Guten Tag from Berlin! EASD is officially under way, and off with a bang doesn’t quite describe it: Our team got to extract the top highlights from nearly 40 cumulative hours of symposia today! More to come tomorrow.

Diabetes Therapy Highlights

1. EASD Kicks Off with SGLT-Centric Symposia: Dr. Rosenstock Talks Type 1 CVOT; Dr. Danne on Emotional Burden + Time-in-Range; Dr. Buse Tackles Risk/Benefit

SGLT therapy for type 1 diabetes took center stage at both Sanofi’s and AZ’s Monday symposia. Following ADA 2018 earlier this summer – where SGLTs for type 1 truly stole the show – the topic is shaping up to be a big focus of EASD as well. Throughout the day, we soaked up valuable commentary on critical issues related to this hot topic, including the implications of the time-in-range improvements with SGLT inhibitor therapy, how to manage DKA risk, and – intriguingly – whether the CV and renal protective effects with SGLT agents in type 2 diabetes could translate to type 1 (patients and type 1 diabetes advocates have been wondering this forever!).

• Dr. Julio Rosenstock offered a glimpse into the possible future of SGLT outcomes studies: “If there was ever a need for a pragmatic CVOT, this is it – SGLT inhibitors in people with type 1 diabetes at high risk for CV disease.” He reminded the audience that elevated CV risk with diabetes is not unique to type 2, and noted that “if we’re all so excited about SGLTs for CV disease, heart failure, and nephropathy in type 2 diabetes, we need to honestly ask ourselves if these effects can be replicated in type 1.” At ADA 2018, Dr. David Cherney offered a similar call for a cardio/renal outcomes trial in type 1 diabetes, and Dr. Anne Peters shared that many of her type 1 patients ask for an off-label SGLT-2 inhibitor primary for the cardioprotective benefits – this is clearly a topic on people’s minds, from patients to providers to KOLs. To be sure, we currently have zero hard evidence on organ protection with these agents in type 1, though the mechanisms of SGLT inhibition – which are not thought to be glucose-mediated – should theoretically play out in type 1 diabetes much like they do in type 2. While the financial and logistical challenges of a full-fledged CVOT in a type 1 population are many (though negligible compared to cardiovascular and renal costs), Dr. Rosenstock’s suggestion of a pragmatic trial design (whether funded by pharma or philanthropy) is an intriguing one – especially coming from one of the most respected clinical trialists in the field. We do think that ongoing clinical trials of SGLT-2s in both heart failure and CKD outside of people with diabetes could shed valuable light on the broad applicability of these cardio- and renal-protective effects, and we hope that some in these trials have type 1 – to our knowledge, Lilly/BI’s EMPEROR and EMPA-KIDNEY trials are enrolling type 1s, but type 1s are excluded from AZ’s Dapa-HF and Dapa-CKD. Given the enormous gaps in treatment for people with type 1, we hope to see more discussion and characterization of a CVOT in people with type 1 as well as, overall, more on the risk/benefit profile of SGLTs in type 1. 

• Dr. Thomas Danne focused on the role SGLT inhibitors can play in easing the emotional burden of type 1 diabetes management. Citing data from a Clinical Diabetes paper authored by Close Concerns, The diaTribe Foundation, and dQ&A, Dr. Danne framed time-in-range as perhaps the most important player in the emotional aspects of type 1 diabetes management, and he positioned SGLTs as a key strategy for improving time-in-range. According to a dQ&A survey of nearly 7,000 people with diabetes, the top three ways in which diabetes impacts day-to-day life for people with type 1 all relate to the constant vigilance required to achieve in-range glucose numbers. These factors were: (1) The time commitment and burden good diabetes management takes; (2) Difficulty managing blood glucose; and (3) Hypoglycemia. With potent improvements in time-in-range (pooled CGM data from Lexicon’s inTandem1 and inTandem2 trials showed an additional 1-3 hours spent in-range with Sanofi-partnered SGLT-1/2 inhibitor Zynquista and AZ’s DEPICT 1 study showed an additional 2-3 hours in-range with SGLT-2 inhibitor Farxiga), SGLT inhibitors could play a key role in offsetting the stress, worry, and constant effort required to achieve time-in-range with insulin therapy alone.

• We additionally appreciated Dr. Danne’s unique take on the DKA risk associated with SGLT inhibitor therapy in people with type 1 diabetes: “DKA has been so forgotten and undermanaged in our clinics that I personally think it’s good that SGLT inhibitors have put a spotlight on it.” To be sure, DKA risk is a legitimate concern, especially in light of DEPICT-2 results that revealed increased DKA incidence with AZ’s SGLT-2 inhibitor Farxiga (not seen in DEPICT-1), essentially solidifying DKA risk as a class effect for SGLTs in T1D at large. That said, we love the idea of reframing this as an opportunity for HCP and patient education on DKA prevention, risk management, and treatment, rather than a deal-breaking safety signal for an otherwise extremely promising drug class. We agree with Dr. Danne that this complication has been overlooked and under-treated for too long, and the silver lining here is that more attention is being placed on it (in a similar way, we see the Invokana amputation signal as an opportunity to enhance patient education on foot care in diabetes). Dr. Danne highlighted the ATTD-sponsored consensus meeting on DKA risk mitigation held at ADA 2018, hinting that a forthcoming manuscript will dive into the specifics of patient selection, education, and monitoring, as well as offer guidance on which patients are ideal candidates for SGLT inhibitor therapy, how often they should check ketones, and how – all extremely important issues with Ad Comm(s), as regulatory decisions on SGLT inhibitors in type 1 diabetes loom large. Get a full take on these questions here.

• In his keynote at AZ’s daylong symposium, Dr. John Buse unequivocally advocated for SGLT-1/2 and SGLT-2 inhibitors to be approved and used as adjunct therapies for patients with type 1 diabetes. Dr. Buse referenced both the DEPICT (dapagliflozin in type 1) program, which demonstrated significant reductions in A1c, total daily insulin dose, and body weight with dapagliflozin vs. placebo, as well as the inTandem (sotagliflozin in type 1) program, which found superiority of sotagliflozin over placebo on a plethora of endpoints. He briefly touched on the EASE program (empagliflozin in type 1; topline reported at ADA 2018), highlighting that the full results presentation on Thursday is what he is most excited for at EASD. On what he called the “fly in the ointment” – DKA, particularly euglycemic DKA – Dr. Buse stressed that both industry and clinicians are working diligently to ensure that SGLT inhibitors are used safely in type 1 diabetes. In his words: “I do believe the benefits for patients with type 1 diabetes are important. Now we need to find safe ways to use them.” We could hardly agree more, but we also believe that many critical specifics on precisely how to use them safely need to be worked out, and implementing a robust education and safety program across the multiple stakeholders at play is no small task. For more answers on this front, we look very forward to the forthcoming manuscript spearheaded by Dr. Danne and ATTD (see above).

2. Dr. Buse Highlights Most Exciting Candidates of 560 Products in Active Development for Diabetes; Censures Current Underutilization of GLP-1s and SGLT-2s as “An Embarrassment”

The venerable Dr. John Buse was given free rein to conclude AZ’s daylong symposium, focusing on the diabetes therapies currently in development that he finds most exciting. According to Dr. Buse there were 560 products in active development for diabetes as of 2017. Of these, 152 were new, never-before investigated molecules and 95 were investigating a novel mechanism. These are the candidates he singled out as most exciting:

• Oral semaglutide: An unsurprising choice, given the overwhelmingly positive results released so far for this first-ever oral GLP-1 agonist. Seven of 10 phase 3 PIONEER trials have read out, including PIONEER 1 (vs. placebo), PIONEER 2 (vs. Lilly/BI’s SGLT-2 inhibitor Jardiance), PIONEER 3 (vs. Merck’s DPP-4 inhibitor Januvia), PIONEER 4 (vs. Novo Nordisk’s own Victoza), PIONEER 5 (in moderate renal impairment), PIONEER 7 (vs. Merck’s Januvia, with dose adjustment), and PIONEER 10 (vs. Lilly’s GLP-1 Trulicity in Japanese patients). In particular, Dr. Buse highlighted PIONEER 1 in his presentation, emphasizing that mean A1c fell below 6.5% in the 14 mg group without increased risk of hypoglycemia – quite remarkable, in his opinion. We’ve been following this candidate since 2013, and our excitement certainly matches Dr. Buse’s.

• Imeglimin: Interestingly, this phase 2/3 candidate blocks oxidative phosphorylation, which Dr. Buse noted is critical to human function: “I’m not sure how they are going to get away with this one.” We, too, have been curious precisely how this mechanism works safely. Right now, the candidate is entering three pivotal trials (n=1,100 total) for the treatment of type 2 diabetes in Japanese patients (under Sumitomo Dainippon Pharma); Imeglimin is phase-3 ready in the US and EU (under Roivant), but the company will conduct more differentiation studies, especially in CKD, before advancing to phase 3 in 2019. A promising ~1.0% reduction in A1c over 24 weeks was identified, at a high dose of 1,500 mg, in a phase 2 trial (p<0.0001 vs. placebo). Moreover, Dr. Buse pointed to a study (n=170) demonstrating an ~0.7% decrease in A1c with sitagliptin + Imeglimin compared to sitagliptin monotherapy. Down the line, we’d be curious about combinations of Imeglimin with SGLT-2 inhibitors or oral GLP-1 agonists, and our sense is that Roivant especially is most interested in pursuing this candidate for effective glucose-lowering in patients with impaired renal function.

• TTP399: In the phase 2b AGATA trial, vTv’s hepatoselective glucokinase activator (800 mg) demonstrated comparable A1c change to sitagliptin (100 mg) over the course of six months, while also conferring greater weight loss, in patients with type 2 diabetes (below). To our understanding, though, vTv has not pursued the candidate further in type 2 diabetes. As highlighted on the company’s 2Q18 call, patient dosing for phase 2 of the JDRF-sponsored phase 1/2 SimplicT1 Study (n=126) of TTP399 in type 1 diabetes recently began. The study will examine change in A1c at 12 weeks in patients with type 1, and expected completion is January 2019. Preliminary phase 1 results (n=5) in this extremely small study were presented at ADA 2018, demonstrating that TTP399 was well-tolerated (no severe hypoglycemia or DKA), glycemic control was improved, and insulin bolus levels were reduced. We’re not sure what the company’s plans are for type 2, and vTv also has an oral GLP-1 agonist in phase 2b.

• Cell-based therapies: Dr. Buse pointed to three initiatives in particular: (i) ViaCyte’s PEC-Encap – fully-encapsulated, indirectly-vascularized, stem-cell derived islets (two-year data from the STEP ONE trial demonstrated formation of viable mature insulin-expressing cells, with some persisting for two years, but issues arose with foreign body response); (ii) DRI BioHub – a bioengineered mini-organ (first patient treated in a phase 1/2 clinical trial has demonstrated stable glycemic control without exogenous insulin and without episodes of hypoglycemia) and; (iii) CLBS03 therapy, utilizing immunoprotective T_regs³ (T-Rex, a phase 2 trial, is underway to evaluate the safety and efficacy of CLBS03 as a treatment for type 1 diabetes). See more on cell therapy for type 1 in our type 1 cures competitive landscape.

• While the forefront of diabetes therapy is certainly exciting, Dr. Buse also stressed that implementation of what we already have in SGLT-2 inhibitors and GLP-1 agonists must come first, stating that current under use of these highly efficacious therapies is, “frankly an embarrassment.” Indeed, very few people are on these therapies compared to how many could benefit. A 2016 analysis found that SGLT-2s and GLP-1s accounted only for a collective 14% of all second-line type 2 diabetes prescriptions in the US, while sulfonylureas comprised a shocking (but declining, in recent years) 46%. Hopefully providing a much-needed tailwind for these therapies will be data demonstrating their efficacy in those without a history of CV disease, which Dr. Buse highlighted could come from DECLARE (AZ’s dapagliflozin, in a ~60% primary prevention cohort) for SGLT-2 inhibitors. And, we’re curious about the potential for REWIND (Lilly’s dulaglutide) to show cardioprotection with a GLP-1 agonist in a majority primary prevention population. Lastly, much more also needs to be done on access and patient affordability, in our view.

• To conclude, Dr. Buse extolled the digital ecosystem for using real-world patient data to improve diabetes management (CGM, Medtronic/IBM Watson’s collaboration, and consumer-driven technology were given as three examples) and delineated the implications that digital health has for clinical trials. As he sees it, digital health can (i) streamline patient recruitment to trials via registries by preselecting the most eligible candidates; (ii) reinforce patient engagement with trials; (iii) eliminate unnecessary clinic visits or bring the trial to the patient’s home; and (iv) support primary and secondary clinical trial endpoints (e.g., using medical devices to provide specific endpoints). Notably, we are already seeing these implications in the real-world. Science 37, a fascinating new company, enables “site-less” clinical trials – a trend we hope to see expand in diabetes as connected glucose monitoring and insulin delivery devices proliferate, enabling passive data collection and a whole new era of evidence generation at scale. Specific to diabetes, Science 37 is listed as a site on ClinicalTrials.gov for Lilly’s currently-recruiting smart pen trial investigating missed meal boluses. Science 37 was also enrolling a diabetes probiotic study in type 2, as well as a NASH study. 

3. Dr. Bergenstal Says Time-in-Range, Hypoglycemia to Become Yardstick of Diabetes Therapy; Cites Emerging Body of Data Linking Time-in-Range to Microvascular Complications, Independent of A1c

In a powerhouse opening lecture to Sanofi’s corporate symposium, Dr. Richard Bergenstal highlighted new data on the correlation between time-in-range (TIR) and retinopathy in support of using TIR and time-in-hypoglycemia to govern care decisions and treatment goals. Dr. Bergenstal identified two major headwinds against full acceptance of CGM/TIR, compared to BGM, in clinical trials, regulatory decisions, and even clinical practice. First, TIR currently needs to be contextualized within already-accepted data, endpoints, and standards – that is, A1c – to be accepted; for example, 70% TIR=~7% A1c; ΔTIR 10%=~ΔA1c 0.5%. Second, and giving rise to that issue, is that there is no data on how TIR is associated with complications – “The DCCT was not done with CGM.” This knowledge gap has prompted calls from thought leaders including Dr. Irl Hirsch for a definitive study examining glucose variability and long-term outcomes. However, Dr. Bergenstal emphasized that the needle is starting to move on this point (which we think will also help to move the former), pointing to a just-published Diabetes Care study that demonstrated a significant (p<0.001) correlation between TIR and vision-threatening retinopathy, with those spending <50% TIR experiencing a ~10% risk of the complication (see below). This was a cross-sectional study (n=3,262) examining TIR over 24 hours (via CGM) and fundus photographs, but the association remained when controlling for A1c, age, BMI, diabetes duration, sex, blood pressure, and lipid profile – in our view, quite a compelling result. Moreover, this study joins other analyses supporting the clinical relevance of TIR, including a very convincing analysis of DCCT TIR data and microvascular complications from Dr. Roy Beck, as well as epidemiological data from Australia (cited by Dr. Hirsch) pointing to a reduction in microvascular complications with the introduction of prandial insulin analogs – despite no overall changes in A1c. Dr. Bergenstal stressed that, as the evidence between TIR and vascular complications, particularly the microvascular, builds (including an article that he and Dr. Beck are working on, to be published soon), “TIR and time-in-hypoglycemia will be the new metrics by which we measure diabetes therapies.”

• As Dr. Bergenstal sees it, TIR is a much more rigorous measure of glycemic control compared to A1c – and also more useful, as it can bring patients to “A-HA moments” in which they see first-hand the effects of not only therapeutic agents, but also lifestyle changes, on their current glucose state. He referenced differing A1c goals – AACE recommends ≤6.5%, ADA <7%, and ACP a highly-debated 7%-8% – and pointed to a very recent Diabetes Care study on the legacy effect demonstrating each target in the first year following type 2 diabetes diagnosis affects microvascular complications. Referencing the AACE guideline of ≤6.5%, the study found a 20% increased risk (HR=1.204, 95% CI: 1.063-1.365, p=0.004) of microvascular complications among those with an A1c between 6.5%-7.0% (ADA guidelines) vs. ≤6.5%, a 39% greater risk (HR=1.391, 95% CI: 1.226-1.578, p<0.0001) among those with an A1c between 7.0%-8.0% (ACP guidelines). Moreover, there was a 60% greater risk (HR=1.603, 95% CI: 1.340-1.917, p<0.0001) among those with an A1c between 8.0%-9.0% in the first year after diagnosis, and a highly-concerning >doubled risk (HR=2.213, 95% CI: 1.892-2.590, p<0.0001) for those with an A1c >9.0% (see the slide below). Of course, this was an observational cohort study, so there is some risk that A1c in the year following diagnosis is more of a marker for overall health and risk, but the consistency and magnitude of the trend certainly deserves attention. However, Dr. Bergenstal went on to argue, A1c probably isn’t the best metric to control or examine in the first place. In his words, “If we can’t even agree what the best A1c is, perhaps it’s time to move on and look at the glucose itself through CGM.” Of course, work still has to be done to define time-in-range goals, but our understanding is very much that TIR (and other CGM-based measurements) can offer a more objective, actionable, and precise picture of glucose control.

• In reference to CGM’s many benefits beyond cardiovascular outcomes, Dr. Bergenstal highlighted the HypoDE study, which provided excellent evidence supporting CGM’s efficacy in patients using MDI with hypoglycemia unawareness; results were originally presented at ATTD 2018 and simultaneously published in The Lancet. In the six-month, 12-center trial, CGM (Dexcom G5) significantly reduced hypoglycemia incidence (≤54 mg/dl for at least 20 minutes) by 72%. Severe hypoglycemia was nearly halved with CGM, a major win for cost-effectiveness. These data certainly bolster the case for CGM as standard of care in people with hypoglycemia unawareness, including type 2 – the evidence for the use of CGM in this population received a “C” level grade in the 2018 ADA Standards of Care (published December 2017), and we certainly hope this will change in the next edition! Dr. Bergenstal made a point to advocate for CGM use far beyond just those with hypoglycemia, though, stating, “I don’t see any reason why every type 1 shouldn’t be offered CGM. Not everyone will take that, but everyone should be offered.”

• Much to our excitement, Dr. Bergenstal set out to motivate his audience with a recording from our very own Adam Brown’s new audiobook version of Bright Spots and Landmines. Dr. Bergenstal elected to use the following quote (check out the video here), “We have too much darkness in diabetes. Negativity, confusion, frustration, exhaustion, blame, guilt, and fear. For those of us living with diabetes and the people we love, the cost of this darkness is high. We often don’t know what to do, aren’t doing what we should be doing, feel bad about what we are doing, or are told we’re getting it wrong. We can do so much better.” Dr. Bergenstal then contextualized this quote by referencing to how far insulin has come, “I think Adam said it well. You heard the word fear. You got the sense of the burden of this disease. We can do better […] and I hope you come away with the sense that we are making some progress.” Indeed, Dr. Bergenstal focused heavily on the idea of lowering the burden that diabetes places on patients’ lives, in multiple dimensions, and the role that time-in-range has to play in that goal.

4. Dr. James Gavin: Categorical “Treatment Boxes” Do Not Adequately Address the Heterogeneity and Diversity of Diabetes

In a riveting keynote lecture on the diversity and heterogeneity of diabetes, Emory University’s Dr. James Gavin advocated for a novel classification system to “illuminate the pathway to comprehensive, better-targeted, and more effective treatment of diabetes.”

• Dr. Gavin criticized how, historically, diabetes has been classified into the narrow “treatment boxes” of type 1 (i.e. antibodies and beta cell destruction) vs. type 2 (i.e. insulin resistance). In his view, the beta cell destruction vs. insulin resistance framework is an oversimplification. He described how antibody positive patients can present as if they have type 2 diabetes, and how type 1 patients can present with insulin resistance (i.e., looking like type 2 diabetes). To parallel the oversimplified classification scheme for diabetes, Dr. Gavin argued that the standard framework for diabetes treatment is equally narrow: Insulin for type 1 diabetes and stepwise addition of oral anti-diabetic agents and eventually insulin for type 2 diabetes. He noted that although diabetes diagnoses may have extensive clinical overlap, differences in etiology, phenotype, and (likely) genotype are important further considerations to determine a more individualized treatment plan.

• Dr. Gavin pointed out that the current glucose-centric diagnostic model for diabetes often “handcuffs” clinicians into solely focusing on reducing A1c without adequately addressing its causes or engaging with opportunities to attenuate comorbidities. To this end, he highlighted a new classification method that describes five subtypes within type 2 diabetes, and a beta cell centric model (the “egregious eleven”) which allows for tailored treatment of 11 specific pathways associated with diabetes at both the physiologic and genetic levels.

  • Dr. Gavin pointed to a 2018 Lancet study which created five “clusters” within type 2 diabetes: (1) Severe autoimmune diabetes (SAID); (2) Severe insulin-deficient diabetes (SIDD); (3) Severe insulin-resistant diabetes (SIRD); (4) Mild obesity-related diabetes (MOD); and (5) mild age-related diabetes (MARD). These clusters are based on six clinical variables: (1) Glutamate decarboxylase antibodies (GADA); (2) age at diagnosis; (3) BMI; (4) A1c; and homoeostatic model assessment estimates of (5) beta cell function and (6) insulin resistance. Lending credence to the idea of distinct subtypes within type 2 diabetes is the observation that these cohorts experience very different rates of progression of diabetes-associated complications (see below). Furthermore, there are genetic differences between the cohorts. For instance, a variant in the TCF7L2 gene (previously thought to be associated with type 2 diabetes in general) was associated with SIDD, MOD, and MARD but not SIRD. Importantly, carriers of this TCF7L2 risk-variant do not respond to incretin therapy (e.g., GLP-1 agonists), so SGLT-2 inhibitors or insulin are a better option for A1c reduction.  As such, there is significant potential to leverage the heterogeneity of type 2 diabetes into more individualized, effective therapies (we’re nervous to say “precision medicine” as this has become a buzzword, though this is certainly a step closer to that coveted level of personalization). Dr. Gavin pointed out that not only would this confer better patient outcomes, but would also help avoid unnecessary patient/provider frustration over a less-than-ideal response to an initial prescription (e.g. a GLP-1 agonist for a TCF7L2 risk-variant-carrying patient). This frustration is all too common with the current treat-to-fail paradigm of diabetes prescriptions.

• Dr. Gavin argued that diabetes is even more nuanced than the famous “ominous octet” would suggest, describing an alternative “egregious eleven” which includes the influence of the microbiome, immune system, and increased glucose absorption in the stomach and small intestine in addition to the traditional players – impaired insulin secretion in the beta cells, increased glucagon secretion in the alpha cells, increased hepatic glucose production, neurotransmitter dysfunction, decreased muscular glucose uptake, increased glucose reabsorption in the kidneys, increased lipolysis in adipose tissue, and a decreased incretin effect in the gut. He argued that factors within the egregious eleven are selectively treatable (or likely to be treatable in the future), making possible a targeted and individually-tailored diabetes treatment plan, depending on a patient’s particular pathophysiology. Taking this one step further, Dr. Gavin emphasized that well-designed, early combination regimens have the potential to address most defects concomitantly – a major win for patients and vote of confidence in up-and-coming dual- and tri-agonists, such as GLP-1/GIP and GLP-1/glucagon agonists, that target multiple aspects of the egregious eleven.

• To conclude, Dr. Gavin touched on the value of real-world evidence to complement and expand upon existing RCTs. He argued that management of a disease as complex and heterogeneous as diabetes depends on many factors that we don’t (or can’t) measure in RCTs. RWE therefore represents perhaps the only way we can get insight into critical issues such as patient preferences, likelihood of adherence, impact of cost, and complexity of certain treatment regimens.

5. Dr. Davies: Patient Satisfaction with GLP-1 Agonists Higher than DPP-4 Inhibitors? Improving Treatment Adherence through Improved Efficacy and Patient Experience

In an illuminating talk on patient responses to GLP-1 agonists during a Novo Nordisk-sponsored session, Prof. Melanie Davies presented data to show that despite the GI side-effects common with GLP-1s, patients are generally very satisfied with the therapy. That said, she also reviewed within-class differences in both efficacy and patient satisfaction. As Prof. Davies aptly put it, “Treatment satisfaction is the whole package: It’s efficacy and tolerability, but it’s also the device and experience […] We can’t assume a patient is less satisfied with an injection than an oral, and we can’t assume that a daily medication is worse than a weekly one.” Prof. Davies presented data from a paper she co-authored with Dr. Jane Speight. Utilizing the Diabetes Treatment Satisfaction Questionnaire (DTSQ), which measures patient satisfaction with treatment efficacy, convenience, and flexibility (among other factors), Drs. Davies and Speight found that patient satisfaction with high-dose Victoza was actually significantly (p<0.05) greater than with Januvia; the difference was numerically but not significantly greater with low-dose Victoza. Importantly, both GLP-1 Victoza and DPP-4 Januvia are taken once-a-day (the former as an injection, the latter as a pill), so there’s no difference in frequency of dosing. Patients who switched from Januvia to either high-dose or low-dose Victoza experienced a significant increase in treatment satisfaction. In some ways, we were surprised to see these results: ~20%-25% of patients experience GI side-effects on a GLP-1, while DPP-4 inhibitors are known to be some of the most tolerable agents in our diabetes treatment toolkit. GLP-1s (thus far) are injectable, while DPP-4s are oral. On the other hand, GLP-1s are more efficacious. It’s important to see that this greater efficacy corresponds to a better experience for the patient.

• Notably, differences were also detected between GLP-1s. In particular, DTSQ scores were significantly (p<0.0001) higher with high-dose Victoza than with Bydureon (this was before the approval and launch of Bydureon BCise; see below for full results). On this point, we’d be curious for more details on what drove this sizable difference. For example, the Bydureon pen uses a 23 gauge, 5/16’ needle, compared to the 32 gauge, 4 mm needle used for the Victoza pen – might this drive greater patient satisfaction? Overall, we think these findings indicate that patient satisfaction can be complex and doesn’t necessarily follow the rules of convenience or tolerability that one might expect; we also think this is an important reminder to ask patients exactly what they want and are looking for in diabetes therapy. It’s not just about collecting one overarching “patient perspective,” but about appreciating each individual’s patient perspective. For many, a trade-off in tolerability, dose administration, or frequency of dosing is acceptable if it means improved efficacy. Prof. Davies did note that weight loss is not included in the DTSQ, so it may underestimate GLP-1 agonist satisfaction. There is also relatively little data on GLP-1 satisfaction vs. other therapy classes. Additionally, we would be intrigued to see more current results, given that this analysis was performed in 2012: Where would Trulicity and Ozempic fall? What will this mean for oral GLP-1 agonists?

• Prof. Davies postulated that adherence may start to improve as more patients start taking more efficacious therapies. Highlighting Ozempic in particular, Prof. Davies was positive about the jump forward in glucose- and weight-lowering efficacy, even compared to other GLP-1s. She detailed that, across the phase 3 SUSTAIN 1-5 trials, 58%-79% of participants on either Ozempic dose achieved an A1c <7% (significantly better at p<0.0001 than Januvia, Bydureon, and Lantus). Further, 37%-66% achieved weight loss ≥5%, and 25%-56% achieved the composite of A1c reduction ≥1% and weight loss ≥5%. Moreover, while “the higher you start, the farther you fall” on A1c and weight, the difference between Ozempic and its comparators was consistent across baseline A1c and BMI groups. Additionally, a 92-trial meta-analysis found that the efficacy of all GLP-1 agonists is fairly consistent across different baseline factors; there was some suggestion that South Asian patients benefit less (with a smaller sample size representing this population), as well as that younger patients may benefit more. However, BMI and duration of diabetes did not impact degree of benefit. This is all critical because, as Prof. Davies outlined, adherence remains a major challenge: In chronic disease overall, non-adherence averages at 50% after one year, 3/10 of patients will stop taking a prescription even before the first fill runs out, and this costs Europe ~$145 billion per year. Certainly, issues of affordability, convenience, and psychosocial dynamics also play a huge role in disrupting adherence to therapy, and more needs to be done to make taking medications less burdensome. We do think drug efficacy and being able to see meaningful benefit is important for patient adherence – and HCPs should strive to show patients data on how their meds are helping. All things considered, though, it’s one piece of a complex puzzle, and we’d love to see more done to improve access to the highly-potent therapies that are on the market.

6. BRIGHT Study Expansion: Granularity on Toujeo’s Titration-Period Hypoglycemia Benefit; Dr. Cheng Discounts Titration Protocol, Concomitant Medications as Cause; Significantly Lower FPG with Tresiba Sustained from Baseline

Dr. Alice Cheng provided granularity on the Sanofi-sponsored BRIGHT study (n=929), the first head-to-head comparison of next-gen basal insulin analogs glargine U300 (Sanofi’s Toujeo) and degludec (Novo Nordisk’s Tresiba). Results were recently published in Diabetes Care. Dr. Cheng built on the topline readout from ADA, which found a statistically significant decrease in incidence of hypoglycemia <70 mg/dl (OR=0.74, 95% CI: 0.57-0.97, p=0.03) and hypoglycemia <54 mg/dl (OR=0.63, 95% CI: 0.40-0.99, p=0.044) with Toujeo vs. Tresiba during the first 12 weeks of the study – the “titration period.” However, there was no significant difference in the latter 12 weeks of the study – the “maintenance period.” The overt implication from these data was that Toujeo conferred a 26% risk reduction for hypoglycemia when compared to Tresiba, although the marginal p-values (0.03 and 0.044) and the fact that this benefit disappeared during BRIGHT’s maintenance phase left the field less than convinced that Toujeo is truly superior to Tresiba on hypoglycemia. That said, we were intrigued by the data Dr. Cheng shared at EASD: She highlighted a significantly higher fasting plasma glucose with Toujeo compared to Tresiba over the study’s 24 weeks (LS-mean difference of 0.43 mmol/L, or ~8 mg/dl; 95% CI: 0.15-0.70). However, the Toujeo group did start at a higher mean FPG than the Tresiba group, and it appears the difference was maintained throughout the trial more than anything. There was no significant difference in fasting SMPG nor A1c (see below). However, A1c equipoise at ~7.0% was achieved by 24 weeks, which might indicate that slightly less glucose variability was seen with Tresiba vs. Toujeo (we expect more glycemic data on Wednesday). Dr. Cheng also shared hypoglycemia incidence by time of day – an “eyeball statistic” (i.e., without rigorous statistical analyses – we’re guessing these would be underpowered) – suggesting that the hypoglycemia benefit of Toujeo during the titration period came between 6 AM and 2 PM. For reference, Toujeo and Tresiba were administered between 6 PM and 8 PM. As shown below, Toujeo carried a slightly higher incidence of hypoglycemia between 12 AM and 4 AM, but Tresiba was associated with more hypoglycemia in the late morning/early afternoon. Full glycemic data will be presented in an oral presentation this coming Wednesday, but see more below on important BRIGHT design aspects – and why they do not account for the hypoglycemia difference. To be sure, we haven’t heard much commentary on why this titration period result occurred, and our sense is that most thought leaders consider both these next-gen basals to be highly-preferable options over a first-generation analog or human insulin, or that they see a slight edge to Tresiba over Toujeo (after all, Novo Nordisk’s product now has hypoglycemia data showing a benefit vs. Lantus on its US and EU labels). We note as well that Novo Nordisk is conducting its own head-to-head trial of Tresiba vs. Toujeo, expected to complete in March 2019 per ClinicalTrials.gov.

• Starting doses for the two insulins differed due to labeling, though titration intensification followed the same schedule. As such, Dr. Cheng believes it unlikely that titration protocol contributed to the difference in hypoglycemia during titration. On the other hand, it seems possible to us that that same titration schedule may be more ideal for one insulin than the other; we know that Tresiba’s half-life is longer than Toujeo’s and wonder if this might be relevant. The BRIGHT study was conducted in North America and Europe, where labels indicate a starting dose of 0.2 U/kg for Toujeo and 10 U for Tresiba. Both were titrated weekly to a target fasting SMPG of 80-100 mg/dl without hypoglycemia (see below), and both therapies conferred a similar (~2 kg, or ~4.4 lbs) increase in body weight.

  • Notably, BRIGHT participants were required to have no prior insulin use and were allowed to continue any and all non-insulin anti-hyperglycemic agents during the trial. As such, Dr. Cheng dispelled the notion that the hypoglycemia difference between Toujeo and Tresiba could have been due to greater use of SU/glinide use in the Tresiba group. There was actually no statistically significant difference in hypoglycemia incidence between those taking an SU/glinide and those who were not, in either of the study groups, at either definition of hypoglycemia (p=0.578 for <70 mg/dL and p=0.733 for <54 mg/dL). There was also no difference in A1c reduction regardless of SU/glinide use.

• “I don’t think the big takeaway from BRIGHT is that it demonstrated non-inferiority in terms of A1c reduction between the two next-gen insulins. The big takeaway is that both insulins were able to lower A1c from an average above 8.5% to 7.0% in just 24 weeks.” We couldn’t agree more with this praise from Dr. Cheng! As we see it, both products offer significant improvements over first-gen insulins (i.e. Sanofi’s Lantus and Novo Nordisk’s Levemir), in terms of glucose control and hypoglycemia. Moreover, BRIGHT offers strong evidence supporting the efficacy of basal insulin when truly titrated to target. That being said, Dr. Cheng did also use this evidence to suggest that the hypoglycemia difference between Toujeo and Tresiba was not due to a glycemic difference. However, we also find it notable that fasting plasma glucose trended significantly lower for Tresiba than Toujeo (see above), which Dr. Cheng did not address in depth.

  • In keeping with Dr. Bergenstal’s sentiments from the opening lecture of Sanofi’s symposium (see above), Dr. Cheng emphasized that the average starting A1c’s of both groups – 8.6% for the Tresiba group and 8.7% for the Toujeo group – were much too high. As she sees it, there should not be an A1c threshold at which insulin therapy is initiated in patients with type 2 diabetes. Rather, this decision should be governed by whether the patient can achieve his/her personal glucose targets without insulin; if not, insulin should be initiated regardless of A1c.

• Dr. Cheng noted that early hypoglycemic events (i.e. during titration) are associated with increased rates of treatment discontinuation, as well as long-term risk of hypoglycemia – of course, both Tresiba and Toujeo cause less hypoglycemia than first-gen basal insulins. On the former, Dr. Cheng referenced this retrospective cohort study, which found that 68% of patients who experienced hypoglycemia in the first six months following basal insulin initiation discontinued, compared to a 54% discontinuation rate in those who did not experience hypoglycemia (p<0.0001). On the latter, Dr. Cheng pointed to this retrospective longitudinal analysis of EMRs which demonstrated that hypoglycemia during the initial three month period of insulin therapy was associated with longer-term risk of these events over the ensuing 3-24 months (OR=5.71, 95% CI: 4.67-6.99) – an exceedingly significant association, though we imagine it’s also very likely that this relationship simply predicts/reflects baseline risk for hypoglycemia more than anything else. In the end, we again think the leap forward that the whole next-gen basal insulin class represents should be the takeaway.

7. DELIVER D+ Real-World Studies Identify Significant Hypoglycemia Reduction in Patients Switching to Toujeo from Other Basal Insulin; No Significant Reduction with Tresiba – But From a Lower Baseline

UT Southwestern’s Dr. Luigi Meneghini provided updates on the DELIVER trial program, a series of real-world studies examining the effects of switching to Toujeo (Sanofi’s insulin glargine U300) from another basal insulin. In particular, Dr. Meneghini highlighted results from the new DELIVER D+ study, comparing glycemic outcomes in people with type 2 diabetes who switched from a first-gen basal insulin to either Toujeo or Tresiba. First presented in poster form at ADA 2018, this retrospective cohort study of EMR data found a significant reduction in overall hypoglycemia upon switching to Toujeo (from 15.6% to 12.7%, p=0.006), but only a non-significant numerical reduction in hypoglycemia upon switching to Tresiba (from 14.3% to 12.7%, p=0.12). While this is roughly consistent with the BRIGHT study data, it is also possible that Toujeo’s apparent superiority is an artifact of higher hypoglycemia rates in this cohort prior to insulin switching – that is, both insulins give the same exact final incidence of hypoglycemia. Is it possible that the population being switched to Toujeo, for whatever reason, was higher-risk at baseline? In our view, it’s critical not to miss the forest for the trees here; it’s clear that both next-gen basal insulins offer meaningful reductions in hypoglycemia. Dr. Meneghini further unveiled that topline results from the DELIVER Naïve D study point to similar A1c reductions and comparable rates of hypoglycemia with Toujeo and Tresiba in people with type 2 diabetes who are new to basal insulin therapy. He didn’t specify when we can expect the full readout; to our knowledge, exact numbers are not yet available. As a reminder, the DELIVER program also includes the DELIVER 2 and DELIVER 3 studies. DELIVER 2 showed that switching to Toujeo from another basal insulin conferred an estimated $1,439 of healthcare savings per patient per year, driven by lower hypoglycemia-related healthcare utilization – namely, hospitalizations, ER visits, and outpatient care. DELIVER 3 demonstrated that switching to Toujeo vs. other basal insulins was associated with significantly less hypoglycemia and similar glycemic control among older patients (≥65 years) with type 2 diabetes.

• In an ensuing panel discussion, an audience member made an astute observation: In real-world studies of next-gen insulins, how can we disentangle the effects of the next-gen agent from the higher quality of care that patients likely receive from HCPs who are savvy enough to prescribe these agents? Indeed, the early adopters of new therapies tend to be expert physicians who are delivering leading-edge care, and we imagine there could also be confounders in the patients they see (i.e. do experts more often treat patients with more resources and access to better care?). Of course, the irony here is that next-gen drugs tend to be safer and could therefore be used more broadly and easily by those who don’t specialize in treating diabetes, but in the real world we see precisely the opposite trend.

8. Heterogeneity Among GLP-1s? Dr. Vanita Aroda Discusses Distinct Molecular and Clinical Characteristics, Possible Impact on Cardioprotection

In giving a rundown of the comparative effectiveness of long-acting GLP-1s, Dr. Aroda detailed the fundamental differences between different GLP-1 molecules (below). This discussion furthered our interest in HARMONY Outcomes, the CVOT for GSK’s discontinued GLP-1 agonist Tanzeum (once-weekly albiglutide), as well as REWIND, the CVOT for Lilly’s Trulicity (once-weekly dulaglutide). Results for HARMONY are set to be released and presented at 12 pm on Tuesday, while topline results for REWIND should be announced by the end of 2018. Will half-life/duration of action shake out to be a key factor in whether a GLP-1 agonist can demonstrate cardioprotection? Of course, the molecule with the longest duration of action – Bydureon (exenatide QW) – narrowly missed out on significance in the EXSCEL CVOT (HR=0.91; 95% CI: 0.83-1.00). However, this result has been widely attributed to the trial’s large secondary prevention cohort (27%) and pragmatic design, which stands in contrast to 19% and 17% primary prevention cohorts in LEADER for Victoza and SUSTAIN 6 for Ozempic – see a side-by-side comparison of GLP-1 agonist CVOTs here. HARMONY and REWIND will shed important light on how baseline CVD status of enrolled patients impacts ability to demonstrate benefit: While the former enrolled 100% participants with baseline CVD (secondary prevention), REWIND has a very large 59% primary prevention cohort – and a longer duration of follow-up to compensate to the lower event rate. To date, the role of GLP-1 agonists for primary prevention remains sharply debated, primarily due to the lack of evidence, and we’re very much looking forward to REWIND results.

• As Dr. Aroda explained, these different pharmacokinetic profiles of GLP-1s have a big impact on their clinical utility. For example, Byetta and Adlyxin are very short acting and have strong effects on postprandial glucose, while the longer-acting but still once-daily Victoza has a stronger overall glucose-lowering effect and carries greater weight loss potential. Moving to once-weekly therapies, Bydureon offers similar efficacy with greater tolerability, Trulicity an improvement in glucose-lowering efficacy with once-weekly dosing, and finally Ozempic with even greater glucose-lowering and weight loss efficacy, as well as CV risk reduction. In Dr. Aroda’s assessment, not all therapies, nor all GLP-1 agonists, are created equally; in many ways, this allows for more flexibility in matching therapies to patient profiles and pathophysiology. But the biggest question we have now is: Is cardioprotection a class effect of GLP-1 agonists, or does cardioprotection vary based on some combination of these inherent molecular differences? With two more CVOTs in the class reading out before year-end, we expect this to be a big topic of discussion for the next few months.

  • Whether a GLP-1 agonist is based on human-GLP-1 vs. exendin has also been widely discussed as a potential mediator of CV effects. Dr. Jorge Plutzky touched on this issue in his subsequent discussion of cardioprotective mechanisms for the class, detailing that the molecules for Victoza, Ozempic, Trulicity, and Tanzeum are all human-based, while Bydureon, Byetta, and Adlyxin are all exendin-based. That said, even the human-based molecules feature significant differences: For example, semaglutide (Ozempic) is 4.11 kDa, while dulaglutide (Trulicity) is 63 kDa. Does a molecule’s size impact its ability to reach certain GLP-1 receptors throughout the body?

Diabetes Technology Highlights

1. FreeStyle Libre 2 Accuracy in Adult (n=95) and Pediatric (n=74): 90% of readings within ± 20%/20 mg/dl of YSI; MARD of 9.5%

Sansum Diabetes Research Institute’s Dr. Kristin Castorino shared results from the FreeStyle Libre 2 adult (n=95, type 1 and 2) and pediatric (n=74, type 1, 4-17 years-old) accuracy studies. The studies were conducted across four diabetes clinical centers in the US with the primary endpoint of percentage of readings within ±20% for glucose levels >80 mg/dl and within ±20 mg/dl for YSI glucose levels <80 mg/dl. Secondary endpoints included MARD, the percentage of results in zones A and B of the Consensus Error Grid, sub-group accuracy analysis, lag time, and adverse events. Adult participants attended four seven-hour, in-clinic YSI sessions on days 1, 6, 11, and 14 (pediatric subjects attended four-hour sessions and those <35 kgs only attended two sessions), in which participants’ plasma glucose levels were tested every 15 minutes. During home use periods, adult participants were instructed to perform fingersticks at least eight times daily (pediatrics were instructed to fingerstick at least four times/day), followed by a scan. See below for adult and pediatric results.

• The adult accuracy study demonstrated 90.3% of sensor results were within ± 20%/20 mg/dl of the YSI reference. By glucose bin, 90.6% of readings were within ± 20 mg/dl for glucose <80 mg/dl, and 90.3% of readings were within 20% of glucose >80 mg/dl. It’s unclear if FreeStyle Libre 2 meets the FDA’s iCGM special controls benchmark of >85% of points within ±15 mg/dl for <70 mg/dl; the 15/15 accuracy was not shared today. 89% of sensor results were in Zone A of the Consensus Error Grid (100% were in Zones A and B), translating to a MARD of 9.5% vs. YSI. Sub-group analyses revealed that consensus error grid results did not differ meaningfully by diabetes type, BMI, or age.

  • For directional comparison, the % 20/20 look almost identical to FreeStyle Libre 14-day in the US. According to FDA’s SSED for Libre 14-Day, it has 89.8% of points within 20/20 and an MARD of 10.1% (FDA SSED) or 9.4% (Abbott press release) – almost identical to FreeStyle Libre 2, and perhaps suggesting the same algorithms/chemistry in Libre 14-Day in the US are now in the EU version. For comparison, Dexcom’s G6 has a slightly higher 94% of points within ± 20%/20 mg/dl of YSI and a slightly lower overall MARD of 9.0%.

  • Our interpretation is FreeStyle Libre 2 has probably improved the number of big outliers – helping to improve the MARD into the 9% range – but it does not seem to have drastically changed the % 20/20 or % 15/15 accuracy. FDA seems focused on the latter, though MARD is obviously a helpful measurement to assess whether accuracy is getting better.

• Dr. Castorino broke down FreeStyle Libre 2 accuracy in adults by day of wear, demonstrating solid consistency over the 14-day period. Day one accuracy showed an MARD of 10.9%, which improved to 8.8% by day six and remained fairly stable at 9.3% at day 11 and 9.0% at 14 days. Dr. Castorino also shared accuracy by glucose level but underscored that the study was not designed to evaluate MARD in hypoglycemia and hyperglycemia – by this, we assume she means the study is not powered to draw any firm conclusions regarding accuracy in these ranges. The reported MAD was 9.9 mg/dl for readings 51-80 mg/dl (n=412) and the MARD was 8.0% for readings 181-300 mg/dl. For comparison, Dexcom’s G6 has a similar MAD of 9.4 mg/dl for <70 mg/dl and a slightly higher MARD of 9.2% for 181-250 mg/dl.

• The pediatric accuracy study found 90.1% of sensor readings to be within ± 20%/20 mg/dl of the YSI reference. Specifically, 87% of readings were within ± 20 mg/dl for glucose <80 mg/dl, and 90.3% of reading were within ± 20% for glucose >80 mg/dl. 90.3% of results were in Zone A of the Consensus Error Grid (100% in Zones A and B), translating to a 9.4% MARD vs. YSI. Day one accuracy was slightly higher at 11.3%; however, by day six MARD dropped to 8.2% and remained stable at 9.5% at day 11 and 9.0% at day 14.

• Dr. Castorino explained that FreeStyle Libre’s lag time is just 5.2 minutes. Interestingly, at ATTD 2015, Dr. Timothy Bailey shared that average lag time found in the FreeStyle Libre EU pivotal trial was 4.5 minutes. Clinical these are comparable, meaning Abbott has maintained the lag time, but not drastically improved it; it seems hard to get far beyond this point, given subcutaneous glucose dynamics. For comparison, lag time for the G6 is 4.0 minutes, per Dexcom’s corporate symposium today.

2. FreeStyle Libre 2 Sensor Transmits to Reader Every Minute (scan still required for glucose value); Signal Loss if 20 Mins Without Communication

Dr. Monika Kellerer (Marienhospital Stuttgart, Germany) discussed the features of FreeStyle Libre 2, confirmed how often the Bluetooth communicates, and the optional hypoglycemia/hyperglycemia threshold alarms – read our deep dive from earlier today. She shared that the FreeStyle Libre 2 sensor actually transmits some data to the reader every minute “that may result in a potential alarm.” We assume the sensor pings the reader only by saying if a high/low alarms has been crossed; users must still scan over the sensor to retrieve the real-time glucose, trend arrow, and eight-hour history via NFC. We’re impressed the sensor and reader communicate once every minute, which means FreeStyle Libre 2 is closer to a traditional Bluetooth-enabled CGM than we appreciated; we had initially believed FreeStyle Libre 2 might be saving on power consumption (and therefore necessary battery size) by only turning Bluetooth on opportunistically when the sensor detected a low/high alarm. Clearly, the sensor is communicating continuously with the reader to some extent – just not sending the actual glucose value in gen 2 –  making it all the more impressive that the form factor remained the same from the first generation. Screenshots of the alarms confirmed that the reader will only display “Low Glucose Alarm” and not the actual number or trend arrow – will people find this annoying? Later in the symposium, we learned from Dr. Ides Colin (Mons-Hainaut Hospital, Mons, Belgium) that the optional signal loss alarm is triggered when the sensor has not communicated with the reader for 20 minutes. Dr. Colin emphasized that if available, alarms should remain optional and construed in such a way as to avoid alarm fatigue. While we certainly appreciate that some patients experience alarms as frustrating, they certainly enhance the efficacy and safety of CGM and we’re glad they will now be available in FreeStyle Libre 2. Of course, alarms could also become much smarter and more intelligent in all systems – more customizable, more predictive, higher true positive rates, and lower false positive rates.

3. Dexcom G6 Launches in Germany (also now in UK, Austria, Switzerland); Novo Nordisk a new smart pen partner; G5 vs. G6 real-world impact on hypo

Dexcom’s corporate symposium celebrated the launch of G6 today in Germany, complementing current availability in the US, UK, Austria, and Switzerland. The OUS launches are on par with 2Q18 expectations for a 2H18 launch following CE Mark in June. Dexcom’s Mr. Jake Leach shared that the Clarity mobile app will also launch OUS for the first time in the “coming weeks,” an excellent win for international users – especially to bring the super valuable once-weekly time-in-range/pattern notifications that we’ve previously praised. G6’s OUS launch also marks the first availability of the touchscreen receiver in Europe, which Mr. Leach emphasized is remotely upgradeable for future products. (That said, the receiver is optional in Europe, and Dexcom has previously said not too many are buying it.) On the partnership front, Mr. Leach noted this morning’s big announcement: Novo Nordisk is now a Dexcom smart pen partner, along with Lilly. (Read our detailed coverage here.) Mr. Leach said the planned Dexcom/Novo Nordisk solution will combine CGM with connected insulin pen data and “guidance information” to “give advice” that makes diabetes easier. Dexcom’s TypeZero acquisition also gives it decision support algorithms for MDI, and we look forward to more concrete timing on when smart pen data will flow into Dexcom’s ecosystem and when real-time decision support for injectors will be layered on top. Mr. Leach also highlighted Tandem’s Basal-IQ as the first pump to be integrated with G6, and a separate slide noted the Control-IQ system is currently in its pivotal study following exciting pre-pivotal data at ski camp (launch in summer 2019; see Tandem’s Analyst Meeting report). See other highlights below on new real-world G6 data, new data from the G6 label we don’t recall seeing previously, our question on Verily gen one, G5 vs. Libre accuracy data, and commentary on German CGM penetration.

• German endocrinologist Dr. Bernhard Gehr shared some fascinating new real-world G6 hypoglycemia data from the US launch, spanning May 1-July 31 and ~25,000 patient days. Those switching from G5 to G6 have seen: (i) an 18% reduction in time <70 mg/dl, from 3.4% to 2.8% (-9 mins/day); and (ii) a 36% reduction in time <55 mg/dl, from 1.1% to 0.7% (-6 minutes per day). Though the delta is small, this is notable, since it means G6 is moving the needle at the extremely low end – even in people previously using G5. In the data comparing the urgent low soon feature turned OFF vs. ON, those with it enabled have seen a: (i) 36% reduction in time <70 (4.4% vs. 2.8%; -23 minutes/day) and (ii) a 36% reduction in time <55 mg/dl (1.1% vs. 0.7%; -6 minutes/day). Seeing these hypoglycemia metrics improve with G6 is an excellent early real-world indication that the new system is performing slightly better than G5 in the wild – nice!

  • We note these are likely very early adopters and they are clearly doing very well already with G5 and G6– in fact, these hypoglycemia metrics are typical of automated insulin delivery trials, and perhaps many of these users are even on Loop/OpenAPS already. For ~25,000 patient days of data taken over a 90-day stretch, we estimate this group is likely <1,000 users – specifically, it could be as low as n=278 if G6 was worn for all 90 days by each person, and it would be n=833 if G6 was only worn for an average of 30 days of the period. We look forward to seeing even larger data sets to come!

• Most of IDT’s Dr. Guido Freckmann’s talk focused on head-to-head accuracy comparisons between Dexcom’s G5 and FreeStyle Libre. The table below summarizes the studies mentioned to date, with a slight edge for G5 in all of the studies; some are investigator initiated and some are Dexcom sponsored. Dr. Freckmann and Dexcom’s Ms. Keri Leone emphasized that CGM accuracy is “not just about MARD” anymore, as the FDA places focuses on %15/15, %20/20, and %40/40 (especially with the iCGM standards).

• In Q&A, we asked about the 14-day wear trial for G6 and if Verily gen one might move down to 10 days. Mr. Leach said that Dexcom is “assessing 14-day wear to ensure it meets the special controls and the longevity we want.” He confirmed our speculation that the Verily product could theoretically be 10 days if needed. Timing on Verily gen one has gotten less and less specific over time. The August call said it remains in validation and verification (no change from Q1) and no launch timing was shared. The 14-day wear trial is clearly the big decision point right now. The slide deck did not actually show the Verily gen one product, unlike ADA.

  • An important question is whether G6 can meet the iCGM accuracy standards out to 14 days, and if not, how Dexcom will proceed: (i) move back to 10 days for Verily gen one, like the current G6; (ii) make some changes to the sensor chemistry/algorithm to get to 14 days and hit the iCGM benchmarks; (iii) push Verily gen one through the traditional PMA route instead of the iCGM 510(k) pathway; or (iv) something else.

• Mr. Leach noted two important future segments for Dexcom: hospital and gestational diabetes. We cannot wait to hear more specifics, as both are very high need areas. Adam has a diaTribe column coming out soon on his diabetes experience in the hospital wearing CGM last month – the nurses could not believe how cool CGM was and were dying to have it.

• As expected, the symposium reviewed the G6 pivotal accuracy data we saw at ADA and emphasized the stringent iCGM accuracy standards. We also picked up a couple pieces of G6 label data: 84% of G6 sensors lasted the full 10 days of wear, including a very impressive 94% in adults and much lower 77% in pediatrics. Mr. Leach noted that G6 has a self-diagnostic algorithm that will shut the sensor off early if it detects poor performance. In adults, 5% of the sensors had early shutoff via the algorithm, comprising the vast majority of the total 6% of sensors that didn’t make it to ten days. Early shutoffs occurred more often in peds: 13% of sensors had algorithm-driven early shutoff, slightly more than half of the total 23% of sensors that didn’t go to ten days. (Could this have played a role in the higher accuracy seen with G6 in peds?) Mr. Leach also noted that G6 also has a mean lag time of just 4.0 minutes, and an impressive 23% of sensors had a lag time less than 1 minute.

• Dr. Bernhard Gehr estimated Germany has ~150,000 FreeStyle Libre users and~40,000 traditional CGM users. He cited “oral information from manufacturers and other sources,” noting he spoke to several companies to get this estimate; we’re not sure how accurate they are. If the data is true, it implies nearly 20% of FreeStyle Libre’s 800,000+ global users are in Germany. Given ~300,000 type 1s in Germany, Dr. Gehr estimated CGM penetration stands at ~63%, which seems far too high to us (even with Libre and Dexcom’s strong uptake). It’s possible he didn’t account for type 2s on CGM, as intensive insulin users with type 2 are covered for CGM in Germany.

4. Harvard’s Dr. Doyle with IDCL Update (Senseonics/Roche/TypeZero Pivotal to Start in October, 150 Enrolled in Tandem Control-IQ Study; What’s Next in AID?

Harvard’s Dr. Frank Doyle provided a status update for the NIH-funded IDCL study, gave a forward-looking assessment of closed loop technology, and dug into his group’s AP trial database for historical insights. The IDCL is composed of four protocols – see them in detail here. With Protocol 1 in the books, Protocol 2 (the EU pivotal trial for the Roche/Eversense/TypeZero) system is now expected to begin in October, and protocol 3 (US pivotal of Tandem’s Control-IQ system) has now enrolled 150 patients so far; according to ClinicalTrials.gov, this study is expected to wrap in April 2019 (see our report on Tandem’s recent Analyst Meeting for the company’s iPump and TypeZero regulatory strategy). Dr. Doyle said there has been a pilot for Protocol 4 (“testing the incremental effect of a next-gen adaptive control algorithm that builds on the Zone MPC paradigm developed at Harvard”), but he didn’t provide further timing – at DTM, we heard that it was likely to start in 4Q18. The Zone MPC algorithm builds on a series of impressive publications in recent years by Dr. Doyle, long-time collaborator Dr. Eyal Dassau – including Dassau et al. 2015, Dassau et al. 2017, and Huyett et al. 2017 – which all demonstrated time in 70-180 mg/dl of 71%-79% and time <70 mg/dl of 1%-2.5%.

• Dr. Doyle’s view of “where we are going” in automated insulin delivery entails advancements on many fronts: (i) Going beyond the subcutaneous insulin delivery model (his group has done clinical work with both MannKind’s Afrezza and Roche’s intraperitoneal Diaport); (ii) Internet-of-Things-enabled systems that tap into connected activity trackers, phone GPS, calendar, diet tracking, etc.; (iii) Portable algorithms contained in a chip that resides on the pump, sensor, or other wearable (e.g., Insulet’s Omnipod, a smartwatch); and (iv) horizontally integrated systems of interoperable components. He displayed an up-to-date chart plotting AID clinical trials since 2015 on axes of “% time <70 mg/dl” and “% time 70-180 mg/dl.” The goal is to get close to the top left corner of the graph, and Dr. Doyle believes the artificial white orb (90+% time-in-range, and <0.5% hypoglycemia) is as close as we can get with subcutaneous insulin delivery. In Adam’s experience, 80%+time-in-range is possible with DIY closed loop and a low-carb diet, and 90%+ is possible with closed loop, very low-carb, and intermittent fasting.

• The Doyle group’s AP database (https://thedoylegroup.org/apdatabase/) is a goldmine for anyone looking to look for patterns in clinical studies performed to date. He demonstrated its potency by querying the database about which types of controllers have been studied in the past five years (51 have been MPC, 18 PID, 4 Fuzzy Logic, and 10 other) and the degree of user mealtime input required in studies since 2005 (unsurprisingly, most have required full bolusing on the patient’s part).   

5. ~750 Senseonics Users in Germany; EU Registry Tracking Long-Term Safety; Smart Pen Pendiq Data Viewable in SmartPix Alongside Eversense Data

Medicover Berlin’s Dr. Dorothee Deiss shared that there are now ~750 patients on Senseonics’ Eversense XL at 200 German centers and that an ongoing observational EU registry of all Eversense users has been established to track long-term safety. In August, we estimated that the global Eversense user base was between 3,000-4,000. Echoing previous commentary we’ve heard, Dr. Deiss said that the insertion and removal procedures are brief and easy to integrate into her daily routine. In Q&A, LDC’s Dr. Kamlesh Khunti conjured subcutaneous contraceptive implants, wondering if nurses could ultimately insert Eversense – though the answer is “no” today, Senseonics is working to receive authorization for nurse practitioners and other mid-level professionals to perform the insertions/removals. Further advantages from Dr. Deiss’ perspective: “one of the best features is the on-body vibe alerts” from the transmitter (if phone is out of range); daily, gentle-on-skin adhesive (she hasn’t seen a skin rash in her clinic yet); great for people who are manually handicapped or blind (presumably because there’s no need to self-insert needle sensors, though the daily adhesive change and charging may still be an obstacle). She also told of a number of her patient’s Eversense successes, including a man who used to get terrible rashes with other CGMs but no longer does, a pregnant woman (off-label use), a professional rugby player (who used to lose his needle CGMs on day one or two of wear), and 2008 Olympic gold medalist Matthias Steiner.

• Dr. Deiss flashed a slide showing Eversense CGM data alongside insulin dose data (from Pendiq), in Roche’s Accu-Chek SmartPix data management platform. Around the time of last year’s EASD, Roche announced that it would be distributing Pendiq’s pen, and Dr. Deiss said that her clinic’s patients have had access to it since the spring. She noted that the device is a bit bulky, but it least it captures data. She was very excited to hear this morning’s news that Novo Nordisk will be launching reusable pens in early 2018 because so many of her patients are now on CGM but not pumps. The graph below shows a CGM’s AGP with strikes for insulin doses, and we think it looks a bit confusing to interpret – a reminder that this area of CGM+injection doses will need some great data visualization options and analytics to make it digestible.

6. Hypo Leaders on Technology (Mini-Dose Glucagon, CGM, Pumps), Diabetes Care in the Elderly, the Need to De-Stigmatize Hypoglycemia

The message from a star-studded Lilly symposium on day #1 were crystal clear: Hypoglycemia, specifically severe hypoglycemia, remains a tremendous problem in diabetes today, our strategies for managing it are not yet good enough (though speakers pointed out that technology like CGM is helping), and despite these facts, we stigmatize and marginalize conversation about it. Following a discussion that also included hope for the use of technology and novel agents in hypoglycemia management, addressing hypoglycemia in the elderly, and the Emergency Medical Service (EMS) take on severe hypoglycemia, VU Medical Center’s Prof. Frank Snoek summed up sentiments bubbling up under each preceding talk: “We need to start normalizing hypoglycemia and the emotions around it. We need to show we understand it’s a difficult balancing between hyperglycemia and hypoglycemia, and if it occurs, it can be really frightening, it can induce avoiding behaviors, and we need to get the shame and the blame out of the way. We should monitor hypoglycemia as a routine part of consultation – it should be there all of the time.”

• Interspersed discussion around the use of technology to mitigate hypoglycemia touched on mini-dose glucagon, CGM, and pump therapy. Kinderkrankenhaus auf der Bult’s Prof. Thomas Danne posited that we are nearing a paradigm shift in hypoglycemia treatment: “I really think five years from now, the approach to hypoglycemia and the use of glucagon will be very different – it won’t only be used in emergency situations, but it could become part of the treatment.” He gave the all-too-common example of patients with low, but not severely low, glucoses who are unable or not wanting to take carbohydrates for a host of reasons, and would perhaps be more inclined to administer mini-dose glucagon; after all, a fully functional pancreas would respond to low blood sugar precisely by secreting glucagon. This could take the form of a mini-dose injection, as in the case of Xeris’ phase 2 study of glucagon for mild-to-moderate hypoglycemia, or automated bihormonal delivery (Beta Bionics is likely closest to market here, targeting approval in 2022 if all goes well, though there is academic work at McGill and OHSU, among others). Prof. Danne also touted the merits of pump therapy for those at risk of hypoglycemia, and Edinburgh’s Prof. Brian Frier called CGM a gamechanger when it comes to identifying and treating hypoglycemia, though he pointed to the “obvious cost and access issues” associated with it.

• Kings College London’s Dr. Pratik Choudhary and Prof. Frier zoomed in on two proximal, addressable risk factors of severe hypoglycemia in the elderly: Changing health status and overly-aggressive glycemic control. Dr. Choudhary noted that the ability to adapt insulin therapy to changing health status is “a skill we don’t really teach. We have sick day rules for type 1s, but the way we approach type 2 diabetes seems to be a bit blunt: ‘This is your dose. This is what you take.’” When a patient contracts a urinary tract infection and has a consequential diminished appetite, for example, they should be able to down-titrate insulin appropriately to accommodate for the lower food intake. For his part, Prof. Frier appealed to pragmatism, claiming that it’s “madness” to target A1cs of 6% or 7% for people whose life expectancy is short and risk of complications low. “Giving someone who is elderly a long-acting sulfonylurea is crazy, a recipe for disaster. A lot comes down to how healthcare providers approach this. I think they need to have much less strict glycemic control and choose therapies that won’t put them at risk of severe hypoglycemia.” Controversial ACP guidance from March set off a firestorm after recommending relaxed pharmacotherapy for patients over 80 years old; we did not take Prof. Frier’s remarks to align with ACP in any way, but rather to personalize interventions with an eye toward what is both feasible and possible. For an 80-year old who climbs mountains and water skis, we don’t think that Prof. Frier would disagree with making therapeutic choices to help the patient achieve her desired level of glucose control. Later in the discussion – but germane here – Prof. Danne underscored the shift toward outcomes beyond A1c such as glycemic variability, time-in-range and hypoglycemia, all of which should be taken into account with the elderly.

• According to Prof. Danne, the “good news” about dead in bed syndrome is that it doesn’t really strike until children reach 11 or 12 years of age. He displayed a table with five studies of the syndrome ranging from 1991 to 2013, which observed a total of 66 dead in bed events, only one of which occurred in a child under age 11 (age 7). It is a bit counterintuitive that young children – the group with the most frequent severe hypoglycemia and seizures – has the lowest dead in bed occurrence, leading Prof. Danne to suggest that there must be something protecting the younger children. It’s not the dearth or glucose in the brain that kills, he said, but cardiac arrhythmia, and the hearts of younger children are somehow less susceptible to this outcome. 

• EMS consultant and 30-year paramedic vet Mr. Chris Cebollero highlighted the disconnect in emergency medical care for severe hypoglycemia: People recover after being treated with 50% dextrose, but nine times out of ten, they don’t follow up with their healthcare provider, and they are more likely to have another severe event. Surprisingly, paramedic organizations have begun to take matters into their own hands, acting more proactively by reaching out to high utilizers of the EMS system and visiting them in their homes up to three times a week to educate them on their diabetes, medication, and nutrition. This seems like a very worthwhile investment of time, considering the sky-high costs of a 9-1-1 call resulting in the dispatch of police, a fire truck, and an ambulance.

• In an audience poll, 69% of providers responded that <10% of their patients have needed glucagon/EMS/hospitalization/treatment from a family member on account of severe hypoglycemia. Yet the data say that this number should be closer to 30%-40%. In Prof. Pratik Choudhary’s view, either we are underestimating/not capturing a ton of severe hypoglycemia, or the providers present were less aggressive with their treatment than the average providers captured in the literature. Our bet is underreporting is likely the bigger contributor here, as providers at EASD (if anything) are likely to be more aggressive than the general population.

7. Roche’s Accu-Chek View Lifestyle Management Intervention in 30 EMEA and LATAM Countries; Health Econ Analysis Underway

Antwerp’s Prof. Luc Van Gaal shared that Roche’s CE-marked app- and web-based weight reduction system will have expanded into 30 European, Middle Eastern, African, and Latin American countries by the end of 2018. Though we’re not sure how many individuals have been through the program, this sounds like a rather rapid commercial ramp, a testament Roche’s global footprint and payer relationships. In a 12-month observational study in which participants chose to undertake either View or usual care, members of the View arm were 6.2-times more likely to achieve 5% weight loss by one year, though achievers in the View group did not lose significantly more weight than achievers in usual care (-18 lbs in View vs. -16 lbs in control). The responders analysis from WCPD was particularly interesting. Prof. Van Gaal said that a health economic analysis is underway.

• Through Accu-Chek View, providers can communicate with patients and co-set goals, as well as track key biometrics (e.g., blood glucose, blood pressure, activity, weight, medications, abdominal girth). The app passively imports activity data from wearables, and presumably from Roche meters as well; HCPs are notified when patients present with critical values or are a dropout risk, a nice feature allowing providers to allocate their time in an efficient manner. Prof. Van Gaal preached about the advantages of an app that facilitates HCP interaction, though provider time is always at a premium and reimbursement structures have to be in place to incentivize use of such a platform. At the same time, 12-month data shows that allowing remote communication may lead to better outcomes, which could cut down on in-person appointment burden. We’d love to see analyses of provider time commitment and satisfaction.

8. FreeStyle Libre Meta-Analysis (n=10 Studies) Finds 0.56% A1c Reduction; A1c Change Associated with Baseline A1c

Aston University’s Dr. Cliff Bailey presented results from a meta-analysis of FreeStyle Libre RCTs and real-world observational studies aiming to: (i) establish the change in A1c associated with FreeStyle Libre; (ii) identify if the change in A1c correlates with baseline A1c; and (iii) determine if the change in A1c differs by length of study, type of diabetes, and children vs. adults. The analysis, which included 10 studies comprised mainly of type 1s, found an overall A1c reduction of 0.56% (95% CI: -0.76% to -0.36%). Not surprisingly, mean change in A1c was significantly associated with baseline A1c (slope = -0.40; 95% CI -0.61 to -0.18); the greater the mean initial A1c, the greater the A1c reduction. Despite substantial heterogeneity found between trials for change in A1c, no differences were reported based on study length, diabetes type, and children vs. adults. Instead, Dr. Bailey suggested that the heterogeneity could be due to the wide variety of populations, range of baseline A1cs, and different study designs, including RCTs, interventional single arm studies, and observational studies. This was a late-breaking poster at ADA 2018.

9. IDF Europe Symposium Focuses on Patient-Centric Care; Panels on Patient Advocacy, Language, and Health Systems

The IDF Europe symposium emphasized that people with diabetes must be at the center of care. Mr. Uros Bogdanovic, a 22-year-old law student with type 1 diabetes and member of the Serbian Diabetes Association, argued this point, explaining how patients have unparalleled knowledge regarding the ways in which their condition manifests in everyday life. Moreover, patient voices hold a “certain weight,” and young patients especially are motivated to instigate change. Still, Mr. Bogdanovic acknowledged that there are barriers to positioning patients as equal to other stakeholders, citing a lack of resources and preparedness. Additionally, Mr. Bogdanovic explained, patients can also be “selfish and want improvements just for themselves.” To this end, he described how the Serbian Diabetes Association successfully petitioned the government to increase the number of test strips provided to patients over the age of 26. In the past, those <26-years-old received 150 test strips/month, while those >26-years-old received just 50 test strips/month – that’s not even two strips/day! The ultimate compromise provided those <18 years-old with 150 test strips/month and those >18 years-old with 100 test strips/month, doubling the number of test strips allotted to adults. However, Mr. Bogdanovic noted, patients between the ages of 18- and 26-years-old were unhappy with the decision, as they no longer received 150 test strips. Given the complexity and diversity of diabetes, unifying patients can be tricky, especially when unintentionally harmful language enters the equation – more on that below. Read on for further insights from each of the three compelling panels on patient advocacy, language, and health systems.

• In a panel focused on engaging patient advocates in diabetes, we were dismayed to hear examples of the social injustices experienced by those living with diabetes. Mr. Laurent Doyen (French Diabetes Federation), who has lived with type 1 diabetes for 44 years, described how certain jobs are barred to people with diabetes. He also explained that insurance companies charge extra premiums for those with diabetes, noting that he has had to pay over three-times what his partner paid when purchasing insurance to buy a house. Shockingly, discrimination even extends to the healthcare system – Mr. Doyen commented: “you can’t imagine the discrimination [of people with diabetes] in some hospitals.” On November 12, the French Diabetes Federation will submit its recommendations to improve the health system, including stipulations that may address these social injustices. In her closing remarks, IDF Europe Chair-Elect Dr. Niti Pall noted that Mr. Doyen’s description of the social injustices “really touched me.” We were similarly affected and eagerly await the outcomes of the Federation’s proposal.

• We were pleased to see the symposium include a critical panel surrounding the importance of language in diabetes. As moderator Dr. Partha Kar (Portsmouth Hospitals NHS Trust, UK) pointed out, understanding patient preferences for diabetes language is “probably better education” for healthcare professionals than hearing the latest scientific advancements. Indeed, newly elected President of the Swedish Diabetes Association Ms. Cajsa Lindberg shared that when she was first diagnosed with type 1 diabetes as a 13-year-old, a nurse in the hospital instructed her not to prick her thumb or forefinger because she would need them when she became blind – “not ‘if’, but ‘when.’” Years later, Ms. Lindberg still does not prick her thumb or forefinger. To this end, Dr. Jose Manuel Boavida (Portuguese Diabetes Association) emphasized that HCP training must be improved, claiming that diabetes language should be considered equally as important as the physiology of the disease. Ms. Lindberg agreed, noting that she is especially frustrated when HCPs tell newly diagnosed patients that they can live a “normal life.” As she put it, people with diabetes can live “good, heathy, long lives, but it will never be normal. Saying that diminishes all the hard work that goes into diabetes.” Still, physicians are not the only offenders – Ms. Lindberg claimed that “some of the toughest things are said from our own community,” especially regarding the distinction between type 1 diabetes and type 2 diabetes. Often, she explained, language can be especially harmful when people try to oversimplify diabetes.

  • Ms. Valentyna Ocheretenko (member of the Ukrainian Diabetic Federation and former IDF Vice President, 2003-2009) emphasized that not only must healthcare providers take care in how they communicate with patients, but also the degree to which they are understood. She referenced a 2017 University of Missouri study, which found that low health literacy was a significant contributing factor of readmission for chronic conditions such as diabetes, heart disease and cancer; if sufficiently improved, the healthcare system could save $105 billion - $175 billion/year.

  • The final panel discussed two bright spots from the Finnish Diabetes Association and the Turkish Diabetes Foundation. Ms. Sari Koski (Finnish Diabetes Association) lauded the Finnish healthcare system as working “quite well” for people with diabetes, noting a particular emphasis on prevention and early diagnosis of type 2 diabetes. She explained that 20 years ago, Finland had an estimated 250,000 undiagnosed people with diabetes; that number is now ~50,000, even with the number of new diagnoses declining annually. Unfortunately, Ms. Koski didn’t go into the specifics of how this improvement was achieved – we think healthcare systems around the world (especially in the US) would be very interested to know! Indeed, Dr. Pall mentioned that she uses the Finnish system of care and referral pathways as a model for her work helping the Philippines develop their own healthcare system. Professor Meltem Kuruyaziki (Turkish Diabetes Foundation) highlighted several ongoing projects in her country. We were quite impressed by advocacy efforts that culminated in the government providing free treatment for all patients under 18 years-old. Professor Kuruyaziki also described a nationwide, peer diabetes education program that has reached 34,000 patients. After just one year, participants’ A1c dropped from 7.6% to 6.9%, underscoring the immense value of patient education. We wonder if the fact that education was provided by peers was important here, or whether education alone drove the positive results.

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