <70 mg/dl and <54 mg/dl increased by 1 hour/day (1%->5%) and 14 minutes/day (0.2%->1.2%), respectively.

• Subjective reports from the full study population were almost invariably in favor of the OneTouch Via over the FlexPen, from both patients and providers. At 24 weeks, patch users were significantly more satisfied overall, particularly with the device’s ease of use. Relative to the pen group, they also reported improved discretion, lack of pain, ability to do things “spur of the moment,” social comfort, having insulin on them always, and likelihood of recommending. At 44 weeks however, they didn’t feel that they were more confident, had more peace of mind about managing diabetes, could fit diabetes management into their lives, or were taking positive steps with diabetes management relative to the pen group managing insulin (not surprising, as the glycemic outcomes were statistically the same across groups) – this is surprising to see, as we would have guessed a stronger response on these. Regarding quality of life, daily functions and diet restrictions were rated more highly in the patch group. In the subject preference survey – since both groups got to use both devices for at least four weeks – every response from both groups was significant in favor the patch (e.g., people felt more satisfied with the patch, preferred it, had to carry fewer supplies around, felt more freedom, and would recommend it over the pen). Both groups also said they wanted to switch from the pen to the patch, but the group that used the patch for 44 weeks followed by 4 weeks of the pen were significantly more likely to endorse this statement than was the group that used the pen for 44 weeks followed by the patch for 4. 

  • One of the most important findings from the study, in our view, is that 91% of providers preferred the OneTouch Via over pens to advance type 2 patients from basal to basal-bolus insulin. In their survey, they endorsed that the device helped them transition patients to basal-bolus faster, facilitated a more gratifying relationship with the patient (though not reflected in the patient survey), will help overcome barriers to initiation, is easy to use and train. They also endorsed that they would prescribe the patch for MDI patients both at and not at goal. This was not a blinded study, so we acknowledge that there may be a bit of “whiz-bang” at play here – “wow, look how cool this device is, if I had diabetes I would love it!” or “this is a new device, I’m supposed to prefer it.” Still, getting providers on board, particularly with the endorsements that it is easy to train and could reduce clinical inertia, would do wonders for driving adoption in the type 2 insulin delivery device field.

  • With the connected pen market just beginning to ramp, we do wonder how the equation would’ve changed for both providers and patients if the comparator arm had been a smart pen/pen cap (same goes for overall glycemic outcomes). Might providers take the potentially-heightened hassle of a pen if they were able to view a patient’s mealtime insulin dosing behavior? Would that lead to more productive conversations and the ability to better support patients with titration and between visits? Of course, OneTouch Via could eventually have connectivity built in, though the beauty of the device is its simplicity (the only user interface is a button for bolusing) and its small, flat on-body profile – neither of those should be significantly compromised!

• OneTouch Via and Calibra Medical (manufacturer) are still part of J&J, though the company continues to pursue strategic options for it. We doubt that the device will remain as J&J’s standalone diabetes care offering, since Platinum Equity acquired LifeScan for ~$2.1 billion earlier this month. We sincerely hope the device doesn’t get shelved, as we still consider it to have strong potential and the results from this study have some positive notes. The question remains, who could buy OneTouch Via? An insulin company could be a great fit – imagine a pre-filled? It would also make sense for a company like BD, Medtronic, or even Insulet to swoop in to add to bolster its insulin injection/delivery portfolio.

2. Insulet/Lilly U500 Omnipod Yields Greater A1c Reduction with Pump vs. MDI: -1.27% vs. -0.85% (VIVID)

Dr. George Grunberger presented positive data from the large, 26-week VIVID RCT of Insulet’s Lilly-partnered U500 Omnipod (vs. U500 MDI, both with Humulin) in type 2s (n=420) with high total daily doses (TDD) of insulin – the first ever study of U500 insulin administered through a pump, to our knowledge. Enrollees were a mean ~57 years old, with BMIs of ~40, high A1cs (~8.75%), and TDDs of ~290 units. During the first week of the study, all participants injected U500 insulin three-times daily – one group continued with MDI for the subsequent 25 weeks, while the other switched to pumping U500 with Omnipod. By the end of the 26 weeks, both groups had significant decreases with U500 insulin, but the Omnipod group’s decrease was significant greater by 0.42%; -1.27% vs. -0.85% (p<0.001). The groups’ A1c began to diverge as early as eight weeks (the first time it was measured per the protocol). Fasting plasma glucose reduction was also significantly greater in the Omnipod arm (~30 mg/dl decrease) vs. MDI (no net change) at 26 weeks. Further, the greater A1c reduction with the Omnipod was not accompanied by an increase in TDD by week 26, while the MDI group had increased its TDD by ~50 units, up to ~340 units per day – lower A1c, with less insulin = a home run. Overall, there was no significant difference in documented symptomatic hypoglycemia <54 mg/dl (~15 events/patient/year) or ≤70 mg/dl (~35 events/patient/year), nor in severe hypoglycemia, which was low in both groups. (We assume this was measured via BGM, but it was not stated.) However, nocturnal hypoglycemia events/patient/year were significantly greater in the Omnipod arm, both at the <54 and ≤70 mg/dl thresholds – we’d point out in the graph below that the absolute difference looks very small (~2-5 events per year!) and therefore not likely clinically significant. One audience member asked during Q&A if the greater nocturnal hypoglycemia materialized because of large pre-sleep boluses; another questioned whether the basal rate needs to be reduced at night. While Dr. Grunberger showed that the bolus:basal ratio increased from 50:50 to 53:47 in the Omnipod arm, it was unclear why they had greater levels of hypoglycemia. With further studies, occasional professional/real-time CGM, and greater education regarding titration, we believe the increase in hypoglycemia could be mitigated. Dr. Grunberger concluded the talk by flashing “U500 delivered in a dedicated pump could be a viable option for patients requiring high doses of insulin.” We’d agree! This study was a big success, particularly because it filled in a large gap in existing literature – ~25% of U500 insulin is used in pumps designed for U100, and the safety and efficacy of this practice was previously unknown. We’re excited for very insulin-resistant people with type 2 diabetes to have a pump option where they won’t have to do arithmetic acrobatics in their head in the near future. Insulet has long guided for this product to launch in 2019, and we believe this study proves its safety and efficacy.

• We saw screenshots of the very well-designed U500 Insulet PDM at DTM 2017.

• A separate ADA poster (P-1011) detailed the same VIVID study, but examined a primary population excluding individuals on GLP-1s and SGLT-2s. Results were nearly identical to those in Dr. Grunberger’s presentation, with both groups seeing significant A1c improvements, but the pump group finishing the 26 weeks with a .44% greater A1c drop (1.3% vs. 0.86%). Nocturnal hypoglycemia (≤70 mg/dl) and severe hypoglycemia were slightly (and significantly) higher in the Omnipod arm, but in general the device still seems safe and effective in the GLP-1 agonist- and SGLT-2 inhibitor-using patients.

3. Medtronic 670G receives CE Mark for 7+ years, launch this fall in 10 EU countries; Bold 670G outcomes guarantee for payers: Medtronic Will Reimburse Any Diabetes-Related Hospitalization/ER Visit up to $25,000 Over 4 Years! Non-Adjunctive CGM PMA Filing This Year

In a huge update at Medtronic’s one-hour ADA Analyst Briefing today (slides, webcast), it is launching a bold 670G outcomes-based guarantee for payers: “If there is a diabetes-related hospitalization or ER visit for patients on the 670G, we’ll reimburse it – up to a cap of $25,000 over a four-year period.” President Hooman Hakami was very impassioned in presenting the slide below: “Based on the outcomes with the  670G…and the compelling data we see from the millions of patient-days, we’re ready to stand behind the system through a business model…There is no other diabetes company that can say this or do this. No other company has the benefit of a system that actually keeps a patient in the right glycemic control. There is no other company that has the data we do that demonstrates the value of that control. This is something we think the community is going to embrace. It’s a further indication of our commitment to value-based-healthcare, and not just driving fee-for-service – but actually selling outcomes.” He later added that “Medtronic is trying to change the conversation. Today’s paradigm, where companies offer a product, they are compensated for the product immediately, but the healthcare system lives with a promise that things will get better because of utilization. ‘Pay me for this, trust me, it’s going to drive better outcomes and lower costs.’ That’s a broken dynamic. We want to change that. Instead, we say, ‘I’m going to prove it to you; if you buy this, we feel so strongly that this was designed for outcomes, we’re going to stand by it.” Wow – this is a very bold and important move for the field, and Susanne Winters said in Q&A that payers are “very interested in this,” especially to have predictability around costs. Will we see more preferred arrangements like the UHC/Medtronic deal?

• This morning, Medtronic also announced CE Mark for the MiniMed 670G hybrid closed loop, with a launch to commence this fall in 10 European countries: Belgium, Denmark, Finland, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, and the UK. Notably, Medtronic obtained approval for 7+ years, meaning it will have pediatric approval from the start in Europe. (In the US, 670G approval for 7-13 years just came on Thursday.) The EU approval comes ~21 months following the September 2016 US approval for adults – a testament to FDA’s remarkable leadership in automated insulin delivery. (It’s also possible Medtronic waited to secure the pediatric label and to get manufacturing ready before submitting in Europe.) The 670G EU launch will also bring the improved Guardian Sensor 3 outside the US for the first time; currently, Medtronic currently uses Enlite Enhanced in the 640G and standalone Guardian Connect mobile CGM. Following 670G’s EU rollout, Medtronic will add Guardian Sensor 3 to Guardian Connect outside the US. This 670G EU launch puts Medtronic ahead of competitors on AID: Diabeloop is planning for a late 2018 EU launch of its hybrid closed loop in only three countries (see Day #3); Insulet is taking over direct Omnipod distribution on July 1, though Dash is not expected in Europe until 2H19 and AID with Horizon is further out; and Tandem will make its first EU sales in 2H18 following CE Mark of t:slim X2/G5, but there is no international timing on its AID systems, Basal-IQ or Control-IQ.

• The Analyst Briefing also gave some new pipeline updates not shared at the Analyst Meeting: a PMA for a non-adjunctive claim will be filed “this year” (unclear if calendar or fiscal); a clinical trial for a Medtronic no-calibration real-time CGM will happen this year with a planned launch within two years (presumably Harmony); talks are ongoing with the FDA to run a trial for a seven-day wear infusion set, with a goal to start before the end of this fiscal year (by April 2019); Medtronic’s Envision Pro (formerly iPro3; launch by April 2020) will be blinded, fully disposable, no-calibration, and Bluetooth-enabled (single-use data transfer, like Libre Pro). Management confirmed the next iteration of 670G will add Bluetooth, with “eventually smartphone control” (the Analyst Meeting implied those could come together).

• We also heard that Guardian Connect will be priced somewhere between Dexcom G5/G6 and FreeStyle Libre. Management reiterated the power of Sugar.IQ and that Medtronic has “1,000” people resources in the US that it can leverage to drive Guardian Connect (we assume this is reps + clinical).

• Sheri Dodd, the new VP of the Type 2 (Non-Intensive) Diabetes Business spoke, sharing plans to combine the telehealth/remote monitoring in Medtronic Care Management Services with professional CGM. She’ll continue to lead both businesses. Her slides talked about risk stratification and figuring out the best tools to care for those patients.

4. Cambridge’s Fully Automated Closed Loop System Increases Time-in-Range (100-180 mg/dl) by 5.8 Hours/Day in Inpatient Type 2s – Published in NEJM!

Dr. Lia Bally (Bern University Hospital) presented very encouraging results from a multi-site, 15-day RCT (n=136) of the Cambridge group’s fully automated closed loop system in inpatient type 2 diabetes. In a huge win for the group and the closed loop field, the study was also simultaneously published in NEJM! To initialize the system – which consists of the Navigator 2 transmitter/receiver, Dana R insulin pump, and a tablet housing the algorithm – only body weight and estimated total daily dose are required. Overall, participants who received closed loop therapy (n=70) spent a significant 5.8 more hours in-range (100-180 mg/dl; 65.8% vs. 41.5%) and 6.2 fewer hours >180 mg/dl (23.6% vs. 49.5%) per day as compared to the control (n=66). Neither group spent any time <54 mg/dl (one could argue that the algorithm could be more aggressive to eliminate more hyperglycemia). Dr. Bally emphasized that these incredibly positive results were achieved by variations in insulin delivery (adjusted every 12 minutes), as the total daily dose did not significantly differ between groups. Standard deviation was also significantly lower in the closed-loop group (46 mg/dl vs. 59 mg/dl), as was mean glucose (154 mg/dl vs. 188 mg/dl). Importantly, the patient population was impressively diverse, admitted to the hospital for a variety of reasons including renal, cardiac, respiratory, and neurological complications. ~Two-thirds of the population were on a basal-bolus regimen. 98% of participants reported being happy to have their glucose levels controlled automatically, and 100% of participants would recommend use of the system to others. Dr. Bally concluded that the closed loop system promises to be a novel approach in managing inpatient hyperglycemia safely and effectively. These results add to similarly positive data from a smaller study (n=12) of the system presented at ADA 2016. As the only group, to our knowledge, working to bring closed therapy to the inpatient setting, we’re certainly rooting for Cambridge’s success. The fact that baseline time-in-range in a place where healthcare is supposed to be delivered is just ~40% is just mind-blowing – particularly considering recent research demonstrating that higher mean glucose in the cardiac perioperative setting significantly correlated with lower 30-day mortality. Dr. Bally mentioned during Q&A that future studies plan to actively involve the hospital staff.

5. Virta Prediabetes (n=116): Of 95 completers, 61% (n=58) Back to Normoglycemia (A1c <5.7%), Zero Progressed to T2D (A1c ≥6.5%) at 1 Year; Mean 11.5% Body Weight Lost

Virta’s Dr. Amy McKenzie added to the evidence on Virta Health’s continuous remote care + ketogenic diet intervention, sharing mightily impressive one-year data in the prediabetes population (n=116) for the first time: Of the 95 completers (82% retention), 61% (n=58) moved from prediabetes to normoglycemia (A1c <5.7%), and not a single person progressed to type 2 diabetes. Virta’s intervention is a low-carb/high-fat diet (to induce nutritional ketosis) combined with tech-enabled remote care, and the study was non-randomized, un-controlled study, and conducted in collaboration with Indiana University Health Arnett. Drilling deeper, the other outcomes from this study look very strong (see below for corresponding photos):

• Body weight dropped an impressive average of 29 lbs (11.5%) from baseline 111 kg (~245 lbs). 70% of completers lost >7% of body weight; only ~4 individuals gained weight, and one lost ~40% of starting weight! It is truly remarkable to see the inter-individual weight variability in the graph below – this suggests a very wide response to the intervention. Of course, on average it produces great results, and we’re just as interested in why some people respond vs. not.

• A1c decreased by 0.3% (baseline: 5.9%). (i) 80% of completers decreased A1c, and 12% saw increases; (ii) 61% of completers regressed to normoglycemia (A1c <5.7%); (iii) no completer progressed to type 2 diabetes (A1c ≥6.5%). We’re surprised to see some A1c increases – was this from not following the program or from a biological response?

• Fasting plasma glucose (FPG) dropped from 109 to 100 mg/dl (51% of completers had FPG drop below 100 mg/dl at one year).

• Systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides (TG), and HDL-C all significantly improved at one year. SBP dropped from 130 to 124 mmHg; DBP dropped from 83 to 80 mmHg; TG dropped from 150 to 107 mg/dl; and HDL-C increased from 52 to 58 mg/dl. LDL-C was not reported. In the type 2 study, there was a mean ~10% increase in total LDL-C, though the more nuanced LDL partitioning changed in a positive direction – and some studies suggest this is a more sensitive CVD risk factor than LDL-C alone.

• These prediabetes management/diabetes prevention results go along nicely with evidence from Virta’s controlled study in type 2 diabetes, which has demonstrated ~60% diabetes reversal (defined as an A1c <6.5% and elimination of all medications except metformin) at one year. Taken together, an over-simplified calculation suggests that Virta may be able to bring 60% of type 2 enrollees into prediabetes at one year, and then bring ~60% of those individuals (36% of the initial population) into the normoglycemic range – for an employer, a two-year intervention that takes 36 out of 100 people off of their diabetes medications, makes them feel better and more productive, and lowers their risk of complications seems like a very solid proposition! We’re not sure that Virta will ever offer a “spectrum-like” continuous program as we just laid out, if they will aim to deliver separate diabetes remission and DPP, or something else – in fact, the company’s stated goal to reverse type 2 diabetes in 100 million people by 2025 says nothing about plans to address prediabetes (though we would love to see more companies with unique approaches enter the space!).  Notably, both type 2 and prediabetes studies will again report results at two years and five years – the type 2 study is already >2.5-years in, and we assume the prediabetes study is as well.

• Only 56% of the completers reached a mean blood beta-hyodroxybutyrate concentration of ≥0.5% mmol/L over the year of treatment (the goal of Virta’s ketosis-inducing diet), meaning 44% did not. Virta has not yet examined the outcomes between the two subgroups, but we think parsing them would be extremely informative. One sentiment regarding Virta goes something like, “I’m not sure about the ketogenic diet, but I’m all in on the remote continuous care.” This was brought up today, as a Pennington Biomedical researcher asked during Q&A if patients would see the same outcomes on a Mediterranean or low-fat diet if they were interacting with coaches an average of three-times per day (as they did in this study). We would at least like to see Virta conduct a study where it positions remote continuous care without a one-track diet recommendation as a control group. Given our own anecdotal experience with low-carb, high-fat, it is extremely effective, assuming someone knows how to navigate situations and titrate medications – hence the remote care.

• Throughout the talk, Dr. McKenzie put Virta’s data into the context of typical, CDC-identified diabetes progression and the results of the landmark DPP study. At a high level, every year, CDC expects 5-10% of people with prediabetes to progress to diabetes, and another 5-10% to regress to normoglycemia; Virta’s data blows this population-wide trend out of the water, with 61% regression and 0% progression. In the DPP study, participants who received the lifestyle intervention lost 7% body weight, and those who received metformin lost 3% body weight at one year – Virta’s program led to 11.5% body weight loss (notes: people in the DPP started at a lower average weight of ~207 lbs; and Virta’s intervention is hands on for a year, while the DPP lasts 24 weeks). In the DPP, the risk of progressing to type 2 diabetes was 56% lower for those that regressed to type 2 diabetes; 61% reverted to normoglycemia in this study.

Questions and Answers

Q: I imagine these people restricted their carbs…

A: When they started the study, we recommend they consume <30 grams of carbs per day. They’re mostly getting their carbs from starchy vegetables.

Q: Outstanding data. Virta has the ketogenic diet, and continuous remote care. I’ve seen data presented before, that the average daily connection for patients and remote coaches is three times per day, maybe more than that. That’s a lot. What if you did the Mediterranean diet or a low-fat diet when you have that much interaction.

A: Great question. I have no idea. And that’s exactly what we have, it’s an average of ~three interactions with coaches per day. In terms of glucose and A1c reduction, the interaction component is definitely very interesting.  

Brian Levine (Close Concerns): 44% of the group didn’t have beta-hydroxybutyrate levels ≥0.5 mmol/L – what were their outcomes?

A: Mean beta-hydroxybutyrate, over the course of a year. No, we didn’t look into that, but that’s an excellent question.

6. OpenAPS Retrospective Crossover Analysis (n=20) Finds Time-In-Range to Increase by 1.5 Hours/Day vs. Pre-OpenAPS

Ms. Dana Lewis presented very impressive data from a retrospective, cross-over study of 20 DIY users, comparing their glucose metrics 4-6 weeks before vs. after initiation of OpenAPS. DIY closed loop conferred improvements in every metric analyzed: time-in-range (70-180 mg/dl) increased from 76% to 82% (+1.5 hours/day); time <70 mg/dl decreased from 6% to 4.5% (-22 minutes/day); and time >180 mg/dl decreased from 18% to 13% (-1.2 hours/day). On DIY, participants saw mean blood glucose decrease by 8 mg/dl (136 mg/dl to 128 mg/dl) and mean estimated A1c declined by 0.3% (from a solid base of 6.4%). Clearly, the improvements are made all the more impressive by the fact that the DIY users were very on top of their diabetes care regimen prior to going on closed loop. Although this study focused solely on glycemic outcomes, Ms. Lewis expressed the hope that all hybrid closed loop studies consider measures of quality of life, including frequency of clinical visits, number of manual interventions required, and sleep. We’re absolutely blown away by these results – in the first ADA DIY oral, no  less – and are delighted to see the DIY community releasing more data (the last data we saw from OpenAPS was at ADA 2016), lending even more credibility to this trailblazing community.

• Ms. Lewis broke out overnight data, and to her surprise, found that greater improvements in glycemia were seen during the day. She postulated that there are so many tasks people with diabetes have to do during the day that OpenAPS can “benefit a lot more in helping us catch up with all the things we’re dealing with.” That logic makes sense – closed loop could feasibly help people better manage meals and exercise – though hybrid closed loop studies frequently show greater improvement overnight. Overnight time-in-range increased from 80% to 86% while daytime time-in-range increased from 74% to 80%. See below for the tabulated data.

• Interestingly, Ms. Lewis noted that a couple of people actually saw their time-in-range decrease on closed loop, as evidenced by the individual pre- and post- results shown below. She stipulated that this is likely due to variations in the set glucose target, as OpenAPS recommends setting a very conservative target (especially for beginners).

7. Insulet Omnipod Dash Product Theater: An Impressive User Experience in Full Demo of Startup, Bolus, Pod Activation; 2H19 OUS Launch

Insulet’s Omnipod Dash product theater offered a full, detailed demo at the new touchscreen PDM and paired mobile secondary display apps. Based on what we saw, Insulet’s Dash has set a new industry standard in the user experience of insulin pumps, even relative to Tandem’s t:slim X2: from the big things (fully integrated food library, simple home screen centered on IOB, very large color interface) to the small things (graphical display of basal insulin, excellent scroll wheels), Insulet has done an awesome job on this product. The attention to detail really shows! We especially loved the startup screens that guide the user through setting up the PDM – Dash has a warm feel, and Dr. Trang Ly’s demo had the entire pump settings set up from scratch in just a few minutes. We imagine healthcare providers will love how much easier the PDM is to train, and the advantage of automatic upload to Insulet-provided Glooko (when connected to WiFi) will be big. Insulet has laid a great foundation for the future goal to dose directly from the phone. The launch timeline is the same in the US (six-month limited market release in 2H18, full launch in early 2019); President Shacey Petrovic confirmed the plan for a 2H19 Dash launch outside the US.

8. HypoDE Sub-Analysis: CGM Can Benefit MDI-Treated Type 1s with Hypoglycemia Unawareness Regardless of Baseline Patient Characteristics

Dr. Norbert Hermanns (Institute for Diabetes Technology, Germany) presented results from a sub-analysis of the landmark HypoDE trial (n=141) investigating the impact of baseline characteristics on successful reduction of hypoglycemia. HypoDE, the very first randomized controlled trial to examine the efficacy of real-time CGM (Dexcom G5) in MDIs with type 1 diabetes and impaired hypoglycemia, found CGM significantly reduced hypoglycemia incidence (≤54 mg/dl for at least 20 minutes) by 72%. Results from the six-month, 12-center trial were presented at ATTD and published in The Lancet. Dr. Hermanns evaluated the effect of 13 baseline characteristics, including: (i) demographics (e.g. age, diabetes duration); (ii) clinical variants (e.g. A1c, severe hypoglycemia in the past 12 months); (iii) patient-reported outcomes (e.g. fear of hypoglycemia, diabetes distress); (iv) biochemical hypoglycemia (e.g. time <70 mg/dl, hypoglycemia events); and (v) biochemical euglycemia (time ≥70 mg/dl and ≤180 mg/dl). None of the factors were found to be significantly linked to successful hypoglycemia reduction, defined as zero hypoglycemia events or at least 50% fewer hypoglycemia events than at baseline. The only factor that actually predicted successful reduction of hypoglycemia was randomization to real-time CGM vs. SMBG (OR: 9.8), strongly suggesting that CGM can benefit MDI-treated type 1s with hypoglycemia unawareness regardless of baseline characteristics. What an incredible confirmation of the value CGM can bring to a wide assortment of patients! In the 2018 ADA Standards of Care, CGM indication for those with hypoglycemia unawareness was graded with C-level evidence –  we’re hoping that the HypoDE results will serve to increase the strength of this important recommendation, especially considering that there’s now RCT evidence.

9. Dr. Denice Feig and Dr. Elisabeth Mathiesen Debate CGM Use in All Type 1 Women During Pregnancy

In an equal parts humorous and insightful debate, University of Toronto’s Dr. Denice Feig and the Center for Pregnant Women with Diabetes’ Dr. Elisabeth Mathiesen went head-to-head on whether all pregnant women with type 1 diabetes should use CGM from planning pregnancy until breastfeeding. Dr. Feig took the pro-argument, commenting to a round of applause: “Maybe this topic shouldn’t be debated because the evidence is clear.” Dr. Feig focused mainly on the compelling CONCEPTT data, showing CGM use in pregnant women to significantly increase time in-range (+100 minutes/day) and decrease time in hyperglycemia (-72 minutes/day). She acknowledged that 80% of participants reported problems with the sensor, although the study used Medtronic’s older Guardian CGM, and she maintained that more recent RCTs outside of pregnancy have demonstrated improved use and satisfaction with use with other, newer CGM systems. Though not the primary endpoint of CONCEPTT, the significantly improved neonatal outcomes were the headline: a 50% reduction in large-for-gestational-age (LGA) newborns, as well as reductions in hypoglycemia requiring IV dextrose and NICU admittances lasting >24 hours. To this end, Dr. Feig believes CGM is likely to prove cost-effective, which her team is currently investigating. She noted that nine months of CGM use in the UK costs ~£1,500, the same as the expenses associated with just one day spent in the NICU. With more advanced CGMs not requiring fingersticks, she pointed out, CGM costs will only decline. Moreover, she asked the audience: “What price would you place on your baby to avoid a prolonged stay in the NICU?” Needless to say, we and many others were moved. As her final argument, Dr. Feig provided a quote from a CONCEPTT participant, which really does say it all: “It’s like being completely blind and then having somebody open your eyes… Managing my sugars without CGM is like driving a car blind-folded.”

• Dr. Feig also made a strong case for CGM use postpartum and during breast-feeding. During the postpartum stage, women require ~54% of their pre-pregnancy insulin dose, while at the same time experiencing marked glucose variability. While breast-feeding, women have to intake more carbs to prevent hypoglycemia. For all these reasons, Dr. Feig asserted that CGM should be maintained through breast-feeding. As for those planning pregnancy, Dr. Feig acknowledged that the CONCEPTT arm investigating CGM use in women planning pregnancy did not find the A1c reduction to be significant; however, there was a clear positive trend, and she believes this arm was underpowered. Ultimately, she argued that there is an enormous amount of literature supporting the use of CGM in non-pregnant patients, so why not provide the added benefit during pregnancy planning.

• Dr. Mathiesen had presente da counter-argument to CGM use in pregnancy. As her main evidence, she cited a 2013 study (n=154; Secher et al.) evaluating intermittent, real-time CGM in women with type 1 and type 2 diabetes during pregnancy. Participants were randomized to wear CGM for six days at a time at weeks 8, 12, 21, and 33 of pregnancy in addition to routine care, which included seven fingersticks/day, or to routine care only. A1c and hypoglycemia events were comparable in both groups, with a tendency towards greater rates of LGA and preterm delivery in the CGM group. In fact, when Dr. Mathiesen examined data from the per protocol users of CGM exclusively (as there were high rates of poor adherence), there were even higher rates of LGA among CGM users. However, Dr. Feig addressed this study during her presentation, reminding attendees that intermittent use prevents reaping the full benefits of CGM data, and only 60% of participants followed the protocol, leading to a small, underpowered sample size. Moreover, she finds A1c to be a “lousy measure of glycemia during pregnancy,” preferring time-in-range, as it more accurately captures “what the fetus is facing.” Dr. Mathiesen also noted that she was shocked to see that very few participants in the study wanted to remain on the CGM. We’re not too surprised though, given that  participants still had to perform seven fingersticks/day and only wore CGM for six days at a time somewhat sporadically.

• Dr. Mathiesen also focused on the cost of CGM, pointing out that the expenses associated with CGM use in 20 women are equivalent to the salary of one nurse. She also asserted that there are extra costs due to increased doctor/nurse time – however, as one audience member noted, CGM tends to massively reduce provider time, as blood glucose readings are easily accessible and can be more quickly evaluated. Another of Dr. Mathiesen’s concerns was that CGM readers do not show glucose values from the last three to seven days, which are necessary when looking to change a pregnant patient’s insulin dose. She remarked that to view such data, patients have to upload readings to a “computer program” and one would “have to be a nerd to do that.” This sounds like a strawman to us – to view seven-day retrospective data from most BGMs, a “computer program” would also be necessary. She also advocated for more real-world data and more than one RCT before making such a costly investment. However, as Dr. Feig opined during her rebuttal, “why wait for real-world data when there is such a good and definitive RCT? Our patients deserve it.” Hear, hear!

Selected Questions & Answers

Comment: That was awesome, but it didn’t change my mind. Most of my patients who are pregnant with diabetes are using CGM in one form or another and I thought it was interesting that you [Dr. Mathiesen] said it adds time to visits. In my clinic, it saves me incredible time. It probably saves five minutes.

Comment: I’ve found CGM and mainly flash CGM to be so instructive to my patients in pregnancy for the timing of insulin, modifying diet… it’s almost been no-brainer. My real-life experience is people with CGM just want to continue.

Q: What about CGM use in type 2 diabetes during pregnancy?

Dr. Denice Feig: I certainly think that it’s possible all patients will benefit but we might need very large numbers to show that. It’s certainly worth looking into.

Dr. Elisabeth Mathiesen: It has to be cost-effective. The prices of sensors have to come down and CGMs have to be simpler to use.

Dr. Feig: Helen Murphy had an uneducated patient who could hardly read or write and she just followed the CGM arrows and did very well.

Q: If you couldn’t give sensors to all of women during pregnancy, who would you give it to?

Dr. Mathiesen: I’d give to women with the highest risk of hypoglycemia and to the very poorly regulated patients.

Dr. Feig: If I couldn’t use it for everyone, I’d do the same. But I’d prefer to give it to everyone.

Q: Do you think there is a place for using CGM in gestational diabetes?

Dr. Mathiesen: Save the economy, go for type 1 diabetes first.

Dr. Feig: I would agree, but I think there’s still a place for research. We’re assuming they won’t necessarily benefit. Type 1 diabetes would be my priority but I wouldn’t rule it out for GDM.

10. Why Is the Economic Impact of Severe Hypoglycemia Underestimated?

Swansea’s Dr. Phil McEwan expounded upon a number of factors that may be causing the true economic impact of to be underappreciated. We’re glad that people like Dr. McEwan are working on this issue – the more visible hypoglycemia gets, the more investment it will receive.

• Fear of hypoglycemia causes people to relax treatment, putting them at higher risk of vascular complications. Dr. McEwan referenced data showing that many providers and patients decrease insulin dose following a severe hypoglycemia, and most providers say they would treat patients more aggressively if they didn’t have to worry about hypoglycemia (no surprise there). This A1c “bounce-back” effect can have significant consequences from a cost perspective: The lifetime costs of maintaining an A1c of 6% is ~20,000 British pounds; for an A1c of 10%, this number more than doubles to ~40,000 british pounds (Baxter et al.). Said Dr. McEwan: “The barriers to obtaining optimal levels of glucose control have a cost, but it’s difficult to assign the cost implication to hypoglycemia in an economic evaluation. It’s known to exist, but tough to capture robustly in evaluations.” Dr. McEwan told us after the session that if he could run a dream trial with no cost constraints, it would be to study this phenomenon with CGM and connected pens/pumps to better understand the economic cost of fear of hypoglycemia.

• A growing body of evidence supports an association between hypoglycemia and CV mortality/morbidity, but these are not yet included in economic evaluations. Dr. McEwan shared that CV risk equations from ACCORD – the BRAVO risk engine – has severe hypoglycemia as a coefficient for a number of CV events. “It’s likely that we’ll start to see equations like this embedded in economic models in diabetes to derive estimate for costs of hypoglycemia directly, as opposed to just fear and quality of life.”

• Cost per hypoglycemic episode is often presented as a mean, which masks underlying variability. For example, a Portuguese study showed that each event of severe hypoglycemia cost a mean ~1,500 euros – however, according to Dr. McEwan, the variability is from 35.00 to26,000 euros! Further, presenting the mean cost per episode doesn’t really tell the whole story. The DART/MEMO study (1996) reported 244 hypoglycemic events costing 92,078 pounds in a year in a Scottish hospital. In 2017 follow-up, the rate of hypoglycemia in type 1s and type 2s had dipped by ~33% and ~67%, respectively, but the overall number of hypoglycemia events rose to 702 and the cost shot up to 246,997 pounds. Of course, the explanation is that the diabetes prevalence had grown 2.7-fold, but the population burden would’ve been missed by a mean cost presentation.

11. Prof. Simon Heller on Gaps in Collective Hypoglycemia Knowledge and Hope for Multi-Stakeholder Hypo-RESOLVE Group to Fill Them

Sheffield’s Prof. Simon Heller peppered throughout his talk numerous assertions that the evidence base around hypoglycemia is limited, but enthusiastically suggested that Hypo-RESOLVE will help to bridge that gap. He pointed to a number of studies supporting 54 mg/dl as a logical second threshold for classifying hypoglycemia in clinical studies – e.g., cognitive function and reaction time deteriorate below 54 mg/dl, glucose levels below 54 mg/dl can reduce awareness of hypoglycemia, there is evidence that arrhythmias are triggered by glucose levels <54 mg/dl – but capped the run with, “admittedly, the evidence is relatively limited.” Plus, he added, the clinical significance of arrhythmia in this context is “uncertain.” Referring to the NICE-SUGAR study that demonstrated increased mortality to be associated with glucose <55 mg/dl to further support the use of 54 mg/dl, he noted that it used 40 mg/dl as the cutoff for severe hypoglycemia, concluding: “One of the problems with this work, we have relatively crude data, but we can demonstrate the hypoglycemia is having untoward effects.” Finally, Prof. Heller listed a few gaps in the understanding of hypoglycemia today: (i) evidence-based data to refine the classification of hypoglycemia; (ii) the level of hypoglycemia predicting adverse (CV) outcomes and mechanism(s) underlying this association; and (iii) health-economic and psychological impact of non-severe and CGM-detected hypoglycemia. Hypo-RESOLVE, “a true international collaboration,” he hopes, will help fill these gaps. He repeatedly praised the group’s multi-stakeholder nature, particularly industry’s participation and willingness to donate and aggregate its clinical study data, JDRF/Helmsley Charitable Trust/T1D Exchange’s funding even though the group is based in Europe, and the patient advisory committee. Hypo-RESOLVE kicked off with a meeting in Denmark in May – we can’t wait to hear what’s on the roadmap!

• Prof. Heller found it “gratifying” that JDRF, ATTD, EMA, and ISPAD have adopted the IHSG’s proposed glycemic thresholds for hypoglycemia: <70 mg/dl and <54 mg/dl. [ISPAD’s guidelines will be published “in the next month or two.”] “At the moment, he said, FDA is presently unclear, and we wait to hear their decision.” We so hope they decide to align with the rest of the world. Regarding the level of hypoglycemia <54 mg/dl, Prof. Heller noted that IHSG had trouble deciding on the correct clinical term – major, serious, clinically relevant, clinically significant? “Major” wouldn’t work due to Spanish linguistics, he said, “serious” sounded “too alarmist,” so they settled on clinically relevant, though he’s not sure that’s where it’ll stay.  

• As a reminder, Hypo-RESOLVE is a major collaboration among 23 other leading international players from academia, industry, and civil society. “Hypo-RESOLVE” means “Hypoglycemia – Redefining SOLutions for better liVEs”. Over the course of four years, €26.8 million (~$32 million) in funding from the Innovative Medicines Initiative (IMI), JDRF, and Helmsley Charitable Trust will help to better understand the causes of hypoglycemia and preventative measures that can be taken. Hypo-RESOLVE will kick off with a meeting in Denmark May 16-17.

Questions and Answers

Prof. Philip Home (Newcastle): I can’t believe I’m saying this, Simon [Heller], but you didn’t use the word ‘symptoms’ once during talk – for patients, hypoglycemia means unpleasant, inconvenient, and embarrassing symptoms. I’m worried that they may get ignored…where should they be in the definition?

Prof. Heller: Symptoms differ between and within individuals. They have a huge consequence to paints in terms of how they feel and clearly contribute to fear, but we know that hypoglycemia thresholds alter depending on the frequency of hypoglycemia events, A1c…In terms of defining hypoglycemia, it’s difficult to include them in definition, which is primarily to be used to undertake clinical studies and to compare clinical benefit. Within an alert value, the symptoms will often provoke the SMBG test, and it’s there in ADA definition, not to supersede the work being done, but to add a new level, particularly for trials and to aid us in incorporating CGM as it is adopted. I predict in 5 years all type 1s will probably be on CGM.

Q: What glycemic bins do you recognize?

Prof. Heller: CGM uses time in range, I think that’ll be pre-specified, 70-180 is one such definition. It’s one way we will talk about benefit. But when using CGM to define hypoglycemia episodes, less than 54 mg/dl, you also have to define the period for single event. It’s been agreed – see this is a work in progress – that the period will be 15 minutes. That’s just the way ATTD have defined hypoglycemia. Now, you might say that’s interstitial glucose, different from plasma glucose – yes it is. But to simplify what we’re trying to achieve here, it’s been agreed we’ll go with a similar glucose level. It’s a work in progress, the definition will probably need refining, but it’s the best we have at the moment.

Q: I think patients with impaired awareness of hypoglycemia are very special – there is brain protected against hypoglycemia, and the heart also.

Prof. Heller: Of course you’re right, one of the protections we have against hypoglycemia when people are first diagnosed is a profound counter-regulatory response, which can counter the effect of insulin. It generates symptoms to alert patients that their glucose is low, which is a fundamental part of education when someone is diagnosed. It’s beneficial, but on the other hand, there is accumulating evidence that it may be harmful to the CV system. It’s a double-edged sword. The other thing to remember is the longer you have type 1 and possibly type 2 diabetes, you begin to lose adrenergic response – most don’t rely on that when they’ve had diabetes for 15-20 years, they begin to rely on neuroglycopenic symptoms – feeling confusion, not right – but by that point, they’re obviously already experiencing the detriments of hypoglycemia, so it’s not ideal.

Q: How long can the heart resist during hypoglycemia, since it requires glucose?

Prof. Heller: The answer is that we don’t know to what extent, indeed some people don’t think hypoglycemia has any major effect on heart, least sudden death. And to their credit, hypoglycemia events might just be identifying already-sick people. You can do mechanistic studies showing that catecholamines can cause arrhythmia, other things that can lead to fatal events, but I suggest its likely to be cumulative. Hypoglycemia can kill – we know about dead in bed – but we don’t know what initiates the fatal arrhythmia. Animal studies show it’s lethal for sure, and at least contributed to by the sympathetic nervous system, but we don’t know how long it takes. Whatever you think, we should be avoiding hypo.

Q: I totally sympathize with ADA stating 70 mg/dl as the cutoff level, because we all understand clinically speaking, if patient gets to 70 and doesn’t start to treat, that’s the patient that will then go to 50. If gets to 50, he will go to 30. We should have two thresholds: One for clinicians, and one for patients. 70 is a great value – if it is left, patients will go to 50, and maybe to 30 or 20.

Prof. Heller: I’m not saying you should remove 70 mg/dl as an important level, we said that level one hypoglycemia is an alert, exactly the same as you pointed out, for both the clinician and the individual. It’s important. Alert, check it, before it goes to 54 mg/dl. By just having 70 in studies, then we’re missing an opportunity to measure the burden of hypoglycemia. We could make the case to payers, treat elderly with agents to reduce the risk of hypoglycemia. We’ve also said in many studies we should include it on top of 54 mg/dl.

12. Medtronic MiniMed 670G Product Theater Emphasizes Time-In-Range; Patients Can “Reasonably Expect” Time-In-Range >70%; Parent: “We Just Sleep”

During a Medtronic MiniMed 670G product theater, we were delighted to hear Yale’s Dr. Jennifer Sherr and IDC’s Dr. Anders Carlson emphasize the importance of time-in-range and the limitations of A1c. As Dr. Sherr put it, “time-in-range really provides clinicians with actionable insights, whereas A1c tells me where you are vs. a target.” Dr. Carlson cited the recently published paper to highlight that patients care about time-in-range – surveyed participants with both type 1 and type 2 diabetes ranked time-in-range as second in a list of factors they care about in their diabetes management. Dr. Carlson pointed to the real-world 670G data from nearly 33,000 patients shared yesterday to assert that a time-in-range of at least 70% can be “reasonably expected” with appropriate use of the 670G. Several thought leaders are interested in defining goals for glycemic outcomes like time-in-range, and many have advocated for using the 670G pivotal data as a place to start. Dr. Sherr wrapped up the discussion by sharing a case study of an eight-year-old patient on the 670G for the very first time. After she had spent years struggling to manage glucose overnight and facing extreme glucose variability during the day, Dr. Sherr finally decided to put her on the 670G (off-label at the time). Once the patient transitioned to auto-mode, Dr. Sherr recalled the tearful mother simply saying: “we just sleep.” We’re delighted that the 670G is finally approved in those as young as seven, and that Tandem recently received approval for its G6-integrated t:slim X2 PLGS system, which will also give parents more sleep and peace of mind.

13. Ketogenic Meal (2% Carbs, 88% Lipids) Requires 12% as Much Insulin as Mediterranean Diet Meal (60% Carbs, 30% Lipids)

A brief oral presentation demonstrated that a classic ketogenic meal (2% carbs, 88% lipids, 10% protein) requires just 12% as much insulin as a classic Mediterranean diet meal (60% carbs, 30% lipids, 10% protein). Wow! In people without diabetes, the Mediterranean meal caused glucose to increase from 90-110 mg/dl in the first hour, and then decrease to and below baseline for the remaining three hours (measured by frequent SMBG); with the ketogenic meal, glucose remains stable for a half hour and then drops in the second hour post-meal. To cope with the Mediterranean meal, insulin shoots up 12-fold in the first 20 minutes post meal, and then remains elevated – with a ketogenic meal, insulin levels increases 2-fold in the first 20 minutes and stays there. C-peptide levels follow similar trends. Overall, total insulin secreted in the three post-meal hours was 8x greater in the Mediterranean group than the Ketogenic group. University of Milan’s Dr. Simona Bertoli, the presenter, posed future research questions: (i) What is the effect of significantly lower circulating levels of insulin in infants, children, and adults? (ii) Could ketogenesis be effective for patients with insulin resistance and/or secretory defects? See the highlight on Virta’s prediabetes data above for more on the ketogenic diet.

14. Hygieia d-Nav BGM/Insulin Titration +HCP Support Drives 1.0% A1c drop vs. 0.3% Drop with HCP Support Alone in Six-Month RCT

University of Michigan’s Dr. Israel Hodish presented data from a six-month RCT (n=181) of Hygieia’s d-Nav device (BGM + insulin titration) plus remote HCP support vs. HCP support without titration in type 2 diabetes at IDC, Henry Ford Health System, and Iowa Diabetes and Endocrinology Center: A 1.0% A1c decrease (baseline: 8.7%) with d-Nav + HCP support vs. a 0.3% decrease (baseline: 8.5%) with HCP support alone. This study appears to have been presented as an ADA 2017 poster; the numbers all appear the same. Notably, the HCPs did not assist with titration, but were there to make those in the intervention more “comfortable following the recommendations of the device,” and presumably offered general diabetes support in the control arm. Despite the significantly greater drop in A1c with d-Nav-led titration, the groups experienced similar levels of hypoglycemia (0.29 events <54 mg/dl per patient per month) and just two severe hypos each in the six months. Dr. Hodish showed a graph of TDD/body weight over time, clearly illustrating that the group that didn’t have titration was not receiving the volume of insulin it needed, at the right time, to drive A1c down. While the two groups started at similar doses, the HCP-only group saw TDD/kg/day rise just from 0.71 at baseline to 0.76 at six months – meanwhile, the d-Nav + HCP group’s TDD/kg/day grew from 0.77 at baseline to 1.24. d-Nav recommended a mean 1.1 adjustments per week in the intervention group, of which only 0.2 per week were down-titrations. These data complement positive Hygieia data from a 90-day BCBS study.

• Dr. Hodish also showed the longitudinal TDD (in units) of an individual across a 4.5-year period, showing occasional dips in insulin requirements, with more-or-less constant A1c. He asserted that this ~yearly dip happens in about half of all patients, and you can’t predict it. This, he said, is why insulin needs to be chased with frequent titrations.

Diabetes Therapy Highlights

1. AZ’s Qtern (Saxa/Dapa) Meets Non-Inferiority Endpoint vs. Insulin Glargine, Superiority Endpoint vs. SU Glimepiride; Achieving Insulin-Level Glucose Control w/o Weight Gain or Hypoglycemia

Two back-to-back oral presentations highlighted Qtern’s (dapagliflozin/saxagliptin) efficacy vs. two powerful glucose-lowering agents – insulin glargine and SU glimepiride. Dr. Serge Jabbour presented the insulin glargine study and Dr. Juan Frias presented the glimepiride one, both talks centering around a common theme: While insulin and sulfonylureas offer relatively quick/steep A1c reductions, they also confer significant risk for hypoglycemia and weight gain. As such, a goal in diabetes drug development has been creating products that can match this glycemic efficacy with a much stronger safety profile, and it seems like AZ’s Qtern (among other fixed-dose SGLT-2/DPP-4 combos) might be one such drug.

• Dr. Jabbour took the stage first: This study randomized 650 patients with type 2 diabetes to the 10 mg dapa/5 mg saxa combination or to insulin glargine (Sanofi’s Lantus) for 24 weeks. The trial met its primary endpoint by showing non-inferior A1c reductions with Qtern (-1.7% from baseline 9.0%) vs. insulin glargine (-1.5% from baseline 9.1%, p=0.118). Body weight fell by a mean ~3 lbs (baseline ~198 lbs) among patients taking the combination and rose ~5 lbs in the insulin glargine arm, leading to an estimated treatment difference of ~8 lbs (p<0.001). Hypoglycemia was significantly less common in the Qtern arm vs. the glargine arm (p<0.001), with 21% and 38% of patients respectively having a confirmed hypo event. There were zero episodes of severe hypoglycemia in the Qtern arm vs. three in the glargine arm.

  • Dr. Jabbour especially emphasized data on the composite endpoint of A1c <7% without weight gain or hypoglycemia, which fit with the theme of these oral presentations – achieving similar glucose control without the undesirable effects of insulin therapy (or sulfonylureas). He reported that 17% of people taking saxa/dapa achieved this composite outcome vs. only 3% of patients on insulin glargine (p<0.001). A similar proportion of each group reached A1c <7% (33% vs. 34%), but arguably the most notable finding from this study was Qtern’s substantial and significant benefit on hypoglycemia and weight loss.

  • Professional CGM was used to assess changes in 24-hour glucose and time-in-range. After two weeks of treatment, mean 24-hour glucose had dropped 49 mg/dl in the Qtern arm vs. -29 mg/dl in the Lantus arm (p<0.0001). This difference lost statistical significance at week 24 (-49 mg/dl vs. -44 mg/dl, p=0.1984), primarily because of continued decline in the basal insulin arm. This makes sense, given that more patients were titrated to their optimal basal insulin dose by the end of the study vs. two weeks in. Dr. Jabbour framed the two-week CGM results by highlighting a real-world misconception among patients/HCPs: that insulin is the most efficient in lowering blood glucose. On the contrary, 24-hour glucose was more swiftly decreased with fixed-dose saxa/dapa, which is easy to prescribe and easy to take (no titration needed!). Dr. Jabbour continued by discussing time-in-range, which improved 34% in the Qtern group and improved 29% in the insulin glargine group from baseline to study end (p=0.0327). He concluded by once again underscoring Qtern’s glycemic efficacy and very mild side-effects, and he shared that a trial extension (another 28 weeks) is ongoing.

  • During Q&A, Dr. Priscilla Hollander raised an interesting point about guidelines. ADA currently recommends insulin or an injectable combination therapy for patients with A1c >10%, but could oral SGLT-2/DPP-4 combos have a role to play here? Dr. Jabbour explained how this study enrolled patients with an A1c up to 12%, suggesting that Qtern would be a safe option in type 2s with very high A1c. Whether it would be better than insulin or a fixed-ratio basal insulin/GLP-1 combination for this patient population is still an open question. And of course, the average baseline A1c in this trial was below 10% (~9%).

• Next, Dr. Frias presented findings from a 52-week trial (n=443) of Qtern vs. glimepiride added onto metformin. From a baseline 8.4%, A1c fell 1.4% with the combination therapy, and from a baseline 8.5%, A1c fell 1% with the sulfonylurea (p=0.001). Dr. Frias showed on a graph how A1c was similar in both groups through week 16, but then rose slightly in the glimepiride arm, which points to the attenuated efficacy seen with sulfonylureas over time (due to beta cell burnout). Weight dropped ~7 lbs with Qtern and climbed ~2 lbs with glimepiride after one year (baseline body weight ~196 lbs, p=0.001). Again, weight gain is a known side-effect of sulfonylurea treatment, while weight loss has been well-documented for SGLT-2 inhibitors and their combinations. Systolic blood pressure decreased slightly in the Qtern arm (-3 mmHg) and increased slightly in the glimepiride arm (+1 mmHg) from a baseline of ~131 mmHg (p=0.007). Hypoglycemia was observed in 19% of people taking Qtern and in 42% of people taking glimepiride; severe hypoglycemia was observed in no Qtern patients and in two glimepiride patients (1%). Hypoglycemia is the third major side-effect of sulfonylureas, alongside weight gain and beta cell burnout, and we also note some uncertainty around CV harm. In our view, this drug class is truly subpar and we wish SUs weren’t the most common second-line prescription for type 2 diabetes around the world, but we also understand that their generic status/low cost makes them the only affordable option for many patients. We sincerely hope that payers heed the results showing superior safety/efficacy to other diabetes therapies, including SGLT-2/DPP-4, and that they improve reimbursement for treatments that will be cost-saving in the long run.

  • Like Dr. Jabbour, Dr. Frias also paused on data showing Qtern’s superiority on the composite endpoint of A1c <7% without weight gain or hypoglycemia: 30% of participants in the saxa/dapa arm achieved this outcome vs. only 7% of participants on glimepiride (p<0.001). Moreover, 35% of people taking Qtern reached A1c <7% without hypoglycemia after one year, compared to 15% of people taking glimepiride (p<0.001). Dr. Frias stressed the clinical relevance of these composite outcomes, and these findings left us all the more convinced that Qtern should be better utilized in diabetes care.

  • Treatment-related adverse events were more common with Qtern vs. glimepiride, and Dr. Frias attributed this mostly to urinary and genital infections.

• We were fortunate to speak with AZ’s Mr. Rod Wooten (VP of CV and Metabolic Disease) and Dr. Jim McDermott (VP of US Medical Affairs for Diabetes) earlier at ADA, and they expressed excitement about this Qtern data. Uptake of this fixed-dose combination product has been sluggish so far, since FDA approval in 1Q17, which matches sales trends of this SGLT-2/DPP-4 class overall (also featuring Lilly/BI’s Glyxambi and Merck/Pfizer’s Steglujan). It was thus reassuring to hear directly from AZ management that the company remains very committed to Qtern and to getting this therapy into more patient hands. To be sure, combination therapy is clearly under-prescribed by diabetes care providers in relation to the vast numbers of patients who could benefit from it, and Mr. Wooten described how HCPs in the US still prefer single agents to fixed-dose (or fixed-ratio) combinations. But there are distinct advantages to a fixed-dose product; beyond clinical benefits, this single pill can improve adherence vs. two separate pills, and in general it introduces more convenience and simplicity to a patient’s diabetes management. We’re keeping our fingers crossed that Qtern can gain more traction on the market in the near-future.

2. Invokana Maintains CV & Renal Benefits Across eGFR Spectrum in CANVAS Post-Hoc; Supports Notion that SGLT-2s Offer CV/Renal Protection Even When Glucose-Lowering Efficacy is Attenuated; Implications for CREDENCE

A positive CANVAS post-hoc indicated that J&J’s SGLT-2 Invokana (canagliflozin) has similar CV and renal benefits regardless of a patient’s renal function at baseline, despite a smaller mean A1c reduction at lower eGFR. Dr. Dick de Zeeuw presented this analysis (n=10,142), which was simultaneously published in Circulation. He highlighted a lack of heterogeneity on CANVAS’ primary three-point MACE outcome (p=0.33) across four groups divided by baseline eGFR: <45 ml/min/1.73 m² (n=554, 6% of participants), 45-<60 ml/min/1.73 m² (n=1,485, 15%), 60-<90 ml/min/1.73 m² (n=5,625, 56%), and ≥90 ml/min/1.73 m² (n=2,476, 24%); ~21% of the CANVAS population had stage 3a or 3b CKD at baseline. In a primary endpoint analysis split at an eGFR of 60 ml/min/1.73 m² (i.e. CKD vs. no CKD), the interaction with three-point MACE was also non-significant (p=0.08). Interestingly, hazard ratios trended more positively in favor canagliflozin at lower eGFR, though CANVAS was not powered to detect differences within or between these groups. That said, we wouldn’t be surprised if patients who are “more sick” overall garner slightly more benefit from the cardioprotection associated with SGLT-2 inhibitors, simply because there’s more room for risk reduction. And, we’re seeing increasing emphasis in the diabetes field on how renal function is an independent risk factor for CV morbidity.

• Looking at components of the primary endpoint, no heterogeneity based on renal function was found for CV death (p=0.53 for both analyses) or MI (p=0.04 by CKD/no CKD and p=0.08 by CKD stage). The interaction with stroke was significant (p=0.01 for both), but (i) we know stroke events are relatively uncommon, reducing the power of this analysis and (ii) Dr. de Zeeuw noted that patients with worse renal function still trended toward benefitting more; he called this “possible heterogeneity.” There was no interaction on hospitalization for heart failure (p=0.20 for CKD/no CKD and p=0.62 by CKD stage) or the composite renal endpoint (p=0.28 for CKD/no CKD and p=0.59 by CKD stage). All of these results support that the benefits of Invokana on CV/renal outcomes are not blunted by reductions in renal function, nor are they driven by a particular subgroup of renal function. Furthermore, interaction p-values suggested no imbalance on key safety endpoints by CKD stage, including amputations (p=0.51), fractures (p=0.87), overall serious adverse events (p=0.30), adverse events leading to discontinuation (p=0.44), serious acute kidney injury (p=0.74), serious hyperkalemia (p=0.24), and serious renal-related adverse events (p=0.85). Results were consistent despite notable differences in baseline characteristics across CKD stages, including on baseline CV disease (73% in lowest eGFR group vs. 62% in highest eGFR group), albuminuria (56% vs. 25%), duration of diabetes (17 vs. 12 years), and age (69 vs. 59 years).

• These results highlighted the attenuation of glucose-lowering efficacy from Invokana in people with reduced renal function. From a 0.76% placebo-adjusted A1c drop in the ≥90 ml/min/1.73 m² group over the course of CANVAS, A1c-lowering efficacy was more than halved in the <45 ml/min/1.73 m² group to -0.35% (p<0.0001 for comparison). Placebo-adjusted A1c reductions were 0.45% and 0.57% in the middle two eGFR groups, indicating a direct and progressive relationship between eGFR and A1c reduction. This finding is more or less in line with what’d we expect: Given the mechanism of action of SGLT-2 inhibitors, glucose-lowering is less substantial in people with kidney dysfunction. Since Invokana is a partial SGLT-1 inhibitor, we wonder if glycemic efficacy is preserved more at lower eGFR compared to Jardiance (empagliflozin), Farxiga (dapagliflozin), or Steglatro (ertugliflozin). In any case, it’s positive that canagliflozin continues to protect against adverse CV outcomes despite less glucose-lowering – this reaffirms that the CV benefit in CANVAS was not driven by changes in A1c (but rather, is inherent to the molecule), and it raises exciting possibilities about SGLT-2 as CV or renal medicine independent of diabetes.

  • FDA currently recommends against using Invokana in patients with an eGFR below 45 ml/min/1.73 m² (only the lower 100 mg dose is recommended below 60 ml/min/1.73 m²). Farxiga and Steglatro are not recommended in those with eGFR <60 ml/min/1.73 m², nor is Jardiance below 45 ml/min/1.73 m². Importantly, these recommendations have everything to do with declining glycemic efficacy, rather than a particular safety signal, but thought leaders have expressed hope that SGLT-2 inhibitors could still be used below these thresholds specifically for CV/renal protection (again, thinking about hard outcomes independent of A1c). At ESC 2017, for instance, Dr. David Fitchett postulated that diabetes patients with eGFR <60 ml/min/1.73m2 may actually stand to benefit the most from treatment with an SGLT-2 inhibitor, in terms of CV and renal outcomes.

• These results bode well for J&J’s CREDENCE trial, which has a composite primary endpoint of end-stage renal disease, doubling of serum creatinine, and renal or CV death and has enrolled patients with type 2 diabetes and an eGFR ≥30 to <90 ml/min/1.73 m² (expected to complete in June 2019). In CANVAS, canagliflozin was associated with an impressive 40% relative risk reduction (HR=0.60, 95% CI: 0.47-0.77) for the renal composite endpoint of 40% reduction in eGFR, end-stage renal disease, or renal death; combined with other positive renal results, this effect pointed to the possibility of significant renal protection with Invokana. It’s hard to overstate the potential implications here: Kidney disease (particularly end-stage) remains a tremendous area of unmet need in diabetes, and there’s an enormously high cost to both patients and the health system associated with dialysis. HCPs lack any tools beyond intensive glycemic and blood pressure control to stem progression of kidney disease, making SGLT-2s and also GLP-1s all the more exciting. CANVAS even saw a 70% increase in regression of albuminuria with canagliflozin vs. placebo (HR=1.70, 95% CI: 1.51-1.91), indicating that the drug might even improve renal function. To this end, Lilly/BI are also investigating Jardiance (empagliflozin) in the upcoming EMPA-KIDNEY trial and AZ has initiated the Dapa-CKD trial for Farxiga (dapagliflozin), expected to complete in November 2020.

  • For reference, CANVAS enrolled patients with an eGFR ≥30 ml/min/1.73 m² (i.e. through stage 3 CKD); ~25% of participants had an eGFR too high to qualify for CREDENCE. Thus, CREDENCE’s population will, overall, be less healthy from a renal function perspective. The aim of CREDENCE is to show an impact on renal outcomes; a key secondary endpoint includes CV death and hospitalization for heart failure which, J&J has previously explained to us, is the company’s reason for not initiating a second heart failure trial (as Lilly/BI and AZ have done).

• Directly following Dr. de Zeeuw, Dr. Priscilla Hollander reviewed a safety analysis comparing the CANVAS program (n=10,142) to the pooled phase 3/4 program (n=8,114) for Invokana. She emphasized that canagliflozin’s amputation signal was only seen in the CANVAS program (HR=1.97, 95% CI: 1.42-2.75), with similar signals in CANVAS (HR=2.12, 95% CI: 1.34-3.38) and CANVAS-R (HR=1.80, 95% CI: 1.10-2.93). There were far fewer events in the pooled program, and canagliflozin was associated with a 77% reduction in amputations with a wide confidence interval (HR=0.23, 95% CI: 0.06-0.89). These results reinforce our understanding that baseline factors have a very strong effect on amputation risk in general and with canagliflozin – that is, the signal is predominantly seen in patients who are high-risk for amputations to begin with (see our ADA coverage of the real-world OBSERVE-4D analysis for more on this dynamic). To be clear, the sum of data suggests that Invokana itself also heightens risk for lower limb amputations, but this might not be concerning in real-world practice unless a patient exhibits other risk factors as well. Notable baseline differences in CANVAS vs. phase 3/4 trials include prevalence of hypertension (90% vs. 65%), history of heart failure (14% vs. 3%), history of CV disease (66% vs. 7%), and history of amputation (2% vs. 0.1%), as well as duration of diabetes (14 vs. 8 years).

3. RISE Peds Highlights Rapid Decline in Beta Cell Function Among Youth with T2D Despite Insulin Glargine or Metformin; Independent Commentary from Dr. John Buse – “Terrifying” That Childhood T2D Presents with Different Pathophysiology w/o Effective Pharmacotherapy

The NIH-sponsored RISE study sent a stark message to the diabetes community today: We know so little about the pathophysiology of type 2 diabetes in youth, except that it differs meaningfully from disease development in adults, and no drugs are able to effectively address the natural history. Participants in RISE Peds (n=91) were children age 10-19 with impaired glucose tolerance (prediabetes) or recently-diagnosed type 2 diabetes. Notably, the baseline body weight in this cohort was equivalent to that in RISE Adult (ongoing and expected to complete June 2019) at ~220 lbs; that put the mean BMI of these children and adolescents at 37 k/m². Participants were randomized to one of two therapy regimens: (i) metformin for 12 months or (ii) three months of insulin glargine followed by nine months of metformin. The two co-primary endpoints, collected via hyperglycemic clamp, were steady-state C-peptide and ACPRmax (arginine at maximal glycemic potentiation), both measures of beta cell function, neither improved in either treatment arm. University of Colorado’s Dr. Kristen Nadeau reviewed primary outcome results, and most of her slides showed continued decline in steady-state C-peptide or ACPRmax with both metformin and glargine + metformin. RISE Peds additionally included a three-month follow-up after treatment was washed out from both groups, and data showed continued worsening of steady-state C-peptide and ACPRmax. Dr. Philip Zeitler (Children’s Hospital Colorado) discussed secondary endpoint results from the study, pointing to a small but statistically significant decrease in BMI with metformin therapy at three months (from 37 kg/m² to 36 kg/m², p<0.05); metformin was also superior to insulin glargine on this endpoint, since BMI rose with basal (p<0.05). A1c declined from a baseline 5.7% to 5.6% with insulin glargine after three months (p<0.05), and also dropped significantly with both medication regimens at six months (p<0.05 vs. baseline). Despite the negative results from this study overall, UNC’s Dr. John Buse positioned it as a positive that the impact on BMI and A1c was as we’d expect with metformin and with insulin glargine.

• Dr. Buse provided independent commentary to close out this symposium, and he stressed the sad reality that we don’t know of pharmacotherapy to address the underlying pathophysiology of type 2 diabetes in youth. HCPs can prescribe metformin to stimulate modest weight loss, and they can prescribe basal insulin to lower A1c, but neither will preserve beta cell function or reverse the trajectory of disease, “and that’s the terrifying part,” he said. In contrast, there is evidence from the DPPOS, SCALE, and other largescale trials that metformin, acarbose, liraglutide, and insulin have beneficial effects on the beta cell and on the trajectory of dysglycemia in adults. Dr. Buse’s biggest takeaway from RISE Peds was the need to address obesity in youth as a public health crisis. He argued that we should demand marketing restraint from the food industry, suggested we explore more aggressive public health policy, and highlighted that research should continue evaluating therapeutic and surgical approaches to obesity, type 2 diabetes, and prediabetes in youth. We too took this as the most important learning from RISE Peds, and we’d particularly like to see more investment in the built environment (it should be conducive to physical activity) and in access to healthy food. In terms of research, we hope to see more rigorous investigation to identify public health strategies that work, reducing the societal burden of childhood obesity. For now, we imagine the greatest ROI may come if we approach population-level obesity in youth as a public health problem rather than a medical challenge.

• Dr. Nadeau also presented a sub-analysis looking at the RISE Peds participants who had impaired glucose tolerance but not type 2 (n=54). Results were similar to the overall study population, with no significant improvement in steady-state C-peptide or ACPRmax with metformin or insulin glargine + metformin. Again, beta cell function actually appeared to worsen in the 12 months of treatment and again after washout.

• Dr. Silva Arslanian compared baseline data from RISE Peds and RISE Adult (n=255). Even before results were presented, she established the clear differences between type 2 diabetes pathophysiology by age. When a child/adolescent with type 2 undergoes hyperglycemic clamp, she typically higher C-peptide throughout (starting with fasting concentration) compared to an adult with type 2. Dr. Arslanian explained that youth show ~50% less insulin sensitivity compared to adults with this disease; for whatever reason, beta cell function declines more rapidly after onset of dysglycemia in youth. During independent commentary, Dr. Buse noted that more insight on these pathophysiological differences will come when Rise Adult reads out during the latter half of 2019.

• At the end of the symposium, these data were published online in Diabetes Care, as was a commentary paper by Drs. Buse, David D’Alessio, and Matthew Riddle. We suspect we’ll be hearing lots of thought leader commentary on these publications at future conferences, and we look very forward to learning more. Lastly, we want to echo Dr. Buse in congratulating the RISE investigators for pulling off this remarkable study.

4. Full-Year DEPICT-1 Data Reinforce SGLT-2 Dapagliflozin’s Efficacy + DKA Risk in Type 1; Pooled DEPICT CGM Results Underscore ~2-3 Hour Time-in-Range Improvement

One-year data from DEPICT-1 was presented on a late-breaking poster, and showed the efficacy + small-but-serious DKA risk associated with AZ’s SGLT-2 inhibitor dapagliflozin when given as adjunct to insulin in type 1 diabetes. This follows the 24-week results presented by Dr. Paresh Dandona at EASD 2017. A1c climbed back up slightly in the DEPICT-1 extension period, but was still significantly lower at 52 weeks with dapagliflozin vs. placebo. The 5 mg dose gave a 0.33% A1c drop vs. placebo, while the 10 mg gave a 0.36% placebo-adjusted A1c drop (both p=0.06). As we heard last September, placebo-adjusted A1c reduction was 0.4% and 0.5% with low- and high-dose dapagliflozin after 24 weeks. At 52 weeks, body weight declined further in the 10 mg dapagliflozin arm for total 5% weight loss vs. placebo; for comparison, placebo-adjusted weight loss was 4% at 24 weeks. Weight loss with 5 mg dapagliflozin was stagnant from 24 weeks to 52 weeks at 3% vs. placebo, suggesting a dose-dependent effect on body weight in particular. On the critical safety endpoint of DKA, there were 12 definite events (11 individuals) in the lower-dose dapagliflozin group (4% event rate), 10 definite events (10 patients) in the higher-dose group (3%), and five definite events in five patients in the placebo group (2%). This reflects a notable imbalance, which wasn’t reported as part of 24-week data on DEPICT-1, but Prof. Chantal Mathieu explained earlier at ADA that there was a higher rate of DKA in the placebo arm of DEPICT-1 in the first 24 weeks. Ten of 27 total DKA events in this study were assessed as mild, 10 were assessed as moderate, and seven were labeled severe. Moreover, seven episodes were attributed to insulin pump failure, nine to missed insulin dose, six to “other,” and five to “unidentified.” An additional 27 events were adjudicated as “possible DKA” and 38 events were “unlikely DKA.” All in all, these data have little bearing on our evaluation of DKA risk with SGLTs in type 1: The risk increase remains small but very clinically meaningful, and it’s a class effect. The field must establish clear standards on risk mitigation and DKA treatment before these drugs are (hopefully) approved with a type 1 diabetes indication. AZ has already submitted dapa for type 1 in Europe and Japan (FDA filing is planned for 2H18), while Sanofi/Lexicon have submitted SGLT-1/2 dual inhibitor sotagliflozin to FDA and EMA. We anticipate an Advisory Committee meeting in the US (sometime around January), and DKA will most definitely be a key topic of conversation there. To hear where thought leaders stand on DKA risk management practices when prescribing SGLTs to type 1s, read our coverage of the ATTD Consensus gathering hosted on Friday; importantly, there’s already strong agreement among KOLs that the benefits outweigh the risks with this therapy class.

• Another poster featured pooled 24-week CGM data from DEPICT-1 and 2 together (n=1,591), showing a 9% increase in time-in-range with 5 mg dapagliflozin and an 11% increase with 10 mg vs. placebo. This translates to ~2.2 and ~2.6 additional hours in range per day, essentially identical to the DEPICT-1-only CGM results presented at EASD 2017. As with the inTandem1 and 2 pooled CGM data (this is Sanofi/Lexicon’s clinical program for sotagliflozin) the time-in-range increase occurred almost entirely at the expense of hyperglycemia, as time spent ≤70 mg/dl or ≤54 mg/dl was not significantly changed. Over 24 weeks, MAGE also fell 13% with 5 mg dapagliflozin and 14% with 10 mg dapagliflozin, from 171 mg/dl to 155 mg/dl, as compared to placebo. Finally, a significant effect was detected on postprandial glucose readings, which fell from 199 mg/dl to 193 mg/dl on average with 5 mg dapagliflozin and from 197 mg/dl to 187 mg/dl with 10 mg. It’s impossible to over-emphasize how meaningful these time-in-range improvements can be for patients, particularly considering they don’t increase risk for hypoglycemia. We only hope that FDA and other regulators understand the tremendous value of this benefit while also discussing DKA risk.

5. STAT Study Results (N=60 Type 1s): 1.5 Extra Hours In-Range with MannKind’s Afrezza vs. Novo Nordisk’s NovoLog; 15% Improvement in Postprandial Excursions

MannKind’s inhaled insulin Afrezza was superior to Novo Nordisk’s NovoLog (insulin aspart) on postprandial glucose and time-in-range in the STAT study, presented Monday afternoon by Dr. Satish Garg. This head-to-head trial used CGM (Dexcom G5) in 60 type 1s (26 randomized to inhalable insulin and 34 to aspart). After four weeks, glucose levels 1-4 hours post-meal were 15% lower (-20 mg/dl) in the Afrezza group compared to the NovoLog group (p<0.05); notably, patients experienced this significant postprandial benefit regardless of whether they were at least 80% adherent to Afrezza. By meal, postprandial glucose excursions were 20% (-24 mg/dl) lower at breakfast and 25% (-36 mg/dl) lower at lunch with Afrezza vs. NovoLog (p=0.04 and p<0.001, respectively). There was no significant difference in postprandial glucose excursions after dinner, and Dr. Garg explained that patients were understandably reluctant to take additional boluses due to fear of overnight hypoglycemia. MannKind’s exhibit hall booth highlighted this unique ability to take additional adjustment boluses with ultra-rapid-acting Afrezza, particularly when used in conjunction with CGM. Continuing to time-in-range data, Dr. Garg pointed to a 12% increase (1.5 hours) in patients who adhered to their Afrezza regimen compared to patients on NovoLog (p<0.005). We see 1.5 additional hours of time-in-range per day as a very meaningful outcome for patient quality of life. Ultimately, Dr. Garg spoke highly of Afrezza as filling an unmet need in diabetes care for faster mealtime insulin that better addresses postprandial glycemia, and he attributed these positive findings to Afrezza’s very rapid onset (~12 minutes to first measurable effect) and offset (~90-180 minutes to return to baseline, depending on dose). We’ve been eager for this readout ever since MannKind announced the STAT study, and we’d love to next see a larger, longer trial assessing glycemic outcomes beyond A1c (Dr. Garg described this as a pilot).

6. DiRECT Post-Hoc: Different Factors Predict Weight Loss vs. Diabetes Remission; Dr. Lean Argues Against Excluding Any Patients

Dr. Mike Lean presented a post-hoc of DiRECT demonstrating that the baseline factors that predict ≥15 kg weight loss (~33 lbs) are different from the factors that predict diabetes remission. He also argued against the implementation of a stopping rule based on early weight loss results. There’s no doubt that DiRECT results (first presented at IDF 2017) were impressive – 50% of people in the intervention group saw type 2 diabetes remission, and among participants losing ≥15 kg, a striking 86% entered remission. Predicting responders would certainly aid in the application of this intervention, although data so far suggest somewhat limited ability to do so. According to Dr. Lean, weight loss of ≥15 kg was significantly predicted by male gender (33% of men vs. 14% of women in the intervention arm achieved this), shorter duration of diabetes (odds ratio 31% greater for each year fewer of diabetes), higher baseline body weight (8% of those <90 kg vs. 40% of those ≥110 kg), and higher starting BMI (9% of those <30 kg/m² vs. 31% of those ≥40 kg/m²). He noted that the gender, weight, and BMI associations are likely at least part a function of starting at a higher body weight. Meanwhile, diabetes remission was significantly predicted by lower A1c (odds ratio 28% lower for each 1% increase in A1c), older age (17% of those <50 years old vs. 61% of those 60-65 years old), and fewer background diabetes medications (odds ratio fell 0.43 per additional drug). Dr. Lean highlighted SUs as particularly deleterious – we imagine the secretion effect makes it harder for beta cells to recover, though this is speculation. We were also struck by the older age/more remission relationship, since presumably older individuals have longer duration of diabetes, and we’d love to learn what if anything mediates this. Dr. Lean issued a warning about diabetes medications, asserting that it’s unclear whether the association exists because people on many medications are doing worse overall or because medication use actually makes remission more challenging. Being on more antihypertensive drugs was actually associated with a greater chance of remission (odds ratio increased 1.37 per drug); high blood pressure made remission more likely, a phenomenon that Dr. Lean admitted is hard to explain. Interestingly, antidepressant use was borderline significant for a decreased chance of achieving weight loss and type 2 diabetes remission (p=0.085 and p=0.064, respectively). Distress and depression are not uncommon in the diabetes patient population and they often preclude optimal outcomes, so we can see how this additional stress could have made it more difficult for people to lose weight and enter remission.

• These data evoked the DiRECT post-hoc analysis that Prof. Roy Taylor presented on Friday, linking the ability of the beta cell to recover to diabetes remission. DiRECT results are increasingly characterizing a group of patients likely to benefit from significant weight loss and achieve normoglycemia: Generally, they are older, have had diabetes for less time, and have lower A1c – an overall less severe phenotype, which further supports the importance of early intervention. Early weight loss was associated with better long-term results in DiRECT, and lower early weight loss more often lead to early withdrawal. As Dr. Lean explained, applying early stopping rules would remove those who are going to stop anyway, but it would also keep those who fail to lose significant weight early on from benefitting in the long run.

• Dr. Lean concluded his talk with an ethical imperative: Patients should be offered optimal and effective non-surgical weight loss before receiving additional treatment for type 2 diabetes. Questions – and no small questions at that – remain as to how to scale this intervention and how to maximize durability of effect (to this end, we’ll be keen to see longer term data). Researchers will finish collecting two-year data in about six weeks and plan to continue for at least four years. We’re also looking forward to promised economic analyses.

7. Dr. Haller Presents TrialNet Study of Low-Dose ATG in New-Onset T1D (“Brazil Lite”); Promising Preservation of C-Peptide Levels + Corresponding Increase in A1c

Dr. Michael Haller presented encouraging TrialNet data to suggest that low-dose antithymocyte globulin (ATG) could prevent or delay the progression of new-onset type 1 diabetes. Participants (n=84, 12-45 years-old) with recent-onset type 1 diabetes (<100 days) were randomized to infusions of ATG alone (2.5 mg/kg), ATG in combination with granulocyte colony stimulating factor (6 mg GCSF every two weeks for 12 weeks), or placebo. Dr. Haller built up suspense before revealing the primary outcome results: After one year, participants on placebo experienced a ~0.45 mmol/L decline in C-peptide levels, but this was significantly attenuated to only ~0.1 mmol/L with ATG monotherapy (p=0.0003) and to ~0.25 mmol/L with ATG/GCSF combination therapy (p=0.031, just missing significance given the study’s p=0.025 threshold for superiority). These improvements in C-peptide were accompanied by improvements in A1c: From a baseline of ~7.5%, A1c fell significantly to ~6.5% with ATG monotherapy (p=0.002) and trended downward to ~7% with ATG/GCSF combination therapy (p=0.011, again narrowly missing superiority). Interestingly, neither therapy produced any reductions in insulin dose, at least over this short time period. Dr. Haller noted that the collection of two-year data will be completed this Fall. He also shared that a paper featuring this one-year data has been accepted for publication in Diabetes Care; we’re looking forward to digging into the full results. Notably, a previous study with ATG/GCSF combination therapy in patients with less recent-onset type 1 (four months to two years) also showed improvements in C-peptide (p=0.05), but no corresponding improvement in A1c. This underscores that this therapy is perhaps best positioned for very recent-onset type 1 diabetes, to address beta cell destruction as swiftly as possible.

• Although we maintain that measured expectations are key when discussing type 1 prevention and cures, these positive results are a welcome bright spot in a challenging R&D landscape. In fact, just one year ago at ADA 2017, we characterized type 1 prevention/cure research as “bleak,” given findings from TrialNet’s Oral Insulin study, DiAPREV-IT (Alum-GAD in children), and a JDRF-backed study of Gleevec (Imatinib) that were “disappointing at worst, and mixed at best.” This year’s ADA meeting is offering much more enthusiasm for improvements in type 1 diabetes treatment, though the focus is primarily on adjunctive therapies rather than “cure” therapies. Nonetheless, the type 1 cure/prevention competitive landscape is robust, as you’ll see here. It’s important to keep in mind that Dr. Haller’s study was small (<100 participants) and involved only one-year of follow-up, but the suggestion that ATG could preserve C-peptide (and possibly beta cell function) is encouraging.

• Dr. Haller characterized these ATG and ATG/GCSF cocktails as “Brazil Lite,” an allusion to the Brazil Cocktail (also known as the Voltarelli Cocktail), which uses extremely high doses of ATG to wipe out immune cells and “rescue” patients with an autologous hematopoietic stem cell transplant (AHSCT). With the Brazil Cocktail, ~60% of patients achieved insulin independence within six months, and nearly 40% remained completely insulin independent at the 18 month mark, per results released at ADA 2014. That said, this benefit did not come without cost: The frequency of severe side-effects was fairly high, and the list included neutropenic fever, alopecia, fever, and one death due to sepsis that may or may not have been related to the therapy. To be sure, this treatment is extremely immunocompromising (34/65 patients experienced an adverse event). Dr. Haller contextualized that TrialNet has been searching for a less aggressive and side-effect-ridden way to achieve the promising effects of the Brazil Cocktail on new-onset type 1 diabetes, and this low-dose ATG monotherapy appears to show at least “lite” promise. 

8. TAKE CONTROL Shows Similar Outcomes with Self-Titration vs. Physician-Led Titration of Sanofi’s Next-Gen Basal Insulin Toujeo, Regardless of Patient Age

Dr. Krzysztof Strojek presented Sanofi’s TAKE CONTROL study, in which self-led titration of Toujeo (insulin glargine U300) was associated with comparable – and sometimes improved – outcomes vs. physician-led titration. After 24 weeks on Toujeo, participants with type 2 diabetes (n=631) saw a mean ~1% A1c reduction from a baseline ~8.5% regardless of whether the insulin titration protocol was self-led or physician-led. This held true for patients over the age of 65 (p=0.46 for heterogeneity) as well as those under the age of 65 (p=0.29), dispelling concerns about older patients’ ability to self-titrate effectively. In fact, we’re hearing increasing emphasis from diabetes thought leaders that age itself is irrelevant – what does matter is cognitive decline and frailty, and in their absence HCPs shouldn’t be relaxing therapy or making any treatment decisions based on age alone. Numerically more patients in TAKE CONTROL achieved their self-monitored fasting plasma glucose target (80-130 mg/dl) with self-titration vs. physician titration, and again this was true for participants >65 (81% vs. 76%) and <65 years-old (73% vs. 64%). There was no heterogeneity in the incidence of hypoglycemia with self-led vs. physician-led titration for either <70 mg/dl hypos (33% vs. 29% for younger adults, 34% vs. 40% for older adults) or <54 mg/dl hypos (7% for younger adults, 8% vs. 9% for older adults).

The diaTribe Foundation/TCOYD’s 12^th Annual Diabetes Forum: Quotable Quotes

At The diaTribe Foundation and TCOYD’s 12^th Annual Diabetes Forum on Monday night, Drs. Jim Gavin, Mikhail Kosiborod, Jeremy Pettus, and Carol Wysham comprised an absolutely stellar panel moderated by Dr. Steve Edleman and our own Adam Brown. They shared their thoughts on the role – and necessity – of CVOTs in the current era of diabetes therapy, the utility and state of CGM in type 2 diabetes, and the need for better access and reimbursement – and so much more. Below, you’ll find the most quotable quotes from the evening – stay tuned for a much deeper dive on the event in our full report!

On the Modern CVOT

• “If you want to be brief – yes, we still need CVOTs. I think that we wouldn’t be talking about most of what we’re talking about today without them. There may be certain reasons a mandate happened but we’re beyond that…If we didn’t have these data, we’d still be telling patients that DPP-4 inhibitors reduce CV events by 45%.” – Dr. Kosiborod
• “CVOTs have served us well and we still need them, not only for giving us evidence on CV safety, but also because it has given us information on other forms of safety.” – Dr. Gavin
• “I think it should be optional. If you have a molecule you think is effective in addition to standard of care, companies can have the option.” – Dr. Wysham

On CGM for Type 2 Diabetes

• “Patients can’t make an appointment with me until they see a diabetes educator, who puts them on professional CGM…When I see them, we’re ready to talk.” – Dr. Wysham
• “If you can really engage patients to look at results, I think that’s the key role of CGMs. I’ve seen some patients really turn around after having a CGM. I do think it’s going to be more accessible and affordable, and I do think it will change the way we practice with type 2 diabetes patients.” – Dr. Edelman
• “A huge change is happening right now that can lower barriers to providing CGM. How accurate is G6? I have no freaking clue. I don’t fingerstick and I don’t want to. People diagnosed today are in a world where fingersticks can be far less important, and they can even go away” – Dr. Pettus
• “We will get to a point with CGMs where they are more accessible and more patient friendly, and we will be able to stop fooling ourselves that there are people with prediabetes: they have diabetes and we just don’t know when it happened. We will be able to use tech to get real time data to better inform decisions about what their status really is.” – Dr. Gavin

On Access and Reimbursement – Or Lack Thereof

• “What worries me is that we produce all of this knowledge and we can’t implement it. A large part of this is that patients can’t afford lifesaving treatments. However, I grew up in the Soviet Union where we had price controls, and then you had situations where you would be in line for 3 hours to get a chicken.” ­– Dr. Kosiborod

• “I always tell patients what I think they should be on, then I say we’ll see what your insurance says. All things being equal, I’m a fan of early intervention with agents shown to have more durability if started early: SGLT-2 inhibitors and GLP-1 agonists.” – Dr. Wysham
• “The elephant in the room is access. We can have all the best technology and drugs in the world, but the elephant is getting access to those that need it most.” – Dr. Gavin

Awards & Award Lectures

1. Dr. Gerald Shulman’s Banting Award Lecture Delves into Physiology of Insulin Resistance; Could Mitochondrial Uncouplers Be the Next New Diabetes Drug Class?

In this year’s Banting Medal for Scientific Achievement lecture, Yale’s Dr. Gerald Shulman delivered a tour de force on the physiology of insulin resistance and how it contributes to the development of type 2 diabetes. He summarized a decades-long body of work into the following framework: Under circumstances of caloric imbalance, fat storage shifts from adipocytes to muscle and liver, leading to insulin resistance in all of these tissues – an event that has disastrous metabolic consequences. This insulin resistance interrupts two of insulin’s major effects: (i) direct action on liver cells to increase glycogen synthesis, and (ii) indirect action on adipocytes to decrease gluconeogenesis. The disruption of glycogen synthesis and the disinhibiting of gluconeogenesis spells increased glucose production, leading to hyperglycemia and eventually the development of type 2 diabetes. Beyond elucidating what he termed the “insulin resistance elephant,” Dr. Shulman emphasized that this framework can provide valuable insight into potential new drug targets. To this end, his lab is exploring a liver-targeted mitochondrial uncoupling agent. In preclinical studies, the agent safely increased hepatic fat oxidation, thereby improving hepatic insulin sensitivity and decreasing the rate of hepatic gluconeogenesis – ultimately lowering blood glucose levels and resolving NAFLD. Alongside this, the agent lowered LDL and triglyceride levels, leading to reductions in muscle fat content and improvements in muscle insulin sensitivity. Dr. Shulman hinted at soon-to-be-published data in non-human primates, and he noted optimistically that the next step is phase 1 studies in humans. To say that we’re intrigued by this potential new class of mitochondrial uncoupling agents for type 2 diabetes and NASH is an understatement. We thank Dr. Shulman for these incredible contributions to our understanding of diabetes.

2. Dr. Mark Atkinson and Carol Atkinson Honored with ADA’s 2018 Humanitarian Award

Dr. Mark Atkinson and Ms. Carol Atkinson received ADA’s Humanitarian Award for 2018 – so well-deserved! Read ADA’s press release here, which emphasizes their tireless efforts to support the diabetes community in Texas, Florida, Puerto Rico and the Caribbean following hurricanes Harvey, Irma, and Maria. Ms. Atkinson and Dr. Atkinson serve as the Director and President of the Board of Directors for Insulin for Life USA, a non-profit dedicated to providing diabetes medications and supplies to people with diabetes in the US and worldwide who lack access for a multitude of reasons ranging from natural disasters to financial limitations. Following these three hurricanes, they led emergency relief efforts to deliver more than 4,600 lbs of diabetes supplies to thousands in need. Insulin for Life USA was a founding member, along with the ADA and JDRF, of the newly formed Diabetes Emergency Response Coalition, a group that is now comprised of 22 leading diabetes care and research organizations that worked to provide aid to those affected by the hurricanes. “We at Insulin for Life are humbled to receive ADA’s Humanitarian Award and beyond this, we’re honored to serve as a member of the Diabetes Emergency Relief Coalition,” Dr. Atkinson said in an email to us. “Moving forward, this newly-formed Coalition seeks to serve the needs of those with diabetes in times of natural disaster to an even greater degree.”

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