We’ve crossed the mid-point of EASD 2018: Day #3 wrapped up after an excellent day of presentations, posters, and exhibits, with a set of industry symposia to close this evening.
Leading our coverage in diabetes therapy is a fascinating finding - an EXSCEL post hoc analysis showing that, when considering (and removing) drop-in medication use in the placebo arm, Bydureon gave a significant reduction on three-point MACE (HR=0.87, 95% CI: 0.78-0.97, p=0.011) – raising stirring questions about trial design and use of “placebo” arms. Also on GLP-1s, Dr. Cliff Bailey gave an extremely interesting talk on oral semaglutide, explaining how oral delivery could actually be a big physiologic advantage for the therapy and extolling oral sema’s impact on A1c and body weight. Also see below for a collation of highly intriguing thought leader insights on the just-reported HARMONY CVOT for Tanzeum put together by Close Concerns.
A very compelling DUAL VII analysis (Xultophy vs. basal-bolus with Lantus + NovoLog) detailed the patient burden differences between each regimen: one daily injection with one pen (Xultophy) vs. two to five injections with two pens (basal-bolus), not to mention meaningfully lower insulin dose and no bolus insulin adjustments with Xultophy.
Below, you’ll also find an irreverent talk on UKPDS misconceptions from the esteemed Prof. David Matthews, as well as Dr. Jay Skyler’s update on “hope vs. hype” in type 1 diabetes.
Renal outcomes from CVOTs were a huge focus on Wednesday: Below, we have a SUSTAIN 6 post hoc hinting at renal-protection but also demonstrating contradictory effects on albuminuria vs. eGFR in lower-risk patients. Additionally, an ELIXA analysis suggested renal protection with a sizable impact on UACR, but lixisenatide didn’t significantly impact eGFR. Finally, a LEADER subgroup analysis found consistent CV benefit across baseline renal function. Stay tuned for more renal analyses in our full report, including one showing equal benefit across baseline renal function in CANVAS and another supporting CV safety in those with renal impairment in EXSCEL.
In diabetes technology, today’s clear headliner was Dr. Roy Beck’s presentation of what CGM data looks like in people without diabetes. The T1D Exchange study used the Dexcom G6 in 153 children and adults with baseline A1c of 5.1%, finding a mean glucose of 99 mg/dl, standard deviation of 17 mg/dl, and time-in-tight-range of 70-140 mg/dl of 97%! Just 2% of values were >140 mg/dl and only 1% were <70 mg/dl. These data are valuable for benchmarking and reminded us how further we have to go to achieve “normal” glucose in diabetes. It also reminds us of how hard patients are working to get to anything resembling “normal.” We also saw extremely positive results from Cambridge’s 12-week, randomized trial comparing hybrid closed loop to sensor-augmented pump therapy in patients with a high baseline A1c (~8.3%). Hybrid closed loop drove a +3 hour/day time-in-range gain and had a 0.4% A1c advantage vs. SAP! Results were simultaneously published in The Lancet as the largest randomized study of closed-loop use in outpatient settings ever. Also in tech, we saw Medtronic’s physician-facing, next-gen CGM-based decision support – Pattern Snapshot 2 – and a sub-analysis of the iHART study (G5 vs. FreeStyle Libre).
We stopped by 17 diabetes technology booths in the exhibit hall, with highlights in pretty much every one. Medtronic’s MiniMed 670G will launch next week in select European countries, and we learned that the awesome Mio Advance inserter actually received FDA 510(k) clearance seven months ago. (Medtronic is ensuring it has enough supply before a US launch of Mio Advance.) Abbott’s booth was buzzing with excitement surrounding FreeStyle Libre 2 with optional alarms and Bluetooth (manual scan still required); we appreciated seeing the demo live. LifeScan showed off the new OneTouch Verio Reflect BGM (CE Mark-pending) with an on-meter “Blood Sugar Mentor” that provides insight and encouragement – a nice innovation as the business moves over to Platinum as of today. We also love this name! At the Metronom booth, we were impressed with its CGM app’s user experience– one of the best we’ve ever seen for a CGM app. Glooko showed off its Novo Nordisk smart pen + CGM reports (leveraging the NFC-enabled pen), while Roche’s booth provided a number of updates on mySugr (NFC plans of its own for Novo Nordisk’s pen). Other booth highlights are below from Dexcom, Insulet, Tandem, Ypsomed, Cellnovo, DiabNext, EOFlow, IDx, Medtrum, and POCTech.
Greetings from Berlin! Our Day #3 EASD highlights in therapy and technology are enclosed below, along with coverage of 17 diabetes tech exhibits. In case you missed our reports from this week:
Day #1 Highlights - KOLs on SGLTs for type 1; Dr. Buse’s diabetes pipeline highlights; Dr. Bergenstal on TIR; Dr. Davies on GLP-1 patient sat; FreeStyle Libre 2’s accuracy; Dexcom G6 launches in Germany
Day #2 Highlights - HARMONY CVOT for Tanzeum; patient report data from inTandem; phase 1/2 for AZ’s MEDI0382; Control-IQ ski camp study
HARMONY Results for GSK’s Tanzeum (albiglutide) - finds significant 22% risk reduction for 3-point MACE; Huge implications for GLP-1 CV class effect
Novo Nordisk to launch durable NFC-enabled pens and Bluetooth smart attachment for disposable pens in 2019; Partners with Dexcom, Roche, & Glooko
- Diabetes Therapy Highlights
- 1. EXSCEL Post Hoc: Three-Point MACE Shifts to Superiority After Accounting for Open-Label Medication Drop-Ins; Dr. Buse Notes Impact of Protocol-Violating Concomitant GLP-1 Prescriptions
- 2. New LEADER Subgroup Analysis Identifies CV Benefits with Liraglutide Across Baseline Renal Function
- 3. Dr. Cliff Bailey Asserts Oral Semaglutide “More Physiologic” than Injectable GLP-1s; Plots A1c and Weight Reduction Favorably vs. All Other GLP-1s + Concomitant Therapies
- 4. Xultophy Offers Reduced Patient Burden (Fewer Injections, Fewer Adjustments, Lower Insulin Dose) Alongside Impressive Clinical Benefits, According to New Dual VII Analysis
- 5. KOLs Weigh-In on HARMONY CVOT Results for GLP-1 Agonist Tanzeum: Support GLP-1 Agonist Class Effects; Uncertain Commercial Future; Cardioprotection Squarely Outside of A1c, Weight Loss
- 6. SUSTAIN-6 Post Hoc Prompts Renal-Protective Hypothesis for Ozempic from Dr. Robert Silver; Contradictory eGFR and Albuminuria Effects in Some Groups Raise Questions
- 7. ELIXA Subgroup Analysis Suggests Possible Renal Protective Effects for GLP-1 Agonist Lixisenatide, Re-sparking Renal-Protective Conversation for GLP-1s?
- 8. UKPDS Investigator Prof. David Matthews Puts Four Misconceptions Surrounding the Study to Bed
- 9. Dr. Jay Skyler: Hope vs. Hype – Where Are We With Type 1 Diabetes?
- 10. AZ Dinner Symposium: Excitement about SGLT-2s for Heart Failure, Kidney Disease, Type 1; Panelists Emphasize Safety, Especially of Dapagliflozin
- Diabetes Technology Highlights
- 1. What is normal CGM data in Kids/Adults Without Diabetes? Benchmarks: Mean of 99 mg/dl, CV of 17%; 97% Time-in-Range (70-140 mg/dl)
- 2. Cambridge 12-week Hybrid Closed Loop Study: +3 Hour/Day Time-in-Range, -0.4% A1c Advantage vs. SAP! Lancet publication; “gold standard” for Randomized AID Study
- 3. Dr. Vigersky: Medtronic Looks to Launch Enhanced Pattern Snapshot 2 Report for PCP-Facing Professional CGM Decision Support in 4Q18
- 4. New Sub-Analysis of iHART Study: Dexcom G5 Prompts Greater Reduction of Weekly Hypoglycemia Events Vs. Abbott’s FreeStyle Libre
- Exhibit Hall – Diabetes Technology
Diabetes Therapy Highlights
In a riveting oral presentation, the great Dr. John Buse presented a much-anticipated analysis of EXSCEL trial data, from the CVOT for AZ’s Bydureon: Did high rates of open-label drug-in diabetes medication use contribute to the trial’s very narrow miss on CV superiority (HR=0.91, 95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.061 for superiority)? Over the past year, we’ve heard dozens of thought leaders assert that EXSCEL does far more to support cardioprotection as a class effect of GLP-1s than refute it – and also that EXSCEL in and of itself is a very positive trial. By and large, the trial’s statistical miss has been attributed to its pragmatic design, enrollment of a larger primary prevention population, use of complicated reconstitution kits, and lack of a run-in period to exclude those with low adherence (even just this last one could make results quite different from other trials that did this). Part of this pragmatic design involved patients continuing to see their usual care providers, who were allowed to prescribe any concomitant medications except another GLP-1 agonist (for context, LEADER protocol also prohibited DPP-4 inhibitors). It had been suggested that those in the placebo group of EXSCEL were prescribed, on average, more concomitant medications compared to the Bydureon group (we’re very curious how it would compare to other CVOTs, as well), tipping the scale in favor of placebo (below). Indeed, there were 36% (709) more antihyperglycemic medication drop-ins in the placebo group compared to the exenatide group (below). To account for this, researchers conducted a post-hoc analysis of the data, censoring patients at the time of drop-in for each of the six “open-label” medications considered (metformin, insulin, TZDs, SUs, GLP-1s, and SGLT-2s) and applying an estimated effect size for each mediation derived from published trials. However, Dr. Buse did note that this effect size is likely overestimated, because patients were censored at the time drop-in medication was added, then an estimated effect size derived from published trials for that agent was applied. Keeping this in mind, the hazard ratio on the three-point MACE shifted to nominal superiority when accounting for only sulfonylurea drop-ins (HR=0.89, 95% CI: 0.81-0.99, p=0.024), as well as for drop-ins of all six therapies (HR=0.87, 95% CI: 0.78-0.97, p=0.011) – certainly a positive result. The former analysis does raise some interesting questions, and though some may find it a bit strange that this would seem to indicate SUs confer some small degree of cardiovascular benefit, this is true short-term, but longer-term, SUs are associated with beta-cell burnout from what we understand. Big picture, of course, there are undoubtedly some confounding factors involved. That said, the confidence interval actually swung slightly in favor of placebo when only DPP-4s or GLP-1s were considered alone (below), leading Dr. Buse to note many limitations to the analysis. Principal among them, many adverse events were lost as patients were censored – events in the placebo and Bydureon groups dropped from 905 to 638 and 839 to 655, respectively, when all open-label medication drop-ins were considered. Nevertheless, we do see this analysis as another piece of evidence in support of the notion that many KOLs have shared with us - that EXSCEL very likely reflects cardioprotection with Bydureon.
Notably, Dr. Buse pointed out that all concomitant GLP-1 prescriptions (182 in the exenatide group and 265 in the placebo group) violated the study protocol. This is certainly not an insignificant number, impacting 2.4% of the exenatide group and 3.6% of the placebo group. As we see it, this likely speaks to HCPs’ dedication to their patients’ wellbeing over a trial’s guidelines, reflecting the difficult trade-off placebo-controlled trials are beginning to present in the era of cardioprotective diabetes therapies. As such, the fact that this seems to have been such a big issue in EXSCEL perhaps suggests that future CVOTs should not be conducted with (i) a comparison arm that can’t receive the modern standard-of-care nor (ii) such “pragmatic” guidelines, so as to avoid pitting a what’s best for a patient against the integrity of a study. Dr. Buse suggested to us that future studies will need to have a pre-specified analysis plan to account for drop ins, which could also be an interesting viable alternative.
Imperial College London’s Dr. Neil Poulter presented a new LEADER sub-analysis revealing that liraglutide’s cardioprotective benefits extend to people with type 2 diabetes and baseline renal disease. The findings were simultaneously published in Circulation. On the primary outcome of three-point MACE (CV death, nonfatal MI, and nonfatal stroke), LEADER participants with moderate to severe renal impairment (eGFR <60 mL/min/1.73 m2, n=2,158, 23% of participants) actually saw a greater risk reduction with liraglutide than participants with milder renal impairment (eGFR ≥60 mL/min/1.73 m2, n=7,182, 77% of participants): HR=0.69 (95% CI: 0.57-0.85) vs. HR=0.94 (95% CI: 0.83-1.07, p=0.01 for interaction). This pattern of numerically stronger risk reduction for people with more severe renal impairment persisted in the individual CV outcomes: On non-fatal MI, HR was 0.74 for participants with eGFR <60 (95% CI: 0.55-0.99) vs. an HR of 0.77 for those with eGFR ≥60 (95% CI: 0.77-1.13). On non-fatal stroke, HRs were 0.51 (95% CI: 0.33-0.80) vs. 1.07 (95% CI: 0.84-1.37). On CV death HRs were 0.67 (95% CI: 0.50-0.90) vs. 0.84 (95% CI: 0.67-1.05). Finally, on all-cause mortality, HRs were 0.74 (95% CI: 0.60-0.92) vs. 0.90 (95% CI: 0.75-1.07). For us, the consistent magnitude of these results reflects a compelling pattern; we imagine renal impairment serves as a strong marker of patients at very high risk for CV events, so it’s not surprising this group would see such strong benefit despite making up less than one-quarter of the LEADER sample. All that said, this suggestion of greater risk reduction for three-point MACE with lower eGFR was not supported by a subsequent analysis of the LEADER data using more granular eGFR subgroups (eGFR <30, 30 to <45, 45 to <60, 60 to <75, 75 to <90, and ≥90 mL/min/1.73 m2; p = 0.13 for interaction), nor another analysis examining eGFR as a continuous variable (p=0.61). Of course, splitting the sample into so many groups decreases the power available to observe such effects; for the same reason, the positive effects in the low eGFR cohort are all the more impressive, while the lack of significance in the group with renal function doesn’t mean those patients don’t benefit. Together, these findings indicate that liraglutide’s effect on MACE is not meaningfully influenced by baseline eGFR – rather, and importantly, liraglutide remains cardioprotective across risk levels. Dr. Poulter was careful to note that, as a post-hoc analysis, the results must be taken with a grain of salt, but overall we are very encouraged by the suggestion that liraglutide is at the very least no less CV protective for the particularly high-risk population of people with diabetes and Stage 3 or above CKD.
Dr. Cliff Bailey provided some fascinating commentary on Novo Nordisk’s PIONEER program for phase 3 oral semaglutide, weighing the pros and cons of an oral delivery route for GLP-1 agonists, plotting oral semaglutide’s impressive A1c reduction and weight loss vs. its injectable competitors, and positing a more “physiologic” mechanism behind its efficacy. In an impressively concise and illuminating figure, Dr. Bailey illustrating that oral semaglutide is the second-in-class GLP-1 agonist for both weight loss and A1c reduction when used as a monotherapy (at each drug’s highest dose), falling only behind its injectable counterpart, Ozempic. Notably, the significant A1c reduction is flat (~1.4% better than comparator) for oral semaglutide regardless of concomitant medications, a trend that also seems to hold more strongly for Novo Nordisk’s other GLP-1s, Ozempic and Victoza, than other GLP-1s.
What exactly contributes to oral semaglutide’s efficacy? According to Dr. Bailey, the oral delivery method possibly confers a more physiologic mechanism compared to injection. As it is absorbed in the stomach, oral semaglutide enters one’s system proximal to the liver, in a manner far more similar to human GLP-1. This confers a greater likelihood, as Dr. Bailey sees it, of triggering the GLP-1 receptors on the cells in the portal system responsible for directing blood from parts of the gastrointestinal tract to the liver, in turn activating the vagal afferents (nerves with sensory properties) which stimulate hypothalamic mechanisms. This (i) enhances the satiety-promoting effect of GLP-1s; (ii) potentiates the delay in gastric emptying; (iii) increases pancreatic glucose-induced insulin secretion; and (iv) decreases pancreatic glucagon secretion – whew! This sounds similar to the GLP-1 discussions back when the compounds were in phase 3, though accentuated - we appreciated that Dr. Bailey simplified this “interesting route effect” in a cartoon, pictured below.
Further, Dr. Bailey noted that this mechanism may also decrease the proportion of GLP-1 agonist reaching the heart vs. injectable GLP-1s, which could alter the cardiovascular effect of oral vs. injectable semaglutide. For reference, the latter conferred an impressive 26% reduction on three-point MACE (HR=0.74, 95% CI: 0.58-0.95, p=0.02 for superiority) in the SUSTAIN-6 CVOT. Needless to say, we cannot wait to see the results from PIONEER-6, oral semaglutide’s CVOT, which was estimated to complete just last week (September 27, 2018) on ClinicalTrials.gov – topline results are expected within 2018. Of note, although this CVOT was not powered for superiority, the results will still be very interesting to see.
As for the downsides of oral semaglutide, Dr. Bailey pointed to the fasting requirements, nausea, and the possibility of having to change other medication schedules as particularly noteworthy. The first of these, he stated, has a huge impact on the bioavailability of oral semaglutide. The SNAC carrier molecule that enables oral dosing facilitates faster absorption of the semaglutide molecule through the stomach wall (gastric mucosa), but this still takes 30-60 minutes. Dr. Bailey practically noted that this means eating breakfast 30-60 minutes later (or an earlier alarm in the morning). We’ve heard many attendees bring this up during Q&A at recent meetings, and while study investigators have generally emphasized that it hasn’t been a big issue for study participants, in the “real world,” it’s hard to tell what patient preferences may be.
Looking to the future, Dr. Bailey identified four things we still “need to know” about oral semaglutide and four things we would “like to know.” For the former, he mentioned (i) durability of oral semaglutide’s efficacy; (ii) long-term efficacy (especially vs. comparators); (iii) CVOT results; and (iv) effect on renal outcomes. For the latter, Dr. Bailey listed (i) the mechanistic benefits of oral uptake (potential for NAFLD?); (ii) whether good responders could be pre-identified; (iii) the feasibility of fixed-dose-combination tablets; and (iv) cost.
Presenting a new DUAL VII analysis, Dr. Eden Miller demonstrated that Xultophy treatment was less burdensome to patients than basal-bolus therapy, in terms of dose adjustments, number of injections per day, and total daily insulin dose. From a patient perspective (even a very heterogeneous group), this is not at all surprising. As a reminder, DUAL VII investigated Novo Nordisk’s Xultophy (insulin degludec/liraglutide fixed-ratio combination) vs. basal-bolus therapy with Lantus (insulin glargine) and NovoLog (insulin aspart). Results reported at ADA 2017 demonstrated Xultophy’s non-inferiority to basal-bolus on A1c lowering, but also indicated superiority on a number of secondary outcomes, including an impressive 89% reduction in severe or blood glucose-confirmed symptomatic hypoglycemia rate, not to mention ~2.1 lbs of weight loss vs. ~5.8 lbs of weight gain with basal-bolus. Dr. Eden Miller explained that, while the clinical benefits of Xultophy are well-known among the academic community, there are additional and equally meaningful benefits that Xultophy provides in terms of treatment complexity and convenience. In the DUAL VII study, the daily regimen for patients in the basal-bolus treatment group included the use of two pens, two to five daily injections, and two to five daily SMBG tests (one for each injection); we also know that, if a patient requires very high doses of basal insulin, number of daily injections can quickly climb even higher depending on which type of insulin/pen they use. Conversely, the Xultophy treatment arm only required one pen, one daily injection, and one SMBG test daily; we often write about the “added convenience” Xultophy offers patients over other injectable therapies, but putting it into these numbers reveals just how stark the contrast is. Considering the superior clinical profile Xultophy offers over basal-bolus regimens PLUS this tremendous improvement in patient experience, it’s hard to imagine many patients would choose the latter over the former – particularly considering the GI side effects caused by GLP-1s are smoothed out in the combination drug. Of course, any patient should be able to make an informed decision about their treatment regimen – any some may choose basal-bolus – but our feeling is that this often doesn’t happen, whether due to issues of cost, lack of information, or provider resistance to combination therapies. Dr. Eden also noted that the decrease in injection requirements with Xultophy translates to lower patient burden, as previous work has demonstrated a strong link between patients’ perception of treatment burden and the number of daily injection they must take. Patient burden was also especially high in the basal-bolus treatment group with respect to insulin dose adjustments during the study period: While both groups required a similar number of basal insulin adjustments on average (~17 total adjustments for both groups over 26 weeks), basal-bolus treatment required 200 bolus insulin adjustments, while Xultophy treatment – by its very nature – required zero such adjustments (see figure below). Burden was also far lower for the Xultophy treatment group in terms of total insulin dose: After 26 weeks, patients in the basal-bolus group took an average of ~84 units of total insulin per day, compared to only ~40 units for the Xultophy group (p<0.0001); basal dose alone was also higher in the basal-bolus group than the Xultophy group. All in all, this is amazing analysis though we are shocked by anyone who is surprised – insulin is one of the very hardest drugs in the world to dose, and it is incredibly variable day-to-day. Xultophy’s glycemic-dependent nature, as well as the stability of next-gen basal insulin and Victoza, are both hugely exciting.
We reached out to a number of thought leaders in diabetes and cardiology about the positive results from the HARMONY CVOT for GSK’s discontinued GLP-1 agonist Tanzeum (albiglutide), presented in an oral session yesterday. See below for a series of illuminating thoughts on cardioprotection as a GLP-1 class effect, the impact of trial design and molecular differences, and future prospects for Tanzeum. We salute the KOLs for taking time to share these valuable insights.
Dr. Daniel Drucker (Mt. Sinai Hospital, Toronto, Canada): “The data clearly dissociate reduction in glucose and body weight (modest with albiglutide) from reduction in MACE and MI. This is very unexpected and provocative data. These results imply different dose response curves for cardioprotection vs. metabolic benefits and bolster the value of the GLP-1 class beyond glucose control. I suspect GSK would not have made the decision to jettison albiglutide more than one year ago if they had a crystal ball that predicted this remarkable result. What company has ever abandoned a drug that reduces MACE events?”
Dr. Philip Home (Newcastle University, UK): “This is an interesting result because really no one disputes that glucose-lowering and weight loss are less strong with albiglutide, and here in particular as most of the participants do not appear to have progressed from the 30 mg, less effective dose. But the finding at headline level is better than liraglutide in LEADER and pretty comparable to semaglutide in SUSTAIN-6. When, however, I look at all the findings for MACE and its components from LEADER, SUSTAIN-6, HARMONY, and yes even EXSCEL, I find I cannot tell that they do not come from the same population.
That raises the issue of mechanism again. If the GLP-1s are so different on glucose and on body weight, then why are they indistinguishable on CV outcomes? Of course, we already knew it was not glucose-lowering, because that takes too long to affect CV outcomes, but the implication is that there is a different response curve for the CV protective mechanism than for glucose/weight. But this CV mechanism may exist outside diabetes and in type 1 diabetes, so we now need to investigate how these medications perform in people with CV disease who do not have diabetes, and people with type 1 diabetes who have CV disease.
I do not suspect that anyone will be interested in acquiring albiglutide from GSK. The albumin is expensive to produce, and the factory has wound down operations. Therefore, the cost of production is high, but then I suppose current GLP-1 prices allow a lot of room for price reduction.”
Dr. Naveed Sattar (University of Glasgow, UK): “I was surprised by the outcomes given background context of modest effects on some risk factors but, then again we are all learning that some, perhaps many, surrogate risk marker changes cannot predict hard outcomes and so trials remain critical. My take is that some direct effect of this GLP-1 must affect the atherothrombotic process and therefore reduce risk predominantly of MI.
In terms of future use, it’s hard to predict but given other drugs in the class perform better in terms of weight and glycaemia, many clinicians might still prefer to recommend those drugs (with proven CVD benefit) over albiglutide. However, in the secondary prevention setting, where cardiologists want to lower subsequent CV risk, and have less concerns about glycaemia reductions per se, it makes this drug with its clear MACE benefit a real potential option especially given its once weekly treatment. But overall interesting result and interesting times for the diabetes field – a general boost to the GLP-1 class.”
Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA): “The impact on clinical outcomes trumps impact on surrogate markers! Yes, the glucose-lowering effect might have hindered its uptake, but it is a shame to withdraw the drug for marketing reasons. The fact this is only the second GLP-1 to yield clear-cut cardioprotective benefits questions the wisdom of that decision! I am sure the patients who signed up for this trial were not made aware during the informed consent process about the possibility of withdrawing the drug for marketing reasons! What are the ethical obligations of the sponsor, the DMSB and the investigators to these patients?
It is difficult to point out exactly the impact of trial design, population, duration of action or molecular composition on trial outcomes. The placebo event rate in HARMONY is higher than what was observed in LEADER or SUSTAIN-6 and approaches that of the placebo arm in ELIXA, an acute coronary syndrome trial. This could be related to the fact all patients in HARMONY had prior history of CVD compared with 81% in LEADER and 83% in SUSTAIN-6. So far, the only trials with positive evidence of benefit are those that have utilized human GLP1-RA. Thus, molecular composition could conceivably contribute to the benefits. However, the pragmatic design of EXSCEL might have contributed to the suboptimal treatment adherence leading to the trial barely failing to meet superiority. In addition, the clustering of events early during the ELIXA trial (post-ACS cohort) might have masked the ability of the drug to yield a positive outcome.”
Dr. John Buse (University of North Carolina, Chapel Hill, NC): “The main thing is that it demonstrates that the GLP-1 cardiovascular effect is probably mediated through the GLP-1 receptor. If you want to win a cardiovascular outcome trial, start with people who have clinical cardiovascular disease and an A1c above 8%.”
Dr. Darren McGuire (University of Texas Southwestern Medical Center, Dallas, TX): “I’m pleasantly surprised by the significant reduction in MACE; this speaks strongly to class effects, and heterogeneity in outcomes across the class I believe may be more to do with chemical derivation and pharmacodynamics than GLP-1 receptor agonism per se. The observed superiority on MACE despite less potency for glucose lowering and less substantial effects on weight loss go a long way to parse these effects from other probable mediators of atherosclerotic vascular disease. I very much hope another company will pick up this baton; it seems to be a valuable option for clinical care and perhaps may force more competitive pricing across the class. I think the heterogeneity in the estimates of effects across the components of the MACE outcomes between LEADER, SUSTAIN 6 and HARMONY are most likely spurious, with limited power in any of the trials for any single component outcome.”
- Dr. Francesco Giorgino (University of Bari Aldo Moro, Italy): "I think the HARMONY Outcomes trial confirms the glucose-lowering profile of this GLP-1 RA and highlights its ability to confer cardioprotection independently of its glucose-lowering effect. I think this trial further suggests that a high CV risk population is required to observe the CV protective effects of GLP-1 RA. I do not think the issue is the molecular structure, since there is no evidence that the effects on the CV system in a preclinical or even clinical setting (e.g., on intermediate CV endpoints) are different for GLP-1 vs exendin-4 based agonists. Trial design and time of exposure to the GLP-1 RA are more important factors. Data from REWIND will be of interest in this regard. Finally, I see potential for albiglutide given the results from HARMONY Outcome and also the recently presented results from HARMONY-10 showing efficacy in addition to basal insulin comparable to basal/bolus insulin therapy. The drug is well-tolerated and administered through a weekly injection, which may improve adherence."
Dr. Robert Silver presented an intriguing post-hoc analysis of the very positive SUSTAIN-6 CVOT for semaglutide (Novo Nordisk’s Ozempic), demonstrating a significant decrease in albuminuria with semaglutide relative to placebo, regardless of baseline renal function. However, a contradictory and moderate decline in eGFR compared to placebo was observed in patients with normal renal function and mild renal impairment. For this analysis, participants from SUSTAIN-6 were grouped by baseline eGFR: normal (≥90 ml/min/1.73m2), mild (≥60 to <90 ml/min/1.73m2), moderate (≥30 to <60 ml/min/1.73m2), and severe (<30 ml/min/1.73m2). The primary composite endpoint of new or worsening nephropathy was examined, defined as new onset of persistent macroalbuminuria (>300 mg/g), persistent doubling of serum creatinine level and creatinine clearance ≥45 mL/min/1.73m2, need for continuous renal replacement therapy, or death due to renal disease. Renal-related outcomes were change from baseline in eGFR and UACR. Semaglutide demonstrated dose-dependent positivity on the primary composite outcome of this post-hoc, as 1.0 mg of semaglutide gave a significant 48% reduction in new or worsening nephropathy vs. placebo (HR=0.52, 95% CI: 0.33-0.80, p<0.01) while the improvement conferred by the 0.5 mg dose was not significant (HR=0.76, 95% CI: 0.52-1.11) – see below. The trends for both doses of semaglutide were driven by significant reductions in persistent macroalbimunuria of 41% vs. placebo with 0.5 mg (HR=0.59, 95% CI: 0.37-0.93, p<0.05) and 50% with 1.0 mg (HR=0.50, 95%: 0.30-0.81, p<0.01).
On eGFR, interestingly, semaglutide conferred variable results depending on renal function. Those with normal renal function or mild impairment experienced an initial, steep drop early on in the trial, followed by a stable, if slight, decrease in eGFR (essentially parallel with placebo) over the remainder. By the end of the 104-week trial, there was a significant drop in eGFR associated with 0.5 mg semaglutide vs. placebo (-10.4 vs. -8.4 ml/min/1.73m2) in those with normal renal function; the clinical relevance of this difference seems minor to us but this is speculation. Dr. Silver labeled the initial steep drop as “somewhat unexpected” but also emphasized the potential for semaglutide to confer long-term renal benefit, as average eGFR had stabilized and converged with placebo by the end – if the trial was extended, would placebo continue to fall below semaglutide? Indeed, the average eGFR of patients on semaglutide compared to placebo in the moderate and severe renal impairment groups were greater than those of placebo for the majority of the trial. Most notably, 1.0 mg of semaglutide conferred a significantly smaller decrease in eGFR compared to placebo at the end of the trial (-0.4 vs. -3.4 ml/min/1.73m2). This discrepancy in eGFR response to semaglutide is certainly puzzling, and Dr. Silver suggested that it could be indicative of a greater renal-protective effect as renal function continues to declines without treatment – an intriguing supposition.
Both doses of semaglutide conferred significant decreases in albuminuria relative to placebo, as measured by UACR (urine albumin/urine creatinine), except for 0.5 mg semaglutide in those with severe renal impairment. This result did not appear to be dose dependent, nor did it appear to depend on the patient’s baseline renal function – contradictory to the data on eGFR.
Based on the results from this study, Dr. Silver hypothesized that semaglutide may have a beneficial renal-protective effect in patients with type 2 diabetes but conceded that a dedicated trial will be necessary to confirm as well as resolve the discrepancy in eGFR and albuminuria data in those with normal renal function and mild renal impairment. As we see it, this data is a bit too blurry as it stands to draw any concrete conclusions, though we would love to see a dedicated renal outcomes trial for every GLP-1. Evidence of renal-protection (as is emerging for SGLT-2s) would prove a major win for patients, outcomes beyond A1c, and the entire GLP-1 class.
A post-hoc analysis of the ELIXA trial suggested GLP-1 agonist lixisenatide offers renal-protective benefits. These results were also just published in Lancet Diabetes Endocrinology. In ELIXA participants with microalbuminuria randomized to lixisenatide, UACR fell an average of 6.4% from baseline over the course of the 108-week trial, vs. a 14.8% increase in UACR for those on placebo (p=0.05). Similarly, in participants with macroalbuminuria, UACR fell an impressive 31.6% with lixisenatide, compared to an 11% rise in UACR with placebo (p=0.0084) – potentially pointing to stronger renal protection in those with more advanced nephropathy. In addition to slowing the progression of UACR, lixisenatide was also associated with a 23% risk reduction for onset of macroalbuminuria in patients without macroalbuminuria at baseline (HR=0.77, 95% CI: 0.62-0.96, p=0.0174). However, on the “harder” renal endpoint of change in eGFR (generally considered the more meaningful indicator of renal function), lixisenatide-treated patients did not significantly differ from those on placebo, though it’s also important to note that ELIXA’s short (by CVOT standards) duration of 2.1 years (median) could have made it difficult to observe substantial changes in eGFR. Nevertheless, this signal does align with microvascular outcomes from LEADER, which identified a 16% reduction in time to first microvascular event (encompassing renal and ophthalmic adverse outcomes with liraglutide (HR=0.84, 95% CI: 0.73-0.97, p=0.02), driven entirely by a 22% reduction in renal outcomes (HR=0.78, 95% CI: 0.67-0.92, p=0.003). While our sense is that GLP-1 agonists have offered less compelling evidence for renal-protection than SGLT-2 inhibitors, we certainly believe this idea deserves further investigation – particularly given that glucose-lowering options for those with renal impairment are limited. If GLP-1s can offer both powerful glucose-lowering and renal protection to people with impaired kidney function, it would be a huge win for patients. It’s worth noting that standalone lixisenatide comprises only a fraction of GLP-1 agonist prescriptions, but these results also have positive implications for the clinical profile of lixisenatide/insulin glargine coformulation Soliqua – an incredibly efficacious (in terms of A1c-lowering) therapy that we continue to believe is terribly underutilized in diabetes treatment.
8. UKPDS Investigator Prof. David Matthews Puts Four Misconceptions Surrounding the Study to Bed
In a standing-room only lecture, Oxford’s Prof. David Matthews methodically dispatched, in a quite impassioned manner, four misconceptions surrounding UKPDS that he says he and co-investigator Prof. Rury Holman hear all the time. The misconceptions were all fairly trivial and fallacious at the end of the day, which perhaps explains why Prof. Matthews was tired of hearing about them. We imagine that after this lecture, which was summed up with a wrap-up slide that left nothing ambiguous (each statement succeeded by “Wrong!”), Prof. Matthews may hear these challenges a bit less. Indeed, the 84-publication-strong UKPDS has driven clinical care guidelines for type 2 diabetes across the globe, and improved long-term outcomes substantially.
Misconception #1: “We cannot trust the UKPDS results about intensive glucose control – another trial showed that lowering A1c to normal led to an increase in death rates.” The principle issue with this statement is that UKPDS was performed in a population with low diabetes duration (quite recently diagnosed) and low CV disease. Subsequent trials to wish the mis-informed may be referring, such as VADT, ACCORD, ADVANCE, and PROactive, enrolled cohorts with advanced duration and established CV disease, an entirely different risk population. Further, there were fundamental differences in therapy: UKPDS used diet and SUs or insulin (with insulin rescue as necessary), while ACCORD used a large array of glucose-lowering therapies and insulin with a treat-to-target scheme. Most type 2 trials since UKPDS do not address issues of early glycemic control.
Misconception #2: “The UKPDS used old-fashioned glucose-lowering techniques which are irrelevant in today’s new drug environment.” The UKPDS was a “trial of policies – glycemic control in newly-diagnosed type 2 diabetes – not of therapeutics.” We’re somewhat shocked to hear this misconception since although it’s true that there are now glycemic-dependent compounds available, such a small percent of type 2 patients globally access them.
Misconception #3: “The metformin arm of the UKPDS was underpowered using only 342 subjects – we don’t know that the result was true.” He responded simply that there was sufficient power because trial sizes are reported on the number of people randomized, not those in an individual arm. There were 342 people in the metformin arm, but 411 in the conventional therapy arm, making total n=753. In the DCCT (n=1,441), the split in primary prevention was n=378 vs. n=348.
Misconception #4: “Many recent trials of new glucose lowering agents showed no difference in cardiovascular outcome – lowering glucose therefore cannot be very important.” FDA-mandated CVOTs are predicated on striving for glycemic equipoise to show that the agent is not unsafe compared to others that lower blood glucose to the same extent, isolating the impact of the molecule. “But,” Dr. Matthews explained, coining the glycemic equipoise paradox, “if we do not allow the drug to have the differential effect for which it was designed, then we don’t get the information we need. This would be like running a statin trial and pre-specifying that the control arm and the active arm needed to have the same cholesterol levels.”
9. Dr. Jay Skyler: Hope vs. Hype – Where Are We With Type 1 Diabetes?
Building off a paper he published in Diabetologia earlier this year, University of Miami’s Dr. Jay Skyler tackled a fascinating topic: hope vs. hype in type 1 diabetes. The first half of his talk focused on “hype” with a tone of sincere frustration, followed by four “ideal therapeutic goals” in type 1 diabetes: (i) prevent immune destruction; (ii) preserve beta cell mass; (iii) replacement or regenerate beta cells; and (iv) automated insulin delivery. He concluded with promising research paths forward, highlighting the very cool DIPIT trial testing combination therapy in new onset diabetes – it has FDA and ethics committee go-ahead, but companies are making it difficult to get the anti-TNF and IL-2 drugs.
Hope: Dr. Skyler emphasized that an “aggressive combination strategy” will probably be needed in type 1 diabetes, as there are there are many pathways that can be activated to target the beta cells. Therapies will ideally hit more than one pathway at a time, aiming to improve immunity (innate, adaptive, regulatory) and beta cell health.
Dr. Skyler has proposed a combination strategy using anti-inflammatory agents, immunomodulation, agents that increase T-regulatory cells, diabetes-related antigen, and agents to preserve beta cell health. The Diabetes Islet Preservation Immune Treatment Trial (DIPIT) aims to use just such an approach, and it has notably received FDA IND approval and ethics committee approval to proceed – testing ATG, GCSF, IL-2, Etanercept, and Exenatide in new onset type 1 diabetes. Unfortunately, companies have not been willing to supply anti-TNF or the IL-2 drugs – airing concerns that other drugs will be used alongside their drugs (“My drug is going to get blamed if something goes wrong”). Dr. Skyler said it has been “very difficult” to navigate this, but the trial will hopefully get started. The ClinicalTrials.gov post currently has a start date of December 2018 and a primary completion date of January 2020.
Dr. Skyler briefly touched on automated insulin delivery, noting “we are getting close” and “should see real progress coming in the next 24-36 months.” See our AID competitive landscape for a summary of the systems, which are mostly converging on ~2020 launches, with Tandem’s Control-IQ expected next summer.
Hype: Dr Skyler showed example after example of overstated headlines in type 1 diabetes research. These included Dr. Doug Melton’s work on betatrophin (retracted last year), the City of Hope’s 2017 goal to cure type 1 diabetes in six years, Andromeda’s DiaPep277, Dr. Denise Faustman’s phase 1 BCG vaccine study (see our July coverage), and many more. Dr. Skyler noted that over 400 interventions have cured type 1 diabetes in mice so far, and most type 1 cure headlines fail to appreciate this fact – mouse studies are just one link in a long research chain. He urged the field to think more carefully about how it articulates research findings, including for device – Dr. Skyler praised Medtronic’s cautious wording around the MiniMed 670G when it came out, but then lamented JDRF’s decision to use the term “artificial pancreas.” (This was impressively candid as JDRF CEO Derek Rapp was a session chair.)
Dr. Skyler seemed most frustrated by the website PreventT1D.org, which urges people to take vitamin D, Omega 3 fatty acids, and a few other over-the-counter supplements to prevent type 1 diabetes – see the “cocktail” protocol here. Dr. Skyler noted that sites like these and social media “can create fake news” in the type 1 diabetes cure landscape. While some of these components are being tested by TrialNet, the claims made on a site like this are untested.
SGLT-2s Only Used in 10% of Patients Who Could Benefit;
In AZ’s Wednesday night mini-symposium “SGLT-2 Inhibitors – Why Not Use One?” we heard from a superstar panel of leading cardiologists and diabetologists. Drs. Mikhail Kosiborod, Juris Meier, Jiten Vora, and Prof. Richard Holt unsurprisingly thrust their collective support behind SGLT-2s, touching on the widely-debated safety profile of the class, benefits beyond glucose lowering, and the highly-anticipated DECLARE CVOT for AZ’s Farxiga (dapagliflozin). Here were some of our favorite moments:
On SGLT-2 Safety and Dapagliflozin:
“There is an amputation signal with canagliflozin, which is a rather non-selective inhibitor of not only SGLT-2, but also SGLT-1 to a certain extent. However, this has not occurred in the phase 3 trials for more selective inhibitors of only SGLT-2, including empagliflozin and dapagliflozin […] The same is seen for low trauma fractures, suggesting that both might be a function of non-selective SGLT 1/2 dual inhibition.” – Dr. Juris Meier (editor’s note – we are also curious about the impact of trial design)
“As it stands, there is no data suggesting that amputations are a class effect of SGLT-2s […] Both the empagliflozin and dapagliflozin development programs have not demonstrated a signal for amputation.” – Dr. Mikhail Kosiborod (editor’s note – there was a signal on the “real-world” trial shown at ESC ….)
“Fournier’s gangrene is not that surprising for a drug with increased genitourinary tract infections (GTIs). Even with the high numbers of patients treated with SGLT-2 inhibitors across the US, there were only 12 [documented] cases. It is something we need to keep in mind, but they are very rare.” – Dr. Meier
On Benefits Beyond Glucose Lowering:
“Ladies and gentlemen, what do I want from a diabetes treatment in 2018? Improvement in blood glucose, improvement in quality of life, and reductions in long-term micro- and macrovascular complications. With the SGLT-2 class, we are starting to see ways in which these will come together in one therapy.” – Prof. Richard Holt
“What I think is the unexpected jewel in the crown of SGLT-2 inhibitors is the emerging idea that they are also beneficial for the kidney.” – Dr. Holt
“What is becoming pretty obvious to us in the CV field is that heart failure is not only the most common comorbidity of diabetes but also the one that is associated with the worst prognosis […] SGLT-2s are the first class of drugs for diabetes with a very promising signal in prevention of heart failure.” – Dr. Kosiborod
On dapagliflozin not achieving superiority on 3-point MACE in DECLARE: “We need to look at the data. One thing I will remind you of is that p-values are not end-all, be-all’s. They are highly dependent on the patient population. When you have agents that are less potent on MACE, such as SGLT-2s, and a high primary prevention population, it makes it a lot less likely from a statistical perspective that superiority in MACE will be found.” – Dr. Kosiborod
“[Using SGLTs for type 1 diabetes] are good idea but not licensed yet – keep an eye on the data […] It is a situation in which you will need to keep an eye on DKA, but all studies presented here suggest great efficacy and that patients love them.” – Dr. Jiten Vora
Interestingly, session chair Dr. Danilo Verge (VP for Cardiovascular and Metabolic Disease, AZ) made a concerted effort to mention AZ’s Epanova (omega-3-carboxylic acids) as a “future therapy” for CV disease, citing recent excitement from the REDUCE-IT CVOT for Amarin’s Vascepa as sparking interest in the area of prescription-strength omega-3s for cardioprotection. Epanova is under investigation in the STRENGTH CVOT, expected to complete October 2019.
“I would posit to you that, as far as I am concerned, the goal of treating diabetes should be to prevent morbid complications of diabetes.” – Dr. Kosiborod
“The simple fact that CV disease kills most patients with diabetes is not as well known in the clinic as it should be.” – Dr. Kosiborod
“More than half of people with diabetes worldwide do not undergo treatment intensification until their A1c is greater than 8.0%.” – Dr. Holt
“Only 10% of patients who could benefit from an SGLT-2 are taking one.” – Dr. Vora
Diabetes Technology Highlights
Presenting T1D Exchange data on behalf of Dr. Anne Peters, who had a last second conflict, Jaeb’s Dr. Roy Beck walked a packed house through extraordinarily useful benchmark CGM values obtained from healthy individuals without diabetes. 10 days of blinded Dexcom G6 data were analyzed from 153 children (6+ years) and adults with baseline A1c of 5.1% (inclusion criteria mandated an A1c < 5.7%, indicating no prediabetes). Across the entire enrolled cohort, mean glucose was 99 mg/dl, and mean standard deviation (SD) was 17 mg/dl, resulting in a coefficient of variation (CV; SD divided by mean) of just 17%. Time-in-tight-range of 70-140 mg/dl was 97% (!) in this group of people without diabetes (2% were >140 mg/dl, 1% were <70 mg/dl), and the AGP (below) puts the truly tiny variability in perspective. These data really show how far we have yet to go in normalizing blood glucose in diabetes! Put differently, benchmarks for excellent control in type 1 diabetes might be a mean glucose of <154 mg/dl, time-in-range of 70%+ (with the wider 70-180 mg/dl), and a CV of <33% - this suggests that even automated insulin delivery is still pretty far from what people without diabetes experience. Dr. Beck highlighted in yellow that mean glucose was 104 mg/dl in individuals over the age of 60 years – 5 mg/dl higher than the group mean – while every other age group was essentially right on the mean. This could indicate age-related glucose intolerance, or perhaps the 60+ group had higher A1cs than did the other age groups in the study by chance. Overall, mean glucose during the day was a pretty negligible 2 mg/dl higher than during the night, and SD was 5 mg/dl higher during the day, which is not surprising given the activity and food intake of the waking hours. Median time in hyperglycemia (>140 mg/dl) for the group was 2.1% (just 30 mins/day), while median time >160 mg/dl was negligible (~4 mins/day!) and median time >180 mg/dl was “0.0%.” Accounting for their elevated mean glucose, the 60+ year-olds’ median time >140 mg/dl was 4%, meaning that half of them spend an hour or more a day >140 mg/dl. Overall, median time <70 mg/dl was 1.1%, which was fairly consistent across age groups. “Surprisingly,” Dr. Beck remarked, over one-third of the participants spent ≥30 minutes below 70 mg/dl each day. Time below 60 mg/dl and 54 mg/dl were both negligible. In Dr. Beck’s mind, these figures support consensus around 54 mg/dl as a meaningful cutoff point for research, clinical, and regulatory evaluation. To us, they also suggest a hyperglycemia benchmark of 140 mg/dl is where the field should push over time. We cannot wait to see this data published, along with all kinds of sub-analyses of factors like sex and race, and imagine it will soon be cited with regularity as a goal of diabetes therapies.
Meal and activity data had the same takeaway: crazy low variability. In the whole group, the mean post-prandial peak was just 129 mg/dl, coming an average of 94 minutes post-meal and equating to an excursion of 32 mg/dl. Of note, the post-prandial peak of the 60+ year-olds was higher at 135 mg/dl. Self-reported exercise didn’t seem to have much of an effect, as peak glucose was just 107 mg/dl on average, and the mean nadir low glucose was 86 mg/dl. Only 9% of the participants had a mean nadir <70 mg/dl during exercise. Dr. Beck pointed out that the data wasn’t broken out by aerobic/anaerobic activity, which could be obscuring some of the glycemic impact. Contrary to the dangerous lows oft seen during the night following exercise in insulin-dependent diabetes, overnight glucose following a sedentary day (84 mg/dl) and an exercise day (82 mg/dl) did not vary significantly.
Selected Questions and Answers
Dr. Lutz Heinemann: Did you use G6 without calibration?
Dr. Guido Freckmann: And do you have the meter calibration values available?
A: Great question. We used G6 with one calibration per day. I don’t have that data.
[Note: The study used an investigational version of the G6 that required one calibration per day at the time. We’re not sure if this is was a pre-commercial real-time G6 or an in-development next-gen professional device]
Q: You’ve previously published that African Americans have higher A1cs for a given mean glucose. Here, only 16% of the participants were non-white. Are you able to reinvestigate question here? Do African Americans have higher A1cs for a given mean glucose?
A: One of advantages of being pulled in yesterday to give the talk is I can plead ignorance. I would guess we’ve looked at that, but I don’t know the answer. We will definitely do that. My guess is it won’t be different but we have enough [data] to explore.
Q: By definition, CGM measures of true glucose values can err. So some of these hypoglycemia measures are error, not true. Can you quantify how much is due to measurement error?
A: Great question. Firstly, it doesn’t matter, since this is a benchmark for other CGM studies. Some of it is error, I’d say. Part is measurement error, some is just erroneous values, compression artifacts, overnight sleeping on it. Clearly some of it is that.
Q: Did you exclude the first day for your analysis? And do you have results for average and total carbs subjects ate in relation to blood glucose values?
A: I believe we just recorded when they ate and how much. For the first question, we did look at the data by day and we did include it, so the data up here includes day 1. Day 1 overall looked pretty much the same, except a little more hypoglycemia on day 1 going into day 2, but the mean was the same. That’s the only thing we found on day 1, slightly more hypoglycemia.
Cambridge’s Dr. Martin Tauschmann presented extremely positive A1c and time-in-range results from a 12-week, randomized trial comparing hybrid closed loop (n=46) to sensor-augmented pump (n=40) in patients with a high baseline A1c of 8.2%-8.3%. Results were simultaneously published in The Lancet, accompanied by a positive commentary co-written by Yale’s Dr. Jennifer Sherr – yet another high-profile publication for the team and the field. The robust, randomized home study included adults, adolescents, and children (6+ years) and used the Cambridge MPC algorithm running on an Android phone, a modified Medtronic MiniMed 640G, and the Enlite 3 sensor. By the end of 12 weeks, time-in-range (70-180 mg/dl) had improved from 52% to 65% on closed loop (+3 hours/day) vs. a minimal 52% to 54% improvement with sensor-augmented pump (+29 minutes); the adjusted difference was +10.8% in favor of closed loop (+2.6 hours/day; p<0.001). In a big win, A1c dropped 0.6% on closed loop (baseline: 8.0%) vs. 0.1% on SAP (baseline: 7.8%), driving an adjusted A1c difference of -0.4% in favor of closed loop (p<0.0001). The big benefit came from reducing time >180 mg/dl, which dropped by 2.9 hours/day on closed loop (44% to 32%) vs. a 29-minute reduction on SAP (44% to 42%). Time <70 mg/dl was pretty low in both groups, but also favored closed loop by ~12 minutes/day. Mean glucose declined by 16 mg/dl in the closed loop group vs. a 2 mg/dl decline in the SAP group (p<0.0001). As the profile plot shows below, the huge benefit was overnight, though daytime also saw an improvement in hyperglycemia. In a subgroup analysis of those with A1c of >8·5% at baseline, time in range increased by nearly 20 percentage points in the hybrid closed-loop group (+5 hours/day!), which was more than six times higher than what was achieved in the control group. There were no significant differences in body weight, total daily insulin dose, or coefficient of variation (CV) between the groups. No severe hypoglycemia occurred, and one DKA event occurred in the closed-loop group due to infusion set failure. Closed loop was used for a median 71% of the time, meaning there is certainly further room to improve on these excellent results.
Notably, the Lancet paper notes that this multinational (UK and US) study is the largest randomized study of closed-loop use in outpatient settings so far, including the longest randomized outpatient study of 24/7 closed-loop use in children as young as 6 years and older. It’s also only the third randomized study to report A1c outcomes, according to the paper’s introduction. Dr. Hovorka has sometimes criticized the 670G’s pivotal study, which was a single-arm safety evaluation that compared three months of hybrid closed loop to two weeks at baseline. It’s truly excellent to see this longer, randomized study added to the AID literature.
The commentary – “Enlarging the Loop” – calls this study “the gold standard of a randomized trial done across the age spectrum in those with glycemic control that is more representative of what is encountered in clinical practice. It lays the framework for patients and providers, as well as regulators and insurers, to understand the true scope of who could benefit from such systems, allowing the circle of those considered reasonable candidates for such technologies to be enlarged.” We’d agree and would emphasize the very robust design: the control group was on pump+CGM and used CGM 90% of the time (tough comparator), patients had a high A1c to start, there was no remote monitoring or investigator-led optimization of insulin therapy, and there was a four-week run-in period for optimization. On the latter, A1c declined by 0.3% from enrollment to baseline, meaning total A1c reduction from enrollment was 0.9% with closed loop – wow!
A consistent difference of 10-15 percentage points occurred between the two groups across the whole range of time-in-range values (second picture below), and a difference of nearly 20 percentage points was seen among users with the highest time in range in the two groups. Time-in-range improvements were present in all three age groups (6-13 years, 13-21 years, 22+ years), in both sexes, and for both high and low baseline A1c.
Cambridge algorithm details: “Every 10 min, the control algorithm calculated an insulin infusion rate, which was set on the study pump. The control algorithm was initialised using preprogrammed basal insulin delivery downloaded from the study pump. Information about the participant's bodyweight and total daily insulin dose were entered at set-up. The treat-to-target control algorithm aimed to achieve glucose concentrations between 5·8 mmol/L and 7·3 mmol/L [104-131 mg/dl], depending on the accuracy of model-based glucose predictions.”
Dr. Robert Vigersky introduced Medtronic’s latest endeavor in PCP-targeted decision support, the new and improved Pattern Snapshot 2 for professional CGM. Projected to launch to a small number of clinics in 4Q18, the second version of this clinical decision support software: (i) gives the PCP up to four detected patterns (filtered by possible cause based on medication information, including oral drugs); (ii) provides tailored recommendations to address the patterns (expandable based on therapy type and considerations); and (iii) moves the glucose trace higher up on the page for easier glance-ability. For example, when the iPro 2 of a patient on metformin and glimepiride shows a pattern of hypoglycemia, the PCP is advised to counsel the patient on possible causes (“less food intake? More exercise? Alcohol consumed?”) and also consider adjusting medications (“Reduce or stop SU; Consider replacing SU with a non-hypoglycemia inducing medication”). These tips are a significant improvement over those in the first version of Pattern Recognition, which could have easily told this provider to look into reducing insulin dose, even though the patient isn’t on insulin. Nice! Medtronic will be looking into provider acceptance, issues, and outcomes in the initial launch, and it has already tested the product in >300 patients with over 75 physicians in the US, Europe, and Asia. PCPs were evidently big fans, making comments such as, “This is so much easier, cause I don’t have to go to the computer [to see the guidelines]…it’s here already,” “It’s very helpful to display for those who want a quick reference,” and “it gets your mind going…gives you choices to think about.” While Abbott is winning the hardware arms race in professional CGM, Medtronic is ahead of the competition when it comes to clinical decision support and analytics (Pattern Snapshot 2 + FoodPrint). Helping PCPs manage type 2 diabetes could prove to be one of the most critical public health projects of the next century – how to do this optimally continues to be a major question of the day.
Pattern Snapshot 2 melds ADA/AACE therapy guidelines for type 2 diabetes + the main pharmacologic effects of each drug class + CGM-derived patterns + patient-specific variables (A1c goal; current A1c either <9% or ≥9%; symptomatic or not; and current therapy – naïve, mono, dual, or triple). The therapy considerations in Pattern Snapshot 2 are based on (i) mean sensor glucose, the number one detected pattern, and target A1c; (ii) current medications and doses; and (iii) presence/absence of hyperglycemia symptoms. There are up to six possible therapy considerations, including increasing or reducing dose of a current medication, or adding/substituting/stopping a medication – this includes the initiation of insulin therapy, which could greatly ease the systemic and personal burdens of clinical inertia.
Therapy considerations do not include specific doses, generic or brand names, or a hierarchy of considerations. Physicians must apply their expertise as well, bringing knowledge of past medication use/tolerance, allergies, and renal/cardiac/hepatic function. The list of disclaimers at the end is long!
Questions and Answers
Prof. Eric Renard (University of Montpelier): Do you have outcomes from the glucose control of patients?
A: Not yet, it’s not launched yet. It will be launched in a small number of clinics so we can look at how it’s accepted, issues, if there are any, and of course, at the outcomes.
Mr. Adam Brown (Close Concerns): Because this is clinical decision support and has disclaimers, does this need to be submitted to FDA? Or does it avoid FDA regulation?
A: The latter. Because this is retrospective glucose data and because the clinician ultimately has final say and has to integrate clinical information, it’s the same class as the previous iteration of Pattern Snapshot, so it doesn’t need regulatory approval as a medical device.
Q: I didn’t see any reference in the system to medication cost, which is the single biggest issue in the US.
A: Good point. In the current version, we don’t have that. As everyone recognizes in the US, cost of medicine is extremely variable based on the plan, formulary, tier – average wholesale price may be one thing, but the cost to the patient is different. We would hope to get this kind of additional information so it at least can be flagged by symbols of cost, but right now we don’t have that.
Prof. Lutz Heinemann: Two concerns: I like this clinical decision support software, don’t get me wrong, but how many will show up in the future, 10 of them on clinicians’ computers in the future? And there’s no recommendation for specific drugs currently, but I assume some company would like to have their insulin listed there…
A: Very good point. I anticipate others will develop similar systems. The principles are published for the SMBG approach by myself and Dr. Rodbard. The strength of this approach is that it is neutral as far as pharmaceutical companies, and it continues to allow physicians to pick and choose what is best for patients. It can be customized for formularies. If a health plan or government system limits medications or has them on different tiers, this can be customized in that way.
Imperial College London’s Dr. Parizad Avari presented results from a new sub-analysis of the iHART CGM study (n=40), a head-to-head comparison of the Dexcom G5 and Abbott’s FreeStyle Libre in type 1s with impaired hypoglycemia (Gold score of ≥4) or at least one severe hypoglycemia event in the preceding year. Results from the eight-week, investigator-initiated study were published in Diabetic Medicine and showed G5 bested FreeStyle Libre on the primary endpoint of time <60 mg/dl (3.3 mmol/l), which compared baseline vs. 4-8 weeks: G5 users spent 30 fewer minutes <60 mg/dl, while Libre users saw no meaningful change. In this sub-analysis, the change from baseline in number of hypoglycemia events/week were examined, with a hypoglycemia event (<70 mg/dl and <54 mg/dl) defined as lasting 20+ minutes with a separation of at least 15 minutes. As would be expected, there was a significantly greater reduction in the number of hypoglycemia episodes with the G5 as compared to FreeStyle Libre (p<0.01) for events <70 mg/dl (3.9 mmol/l) and <54 mg/dl (3.0 mmol/l). Following eight weeks of the study, participants were invited to stay on CGM for an additional eight weeks, during which FreeStyle Libre users switched to the G5 (all but four G5 users remained in the trial). In this time period, for hypoglycemia events <70 mg/dl and <54 mg/dl, original FreeStyle Libre users saw a comparable drop in weekly hypoglycemia events maintained by the G5 users. Not surprisingly, Dr. Avari concluded that the G5’s alarms were likely the source of the distinction; we also wonder if G5’s stronger hypoglycemia accuracy played a role. Of course, as chairman Dr. Lutz Heinemann noted during the Q&A, Abbott’s FreeStyle Libre 2 now comes equipped with optional high/low threshold alarms (must still scan to get a glucose), perhaps warranting a repeat of the study! Dr. Avari agreed, adding that more data on the accuracy of the FreeStyle Libre 2 alarms will be important. Based on real-world data Dexcom showed on Monday, the G6 is actually slightly better on reducing hypoglycemia vs. G5, especially with the urgent-low-soon feature enabled. FreeStyle Libre 2 does not provide predictive alarms, though certainly it would perform better than FreeStyle Libre 1 in a study like this.
Exhibit Hall – Diabetes Technology
The Abbott booth was absolutely packed with attendees eager for a demo of the freshly CE-marked FreeStyle Libre 2 with optional alarms (read our deep dive on the device here). We were impressed with the easy alarm setup (the touchscreen reader guides users through step-by-step instructions), though the in-person demo reminded us that this user experience is taking a hybrid approach – when the reader is pinged, it makes a noise/vibration and only says “Low Glucose Alarm,” at which point a person must manually scan to get a reading. We look forward to seeing how current FreeStyle Libre users like this feature – we imagine many will love the additional safety net, while some will wish it pushed the actual glucose value to the reader. We were surprised to hear from the rep that FreeStyle LibreLink app integration will not extend alarms to LibreLinkUp, the remote monitoring app. In other words, while caregivers following patients using LibreLinkUp will still be able to view users’ scanned real-time glucose values, alarms will apparently not push through to LibreLinkUp. Allowing for remote monitoring via alarms would have been a major win for caregivers, especially parents of young children. (FreeStyle LibreLink app integration to add alarms is expected in ~6 months in Europe.) We also wonder if the reader and the FreeStyle LibreLink app can be used simultaneously; i.e., could a parent within Bluetooth range hold onto the reader and receive alarms in another room while the child uses the LibreLink app?
The Cellnovo booth heavily advertised its new Gen 3 system, which switches the controller to a locked down Android phone. The booth representative confirmed that the system began rolling out in September and is available in all 10 countries in which Cellnovo pumps are sold (i.e., Australia, Cyprus, France, Greece, Italy, Israel, the Netherlands, New Zealand, the UK, and Spain). We also confirmed that Cellnovo has filed the Gen 3 system with FDA, following the filing pushback announced in 1Q18. We've since learned from management that this information was shared mistakenly – Cellnovo plans to submit the Gen 3 system to the FDA in early 2019. Given the US competition Cellnovo will face from more established pump companies and AID offerings, we’re glad it modified the submission to the latest handheld. Cellnovo is aiming for a US Gen 3 launch next year, which will presumably require a significant fundraise or partnership. We also received updates on the three AID studies in which Cellnovo is involved. Cellnovo is “getting ready for a trial” with TypeZero (now owned by Dexcom) – we wonder if this is the three-day trial previously planned for June or a subsequent study. The booth representative noted that the first arm of the Diabeloop study was completed with the Cellnovo pump, but the second arm is ongoing with the Kaleido pump. She speculated that Diabeloop will likely pursue a CE Mark similar to TypeZero, providing licensing to multiple systems and remaining pump-agnostic. Lastly, the booth representative noted that a feasibility trial from the EU-funded PEPPER project is “ending” in Spain and the UK, and the system is about to go into a pre-CE Mark validation study. It’s smart for Cellnovo to pursue multiple projects, though this seems like a lot for the small company to tackle.
EASD also marked the official European exhibit hall debut of G6, which launched on Day #1 in Germany and is also available in the US, UK, Austria, and Switzerland. While the booth’s external signage focused a lot on the G6 system and snappy quotes (“no fingersticks,” “pain free,” etc.), the inside of the booth placed a bigger-than-usual focus on Dexcom Clarity – both on the web and the soon-to-launch-OUS Clarity app. According to Dexcom’s Day #1 symposium, the Clarity mobile app will launch outside the US in the “coming weeks.” When we walked through the booth, a half dozen healthcare providers were huddled around a laptop as a rep demoed Dexcom Clarity on the web. Handouts in the booth summarized some of Dexcom’s recent literature, especially the iHart CGM study (showing G5’s hypoglycemia superiority over Libre) and HypoDE (CGM in MDIs with hypoglycemia unawareness).
Diabnext will be launching its connected pen attachment (Clipsulin) and Gluconext (plugs into non-Bluetooth BGM and transmits data) globally in November; it is looking for distributors and plans to sell each for $40. The devices are already in a number of countries, including Taiwan, Singapore, and Japan. The company will also introduce DiabNet Pro, a digital management platform to sell to health systems, payers, and clinics. Pro would bring patient data and risk stratification to providers, and also allow them to send written and video educational content to their patients. This initiative fits nicely into a remote monitoring/telemedicine reimbursement model in France. It sounds like this is still fairly early stage and the details haven’t been fully ironed out, but it could turn into a solid business option for the startup.
EOFlow currently has three major projects in the works: (i) a patch pump; (ii) an AID system with POCTech’s CGM and TypeZero’s inControl AP algorithm; and (iii) an integrated AID system with a built-in CGM sensor supported by a recent, two-year JDRF grant. Management at the booth confirmed that EOFlow is in the process of submitting for FDA approval and CE Mark for the patch pump, with an expected 2H19 launch in Korea, followed by launches in the US and EU in late 2019 “if we are lucky.” If not, early 2020 launches are more likely. As for the closed loop system, EOFlow plans to run closed loop tests this year in animals and expects to be ready for in-human testing in 2019. The company has already run simulations of the system. While EOFlow is officially including POCTech in the system, the company is also “working with others” – Dexcom G6 would probably be the most obvious choice, given the existing partnership with TypeZero. Lastly, management acknowledged that the initial hope of having a functional, integrated closed loop system ready for FDA submission by the end of 2020 was “a little too aggressive” – this puts everything under a single on-body patch (CGM, pump, algorithm). EOFlow is now in the process of adjusting the proposed timing. Management expects to have a poster on the integrated system at DTM in November, and will “probably” have “something” to show at ADA 2019. See below for a mockup of the integrated system on display. We like the idea of an integrated AID system, though wear time makes this a real challenge – unless the infusion wear time can move to seven days, the business model feels impossible to make work. JDRF’s support is a positive sign, though much remains to be proven here and we’re not aware of the level of the support.
Glooko/Diasend reps touted newly released cloud-to-cloud integrations for Omnipod’s Dash system and the Dexcom G6, as well as a new version of the Glooko Population Tracker that includes a “new and easier to leverage logbook, summary stats, and tools for creating personalized .pdf printouts “which clinicians love in their practices!” Population Tracker is one of our favorite features of Glooko’s software, so we’re glad to its user experience iterated and improved! In other Glooko news, reps described the “major effort” of getting Insulet-provided Glooko up and running in the EU (this could be a solid source of revenue going forward), suggested that a formal EU roll out of the Glooko Transmitter with NFC would be done in phases (details coming later this year), and hinted that the 2018 Glooko Annual Diabetes Report is coming soon! In 2017, we were surprised to learn that a higher mean blood glucose was reported on Valentine’s day than on Halloween. What will be the surprise insight this year?
In what may as well have been a secret corner of the Novo Nordisk booth – the drug company reps didn’t know about it when asked – we witnessed attendees uploading (fake) doses from NovoPen 6 to the NFC-enabled Glooko Transmitter. The process is impressively quick, not to mention pleasing, as you watch the progress-indicating circle quickly form before your eyes (we got to do this at ADA). Glooko sent us a mock provider view of “Amy Dawkin’s” day-by-day diabetes data, complete with CGM, CGM calibrations, carbs, and insulin data (including dose, type, timing, and basal:bolus ratio)! The insulin dose data is fairly bare bones – making no depiction of bolus insulin dose’s action over time – but it gets the job done and fills a huge unmet need. For example, if we were Amy’s clinician, we might suggest caution overtreating the breakfast low, an earlier and possibly bigger bolus at 2 pm, and a slightly lower dose of Tresiba to avoid overnight lows. Any advice of this sort would’ve been impossible to even warrant a guess previously with no insulin data record! Stemming from the Novo Nordisk Sweden connected pen pilot, Glooko plans to integrate insulin data “broadly,” as soon as the pens launch beyond Sweden. Not surprisingly, the company further plans to allow patients to upload insulin data into the mobile app (though noting that NFC features on phones can be “cumbersome”), and build out both HCP- and patient-facing decision support.
The IDx booth displayed IDx-DR, a diagnostic system equipped with artificial intelligence to detect diabetes-related retinopathy. The platform was permitted for marketing by the FDA in April and is CE marked as a class IIa medical device. IDx-DR is being distributed throughout the EU in partnership with IBM. The booth representative was very excited about the recent $33 million financing round led by venture capital firm 8VC, with participation from Optum Ventures, Alpha Edison, and Heritage Provider Network. Given that IDx continues to be in discussions with payers in the US, having the backing of Optum Ventures, the investing arm of Optum, a UnitedHealth company, should help. Currently, in the US, IDx-DR is used only in the University of Iowa health system, but discussions with “a number of large healthcare systems” are ongoing. The booth representative anticipates announcements in this area “within the next couple of months.” She also noted that pilots are being conducted in Europe and that the company’s long-term plan includes adding on other disease states, such as macular degermation and glaucoma, to the platform.
EASD was Insulet’s first European exhibit hall appearance after taking Omnipod distribution over from Ypsomed on July 1. It was immediately apparent how much of a marketing and branding advantage this move is going to be for Insulet – relative to Ypsomed’s large green booths that had none of the Omnipod feel, this one had the positive branding and quality of life data we see in the US. Reps excitedly referenced the morning’s press release on the addition of Fiasp insulin compatibility to the Omnipod in Europe. Reps told us this did not require a clinical trial in Europe. We do not believe Fiasp has official FDA approval for Omnipod compatibility, though obviously many are already using it off label. As expected, the booth did not show (or hint at) the FDA-cleared Omnipod Dash PDM, which is currently in its limited US market release and expected for a broader US launch in early 2019. Per Keystone 2018, a global expansion for the Dash PDM is expected in 2H19.
Unexpectedly, the LifeScan booth debuted its brand-new OneTouch Verio Reflect BGM, which includes a “Blood Sugar Mentor” that provides on-meter patterns, insights, and encouragement to the user. The Verio Reflect is CE Mark-pending, although the booth representative commented that launches in France and Germany are expected “very soon,” followed by Italy and a gradual EU rollout. The hardware resembles the VerioFlex, but with a better screen, slightly larger meter size, and continuing pairing to the very popular Reveal app. Eventually, LifeScan plans to bring the Verio Reflect to the US. Blood Sugar Mentor, which reminds us of Ascensia’s new trend analysis feature for the Contour Next app, analyzes patterns, provides basic guidance, detects glycemic excursions, and supplies encouraging messages on the meter itself – see examples below. Immediately following a fingerstick, messages appear on the BGM screen and push to the Bluetooth-paired OneTouch Reveal app. Examples include: “You’ve been high in the last four days at this time. Has anything changed?” and “Keep it up! 19 of the past 25 results have been in range over the past seven days.” We think these little nudges have the potential to be massive in driving better outcomes – regardless of the advice, prompting patients in real time to consider reasons behind a pattern could make the numbers more meaningful and drive better behavior change. The new BGM also comes with an updated Color indicator, expanding upon LifeScan’s previous system for hypoglycemia, in-range, and hyperglycemia readings. This version includes seven levels to notify users when they are in-range but “near” a high or low. We love the use of emojis, which give the meter a lighter, less clinical feel. Impressively, when one of these “near” fingersticks is detected, a message in the OneTouch Reveal app asks users if they’d like to set a reminder to check their blood glucose again in 15 minutes. The app looks clean, modern, and retains the nice pattern recognition from previous iterations. Given the Platinum Equity acquisition of LifeScan from J&J, we were a bit uncertain as to the future of LifeScan – it’s therefore a great sign to see the company rolling out a new product, as it suggests that LifeScan is here to stay. While the rep understandably could not comment on Platinum Equity’s acquisition, he noted that Tuesday, October 2 marked the first day LifeScan is identified under Platinum. Indeed, J&J just announced today that the ~$2.1 billion acquisition was completed. We look forward to hearing more updates during the LifeScan corporate symposium tomorrow night.
Medtronic’s expansive booth was packed when we passed by, eager to hear Dr. Robert Vigersky’s presentation reviewing the MiniMed 670G pivotal trial results. EASD marks the international exhibit hall debut of the 670G following the CE Mark announcement at ADA. A rep told us that the MiniMed 670G will launch starting next week in Europe – the initial launches (specific dates vary by market) will include Belgium, Denmark, Finland, Italy, Netherlands, Slovenia, Spain, Sweden, Switzerland, and UK/Ireland. This is right on time for the fall OUS launch expectation and means the 670G is launched in the US ~1.5 years prior to Europe. Interestingly, some of Medtronic’s marketing seemed to have moved away from “hybrid closed loop,” as signs around the booth advertised the “World’s first self-adjusting insulin pump” – we’re not sure if hybrid closed loop is confusing, if it prompts pushback related to the term “closed loop” (i.e., it’s not fully automated), or if Medtronic is simply using different terminology OUS. The booth also displayed the Guardian Connect standalone CGM on iPhones and the excellent MiniMed Mio Advance infusion set inserter (automatic applicator, fully hidden needle) that launched outside the US at ATTD in February.
Upon searching the FDA database, we’ve discovered that the Unomedical MiniMed Mio Advance set inserter actually received FDA 510(k) clearance in March! Medtronic has not talked about an actual US launch of the set in its June Analyst Day or recent calls, though we might guess a US launch this year is possible; as of ATTD, “other countries” were expected “later in 2018.” Medtronic told us that it is seeing major demand for the set outside the US, and the lag time reflects the need to build sufficient supply – that make sense since shortages really frustrate patients and create enormous headaches for companies. We also wonder if Medtronic is being extra careful following the rough limited launch with BD’s MiniMed Pro-set, which has yet to relaunch. Given the excellent design of this set, we imagine it will fly off the shelves at huge volume. We’ve demoed Mio Advance a few times and think it is a stunning improvement over current infusion set form factors, very similar to Dexcom’s move from the G5/G5 applicator to G6; see our review from ATTD 2018.
A flyer at the Medtrum booth trumpeted the recent launch of the A6 PLGS (“semi closed loop”) system, entailing the company’s proprietary patch pump, CGM, and algorithm, in Germany. A6 is already in a number of Nordic countries, the UK, Turkey, and other markets, and hopes to hit France and the majority of the EU by next year. A rep told us that a hybrid closed loop, proprietary hypoglycemia/hyperglycemia minimizer had also just made it through the CE mark process. A rep told us he would send clinical data our way on both systems, though we have not received it at the time of writing – we couldn’t find any papers on searches of PubMed, ClinicalTrials.gov, nor the Medtrum website. We’ve heard from UK clinicians that Medtrum’s CGM is “spotty.” We did snag pictures of the A6 and A7 systems (A7 consisting of next-gen devices), as well as the CGM companion app.
Following a public debut in the ATTD 2018 exhibit hall, we received a few notable updates on Metronom’s 14-day wear, optical-based, factory calibrated CGM. On timing, things are a bit delayed: Metronom now expects regulatory clinical trials in October 2019, followed by a CE Mark filing in early 2020 and a mid-2020 approval. Relative to ATTD, the CE Mark filing is about a year delayed. CSO Troy Bremer told us the delay will be worth it, since the company plans to switch to a fully disposable transmitter (not reusable), a smart move to keep pace with FreeStyle Libre and where Dexcom is going with Verily. R&D efforts are currently focused on miniaturizing the disposable transmitter, which will include Bluetooth and go direct-to-watch and direct-to-phone. We got a look at the updated phone user experience for Metronom’s CGM, which looks truly outstanding and is one of the best we’ve ever seen for a CGM app – the home screen shows all the key real-time details, but also allows users to scroll down and see separate sections for time-in-range, patterns, and an AGP without having to leave the main screen or go to another app (pictures are below, though the design is obviously subject to change as it gets closer to market). We love it! We were also struck by the cool alarm customization options, which are differentiated from other CGMs and allow users to set their preferences – e.g., high alarm only if glucose is >180 mg/dl for 20 minutes and trend arrow is not falling. It’s actually quite impressive that this aspect of the product looks quite ready for launch; often the paired app/software is an afterthought. Metronom is targeting a price of $5/day (roughly matching FreeStyle Libre in Europe) and is considering a launch alone or via partnership.
As noted in our ATTD 2018 coverage, the Metronom sensor technology includes direct oxygen measurement (which can monitor sensor reliability and prompt for a “smart” calibration when needed); dedicated sensors for hypoglycemia, euglycemia, and hyperglycemia; an insertion that is more like a lancet (applicator device like FreeStyle Libre); and a durable transmitter that sends data via Bluetooth to phone and watch apps (it can already go direct-to-Apple Watch, according to the company). Notably, the plan is to manufacture the sensor like a test strip (“reel-to-reel”), enabling lower expected cost of goods. The first-in-human feasibility data (hand assembled sensors) demonstrated a 9.0% MARD and 94% of points within 20/20 (n=1,641 paired points, range of 50-300 mg/dl) in 20 people with diabetes (n=10 T1D, n=10 T2D). The study used retrospective calibration and obviously was not making sensors at scale, so upcoming studies will need to prove accuracy and reliability on a bigger scale.
POCTech’s small but busy booth showed off the company’s CE-marked CGM. The 7-day, one calibration per day sensor with a reusable, battery-powered transmitter lasting up to two years has not yet been commercialized, though it is “in the process of being registered” in countries including the UK, Korea, Greece, and Malta. A year ago, we heard that it would be available in France, Spain, and Italy in 2018, though we weren’t able to get an update on these sizable markets. In new news, a second-generation, 15-day sensor could be filed in early 2019. On the partner front, POCTtech reported “talking with” numerous pump companies about integration, with the rep specifically naming SOOIL. At EASD 2017, the company told us that its CGM could be integrated into EOFlow’s hybrid closed loop system, but there was no update on that front. In a final update, we are told that there are further clinical trials on the horizon comparing POCTech’s sensor with SMBG and other CGM (“probably Dexcom”); we imagine these will be accuracy rather than outcomes studies.
The sprawling Roche booth was divided into three sections: Payer solutions, patient solutions, and healthcare provider solutions, plus a Senseonics Eversense demo insertion station in the corner. In our rounds, we learned that the BETAtogether program, which is seeking beta users to test drive insulin pump companion apps, will feed into the R&D of an app to remotely control the Accu Chek Insight pump. As a reminder, this is the pump to be used in the Senseonics/Roche/TypeZero AID system (pivotal study is protocol 2 of the IDCL, set to begin in October). The majority of the updates came from mySugr reps, who told us that 55% of the ~1.4 million app users are now type 2s (many on orals), a surprising but welcome trend! It’ll be interesting to watch how the product’s feel and content changes – or forks into two? – as a product initially designed by and primarily for type 1s picks up greater type 2 traction. Related to the recent Novo Nordisk announcement that it will launch connected pens in early 2019 and partnered with Roche, mySugr told us that they intend to allow users to scan their Novo Nordisk pens into the mySugr app using the phone’s NFC. This would be a big win for more engaged patients – Android users, at least, as Apple’s NFC chip is blocked barring a partnership (Abbott scored an unprecedented deal with Apple on this front) – who don’t want to wait until clinic visits to have their insulin downloaded and interpreted by their HCPs. A mySugr industry update from a couple days ago touted further momentum: (i) Six German payers, covering 15 million total lives, now reimburse for mySugr’s population management service; (ii) the first US payers – Montana Primary Care Association, Northwest Community Health Center, and Bighorn Valley Health Center have come on board for the service; (iii) data on the mySugr bundle in type 1 and type 2 diabetes will be presented at DTM in November; and (iv) the team recently hired a Medical Director: Dr. Harald Mayer.
A bustling SOOIL booth showed off its Dana and Dana RS (Bluetooth-enabled) pumps. We brought up integrated pump (“iPump”) with an engineer, who reiterated that the company is working with FDA on a de novo request (we’re not sure how both they and Tandem could submit to FDA with de novo status – someone will have to be first, and the other would be a 510(k)). He told us that the iPump would be based on Dana RS, but would have a “black box” and a AAA battery. FDA wanted a black box – similar to that found on a plane – he said, so that it can dig into a pump’s behavior in the aftermath of an adverse health event, should one happen. “Most of all, FDA wants safety and security.” The company also continues to work with OpenAPS and other developers on getting to an open protocol AID system – specifically licensing an OpenAPS algorithm for the pump as an integrated algorithm (iAlgorithm). Ambitious ADA guidance “guaranteed” the launch of an open protocol, smartphone-controlled insulin pump in the US by ADA 2019.
Tandem made its first ever European exhibit hall debut here at EASD, showing off the CE-marked t:slim X2 with Dexcom G5 integration in a cozy booth. We learned about one notable feature in the European version of the pump: the bolus calculator automatically populates with the Dexcom G5 readings, a convenient and safer feature. Interestingly, the US version does not have this, something we’d guess relates to regulatory – though G5/G6 are approved for insulin dosing, the FDA has historically been tough on bolus calculators. We were reminded that Tandem’s bolus calculator has the blood glucose and carb entry boxes side-by-side – mixing them up would be unfortunate and possible if a user was moving fast. Automatically populating the bolus calculator with CGM, however, would likely improve safety and certainly enhance convenience.
Geographically, the t:slim X2/G5 has launched outside the US in Italy, Scandinavia, Spain, the UK, South Africa, Australia, New Zealand so far. France, Germany and the Netherlands are the next international targets for Tandem, per its Analyst Meeting last week. A rep told us part of Tandem’s EASD presence was to meet with German distributors for the pump.
In the pipeline, Tandem’s Analyst Meeting called for an early 2019 international launch of Basal-IQ with Dexcom G6 Integration. The team is working on translating the Tandem Device Updater for foreign countries, which will enable current X2/G5 users to software update their pumps. Presumably Basal-IQ will also need a CE Mark.
The Ypsomed booth featured its mylife touchscreen durable YpsoPump, available in 16 markets (EU, Australia, India) as of Ypsomed’s June FY18 call. A booth representative confirmed that the YpsoPump is still under FDA review – in June, we learned that FDA submission occurred on May 30. Per the representative, a US launch is expected “next year” in line with management’s expectations on the FY18 call for a launch by summer 2019. Though a Canadian YpsoPump launch was expected in October 2018, we learned at the booth that Ypsomed is still “working” with Health Canada; a Canadian launch is now expected in the beginning of 2019. This will likely place Ypsomed a bit behind Tandem’s t:slim X2, which as of September is still within the Health Canada regulatory process but slated for a Q4 launch. The Ypsomed representative shared that the mylife Unio Neva BGM is integrated with mylife app, on par with expectations. This was the first conference where Ypsomed did not have Insulet’s Omnipod in its booth, and representative confirmed that Ypsomed’s efforts to develop its own patch pump are ongoing. The FY18 call expected “final conceptualization” of the mylife YpsoPod patch pump by March 2019. Also in the pipeline, Ypsomed received two-year funding from JDRF in August for the development and regulatory approval of an open protocol, fully interoperable mylife YpsoPump. Ypsomed is now the fourth company to join JDRF’s Open Protocol Automated Insulin Delivery Initiative. Understandably, the representative could not comment on this front.
-- by Adam Brown, Ann Carracher, Abigail Dove, Martin Kurian, Brian Levine, Peter Rentzepis, Maeve Serino, and Kelly Close