June 7-11, 2019; San Francisco, CA; Full Report – Draft

This report contains our full coverage of diabetes/obesity therapy, diabetes technology, and big picture topics from the ADA’s 79th Scientific Sessions. Talk titles highlighted in yellow denote the presentations and commentary that we found most notable. Talk titles highlighted in blue represent new coverage that wasn’t included in our daily highlights (day #1, day #2, day #3, day #4, or day #5). Note that some talks may appear in multiple sections (e.g., content on basal insulin/GLP-1 fixed-ratio combinations appears under the “GLP-1” category as well as the “insulin” category).

Our sections proceed as follows (you can navigate through by using our click-able table of contents below):

Themes

GLP-1 Agonists

SGLT Inhibitors

Insulin Therapy

DPP-4 Inhibitors

Novel Therapies

Automated Insulin Delivery, Pumps, and Pens

CGM and BGM

Digital Health and Connected Care

Beyond A1c and Hypoglycemia

Type 1 “Cure” Therapies and Pathophysiology

Adjunct Treatments for Type 1 Diabetes

Treatment Algorithms and Strategies

Obesity, Prediabetes, and Remission

Diabetes Complications

Policy, Epidemiology, and Education

NAFLD/NASH

Award Lectures and Additional Topics

TCOYD/The diaTribe Foundation’s 13th Annual Diabetes Forum

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

Exhibit Hall

Themes

Diabetes Therapy

To Primary Prevention and Beyond: Will REWIND Accelerate the Field Toward Earlier Adoption of Cardioprotective Therapies?

• As one of the most highly anticipated readouts at ADA 2019, REWIND results underscored the potential benefits of earlier, more aggressive intervention in type 2 diabetes. REWIND provided the first concrete evidence that GLP-1-mediated cardioprotection extends to those without established CVD, with strong consistency on the primary outcome between the trial’s primary (69% of participants) and secondary (31%) prevention cohorts (HR=0.87 on 3-point MACE for both cohorts). Importantly, many consider REWIND to be more applicable to the general type 2 population than any other previously conducted CVOT, bolstered by a long duration of follow-up (median 5.4 years), as well as a low baseline A1c (median 7.2%) and large enrollment of women (46%). KOLs interpreted REWIND results as solidifying a class effect for cardioprotection (we think this is generally great for the class as it prompts greater understanding and acceptance of GLP-1 as a class – this is good for patients when HCPs feel they better understand classes), and many speculated that benefits seen in primary prevention probably extend to other GLP-1s in the class. Consequently, there’s hope that these results may spur clinicians to adopt GLP-1 therapy earlier on in the progression of type 2 diabetes. University of Glasgow’s Dr. Naveed Sattar noted that “this new evidence will continue to push towards these agents to be used sooner in algorithms and clinical care” but that cost considerations will still pose a barrier to widespread adoption. Cost considerations could dissipate, of course – we hope that they will, and we’d certainly think that those with established heart disease should certainly find it easier to get GLP-1. From our view, patient and doctor lack of familiarity with the class is a bigger problem – we continue to be amazed how many HCPs we meet who do not know the GLP-1 or SGLT-2 classes or anything about cardioprotection; recent research from The diaTribe Foundation and dQ&A supports that patient education and awareness of CVD and cardioprotective therapies could be improved. UCSF’s Dr. Alice Cheng expressed similar optimism as Dr. Sattar, commenting that she hopes that REWIND “will shift treatment paradigms to first focus on outcome-based therapies.” While we love the idea, we also believe many payers will take some time until they are investing in primary prevention – we hope for the sake of patients as well as our economy that this changes. Relatedly, Dr. Subodh Verma and colleagues penned an editorial accompanying the publication of REWIND results that advocated for earlier intervention with GLP-1s (and SGLT-2s) in type 2: “If we are to reduce the burgeoning pump, pipes and filter complications of diabetes, we will need to overcome clinical inertia, and embrace these disease-modifying therapies early, and preferably in combination. The REWIND trial makes a strong case in this regard.” We’re thrilled to see some of the community moving toward earlier adoption of these treatments as a way to focus on prevention of adverse cardiovascular and renal outcomes. We also believe patient education must be bolstered – it is also true that this is a barrier as is patient time with doctors to discuss new and preventive therapies.

• Buttressing this point, a new CREDENCE analysis highlighted similar CV and renal risk reduction in primary and secondary prevention cohorts for SGLT-2 Invokana. Very encouragingly, and somewhat startlingly, the analysis showed a trend toward greater CV benefit in the primary prevention group in CREDENCE. On three-point MACE, canagliflozin treatment was associated with a 32% RRR (HR=0.68, 95% CI: 0.49-0.94) in the primary prevention group and a 15% RRR (HR=0.85, 95% CI: 0.69-1.06) in the secondary prevention group – quite a big difference. A similar trend was also seen on renal outcomes, solidifying a favorable risk/benefit profile for using canagliflozin in primary prevention groups, both for reducing CV and renal risk. Of course, we do note that all participants in CREDENCE had macroalbuminuria, which is a known risk factor for silent ischemic heart disease – some KOLs have pointed this out to argue that CREDENCE’s cohort of those without CVD does not represent a truly primary prevention cohort. Of course, this does not completely nullify the utility of earlier use of these therapies!

Renal Outcomes: Buzz Around SGLT-2s for CKD Prevention and Treatment Continues to Grow; Potential Role for GLP-1s and Combination Therapy

• ADA 2019 saw an explosion of data focusing on the role of diabetes therapies in improving renal outcomes. Following enticing secondary endpoint data from CVOTs for SGLT-2 inhibitors that was topped by last July’s field-altering news that J&J’s CREDENCE renal outcomes trial was stopped ~one year early due to overwhelming efficacy, we’ve seen the diabetes community (at least the KOLs in greater earnest) start to seriously focus on how newer therapies may have extra-glucose effects that protect the kidney. This emphasis seemed to grow sharply at ADA 2019, where new data on GLP-1 agonists and SGLT-2 inhibitors further underscored their potential in this space.

  • Exploratory renal results from REWIND helped to solidify thought leader opinion on the comparative efficacy of GLP-1s and SGLT-2s on renal outcomes. As a reminder, on the primary composite of new macroalbuminuria, ≥30% fall in eGFR, or progression to renal replacement, REWIND showed that dulaglutide conferred a significant 15% risk reduction (HR=0.85, 95% CI: 0.77-0.93, p=0.0004) vs. placebo. This was driven primarily by reduction in new macroalbuminuria (HR=0.77, 95% CI:0.68-0.87), followed by sustained eGFR decline (HR=0.89, 95% CI:0.78-1.01, p=0.066), and slightly by a reduction in renal replacement therapy (HR=0.75, 95% CI:0.39-1.44, p=0.39). Importantly, it appears that much of the renal benefit seen here was driven by reduction in microalbuminuria, which some researchers argue is the least important component of renal outcomes. KOL consensus regarding these results was summarized by Dr. Naveed Sattar, who noted that “to prevent deterioration on harder renal outcomes, SGLT-2 inhibitors have an advantage and one imagines that more clinicians are more impressed by the SGLT-2 inhibitor effects on renal outcomes.” Indeed, landmark CREDENCE results for SGLT-2 inhibitor Invokana have dramatically raised the threshold for excitement over renal data. Nonetheless, we still view REWIND’s data quite positively, especially in light of the lower-risk population vs. other CVOTs and CREDENCE. It’s important to note that no therapies have been approved for CKD management in nearly 20 years, so there’s a desperate unmet need that ideally could be filled by multiple classes to better suit the diversity of patients with type 2 diabetes. Further, since the SGLT-2 inhibitor and GLP-1 agonist classes operate by such different mechanisms, we believe there could well be additive or synergistic CV/renal benefit, on top of additive glycemic benefit though that would need to be studied in bigger groups than it has been. Currently, only Novo Nordisk has begun dedicated investigation of a GLP-1 in CKD, with the FLOW renal outcomes trial (n=3,120, up to five years, expected completion August 2024) for Ozempic (injectable semaglutide). It goes without saying there will be interest in an oral sema outcomes trial for CKD as well, if this one goes well – it will be interesting to see if Ozempic CKD outcomes are viewed as generalizable to oral sema.

  • Encouraging data for both Janssen’s Invokana and AZ’s Farxiga were presented and further build on strong interest in SGLT-2 inhibitors for improving renal outcomes. A new CREDENCE analysis presented on the last day of ADA 2019 showed remarkably consistent renal outcomes in both primary and secondary prevention CVD groups, offering strong evidence for the earlier use of canagliflozin in these populations and highlighting the robustness of its renal efficacy. We also saw very positive in-depth renal outcomes from the DECLARE CVOT for Farxiga, detailing its potential in CKD prevention and treatment. Also on Farxiga, an economic modeling study suggested potential for dramatic renal-related healthcare savings with Farxiga ($2.8 billion in total; $285/patient over four years). We’re tremendously excited about the potential these therapies hold in bending the curve when it comes to renal outcomes, and the potential cost savings they could generate with broader application – we are concerned, however, at how payers will interpret these results.

What’s Coming Down the Pipeline? Oral Semaglutide, Easier Emergency Glucagon, Dual Agonists, New Insulins, PPAR Agonists and MetAP2 Inhibitors

• A slew of data readouts gave a peek into the future of diabetes pharmacotherapy, headlined by PIONEER 6 results for oral semaglutide. Without a doubt, the first-ever oral GLP-1 stole a big part of the show with its significant, 49% relative risk reduction in all-cause mortality (HR=0.51, 95% CI: 0.31-0.84) – though the small size of the trial seemed to temper the excitement for some. Currently under regulatory review (in the US, EU, and Canada), it’s also one of the most advanced candidates in the diabetes pipeline at present – but there was much more to be excited for at ADA 2019. Without a doubt, one of our main takeaways from the ADA is that diabetes R&D continues to progress, with multiple new classes showing great promise, even though doctors’ offices have multiple problems that are preventing optimal discussions and plans for patients. Still, first, on the science:

  • Next-gen glucagons. On day 1, we saw promising data for Lilly’s nasal glucagon, demonstrating non-inferiority to intramuscular glucagon in type 1 and type 2 Japanese patients, though the recovery time was significantly slower than traditional glucagon. While presenter Dr. Munehide Matsuhisa contended that this difference was not clinically relevant in his opinion, we’ve recently seen Zealand management highlight faster time to recovery with its dasiglucagon candidate (as compared to nasal glucagon and Xeris’ Gvoke HypoPen) as the key differentiating factor among these three emerging candidates. Indeed, in the full results presentation for Zealand’s phase 3 pivotal results on day 4, we learned that the calculated, “true time” to recovery (glucose levels were measured discretely, every 2-minutes, so Zealand calculated an estimated time that could fall between 2-minute segments) was 9 minutes, compared to 10 minutes with Novo Nordisk’s reconstituted glucagon. That said, no head-to-head trial of next-gen candidates have been conducted, and all of the newer agents, all else equal, represent very clear usability improvements over current glucagon kits.

  • Zafgen’s MetAP2 inhibitor ZGN-1061. A candidate extolled by Emory’s Dr. James Gavin for its weight, glycemia, and liver benefits, dose dependent reductions in A1c (1.1% placebo-adjusted) and weight (~5.1 lbs) were found in full phase 2 results from day 1, with no flattening of the reduction curves at week 12. Perhaps most importantly, no treatment-related serious adverse events occurred, and there was no elevation in D-dimer concentrations (a biomarker of thrombosis). ZGN-1061 is currently on clinical hold in the US because of FDA safety concerns related to thrombosis concerns with Zafgen’s previous MetAP2 inhibitor, beloranib, which was discontinued in 3Q16. On this front, however, Zafgen just provided an update on this clinical hold, stating that the agency has acknowledged positive in vitro assays for plasma coagulation and tissue factor expression. Next up will be an in vivo assay to confirm safety, which Zafgen and FDA are jointly developing.

  • Tirzepatide. Along with oral semaglutide, Lilly’s GLP-1/GIP dual agonist tirzepatide seems poised to be the next major advancement in GLP-1 and type 2 diabetes – and perhaps NASH and obesity – pharmacotherapy, and it remains the only dual agonist in phase 3. Highly-anticipated phase 2 titration results for the dual agonist showed that high discontinuation rates for tirzepatide due to adverse events seen in the candidate’s main phase 2b study could be ameliorated through slower titration, bringing rates down from 25% at the highest dose to <5% across all doses. It was favorable for Lilly to see this concern mitigated – doctors are too busy to deal with side effects and it’s much better for patients if therapies are as simple as possible to take.

  • URLi (ultra-rapid insulin lispro). Phase 3 results in both type 1 and type 2 diabetes for Lilly’s next-gen insulin were presented on day 3 to a standing-room-only crowd. In summary, URLi demonstrated significant improvement over Humalog on postprandial excursions when dosed pre-meal and was noninferior when dosed 20 minutes after the meal (prompting Lilly to submit for a post-meal dosing indication, similar to that of Novo Nordisk’s Fiasp). However, there were no differences on A1c. Time in range data wasn’t given, which was disappointing, since no change in A1c could mean multiple things. We’ll be particularly intrigued to hear how thought leaders process these results and how Lilly positions URLi relative to Humalog (so far, it has only been filed in the EU and Japan, though US submission is slated for 2019). Thought leaders seem split over Fiasp’s added value vs. current mealtime options: Some feel the advantages it brings over NovoLog are essentially marginal, while others have identified potential for its use in closed loop systems due to the molecule’s faster PK/PD profile – we’ll have to wait and see on the latter.

  • Non-TZD PPAR pan-agonist chiglitazar. Developed by Chinese company Chipscreen Biosciences, the phase 3 candidate demonstrated significant improvements vs. placebo and non-inferiority to sitagliptin on A1c over 52 weeks, with strong tolerability and safety. Despite this candidate’s promise, we imagine US development is not a priority (or even on the table), as we’re very confident FDA would require a full CVOT. Although tolerability on multiple fronts may be positive, weight gain is virtually always an issue with PPARs.

Type 1 Prevention Efforts Score Breakthrough Win with Teplizumab (First Drug to Delay Type 1 Diagnosis); Positive Two-Year Low-Dose ATG Results to Drive Further Investigation; A Role for Liraglutide – Adjunct or Disease Modifying Therapying?

• After an ADA 2018 that we characterized as “mixed” for the type 1 cure/prevention/therapy landscape, ADA 2019 saw a major breakthrough in the field with positive results from the highly-anticipated phase 2 trial of teplizumab in type 1 prevention. Additionally, we saw new data from TrialNet’s study of low dose ATG (+/- GCSSF) in type 1 (positive two-year results strengthen those presented last year at ADA 2018), contributing to a meeting strong in terms of emerging research in the field.

  • Teplizumab made the biggest splash in terms of type 1 data at ADA 2019, becoming the first drug to show clinical potential in delaying a type 1 diagnosis. Teplizumab treatment was associated with marked reductions on cumulative diabetes onset (72% vs. 43%, HR=0.41, p=0.006) and time to diagnosis (48 months vs. 24 months) compared to placebo. With these phase 2 results, teplizumab reshapes the paradigm of pursuit for type 1 prevention, validating the idea that a drug could actually delay progression for a period of time. Of course, the treatment is not perfect – adverse events were significantly more common during administration of the treatment, not all patients in the trial responded strongly, and the patient population studied was very narrow (e.g., ≥2 autoantibodies) in comparison to all those who might be at risk for type 1. Further work must try to pinpoint responders and investigate the potential of combination therapies with teplizumab for further efficacy. Still, it’s important to realize the gravity of these findings in context. We thought that University of Florida’s and nPOD Director Dr. Mark Atkinson described the impact of this data best during a conversation with our team, calling it “not exactly a homerun” but an important step forward in the field in actually showing that type 1 prevention is possible. Nonetheless, these results hold the potential to significantly impact research priorities in the field and future clinical practice. At ENDO Fellows 2019, we heard TrialNet’s Dr. Carla Greenbaum gush about the potential that teplizumab could have. Looking ahead, there’s still a long road toward commercialization for teplizumab, for which rights are owned by Provention Bio.

    • Teplizumab’s developmental story underscores the complexity of trying to develop type 1 therapies. The compound has a mixed history, colored by positive and neutral results alike and marked by a high-profile phase 3 disappointment in 2010 with Lilly and MacroGenics. We can’t applaud the researchers associated with this project enough for their persistence, belief, and hard work in driving this therapy forward and advancing the entire field. As investment in the type 1 field increases – 2018 saw major players in Novo Nordisk and Lilly make significant investments in type 1 cures – we hope that lessons from teplizumab’s winding story underscores the non-linearity of type 1 research progress.

  • We also saw positive data on low-dose ATG in new-onset type 1. In the TrialNet sponsored study, on the primary outcome measure of preserved C-peptide after two years (measured by mean mixed-meal tolerance test), ATG treatment alone was associated with a significant increase compared to placebo (p=0.00005). TrialNet fully intends to further pursue ATG in the type 1 landscape, and we’re optimistic about its future. These results follow positive one-year data presented last year at ADA 2018.

  • Liraglutide’s role as a both a type 1 adjunct and potential disease-modifying therapy continues to be fleshed out, with moderately positive results in new-onset type 1 presented at ADA 2019. The small, independent NewLira study showed that after one year of treatment with either liraglutide 1.8 mg and insulin or placebo and insulin, those randomized to liraglutide had a 44% higher AUC C-peptide than the placebo group (the study’s primary endpoint), meeting significance at p=0.04. Despite the borderline significance on this endpoint, our sense is that the community was not overwhelmingly excited about the positivity of these results.  However, a Novo Nordisk sponsored study of liraglutide plus anti-IL 21 for beta cell preservation just completed and could shift the narrative on liraglutide for type 1. Additionally, although we continue to believe that GLP-1s have serious potential as a type 1 adjunct and definitely deserve further investigation (many clinicians and patients have spoken positively about their experiences with this adjunct therapy), our sense is that sponsors remain hesitant to pursue an actual indication in type 1 given the significant financial investment and clinical challenges involved. Nonetheless, despite tempered engagement from sponsors, enthusiasm from researchers remains high: for example, JDRF is sponsoring a type 1 triple therapy study that includes semaglutide, and Dr. Paresh Dandona continues to tout liraglutide in type 1. As for us, we’d like to see a CVOT and we’d like to see oral sema tested in type 1.

DiRECT, PREVIEW, and D2d Bring Prevention and Remission to the Forefront; Adherence Remains a Major Barrier; Recent CDC Incidence/Prevalence Paper a Major Discussion Point Amongst Providers

• Prevention and remission discussions were imbued with new vigor by very positive results from DiRECT (diabetes remission and beta cell recovery with a very low calorie diet) and PREVIEW (reduced diabetes incidence with high/med protein diet + high/med intensity activity) as well as a trend toward diabetes prevention benefit with vitamin D in D2d. Several subthemes emerged from these discussions:

  • Adhering to lifestyle and dietary changes is hard, but not necessarily harder than adhering to medication. While only 43% of participants completed the three-year PREVIEW program, 68% (102/149) completed the two-year DiRECT intervention. This is comparable to a 2016, Novo Nordisk-funded study that found that 65% of people with type 2 diabetes were adherent to their diabetes medications (defined as filling their diabetes prescriptions more than 80% of the time – of course whether or not they take them is another question, even if this study did reflect the “real world”). There is certainly room for improvement in both paradigms, but there is also much potential for improvement in visibility and accessibility to these programs. For example, not only does DiRECT achieve an impressive rate of diabetes remission, but it shows that can be done in the primary care setting through nurses and dieticians with fairly minimal training on the intervention. We are thrilled to think about this moving to standard-of-care and all the people who could do so much better with appropriate investment in this intervention. 

  • Both PREVIEW and DiRECT included extensive support, meaning these attrition rates might be best-case scenarios – or they may be major opportunities. Indeed, Nottingham’s Dr. Ian MacDonald, who presented PREVIEW results, believes adherence to lifestyle changes will prove a key barrier, and one that is deserving of more research. During his review of clinical diabetes developments over the last year, Toronto’s Dr. Dan Drucker highlighted this aspect of treatment as the most high-need area in diabetes, calling for more investment in implementation research. Of note, other behavioral change interventions with more significant coaching, such as Virta’s low-carb + continuous remote care program, have demonstrated relatively high (but still declining over time) retention rates – 91% after ten weeks, 83% after one year, and 74% after two years.

  • Earlier intervention translates to more likely remission. In DiRECT, characteristics of the responder and non-responder populations were nearly identical at baseline, with the exception of diabetes duration: 2.7 years for responders vs. 3.8 years for non-responders. We think this concept could be applied more broadly across all of diabetes treatment to promote better health outcomes and cost-effectiveness in the long-term.

  • University of Florida’s Dr. Mark Atkinson told our team that a prominent discussion point of providers at the conference, unrelated to what was presented, was the recent CDC analysis suggesting that US adult diabetes incidence has steadily declined since 2007 and prevalence has remained stable since 2009. Unfortunately, it seems as though no one has yet been able to pinpoint a clear-cut explanation for these abrupt and sustained shifts that contradict other trusted datasets, including both NHANES and the CDC’s self-report Behavioral Risk Factor Surveillance System. The sense we’ve received from speaking to experts is that changes in diagnostic criteria, for example, are likely a bigger driver than large-scale shifts in population health, though we look forward to learning more.

STENO-2 and GOULD Underscore Benefits of and Need for Widespread CV and Diabetes Risk Management; Clinical Inertia More Important Than Cost (in the Long-term); Primary Care a Key Target for Education

• New stroke results from the 21-year follow-up of STENO-2 demonstrated how much there is to gain by achieving therapeutic targets – namely, one year of life expectancy per each year at recommended A1c, weight, blood pressure, and LDL goals. However, baseline results from the nationwide GOULD registry showed how far we have yet to go: A “soberingly poor” 6% of participants were on guideline-recommended optimal medical therapy. While this doesn’t necessarily mean that only 6% of US adults are achieving targets, Steno’s Dr. Peter Gæde pegged that number at a similarly disheartening 14.3% based on a long-term survey from 1999-2010. The key takeaway from both presentations? We need more widespread and comprehensive diabetes and CV risk management, whether through lifestyle or pharmacotherapy, because it saves, extends, and improves lives. Not only that, but the therapies and interventions in STENO-2 were also cost neutral in the long-term due to the prevention of complications. On this thread, Dr. Mikhail Kosiborod dismissed cost as the primary driver of poor medication use, instead offering clinical inertia as the main culprit. Seeing as only 55% of those with diabetes in the GOULD registry were prescribed metformin, it would certainly appear that clinical inertia was present, though we think it likely that cost contributed at least in part to the low uptake of cardioprotective medicines (only 15% with type 2 were taking SGLT-2 inhibitors or GLP-1 agonists). To truly move the needle on therapeutic inertia, we believe a strong emphasis must be placed on the role and education of PCPs. As it stands, primary care offices are where most diabetes diagnosis/treatment occurs, yet diabetes education is inadequate during medical school and residency. According to Primary Care Education Consortium’s Dr. Steven Brunton: Doctors are more likely to do something if they feel like they have the skills to do it, so concentrated but brief education on diabetes could be hugely impactful. To this end, we wonder how initiatives such as the ADA’s Diabetes is Primary campaign could more effectively penetrate PCP offices.

  • Novo Nordisk’s oral semaglutide could be a paradigm-shifting candidate, in our opinion. Combining cardioprotection, weight loss, and A1c benefit into an oral medication has the potential to improve adherence and reduce providers’ hesitancy to start a traditionally injectable therapy, particularly earlier in the disease course. That said, only 9% of the GOULD cohort was on an SGLT-2 inhibitor, which contains many similar benefits. Also, adherence to therapy, regardless of administration route, remains a difficult nut to crack.

Diabetes Garners Significant Visibility through Simultaneous High-impact Data Publications and Editorials

Diabetes was heavily featured across multiple high-impact journals during ADA 2019; we’ve compiled all that were featured in our daily highlight reports below. Let us know what else should be added:

• Day #1

  • “Soberingly poor” baseline results from the GOULD (Getting to an imprOved Understanding of Low-Density lipoprotein cholesterol and dyslipidemia management) registry – Our highlight; Circulation

  • The D2d trial, which found no significant decrease in risk of progression to type 2 diabetes with vitamin D – Our highlight; NEJM

  • A 13-month RCT comparing finding greater A1c reduction with a Voluntis Insulia (basal insulin titration app) vs. standard-of-care – Our highlight; DOM

• Day #2

  • Full PIONEER 4 results, demonstrating oral semaglutide’s superiority to liraglutide on weight loss and possible glycemic control – Our highlight; The Lancet; Accompanying Editorial

  • An updated report on Fournier’s Gangrene with SGLT-2 inhibition, adding 43 new cases to the 12 initially reported by FDA last August – Our highlight; Annals of Internal Medicine

  • The international consensus on time-in-range – Our highlight; Diabetes Care

• Day #3

  • CV outcomes from the positive REWIND CVOT for GLP-1 agonist Trulicity – Our highlight; The Lancet

  • Renal outcomes from the positive REWIND CVOT for GLP-1 agonist Trulicity – Our highlight; The Lancet

  • Phase 2 teplizumab results; the first-ever drug to delay type 1 diagnosis – Our highlight; NEJM

  • Full PIONEER 5 results, demonstrating efficacy and safety of oral semaglutide in people with type 2 diabetes and moderate renal impairment – The Lancet Diabetes & Endocrinology; Accompanying editorial

  • Full PIONEER 7 results, demonstrating oral semaglutide’s superiority over DPP-4 inhibitor sitagliptin on A1c and weight loss – The Lancet Diabetes & Endocrinology; Accompanying editorial

  • Very positive, in-depth renal outcomes from the DECLARE CVOT for SGLT-2 inhibitor Farxiga – Our highlight; The Lancet Diabetes & Endocrinology

  • DUAL VIII results showing longer sustainment of A1c <7.0%, halg the weight gain, reduction in hypoglycemia with GLP-1/insulin fixed-ratio combination Xultophy vs. basal insulin Lantus – Our highlight; Lancet Diabetes & Endocrinology; Accompanying editorial

• Day #4

  • Impressive stroke results from the 21-year STENO-2 follow-up for multifactorial intervention (simultaneous glucose, blood pressure, and lipid lowering) – Our highlight; Diabetologia

  • AWARD-7 post-hoc showing lesser decline in eGFR associated with dulagutide treatment was not influenced by body weight loss – Our highlight; DOM

Diabetes Technology

Control-IQ Pivotal a “Landmark” Study, “Benchmark” for Future Trials; Pre-Pivotal Data from Insulet (Ages 2-6 years), Beta Bionics (Insulin-Only), Medtronic (780G)

• The clear technology headline from ADA 2019 was strong results from the pivotal trial of Tandem’s Control-IQ hybrid closed loop with automatic correction boluses and Dexcom’s no-calibration G6. The six-month, NIH-funded, International Diabetes Closed Loop study compared Control-IQ (n=112) to sensor-augmented pump therapy (t:slim X2/G6 with no automation; n=56). Control-IQ drove impressive glycemic improvements: Time-in-range (70-180 mg/dl) was 2.6 hours per day better with Control-IQ – 70% vs. 59% (p<0.0001) – mostly from minimizing hyperglycemia (-2.4 hours/day spent >180 mg/dl). Control-IQ also boasted a 0.33% advantage in A1c at six months (baseline: 7.4%) and improved mean glucose as measured with CGM by 13 mg/dl. Remarkably, study retention was 100% in both arms, Control-IQ users spent 92% of the six-month period in closed loop, and users scored ease of use, usefulness, trust, and desire to continue use all between 4.5 and 4.8 out of a possible 5. In the words of the greats – Drs. Roy Beck and Boris Kovatchev – this study was “landmark” and “a new benchmark.” (The typically reserved Dr. Kovatchev even proposed a “Data Awesomeness Index” – study retention rate + closed loop use + the difference between time-in-range between control and experimental. In this study, that was an 100% + 92% + 11% = 203%!) On a call following the presentation, Tandem confirmed Control-IQ will be submitted to the FDA in the “coming weeks” (14+ years), with US launch still expected this year. Given years of FDA experience with this algorithm – along with two of the three system components already cleared as interoperable devices (G6, t:slim X2) – we expect a smooth and quick FDA regulatory review. This will be the first hybrid closed loop on the market with correction boluses, a no-calibration CGM, Bluetooth, and remote software updating – significant advantages over the MiniMed 670G, which was the first hybrid closed loop approved back in 2016.

  • As a bonus, we saw interim results from France’s Freelife Kid AP study of Control-IQ, comparing nocturnal-only use with 24-hour use of the system in children (n=30, mean age 9 years). Time-in-range (70-180 mg/dl) for the 24-hour group improved from 60% at baseline to 72% during treatment (+2.9 hours/day) vs. a smaller improvement from 63% to 68% in the nocturnal-only group (+1 hour/day). This early data confirms the system should perform equally well in the pediatric population – in that vein, an n=50 pivotal study in ages 6+ is currently recruiting in the US.

• Notable pre-pivotal AID data came from Insulet, Beta Bionics, and Medtronic – all showing meaningful impact on time-in-range, better user/on-body experiences, and less burden as the field moves from “first” approvals to next-gen products. ADA 2020 could potentially bring pivotal trial data on Medtronic’s next-gen 780G (pivotal underway), Insulet’s Horizon (pivotal in 4Q19), and Beta Bionics (insulin-only) iLet – depending on when these wrap up. Observational DIY Loop results could also feasibly be presented at ADA next year.

  • We saw very positive results (+4 hours in-range/day) from Insulet’s three-day Omnipod Horizon hybrid closed loop hotel study in 2-6 year olds. The data demonstrated great safety and effectiveness in kids sometimes too young to communicate when they might be feeling high or low. A pivotal is expected to start in 4Q19, and we expect this tubeless hybrid closed loop – with the algorithm built right into the pod and talking directly to the G6 CGM – will set a new bar for on-body simplicity. (A number of people are experiencing an early version of this now through DIY Loop with Omnipod, though it still requires the phone nearby and the RileyLink bridging device.) We also learned that Horizon – at least in its investigational configuration – can be set for target glucoses of 110, 120, 130, 140, and 150, allows for extended boluses, and has a “hypo protect” mode (150 mg/dl target and reduced basal delivery). 

  • A Beta Bionics oral showed that the integrated Gen 3 iLet insulin-only system performed very well with both Dexcom’s G5 and Senseonics’ Eversense CGM. Compared to usual care, the iLet Bionic Pancreas increased time-in-range by 1.9 hours/day (70% vs. 62%). A poster showed a sub-analysis of this study, suggesting that the iLet is safe to initiate directly following MDI therapy – all the system asks for is bodyweight. Curiously, a second poster showed that the same system didn’t significantly alter CGM metrics in a pediatric cohort (mean age 12 years) overall, though time-in-range climbed meaningfully overnight. This kind of comparison is sometimes typical given the high-baseline time-in-range in  well-managed, early adopter clinical trial participants. Beta Bionics expects to start an insulin-only pivotal trial in 1Q20.

  • Medtronic’s next-gen MiniMed 780G (or investigational versions thereof) was the subject of at least three posters, adding automatic boluses and a more aggressive algorithm (time-in-range goal: >80%, 100 mg/dl target). Overall results were very encouraging, though it’s clear that, despite the automatic correction boluses, bolusing for meals will be very important for minimizing hyperglycemia. There were also a fair number of abstracts concerning 670G, emphasizing the solid glycemic outcomes it confers for those who continue to use it – there is some tension here as the earliest hybrid closed loop approved, nearly three years ago, and the constant improvements with other systems. Medtronic began the MiniMed 780G pivotal trial during this ADA (enrolling up to n=350 adult and pediatric participants), with primary completion now expected by January 2020. Like the precursor 670G, the 780G pivotal will be tested in a three-month safety evaluation (home study), with co-primary end points – change in A1c and change in time-in-range (70-180 mg/dl) from baseline.

• On the academic side, we were impressed by a Cambridge presentation showing strong outcomes with a fully closed loop system in type 2 diabetes regardless of use of Fiasp or Novolog. OHSU’s bihormonal system (with Xeris liquid-stable glucagon) maintained the same time-in-range as single-hormone system, while, notably, cutting down on time <70 mg/dl. 

• It’s early days for in-hospital closed loop, but there were two strong abstracts at this ADA: (i) The Bionic Pancreas algorithm was configured to be compatible with IV insulin+dextrose, Abbott’s Navigator CGM, and a hospital Symbiq pump – time-in-range was an incredible 98% in type 1 diabetes and 94% in type 2 diabetes, far higher than would typically be seen in the hospital on traditional glucose management; and (ii) An Admetsys poster showed that the company’s inpatient IV insulin+dextrose closed loop system successfully brings glucose into range over 24 hours without hypoglycemia. Given the growing evidence that highly-variable and consistently out-of-range glucose is a multiplier of poor inpatient, surgical, and readmission outcomes, we see it as mission critical that these systems find their way into the hospital as soon as possible.

Interoperability Momentum: Medtronic/Dexcom Sign on to Tidepool Loop, FDA Talks Possibility of Class II “iController,” and Data Support DIY Efficacy

• The #WeAreNotWaiting and interoperability movements received more attention at ADA 2019 when Dexcom and Medtronic signed on to integrate with Tidepool Loop. While it was not surprising to see Dexcom – which will integrate via its G6 iCGM – to join Insulet in supporting the initiative, the move from Medtronic was unexpected and the field will be watching to see how much focus Medtronic puts here. Medtronic said it will integrate with Tidepool Loop via a future Bluetooth-enabled ACE Pump and a future Guardian Sensor 3 iCGM, both yet to be submitted to FDA (timing unknown). Medtronic’s move signals that it understands the importance of showing support for AID component interoperability and patient choice as key innovation drivers, and we’re interested to see how fast it moves and how it impacts the organization’s diabetes strategy. Dexcom has long been committed to interoperability and remains the CGM industry leader here, both in terms of number of partnerships and the only company with a public API program. We didn’t hear any plans from Abbott, Senseonics, or Tandem to integrate with Tidepool Loop, though the FreeStyle Libre 2 is under FDA review as an iCGM, Senseonics plans to obtain iCGM designation, and Tandem already has the ACE Pump indication. In other news, following the DIY community’s successful integration of Insulet’s (non-Dash) Omnipod into the Loop armamentarium, Tidepool/Jaeb’s Loop observational study now has 550 people actively sharing Loop data, with over 100 more who have enrolled in the study and have ordered a RileyLink but have not actually started to Loop yet. About 80% of the cohort of new Loopers in the study are using an Omnipod. We conservatively estimate over 2,500 people are using the DIY Loop iPhone app globally, with either an Insulet or Medtronic pump.

• FDA representatives Drs. Courtney Lias and Alain Silk both discussed the potential to make the AID control algorithm class II, 510(k)-regulated software with special controls. This would bring the whole closed-loop category down from the current class III PMA level (since iCGM and ACE pumps are both class II already), allowing for quicker updates, less regulatory burden, and greater interoperability and patient choice. One of Dr. Lias’ slides read, “We are evaluating whether special controls may exist to make standalone AID controller software class II,” and Dr. Silk also discussed it as a possibility at DiabetesMine’s D-Data. Dr. Lias has also previously shared optimism on the subject. Though we haven’t heard any speculation as to what the special controls may look like, we suspect they could take a similar approach to the model that FDA has proposed for AI regulation – e.g., the manufacturer outlines anticipated modifications to the performance, inputs, or intended use of the algorithm, alongside some required in silico testing pre-clearance and when a change is made.

• DIY AID systems have moved toward more scientific validation – notably, ADA 2019 featured DIY systems in an oral presentation and in several posters. The oral looked at 80 OpenAPS data donors comprising 53 years of total CGM data – an impressive 19,251 days of use. Overall, DIY users spent 78% time-in-range (70-180 mg/dl), with 18% >180 mg/dl and 4% below 70 mg/dl. CV was 36%. Mean glucose was 137 mg/dl, corresponding to an estimated A1c of 6.4%. Meanwhile, an impactful poster detailed results from a survey of 101 DIY APS users who were overwhelmingly positive about their experience with their systems. Another major takeaway from the poster was that >80% of respondents’ providers encouraged them to keep using their DIY systems. At DiabetesMine’s D-Data Exchange, Stanford’s Dr. Rayhan Lal even discussed his experience getting patients on DIY system. It’s great to hear positive healthcare provider experiences with these DIY systems – a plus as the commercial product landscape develops.

Large CGM Trials Show Benefit In Broad Age Groups: WISDM (Type 1s ≥60 Years), CITY (Type 1 Young Adults), SENCE (2-8-Year-Olds)

• Evidence of CGM’s benefits continued at ADA 2019, with four dedicated trials demonstrating improved glycemic metrics regardless of age or insulin delivery method. Results from the six-month WISDM study (n=203) investigating CGM in older adults (≥60 years) with type 1 were strong: CGM conferred a significant advantage over BGM in every outcome measured, including a two-hour per day advantage for CGM on time-in-range (70-180 mg/dl). On the other end of the age spectrum, the six-month SENCE study (n=143) tested CGM in 2-8 year-olds in a three-arm trial: CGM + a family behavior intervention (FBI) vs. CGM-only vs. BGM-only. CGM + FBI drove a 43 minute/day gain in time-in-range (70-180) vs. no change in the CGM-only and BGM groups. Both CGM groups saw significant improvements in time <70 mg/dl and significant reductions in severe hypoglycemia. Moving to one of the most challenging populations, type 1 adolescents and young adults (14-25 year-olds), CITY results (n=153) were also positive, showing CGM  drove a 0.4% advantage on A1c and a +1.7 hour/day benefit on time-in-range in a challenging type 1 adolescent (14-25 years) population (baseline time-in-range: 37%) over six months. Equally important, all three trials found high use of Dexcom’s G5 CGM at six months (>6 days/week): 84% of WISDM participants, 92% of SENCE participants, and 59% of CITY participants. We’re thrilled to see strong engagement and outcomes, in these robust six-month studies – hopefully they will be published in big-name journals, further building the case for CGM as standard of care in type 1 diabetes (and ideally removing reimbursement barriers). All of these studies used Dexcom’s G5, so it’s likely that the G6 and its less-intimidating insertion process, factory calibration, 10-day wear, and smaller profile would lead to even greater usage.

  • These trials are also a reminder of how slowly the evidence landscape moves – 11 years after the JDRF CGM trial was published in NEJM, the field is still testing if CGM provides benefit vs. fingersticks in type 1 diabetes! Of course, the sensors have improved markedly since then, so new trials make sense. We hope that in 2030 (11 years from now), the idea of testing CGM vs. BGM in any insulin user would be considered unethical!

  • Three-year data from COMISAIR (n=94 type 1s) found that adding CGM to MDI drove similar glycemic outcomes as adding CGM to a pump. These results were mirrored in WISDM, which similarly showed no difference in CGM-driven outcomes by insulin delivery method, as well as earlier studies DiaMonD and GOLD and oft-cited T1D Exchange data.

• While CGM can provide value to everyone with diabetes (in our view), Dr. Anne Peters powerfully underscored the barriers that underserved patients face in accessing diabetes technology. Drawing from her experiences treating patients in East Lost Angeles, Dr. Peters described challenges ranging from patients’ distrust of the traditional healthcare system to an inability to receive packages at home. She firmly believes that patients should be offered high quality diabetes care regardless of socioeconomic status and called for a “DIY diabetes survival kit” to help manage care for underserved communities. We’ll be interested to see full data from the STEPP-UP study, which Dr. Peters referenced as evidence that tailored educational tools can be effective in helping low-literacy patients reap the benefits of diabetes devices.

• We were also delighted to see a slew of posters describing small demonstration projects of CGM use in different populations and settings – groups and settings in which many have argued CGM may be too burdensome or not effective. A group of Washington (state) researchers assessed the feasibility of CGM in type 2 youth; IDC researchers implemented CGM in a primary care setting as part of a quality improvement initiative; and Stanford clinicians gave CGM to young type 1s within a month of diagnosis. All these posters showed positive to extremely positive outcomes.

Time-In-Range Movement Picks Up: CGM Targets from International Consensus, Dr. Rich Bergenstal on “Individualized A1c”

• The Beyond A1c movement saw a meaningful uptick in discussion this year, highlighted by the publication of time-in-range consensus recommendations. The recommendations were presented in a late-breaking poster and published in Diabetes Care. Targets are provided for four groups: (i) Type 1 and type 2 diabetes; (ii) Older/high-risk type 1 and type 2 diabetes; (iii) Pregnancy: type 1 diabetes; and (iv) Pregnancy: gestational and type 2 diabetes. Most will fall into the first group, where the time-in-range goal is >70% within 70-180 mg/dl, with <4% below 70 mg/dl and <25% above 180 mg/dl. This landmark consensus statement will be widely used and hopefully serve to improve clinical care and give individuals something to aim for. Moreover, we’ll be interested to track how these targets change clinical adoption/implementation of CGM and whether they impact payers or the research landscape. A Tidepool/T1D Exchange poster found that glycemic excursions >140 mg/dl were associated with poorer quality of life – even in well-managed patients. It’s possible that future work will reveal greater significance of 140 mg/dl as a key hyperglycemia benchmark – might these targets eventually be tightened, especially as hyperglycemia-minimization? Dr. Rich Bergenstal presented an exciting oral on individualized A1c, which accounts for variations in red blood cell turnover between individuals. The team found that 70% (!) of individualized A1c values differed from their lab A1c by over 0.5%. As long as A1c is still being used on an individual level – to which someone aptly questioned: “why not just kill A1c all together?” – Dr. Bergenstal proposed that an individualized A1c be implemented, personalized by the patient’s RBC turnover.

  • A poster from Dr. Bergenstal and Novo Nordisk researchers  presented the results of www.glucoseprofile.com, a Novo Nordisk/DTS collaboration to crowdsource the determination of what constitutes an “ideal” Ambulatory Glucose Profile (AGP). Agreement, particularly among non-experts, left something to be desired – and we’d hazard that many of the HCPs seeing people with diabetes are even less expert than many of these survey respondents. Now that the field has moved to integrate AGP into diabetes software across the board, the next step is to educate providers how to most effectively use it. IDC clinicians and researchers set out to do just that in a recent DT&T paper.

Real-World Data Grows, with 25+ Abstracts/Posters from Nearly Every Major Device and Digital Health Company

• Six of our day-of highlights and nearly 20 of the posters we covered on the technology side of ADA specifically detailed real-world data. Every major device manufacturer got in on the action – see the bullets immediately below for specifics. At a high level, we expect the real-world data presentation mix at major meetings to expand, especially as every diabetes device adds connectivity/apps that enable passive data upload to the cloud – e.g., all four current standalone CGMs (Abbott, Dexcom, Medtronic, Senseonics), Insulet’s Omnipod Dash, and upcoming mobile apps for Tandem and Medtronic pumps. Real-world evidence will augment randomized, controlled trials, enabling population expansions, real-world safety and efficacy monitoring, and benchmarking. As real-world data grows in quantity and quality, we’re also very eager to see more studies initiated by third-party investigators, clinics, health systems, etc. Seeing how different devices fare in large populations (e.g., a clinic or registry) could give a better idea of how their head-to-head safety and effectiveness compare for various subsets of patients. For example, though discontinuation rate was minimal in 670G pivotal studies, real-world studies at MGH (ENDO 2018) and now ADA (both Barbara Davis Center and Stanford) suggested that 30%-40% of users may elect to discontinue use of Auto Mode out past six months. It is these signals – which can only be picked up through real-world observation – that can indicate to providers, other patients, and especially manufacturers when a technology is too burdensome to operate for many, and which people are more likely to be successful on a given therapy.

  • Abbott came to ADA with at least seven real-world posters, most notably an expanded analysis of over 590,000 FreeStyle Libre users worldwide – this is ~120,000 users larger than ATTD, remaining the largest real-world CGM data set. The data reinforced the link between higher scanning frequency and better outcomes, and separate analyses showed the utility of FreeStyle Libre in type 2s on insulin. A UK-wide audit showed FreeStyle Libre was linked to declines in hospital admissions for hyperglycemia/DKA and hypoglycemia, along with a 0.6% A1c benefit.

  • Insulet boasted five posters detailing Glooko-aggregated real-world glycemic results from Omnipod users. Cuts of data break out type 2 adults, older adults, type 1s, pediatric/adolescent type 1s, and type 1s with CGM data.

  • In addition to the two 670G orals on real-world use (from Barbara Davis and Stanford), Medtronic presented real-world glucose management indicator (GMI; formerly eA1c) and time-in-range data from ~78,000 670G users; there was also a Joslin poster examining subject-reported outcomes and A1c changes in 670G users. Medtronic also had a poster detailing real-world performance of the Guardian Connect CGM with Sugar.IQ.

  • Senseonics CMO Dr. Fran Kaufman presented data on the first 205 US patients to complete 90 days of Eversense wear, as well as data from a poster detailing the long-term safety of the implantable CGM in its post-market safety registry in Europe.

  • A Tandem poster detailed stellar real-world hypoglycemia outcomes with the Basal-IQ PLGS system, which even compare favorably to those in the pivotal PROLOG study.

  • A Dexcom poster showed how the G6’s “Urgent Low Soon” alert decreases time in hypoglycemia.

  • mySugr’s poster showed sustained improvements in glycemia out to four months. Data was broken down by baseline eA1c, with the only significant improvements seen in individuals with baseline eA1cs between 7.1%-10.6%.

  • Two of Livongo’s posters delved into predictors of success in the company’s diabetes management and DPP programs.

  • A Sanofi poster outlined results – including a near-60% discontinuation rate – from My Dose Coach in India. Of those who continued to use the basal insulin titration app, >80% had reached goal.

  • Omada’s poster showed that its virtual DPP reduced eight-year diabetes risk in a large cohort of Quest Diagnostics employees.

  • DarioHealth showed greater improvements in the percentage of in-range blood glucose readings in those who engage with the app more frequently. 

Promising Digital Health Frontiers: Smart Pen Data from NN, App-Based Titration from Sanofi and iSage Rx; Forecasting BG from One Drop and Medtronic/IBM

• Smart insulin pens have long been considered an important missing link in diabetes care, though data was still sparse at this ADA. The highlight was two Novo Nordisk posters demonstrating strong results from a subset of the Swedish pilot that investigated its NFC-enabled pens. In an analysis of 94 adults, the addition of smart pens (plus clinic visits) drove +1.9 hours/day in-range, a dramatic reduction in time <54 mg/dl (2% to 0.6%), and an impressive 43% fewer missed meal boluses. This positive readout follows a March Diabetes Care publication detailing results from the use of Common Sensing’s Gocap. We did not see any data on Companion’s InPen at this ADA (it is currently on the US market and well reimbursed), though the company announced a slew of important data partnerships with Dexcom, Glooko, and Rimidi, as well as a public API. (Companion’s post-market study (n=60) is still recruiting.) Next year’s ADA should have more data on smart pens, as Novo Nordisk expects 2019 launches of its reusable smart pens (NFC-enabled) and a Bluetooth-enabled disposable pen attachment, and Lilly’s connected insulin pen has been filed with the FDA. Will we see both insulin players with smart pens on the market before next ADA? The commercial landscape is obviously still early here, so it will take a few years for the evidence base to build.  

• Similar to smart pens, the evidence base for automated basal insulin titration apps is just beginning. This ADA, a Sanofi poster detailed results from My Dose Coach implementation in India, and an Amalgam Rx poster showed results from an iSage Rx pilot in Kansas. Both were very successful from a glycemic perspective. Aside from the fact that these apps work if you use them, we had two additional takeaways from the posters: (i) Type 2s on basal insulin are, unsurprisingly, under-insulinized – the group of My Dose Coach users who reached goal had to increase their basal dose by 20%, and the iSage users increased their dose by 38%; and (ii) there was a 58% discontinuation rate in Sanofi’s cohort – a reminder that sustaining engagement with these digital titration tools may be the biggest challenge for the field. (We also saw this same takeaway at ATTD in the ongoing NN Smart Pen/Dexcom CGM/TypeZero MDI titration study.) What will improve stickiness? How will these systems drive outcomes if people don’t open the app? (Bigfoot has a novel design here, as it expects to put the insulin titration algorithms directly on the Unity smart pen caps – read more here.) There are countless titration pilots around the US from a number of players, but this technology has yet to scale meaningfully. Will these demonstrations convince payers and clinics that an investment in insulin titration pays off? The new CPT codes for remote patient monitoring may also help nudge providers to give the systems a try.

• One Drop and Medtronic/IBM Watson (Sugar.IQ’s IQcast) both featured forward-looking blood glucose forecast features at ADA. One Drop announced eight-hour glucose forecasts for people with diabetes on basal insulin only, and shared that predictions for basal-bolus users (including type 1s) are next in line. A poster showed how One Drop has iterated to make its existing 12-hour projections for non-insulin-using type 2s more useful. This feature launched in October – we first saw it at ADA 2018 – and we’ll be interested to see what kind of efficacy this can drive, especially in people taking few fingersticks. (How accurate and useful will this be for people on basal-bolus insulin?) Similarly, Medtronic/IBM discussed how the IQcast feature works, offering a hypoglycemia warning up to four hours in advance – accuracy is reportedly quite high, though there are hurdles to better performance (e.g., lack of insulin data in the model). We are eager to learn more about the benefit vs. burden balance of these prediction features – How many people are using them, and how they are using them? How does someone respond to an alert that they are expected to go low in the next four hours or high in the next eight hours? How persistent is use, given the potential for more false positives? Can 3+ hour predictive alerts improve outcomes and drive long-term behavior change?

GLP-1 Agonists

Symposium: Once-Weekly Dulaglutide and Major Cardiovascular Events—Results of the REWIND Trial

In one of ADA 2019’s most highly-anticipated presentations, the full readout of Lilly’s REWIND CVOT (n=9,901) for GLP-1 agonist Trulicity (dulaglutide 1.5 mg) revealed a 12% relative risk reduction (RRR) on 3-point MACE (HR=0.88, 95% CI: 0.79-0.99) vs. placebo. Results were simultaneously published in The Lancet in two separate papers (CV outcomes, renal outcomes). Of critical importance, there was strong consistency on the primary outcome between the trial’s primary (69% of participants) and secondary (31%) prevention cohorts. The hazard ratio on MACE was 0.87 for both groups, with identical confidence intervals (95% CI: 0.74-1.02) – meaning that REWIND offers the first evidence that a GLP-1 agonist can reduce MACE risk in people with type 2 diabetes but without established CVD. Moreover, the “exploratory” renal analysis identified a (nominally) significant impact on the progression of renal disease and a number of other microvascular outcomes – find far more on that below. In addition to the large primary prevention cohort, REWIND is particularly notable for its duration of follow-up (median 5.4 years), the longest of any GLP-1 CVOT, as well as a low baseline A1c (median 7.2%) and large enrollment of women (46%) – the presentation emphasized that REWIND is more applicable to the general type 2 diabetes population than previous CVOTs. Below, dig into our rundown of the eight-part, two-hour symposium, and take a look at our updated CVOT landscape. As a reminder, these data have already been submitted to FDA and EMA.

Introduction and Research Question

Gilles R Dagenais, MD (Laval University Heart and Lung Institute, Quebec, Canada)

Dr. Gilles Dagenais gave an introduction to REWIND and GLP-1 agonist CVOTs, referencing the demonstrated three-point MACE risk reductions from LEADER for Novo Nordisk’s Victoza (liraglutide), SUSTAIN 6 for Novo Nordisk’s Ozempic (semaglutide), and HARMONY for GSK’s discontinued Tanzeum (albiglutide).  However, he noted, these trials were in people with mean baseline A1c ≥8.0% and an annual risk of CV events ≥4% – a comparatively higher risk population than that enrolled in REWIND.

Background, Design, and Outcomes

Rafael Diaz, MD (Estudios Clínicos Latinoamérica, Rosario, Argentina)

Dr. Rafael Diaz dug deeper into the evidence to-date and baseline characteristics from GLP-1 CVOTs. On a meta-analytic level, all five previously completed GLP-1 CVOTs combine to give a 12% RRR (95% CI: 0.84-0.94) on three-point MACE, including a 13% RRR (95% CI: 0.82-0.92) among those with established CVD but no demonstrated benefit in those with multiple risk factors (HR=1.03, 95% CI: 0.87-1.23). For reference, REWIND enrolled those ≥50 years old with vascular disease, ≥55 with subclinical vascular disease, or ≥60 with two CV risk factors, on any therapy save prandial insulin. All participants had an A1c ≤9.5% (which he characterized as a relatively high limit) and BMI ≥23 kg/m². Secondary outcomes included a microvascular composite (retinopathy + nephropathy), hospitalization for unstable angina, hospitalization for heart failure, individual MACE components, and total mortality.

Participants and Follow-Up

Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)

Dr. Matthew Riddle outlined baseline characteristics of the trial’s 9,901 participants, including mean age of 66 years, 46% female and 76% white enrollment, 31% baseline CVD, 21% prior MI/stroke, 93% hypertension, and 9% heart failure prevalence. Prior CV disease was defined as history of MI, ischemic stroke, unstable angina with ECG change, myocardial ischemia on imaging or stress test, or revascularization (coronary, carotid, or peripheral). Mean baseline A1c was 7.3%, BMI 32 kg/m², eGFR 75 ml/min/1.73 m², and diabetes duration 11 years; retinopathy prevalence was 9%, Stage 3 or greater CKD 22%, and albuminuria 35%. Additionally, 81% were on metformin, 46% SUs, 24% insulin, 6% DPP-4s, 2% TZDs, and <1% other; 82% were taking an ACE/ARB, 46% a beta blocker, 57% other blood pressure medication, 66% statin, 9% fibrate, and 54% antiplatelets. In an interview with our team, Dr. Brad Woodward (Global Brand Development Lead and Senior Medical Director, Lilly) noted that 5%-7% of participants were taking an SGLT-2 at the end of the trial. Median follow-up was 5.4 years, and total person years of follow-up was 51,820.

• At the end of REWIND, final status was known in 99.7% of participants in each arm; 97% attended the final visit, had a primary outcome event, or had a non-CV death. Additionally, for Trulicity and placebo respectively, 82%/83% of total follow-up time was on study drug, 73/71% were on study drug at their last visit, 58%/56% never stopped study drug, and 11%/8% stopped due to an adverse event – this last he characterized as low for a five-year study. Dr. Riddle seemed quite impressed by the overall retention and adherence in the study, as well as the 0.61% treatment difference on A1c at the end of the study (p<0.001) – which he called “rather significant and probably clinically significant,” particularly given the trial was not designed for A1c lowering. See the summary of clinical measures below:

Cardiovascular Outcomes

Hertzel Gerstein, MD (McMaster University, Hamilton, Canada)

Prof. Hertzel Gerstein presented cardiovascular results in the REWIND trial, headlined by a 12% RRR on three-point MACE (HR=0.88, 95% CI: 0.79-0.99). Kaplan-Meier curves for the composite cardiovascular outcome and each separate component (CV death, non-fatal MI, and non-fatal stroke) can be seen below. The K-M curve for the composite outcome separates after the first year and demonstrates a steady separation over time, consistent with hypothesized anti-atherosclerotic effects driving GLP-1 cardioprotection. Interestingly, it appears as if benefits in non-fatal stroke (HR=0.76, 95% CI: 0.61-0.95, p=0.017) drove much of the primary outcome benefit, which is similar to a 39% RRR on stroke with Ozempic in SUSTAIN 6.

• Dulaglutide’s CV benefit was importantly consistent in those with and without established CVD. Remarkably, the point estimate HR for both subgroups was identical (HR=0.87, 95% CI: 0.74-1.02). No significant interactions were seen in most subgroup analyses, with consistent effects across age, sex, diabetes duration, baseline A1c, and BMI above or below 32 kg/m². A disparity was seen in terms of geography, but this was attributed to the small sample size of participants from the Asia Pacific region; further analysis by ethnicity showed no interaction.

• There was a trend toward mortality benefit, both CV and all-cause, with Trulicity, but neither reached significance. The hazard ratio for all-cause death was 0.90 (95% CI: 0.80-1.01), and the HR for CV death was 0.91 (95% CI: 0.78-1.06). To our understanding, the lack of significance could be an effect of the lower-risk population, though it’s hard to say for certain.

Renal Outcomes

Helen Colhoun, MD (University of Edinburgh, Scotland)

University of Edinburgh’s Dr. Helen Colhoun took the stage for the renal outcomes; on the primary composite of new macroalbuminuria, 30% fall in eGFR, or progression to renal replacement, Trulicity conferred a significant 15% risk reduction (HR=0.85, 95% CI: 0.77-0.93, p=0.0004). This was driven primarily by reduction in new macroalbuminuria (HR=0.77, 95% CI:0.68-0.87), followed by sustained eGFR decline (HR=0.89, 95% CI:0.78-1.01, p=0.066), and slightly by reduction in renal replacement therapy (HR=0.75, 95% CI:0.39-1.44, p=0.39). Seeing as the eGFR component just barely missed out on superiority, Dr. Colhoun presented sensitivity analyses with more stringent guidelines (which are often used in dedicated renal trials or other CVOTs, e.g., DECLARE). If the eGFR decline threshold had been set at ≥40%, then the component would’ve reached nominal significance in favor of Trulicity (HR=0.70, 95% CI:0.57-0.85, p=0.0004), which further improved when tested at ≥50% (HR=0.56, 95% CI:0.41-0.76, p=0.0002). Dr. Colhoun attributed this trend to less random misclassification at more stringent thresholds. Notably, there were no subgroup differences on the composite outcome based on baseline eGFR (>60 or ≤60 ml/min/1.73 m², p for interaction=0.65), albuminuria (p=0.66), and ACE or ARB use (p=0.23). The last is particularly intriguing to us, as it suggests the renal benefit from Trulicity comes on top of antihypertensives, some of which are renoprotective themselves.

• Given the recent, very positive readout of CREDENCE (SGLT-2 inhibitor Invokana in DKD), we find it important to place REWIND’s renal results in perspective. While CREDENCE may have raised the threshold for excitement over renal data, we still view REWIND’s data quite positively, especially in light of the lower-risk population vs. other CVOTs and CREDENCE. It’s important to note that no therapies have been approved for CKD management in nearly 20 years, so there’s a desperate unmet need which ideally could be filled by multiple classes to better suit the diversity of patients with type 2 diabetes. Further, since the SGLT-2 inhibitor and GLP-1 agonist classes operate by such different mechanisms, we wonder whether there could be any additive or synergistic CV/renal benefit, on top of additive glycemic benefit.

Safety

Jeffrey Probstfield, MD (University of Washington School of Public Health, Seattle, WA)

Dr. Jeff Probstfield’s safety presentation was brief and reassuring: There was no significant difference between the Trulicity and placebo arms on 1^st study drug stopping, acute pancreatitis, any cancer, MTC or C-Cell hyperplasia, thyroid cancer, pancreatic cancer, serious renal/urinary event, serious GI event, SVT/CV conduction disorder, or severe hypoglycemia. There was a slight trend toward more hepatic events with placebo (p=0.057) and more immune reactions with Trulicity (p=0.022), but with very low numbers of events. Comparing all GI adverse events, 47% on Trulicity and 34% on placebo were affected (p<0.0001). Dr. Probstfield closed by underscoring a final measure of study population risk: The annual placebo MACE rate in REWIND was 2.7%, compared to 3.9% in LEADER, 4.0% in EXCEL, 4.4% in SUSTAIN 6, 5.9% in HARMONY, and 6.3% in ELIXA.

Summary and Implications

Lars Ryden, MD, PhD (Karolinska Institutet, Stockholm, Sweden)

Dr. Lars Ryden provided context for the REWIND trial, highlighting its influence on our interpretation of existing data for the GLP-1 class. Building on a recent meta-analysis published in Circulation by Zelniker and colleagues, Dr. Ryden showed that incorporating REWIND results leads to an overall weighted MACE hazard ratio of 0.88 (95% CI: 0.84-0.93), solidifying a class effect for GLP-1s. Importantly, REWIND contributes nearly 1/5 of the “weight” for the analysis, due to its large number of participants and long follow-up. In the population with established CVD, incorporating REWIND gives a 13% RRR (HR=0.87, 95% CI: 0.82-0.92, weight=12%); in those without CVD, the HR becomes 0.94 (95% CI: 0.84-1.06, weight=54%). Interestingly, the inclusion of REWIND data shifts the hazard ratio in the “no prior CVD” population from >1.0 to <1.0, as other trials for GLP-1s that included primary prevention cohorts (LEADER for liraglutide, SUSTAIN-6 for semaglutide, and EXSCEL for exenatide) all showed neutral effects on MACE in this subgroup. Seeing as thought leaders have mostly agreed upon cardioprotection as a GLP-1 class effect, we’re curious to see whether this data is compelling enough to convince the field of a cardioprotective effect for the class in primary prevention populations as well – especially since other GLP-1 trials have not shown such benefit.

Independent Commentary

Sophia Zoungas, PhD (Monash University, Melbourne, Australia)

Monash University’s Dr. Sophia Zoungas provided the independent commentary for REWIND, underscoring the study’s long follow-up and generalizable population as particularly noteworthy, especially when compared with other GLP-1 CVOTs. We appreciated the thoroughness of her analysis, which dissected the trial methods, results, and clinical implications one-by-one:

• REWIND’s low annual placebo MACE rate (2.7 events/100 patient-years) reflects its low-risk population and generalizability vs. all other GLP-1 CVOTs. By comparison, ELIXA had a placebo MACE rate of 6.3%/100 py, LEADER 3.9%/100 py, SUSTAIN-6 4.4%/100 py, EXSCEL 4.0%/100 py, and HARMONY 5.9%/100 py. To this end, Dr. Zoungas posited that the positive CV results across both the primary and secondary prevention cohorts of REWIND could lay the first brick in a case to update the ADA/EASD Consensus Statement, promoting GLP-1 agonists not only for those with established ASCVD but also for those with CV risk factors. Our sense, however, is that it will take further study, and perhaps more robust data specific to the primary prevention population, to truly move the needle.

• Although the excellent retention and adherence create a nearly flawless RCT analysis, they do not lend themselves to real-world generalizations. As suggested by Drs. Steven Edelman and Bill Polonsky in Diabetes Care in 2017, real-world data suggest that discontinuation rates for GLP-1 agonists may approach nearly 60% by 1-2 years – far shorter than the 5.4 year follow-up assessed in REWIND. To this end, while the results from REWIND are exciting for a multitude of reasons, providers must focus on promoting adherence to Trulicity to realize the CV and renal benefits, which may present cost-issues for some patients in the long-term. In general, Dr. Zoungas called for more patient-reported-outcomes (yes!) in CVOTs, such as quality-of-life data, though she acknowledged that their primary purpose is to assess the safety of novel therapies.

• Despite an apparent difference in Trulicity’s effect on stroke (significant reduction) and MI (nearly neutral), we should be cautious about drawing any conclusions on the molecular or class levels. Firstly, the confidence intervals for both endpoints were wide and overlapping in REWIND. Within the GLP-1 class, only SUSTAIN-6 has followed a similar pattern to REWIND (significant stroke reduction, non-significant trend on MI). Other CVOTs for human-based GLP-1s have had very different trends: In LEADER, MI and stroke trended very similarly toward liraglutide, without significance, while MI was significant in HARMONY for albiglutide but stroke was not.

• Consensus points toward kidney benefit and numerical increases in eye events in GLP-1 CVOTs. The renal benefit seen with Trulicity was positive, “any way you look at it,” while the eye outcome trended toward placebo (HR=1.24, 95% CI:0.92-1.68). As a reminder, the retinopathy signal in SUSTAIN-6 for Novo Nordisk’s Ozempic (semaglutide) prompted an FDA Advisory Committee prior to its approval.

• The number-needed-to-treat (NNT) to prevent one MACE event in REWIND was comparable to other CVOTs – 60 for the overall population and 18 in those with established CV disease, each over 5.4 years (the median follow-up). Intriguingly, Dr. Zoungas compared this value to SGLT-2 inhibitors instead of GLP-1 agonists: 39 over 3.0 years for Lilly/BI’s Jardiance in EMPA-REG and 40 over 2.5 years for J&J’s Invokana in CREDENCE. For GLP-1’s, this metric is only available for Novo Nordisk’s products: 66 over 3.0 years for liraglutide in LEADER and 45 over 2.0 years for semaglutide in SUSTAIN-6. Notably, NNT is heavily dependent on the study population’s risk level, making comparisons only useful at a very high level.

• With its diverse population and long follow-up, REWIND contributes significantly to consensus on GLP-1 CV class effects. When added, to Zelniker et al.’s meta-analysis of GLP-1 CVOT outcomes, REWIND contributes 25% of the weight toward an estimated 12% risk reduction on MACE (95% CI:0.84-0.93) for the entire class. Considering only the primary prevention data from these trials, REWIND shifts the overall point estimate from slightly trending toward placebo, to trending toward the GLP-1 class (see below).

• As parting words, Dr. Zoungas quoted the accompanying editorial for REWIND penned by Drs. Subodh Verma, CD Mazer, and Vlado Perkovic (we highly recommend), advocating for earlier intervention with novel agents in type 2 diabetes treatment: “If we are to reduce the burgeoning pump, pipes and filter complications of diabetes, we will need to overcome clinical inertia, and embrace these disease-modifying therapies early, and preferably in combination. The REWIND trial makes a strong case in this regard.”

• For future study, Dr. Zoungas identified three knowledge gaps related to the clinical impact of GLP-1 agonists: (i) Should GLP-1s with CV or renal benefits be used as first line therapy with lifestyle interventions? (we think displacing metformin would be a tough sell from both cost and efficacy standpoints); (ii) is there any additive CV or renal benefit with GLP-1s and SGLT-2s? If so, in what populations? (as a reminder, additive improvement in CV risk factors has been demonstrated); and (iii) are GLP-1s truly disease modifying? Are there any long-term pleiotropic effects or impacts on metabolic memory?

Key Opinion Leader Thoughts on REWIND

We at Close Concerns collected opinions on REWIND results from a number of thought leaders; find them organized topically below.

On how REWIND fits into existing GLP-1 CVOT data, and whether cardioprotection in primary prevention might be a class effect:

• Dr. Alice Cheng: There are important differences between GLP1 molecules in terms of half-life, derivation, size etc.  The effects on secondary prevention seem consistent for the GLP-1 class. The story is less clear cut for the CV benefits for primary prevention as a class effect because of the small numbers in the other studies (LEADER, SUSTAIN-6).  I would like to see more data to be more confident. 

• Dr. Naveed Sattar: One suspects it is true for several GLP-1 agonists - there may be subtle differences between the main GLP-1s, but for now, the broad effects and outcome benefits seem more similar than different.  That said, guidelines will continue to recommend those GLP-1s which have proven significant CVD benefit. 

• Dr. Francesco Giorgino: I do not see why it should not be a class effect, provided that adherence to treatment and time exposure to the drug is high (e.g., >80%).

• Dr. Charles Alexander: Most prescribers are likely to see the positive results from REWIND as a class effect. There is no reason to believe that the results are unique to dulaglutide.  I would not expect to see additional outcomes trials initiated since they are so expensive and labor-intensive.  Once a company has accumulated outcome results sufficient to satisfy FDA, they will not have any incentive to launch another one at this point. 

• Dr. Zachary Bloomgarden: The long-acting GLP-1RA now appear to have a class effect of reducing adverse CV outcome - this is good news!

• Dr. Philip Home: REWIND places another piece in the CV protection jigsaw. But clearly the findings of all the GLP1-RA studies taken together show many inconsistencies, likely as a result of chance.  The finding of no interaction for MACE between CV and CV risk populations is encouraging, but not consistent with the other CVOTs, and thus not conclusive. Accordingly, this does not allow the conclusion that we should be prescribing GLP-1RAs for CV protection in people who do not already have CV disease.

• Dr. Dan Drucker: REWIND provides further support for the cardioprotective actions of the long-acting GLP-1 class. While each trial population, design, and study drug is unique, it is highly reassuring to again see a reduction in MACE, now in a lower baseline A1c population with less pre-existing CV disease.

Interpreting exploratory renal analysis from REWIND:

• Dr. Naveed Sattar: As I understand it, the main effect was on albuminuria but not on eGFR. I think to prevent deterioration on harder renal outcomes, SGLT-2 inhibitors have an advantage and one imagines more clinicians are more impressed by the SGLT-2 inhibitor effects on renal outcomes.   

• Dr. Dan Drucker: The renal data, while perhaps mildly disappointing, may reflect the low rate of pre-existing renal disease and more studies of different populations are warranted. 

• Dr. Charles Alexander: The renal results were good across the board, but not as good as the SGLT-2 inhibitor results (e.g., CREDENCE) where you see amelioration of the decline in eGFR. REWIND showed continued decline in eGFR despite the positive renal outcomes.  Subsequently, when treating a patient with diabetic nephropathy, the preference will continue to be SGLT-2 inhibitor.  The data in CREDENCE is very convincing that the previously certain inevitable progression of diabetic nephropathy can be aborted by a SGLT-2i.  Although GLP-1 RA improved renal outcomes in REWIND, it did not do as well as SGLT-2i.

• Dr. Zachary Bloomgarden: The renal data also indicates a class effect, reducing albuminuria and additionally with modest benefit in slowing the rate of fall in GFR.

• Dr. Francesco Giorgino: It looks like the effect is on albuminuria largely, as for other GLP-1RA. I am a little surprised that baseline eGFR did not impact on the renal outcomes.

• Dr. Sanjay Kaul: The renal data are interesting exploratory results which are driven by the most prevalent, but arguably the least important component (microalbuminuria). Of note, the choice of eGFR decline >30%, while amplifying the event rate, did not enhance the chance of success. Had they chosen eGFR decline >40% or >50% in the composite, there would be a larger effect size on the renal composite, albeit with lower frequency of events. Thus, softening the criterion for a win by lowering eGFR decline threshold might not be a successfully strategy.

• Dr. Philip Home: The most intriguing exploratory results reported in REWIND is the much greater statistical power for change in creatinine for reduction of 50% compared to 40% or as pre-specified here 30%. This suggests we should re-examine some of the data for GLP-1RAs and SGLT2 inhibitors using these discriminants, as we may be missing an important message. But again, chance may be misleading us. 

• Dr. Alice Cheng: As for the renal data, the majority of the benefit was driven by the urine ACR which was seen with other GLP1RA studies so there is consistency. 

On the robustness of REWIND data:

• Dr. Sanjay Kaul: The effect size on the primary endpoint is modest and statistically not robust (p=0.03). These results fall short of the “substantial evidence” criterion required for approval based on a single trial. A couple of extra events in the dulaglutide arm or a couple of fewer events in the control arm would overturn statistical significance. The fragile data are particularly prone to missing data. I did not see sensitivity analyses accounting for missing data.

Unlike LEADER where the point estimate was a HR of 1.20 and SUSTAIN-6 and EXSCEL where the point estimate was a HR of 1 and 0.99, respectively, the point estimate in REWIND is a HR of 0.87. .  Guidelines appropriately restrict the use of approved GLP-1 RA for mitigating CV risk to patients with established CV disease. . 

I would have liked to see a greater treatment benefit in the cohort with established CV disease. In contrast with semaglutide that showed a 4.5% absolute risk reduction in SUSTAIN-6 in patients with established CV disease, the absolute risk reduction in REWIND was 2.4%. 

• Dr. Zachary Bloomgarden: The benefit on cardiovascular outcomes is somewhat modest - certainly less than that of statins and of BP-lowering treatment. The NNT is likely not to be very impressive [Editor’s note: the NNT is 60 for those without established CVD, and 18 for those with established CVD].

On how REWIND may impact clinical practice:

• Dr. Alice Cheng: These results are definitely going to influence clinical practice. If you had asked me back in 2015 if any of our diabetes therapies would reduce CV outcomes in a majority primacy prevention population, I would have said that is wishful thinking. Now, it is reality. I hope this will shift treatment paradigms to first focus on outcome-based therapies that happen to lower A1c then if still needed, add other therapies to further lower A1c. 

• Dr. Naveed Sattar: Evidence adds to now strong belief that GLP-1 receptor agonists lessen vascular disease risk in diabetes patients whether or not they have existing CVD - this new evidence will continue to push towards these agents to be used sooner in algorithms and clinical care but of course the higher costs means this will be a slow process for now. Budgets are not boundless so higher risk patients will likely be targeted first. That the results show benefit despite excellent baseline A1c further supports an effect which is not mediated only by glucose.  

• Dr. Francesco Giorgino: I think the issue of the CV risk level of the patient should be reconsidered on the basis of the REWIND data. In the context of several-year treatment and more stringent glucose control without hypoglycemia GLP-1RAs seem to be protective also for individuals without CVD. 

• Dr. Charles Alexander: I don't think that REWIND will change ADA guidelines (especially given the recent ADA update) and don't think that it will change prescriber behavior beyond what they were already doing or going to be doing based on other recently reported CV outcomes trials (e.g., CREDENCE, LEADER, etc.).  That said, it was a great result for Lilly as they now have a GLP-1 RA that shows superior CV outcomes like the results for liraglutide and semaglutide. The DPP-4 inhibitor class cannot compete with the SGLT-2i/GLP-1 RA results and you will see that class being used less and less especially after oral semaglutide is approved.

• Dr. Zachary Bloomgarden: I would like the results to influence clinical practice, since I happen to believe that glucose control matters, and therefore that these drugs should play a role throughout the natural history of type 2 diabetes.

• Dr. David Harlan: Being a clinician scientist who is, when it comes to the patients I serve, concerned first, last, and always in doing all that I can to promote their health -- this study just strengthens my belief (based on good data) that nearly all patients with T2D with suboptimal glycemia control and/or other factors like worsening obesity should be considered candidates for a GLP1R based therapy.

Interpreting individual MACE component effects:

• Dr. Philip Home: REWIND again emphasized the importance of the GLP-1RAs in stroke reduction.  This is important as the SGLT2-blockers show no effect at all on stroke.  Furthermore, in the REWIND population stroke was nearly as frequent as MI as an endpoint, and a cause of more deaths. 

• Dr. Sanjay Kaul: The reduction in nonfatal stroke (the only component that was significantly reduced) is consistent with semaglutide in SUSTAIN 6 and PIONEER 6, but not with albiglutide in HARMONY. 

• Dr. Zachary Bloomgarden: The CV data is strongest for stroke prevention - very interesting, and this also confirms some of the other GLP-1RA data. The mortality data is suggestive, again, not a strong effect

• Dr. Charles Alexander: I was also surprised that nonfatal stroke was the endpoint that was driving the statistical significance of the MACE composite endpoint in this study. CV death was next and nonfatal MI had the least effect on the composite endpoint and was not different between the 2 groups.  That is very strange.  Other GLP-1 RA studies have shown benefit for MI.

Symposium: Oral Semaglutide—The PIONEER Program Trials

Trial Design and Baseline Characteristics

Stephen Bain, MD (Swansea University, UK)

Dr. Stephen Bain presented trial design and baseline characteristics. PIONEER 6 was an international trial, enrolling participants from 21 countries. Around half were from North and South America, one-third from Europe, and the remaining from Africa and Asia. Participants were randomized to either 14 mg oral semaglutide or placebo. Key inclusion criteria for those with type 2 diabetes included either being over 50 years and having established CVD or moderate CKD (this ended up being ~85% of trial participants), or being over 60 years and having CV risk factors (~15% of trial participants). Notable key exclusion criteria included recent treatment with a GLP-1 or DPP-4 and having proliferative retinopathy (in light of the retinopathy signal seen in SUSTAIN-6, which did enroll this patient group). In total, 3,183 patients were randomized in the trial, with a high 99.7% trial completion percentage – Dr. Bain highlighted this achievement as a testament to the commitment of the trial participants and the study investigators. In terms of glucose-lowering agents used at baseline, 77% were on metformin, 60% on insulin, 32% on a sulfonylurea, 9% on an SGLT-2 inhibitor, and 4% on a TZD.

Cardiovascular Outcomes

Mansoor Husain, MD (University of Toronto, Canada)

The final session of ADA 2019 featured results from the PIONEER 6 CVOT (n=3,183, median follow-up 16 months) for Novo Nordisk’s phase 3 oral semaglutide, building on topline results released last November: While oral semaglutide did not demonstrate superiority vs. placebo on the primary outcome of three-point MACE, it did trend strongly in that direction with a hazard ratio of 0.79 (95% CI: 0.57-1.11, p<0.001 for non-inferiority, p=0.17 for superiority). See the full results in NEJM. Toronto General Research Institute’s Dr. Mansoor Husain detailed full CV outcomes, including the impressive Kaplan-Meier curves for all-cause mortality and CV death (see below). A 49% risk reduction was found with oral semaglutide on the former (HR=0.51, 95% CI: 0.31-0.84, p=0.008), and a 51% risk reduction was found on the latter (HR=0.49, 95% CI: 0.27-0.92, p=0.03), which drove the nonsignificant trend in favor of oral semaglutide on three-point MACE. On the other components, a trend in favor of placebo was beginning to form on MI toward the end of the trial (HR=1.18, 95% CI: 0.73-1.90) while the stroke result also favored oral semaglutide (HR=0.74, 95% CI: 0.35-1.57). However, considering the trial was powered only for safety, meaning the total number of events was much lower than other CVOTs and the trends should be interpreted with caution. On balance, this low event rate also makes the significant reductions in mortality particularly spectacular. On all-cause mortality, ~two-thirds of events were CV-related, and equal reductions were seen in both CV and non-CV death. Importantly, expanded CV outcomes revealed no safety signals on hospitalization for heart failure (trend in favor of oral semaglutide) or unstable angina requiring hospitalizations (trend against oral semaglutide). Three-point MACE estimates were consistent across subgroups, suggesting the primary endpoint results to be consistent across the enrolled population. The room was very full, notable for Tuesday morning at ADA, and the room was rapt listening to a full range of top-notch notable, (very) respected researchers. It was an important set of presentations, given the importance of removing a perceived / real barrier – we’re excited to see what could happen next.

• As a reminder, oral semaglutide has been submitted to FDA with a priority review voucher, meaning a decision is expected by September 2019. Novo Nordisk has also requested CV indications for both oral semaglutide and Ozempic (injectable semaglutide), based on PIONEER 6 and SUSTAIN 6, and decisions on both are expected ~January 2020. Submission in Europe and Canada is also complete.

Metabolic and Safety Outcomes

Ofri Mosenzon, MD (Hadassah Hebrew University, Israel)

Dr. Ofri Mosenzon shared metabolic and safety outcomes: Oral semaglutide significantly reduced A1c (-1.0% vs. 0.3%) and body weight (-4.2 kg weight loss vs. 0.8 kg weight gain) vs. placebo, from baselines of 8.2% and 90.9 kg, respectively – very strong results after a median 16 month of follow-up. Very notably, both of these come despite significantly more initiation of other antihyperglycemic agents, including SGLT-2 inhibitors, in the placebo arm (see below). Of course, it’s entirely possible that these reductions may have contributed to the CV safety and efficacy observed with oral semaglutide, though results from other GLP-1 CVOTs achieved smaller treatment differences and still reduced CV risk. However, it’s worth noting that nearly the exact same reductions were seen with the higher dose of injectable semaglutide in SUSTAIN-6 – 1.05% A1c drop and 4.35 kg weight loss (both placebo-adjusted). Dr. Mosenzon also highlighted a modest but significant reduction in systolic blood pressure with oral semaglutide (-5 mmHg vs. -2 mmHg), despite more antihypertensives and diuretics being initiated after baseline in the placebo arm (see below). On safety, oral semaglutide conferred an elevated number of gastrointestinal events (108 vs. 26), consistent with the GLP-1 class, but there were no other imbalances. There was a modest increase in diabetic retinopathy with oral semaglutide vs. placebo (7.1% of patients vs. 6.3%), but this was not significant. Importantly, Dr. Vivian Fonseca noted in his independent commentary that diabetic retinopathy at baseline was excluded from the trial – a population that had an increased risk of retinopathy complications in SUSTAIN-6 and a population that we’re disappointed to see left out though it makes sense from a risk/benefit perspective.

Summary

John Buse MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC)

Session chair Dr. John Buse presented a post hoc analysis combining the data from PIONEER 6 and the SUSTAIN 6 CVOT for Ozempic (injectable semaglutide), showing a significant 24% RRR on three-point MACE (95% CI: 0.62-0.92) and a 35% RRR on stroke (95% CI: 0.43-0.97) – see full results below. While there was no significant risk reduction on CV death or non-fatal MI, both trend strongly in favor of the semaglutide molecule. Our sense is this pooled analysis may play into FDA’s review of Novo Nordisk’s requested CV indications for both oral and injectable semaglutide. Additionally, Dr. Buse reviewed the totality of primary endpoint results from GLP-1 and SGLT-2 CVOTs, pointing to consistently positive effects on three-point MACE with all long-acting GLP-1s (only ELIXA for lixisenatide did not demonstrate superiority or trend strongly in favor of the GLP-1). Dr. Buse concluded his talk by expressing hope that eliminating the injection barrier with GLP-1s will lead to more widespread use, characterizing oral semaglutide as a great addition to this new and exciting era of diabetes management.

Independent Commentary

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

In delivering the independent commentary, Dr. Vivian Fonseca expressed great excitement over the clinical potential of oral semaglutide – it turns out that there are a low number of events and some differences between PIONEER 6 and SUSTAIN 6. While effects on three-point MACE and stroke were similar between PIONEER and SUSTAIN, there were disparate trends on CV death and MI between the trials (see just above) – PIONEER 6 also differs from LEADER (for liraglutide) on MI. He postulated that a difference in CV effects could arise through the different routes of administration, though this could also be a function of the relatively low number of events. Other important questions remain: How will oral semaglutide perform in the real world, particularly due to fasting requirements? Are there other drug interactions, and will fasting requirements make polypharmacy challenging? What is oral semaglutide’s impact on retinopathy? All of this said, Dr. Fonseca was very positive on the glycemic, weight loss, and CV efficacy as well as the safety and tolerability (slightly better than injectable semaglutide, in his assessment) of oral sema – suggesting that it even has the potential to replace all injectable GLP-1s.

Select Questions & Answers

Q: Have you looked at the impact of SGLT-2s specifically regarding MACE?

A: We haven’t specifically examined it, but if you read the discussion in the paper it does address their potential impact. Use was well balanced between the two treatment arms – there was a slight imbalance but I don’t believe it undermines the effects observed.

Q: In PIONEER 4, it seems semaglutide had a higher rate of serious adverse events vs. liraglutide. Did you mind any other side effects that were higher with semaglutide?

A: I think what you see in the trials as a whole is that there’s some variability in the rate of adverse events – in all clinical trial. The take home message is that adverse events are pretty well balanced against comparators and the rates of nausea and vomiting are consistent with the GLP-1 class.

Q: When it comes to responders and non-responders, I’d be interesting in knowing the subgroup of those defined by response. Is there gradation in risk for cardiac events?

A: With the prespecified subgroup analyses we did do, there’s no obvious interaction or statistical p values suggesting people with higher BMI, younger, or older have differences. Again, it’s a relatively small number of events.

A: And reflecting across other studies, I don’t think anybody has a great angle on the characteristics of responders. To date, the benefit is largely in patients with prior CVD with the exception of the REWIND trial that had a large group without CVD.

Q: I’m interested in more details on CV death vs. ACM. About 1/3 to 25% have an undetermined cause of death; it might be useful to get a full list of causes of death in the trial because in ACM there could also be renal death or liver problems.

A: You’re right in that assessment; about 2/3 of death in both arms was cardiovascular, and amongst the CV group there are some undetermined causes. With no clues what happened, it’s correct to assume CV death. There’s no imbalance there, which is why I took care to show all cause death. Any potential imbalance could have swayed the result one way or another. I don’t have an explanation for the non-CV deaths; there is a numerical difference, but those are the data.

Q: Is there any comparative data between oral and subcutaneous routes in serum levels at max or other doses?

A: There has been phase 2 testing against the SC dose, with up to 20 mg oral; this is how PK/PD data established the 14 mg dose. It’s seen with glycemic and weight loss efficacy that we’re getting good active levels at 14 mg.

Symposium: Cardiovascular and Renal Protection in Diabetes—Emphasis on SGLT-2 Inhibitors and GLP-1 Receptor Agonists

Cardiovascular Effects of GLP-1 Receptor Agonists—From Basic Mechanisms to Clinical Data

Jens Holst, MD (University of Copenhagen, Denmark)

In a talk on CV effects of novel therapies, University of Copenhagen’s Dr. Jens Holst picked out an intriguing recent study suggesting that A1c lowering in CVOTs may have a more profound effect on CV outcomes than previously thought. Despite CVOTs being designed for glycemic equipoise (i.e., both arms achieving the same A1c to assess CV effects independent of glucose lowering), they often fail to achieve balance due to the strong efficacy of novel therapies (SGLT-2s, GLP-1s) vs. “placebo” (or, rather, standard care). To this end, Second University of Naples’ Professor Dario Giugliano conducted a meta-analysis for all completed CVOTs for DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists, finding a significant relationship between achieved A1c and the hazard ratio reduction for MACE (p=0.002). Notably, this relationship explained nearly all (94.1%) of between-study variance. Per the analysis, lowering A1c by 0.5% conferred a significant risk reduction of 20% (95% CI: 4%-33%) on MACE. By component, there was no relationship between achieved A1c and the risk ratio for nonfatal MI or CV death, but there was a significant correlation with nonfatal stroke (p=0.002). Together, these results suggest that the cardioprotection found in many of the recent CVOTs may by partly related to A1c lowering, rather than an independent cardiometabolic effect. That said, we note that DPP-4 inhibitors were very neutral across the board, regardless of A1c lowering (though no trial breached the 0.5% difference mark), meaning that the trend was carried heavily by SGLT-2 inhibitors and GLP-1 agonists. Indeed, there isn’t a huge diversity of data feeding into this analysis, and, to our understanding, trials of intensive glucose lowering have also generally struggled to show an impact on CV risk (though this is another question in and of itself). Of course, weight change is also prominent with these agents, and we’d love to see an analysis which takes this variable into account.

• Notably, the three CVOTs which read out at ADA – REWIND for GLP-1 agonist Trulicity, CAROLINA for DPP-4 inhibitor Tradjenta vs. sulfonylurea glimepiride, and PIONEER 6 for GLP-1 oral semaglutide – all fit well into this model. REWIND achieved an A1c difference of 0.61% with Trulicity and conferred a significant 12% reduction on 3-point MACE, placing it solidly in the far right bin of the below figure. CAROLINA had an A1c difference of <0.1% and a HR of 0.98 on MACE, placing it in the far left bin, and PIONEER 6 had an A1c difference of 0.7% and a MACE HR of 0.79, placing it in the far right bin.

Mini-Symposium: Cardiovascular Disease in Patients with Diabetes

Controversies in Clinical Implementation—Should the Use of Novel Therapies Be Conditional on Background Metformin and Baseline A1C? Extended to Lower Risk Patients? Those with Chronic Kidney Disease?

Jean-François Yale MD (McGill University, Canada)

In a comprehensive talk reviewing the clinical implementation of SGLT2 inhibitors and GLP-1 agonists, Dr. Jean-François-Yale urged clinicians to leverage price equivalence of higher doses into lower patient costs. After a thorough rundown of clinical trial data that has illuminated the impressive effects SGLT2i and GLP-1RAs on A1c, weight, and cardio and renal protection, Dr. Jean-François Yale turned to what he views as the last hurdle for these therapy classes: cost. Very few people with diabetes are actually on either of these classes (see this 2017 Diabetes Care article), a fact he attributed to often-prohibitive costs that makes their broad scale use as a first- or second-line therapy challenging. Dr. Jean-François Yale highlighted this barrier by contrasting the patient cost of a “classical” treatment approach that does not involve newer drug classes (i.e. using metformin, a sulfonylurea, and a DPP-4) against costs with an “innovative” approach using newer drug classes (i.e. metformin, an SGLT2i, and a GLP-1RA). The total daily cost of the classical approach would be ~$16.60/day compared to ~$43.60/day for the innovative approach (and we note that even the classical approach may be cost-prohibitive for many!); to our understanding, this doesn’t account for reimbursement. How might clinicians work around this barrier? Dr. Jean-François Yale detailed a simple yet novel strategy that he uses in practice that can make a dramatic difference for patients: Costs for low and high doses of SGLT2i pills are currently identical, and this price equivalence can be uniquely leveraged to help patients reduce the costs of SGLT2 inhibitors, especially if they only require a lower dose. Dr. Jean-François Yale recommended that clinicians prescribe the higher dose of the pill, and then have patients cut the pills in half and take them separately – effectively halving the price of their medication (see slide below) while still getting the full lower dose. Of course, we can imagine several barriers that might limit the effectiveness of this strategy: Will patients view pill-splitting as too much of a burden? Could there be potential for over-dosing if a patient forgets to split? An alternative is to use an SGLT2i-Metformin combination pill of the higher dose but only 1 pill a day effectively giving a low-dose SGLT2i at a low cost with half of the daily metformin. We’re intrigued by the approach and curious about how widespread its adoption could be – surely, for the right patient it could work! Even more encouragingly, Dr. Jean-François Yale pointed out that a similar approach can also be taken with semaglutide, for which the high dose (1.0 mg/week) pens are priced the same as low dose (0.5 mg/week) pens. Adding both of these “hacks” to the equation, the cost of the innovative treatment approach can be lowered to $14.90/day – actually lower than the $16.60/day for the classical approach!

Oral Presentations: Incretins Marching On

Oral Semaglutide vs. Empagliflozin Added On to Metformin Monotherapy in Uncontrolled Type 2 Diabetes: PIONEER 2

Eduard Montanya, MD, PhD (University of Barcelona, Spain)

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

• Of note, discontinuation was more common in the semaglutide group compared to the empagliflozin group: 75% of patients randomized to the GLP-1 remained on-treatment without rescue medication (n=310) vs. 79% of those randomized to the SGLT-2 (n=322). There are some concerns circulating about tolerability of oral semaglutide and whether this will translate to suboptimal adherence in the real world, but Dr. Montanya emphasized that the GI side-effects seen in the PIONEER program largely match what’s expected of any GLP-1 agonist, oral or injectable. In PIONEER 2, nausea affected 20% of patients on oral semaglutide and 2% of those on Jardiance; 7% and 2% experienced vomiting, respectively. Decreased appetite occurred in 5% of semaglutide patients and <1% of empagliflozin patients (although this was listed as an adverse event, we note that suppressing appetite is one component of a GLP-1 agonist’s mechanism of stimulating weight loss). GI symptoms led 8% of study participants on oral semaglutide to discontinue therapy, vs. <1% of people taking Jardiance.

• Results from the entire PIONEER program have been submitted to FDA to support approval of the first-ever oral GLP-1 agonist. Dr. Hobbs told us that he’s “very optimistic about approval this year.” Novo Nordisk filed its oral semaglutide NDA in March with a priority review voucher, meaning a regulatory decision is expected by September 2019. Despite ongoing discussion in the diabetes community about intent-to-treat vs. on-treatment analyses of the PIONEER trials, we ultimately believe that both sets of results contain valuable knowledge. We’re excited about oral semaglutide and its potential to get more patients on a GLP-1. To this end, we were interested to learn from Dr. Hobbs that oral semaglutide marketing will be targeted toward primary care physicians, who have previously shied away from prescribing injectable GLP-1s. This is a great idea from our view – we’d love to see the suggestion as soon as possible.

• As for how oral semaglutide will compete with oral SGLT-2 inhibitors? That remains an open question. Much will depend on how Novo Nordisk prices oral sema (nothing has been disclosed on this front), and on how payers interpret PIONEER 2. We view oral semaglutide as a fantastic addition to the diabetes treatment toolkit, a new therapy that should improve diabetes care overall rather than compete with existing oral drugs per se. We suspect that different patients may do better on an oral GLP-1 agonist vs. an injectable GLP-1 agonist vs. an SGLT-2 inhibitor, and we’re curious to see how oral sema could be used in combination with an SGLT-2 to achieve even better outcomes.

Oral Semaglutide vs. Liraglutide and Placebo in T2D: PIONEER 4

Richard Pratley, MD (AdventHealth Translational Research Institute for Diabetes and Metabolism)

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

A1c Results

Weight Loss Results

* = p<0.05 vs. placebo

⁺ = p<0.05 vs. Victoza

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

• In addition to these results, Dr. Pratley presented data on (i) percent achieving A1c <7.0%; and (ii) FPG. The former was achieved by 68% on oral semaglutide, 62% on Victoza, and 14% on placebo at 26 weeks in the ITT analysis; at 52 weeks, these numbers decreased similarly across the two treatment groups, to 61%, 55%, and 15%. In the on-treatment analysis, the percent achieving A1c <7.0% was 72%, 65%, and 16% at 26 weeks and 69%, 63%, and 18% at 52 weeks, respectively. FPG results align with the A1c findings: Oral semaglutide gave a 36 mg/dl reduction, Victoza 34 mg/dl, and placebo 7 mg/dl at 26 weeks, slightly attenuated to 34 mg/dl, 27 mg/dl, and 13 mg/dl by 52 weeks – at which point oral semaglutide gained superiority over Victoza. We’d like, as with other trials that didn’t use CGM, to see Time in Range in addition to A1c and FPG differences.

• PIONEER 4 randomized people with type 2 diabetes on metformin, with or without an SGLT-2 inhibitor and in need of additional glycemic control in a 2:2:1 ratio to 14 mg oral semaglutide, 1.8 mg liraglutide, or placebo. Titration for oral semaglutide took place over eight weeks (four weeks on 3 mg, then four weeks on 7 mg), and titration for liraglutide took place over four weeks (two on 0.6 mg and two on 1.2 mg). 97% of participants in the oral semaglutide and liraglutide groups completed the trial, with 85% and 87% completing treatment overall and 78% and 81% completing treatment without rescue medication. Baseline A1c was 7.9%-8.0%, age 56-57 years old, diabetes duration 7-8 years, and BMI 33 kg/m².

Select Q&A

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

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

Liraglutide for Perioperative Management of Hyperglycemia in Cardiac Surgery Patients (GLOBE): A Multicenter, Prospective, Superiority Randomized Trial

Abraham Hulst, MD (Amsterdam University Medical Center, Amsterdam, Netherlands)

Dr. Abraham Hulst shared findings from the GLOBE trial, demonstrating that preoperative liraglutide may improve peri-operative glycemic control during cardiac surgery. Patients undergoing cardiac surgery often become hyperglycemic during the procedure and need insulin delivered intravenously, which creates an increased risk of hypoglycemia for the patient and an additional burden for the team performing the surgery. Adult patients undergoing cardiac surgery at multiple Dutch hospitals were given 0.6 mg liraglutide (the low, titration dose of Victoza) or placebo the night before surgery, followed by 1.2 mg liraglutide or placebo after anesthesia at the time of the procedure. Only 43% (55 out of 139 total) of patients given liraglutide needed insulin during the cardiac procedure, while 61% (80 out of 139 total) given the placebo needed insulin during the procedure. This led to an 18% absolute difference (95% CI: 5.9-30.0, p=0·003) between the liraglutide and placebo groups, with participants in the liraglutide group also requiring both significantly lower doses of insulin and fewer insulin injections, as well as achieving lower mean blood glucose levels. There was no difference in complications (i.e. hypoglycemia, nausea, mortality, postoperative complications) between the liraglutide and placebo groups; we wonder if a larger study might have shown fewer post-op complications with liraglutide. Findings from this study may lead to improved management of blood glucose via changes in cardiac surgery procedures, especially for patients with diabetes. In the future, Dr. Hulst plans to focus on more real-world situations and further reducing glucose-related complications from cardiac surgery.

Efficacy of Efpeglenatide in Patients with Obesity and Prediabetes: A Sub-Analysis of the BALANCE 205 Study

Richard Pratley, MD (Florida Hospital, Orlando, FL)

In BALANCE 205, Sanofi’s phase 3 GLP-1 candidate efpeglenatide stimulated reversion to normoglycemia in patients with prediabetes and overweight/obesity (n=140). Florida’s Dr. Richard Pratley presented these findings to kick-off a session filled to the brim with new data on GLP-1 agonists. By the end of the study (21 weeks), 48.2% of people on efpeglenatide reverted to normoglycemia compared to only 10% of people on placebo. (Note that participants were also instructed to cut food intake by 500 calories/day.) Normoglycemia was defined as A1c below 5.7% and fasting plasma glucose (FPG) below 100 mg/dl; average baseline values in this cohort were 5.7% and 102 mg/dl, respectively. Dr. Pratley did not report a p-value, but he went on to show a highly-significant 0.4% placebo-corrected A1c drop with efpeglenatide (p<0.0001) and an 11.2 mg/dl decrease in FPG (p<0.0001). From a baseline ~202 lbs, efpeglenatide resulted in a mean ~14.5 lbs placebo-corrected weight loss (p<0.0001). And from a baseline 36 kg/m², BMI dropped by 2.4 kg/m² with efpeglenatide vs. placebo on average. Dr. Pratley suggested that the greatest preventative benefit was seen with the 4 mg dose of efpeglenatide given once-weekly: Nearly 50% of patients randomized to this GLP-1 regimen no longer had prediabetes after 21 weeks, which strikes us as quite remarkable. BALANCE 205 also investigated a 6 mg once-weekly dose of efpeglenatide alongside a 6 mg twice-monthly dose and an 8 mg twice-monthly dose. Sanofi is currently examining three potential dosing schemes (low, medium, and high) in a phase 3 trial, which is expected to complete in August 2020, in time for a planned filing in 2021. If approved, efpeglenatide would be the fifth-to-market once-weekly GLP-1 agonist for type 2 diabetes, after AZ’s Bydureon (exenatide), Lilly’s Trulicity (dulaglutide), Novo Nordisk’s Ozempic (semaglutide), and GSK’s Tanzeum (albiglutide), though the latter was discontinued in 2017. We’ll be curious to see whether Sanofi pursues an obesity indication for the drug, especially since the obesity market is mostly untapped, with the vast majority of patients untreated. A prediabetes indication would be even more exciting from a public health standpoint, though FDA’s willingness to approve a therapy for prediabetes remains uncertain and challenging.

Select Questions and Answers

Q: Can you put these results into context with how efpeglenatide performs in type 2 diabetes?

A: In patients with diabetes, weight loss was similar but we saw larger reductions in A1c because of a higher baseline. Safety and tolerability of the agent were consistent with the diabetes population.

Q: Do you think this therapy would affect regression to diabetes? Did you assess beta cell function or insulin resistance, anything like that?

A: Unfortunately, we didn’t collect that information in this study. It was a short-term study, so it would be hard to assess those parameters.

Dr. Michael Nauck: I’m a little bit surprised that a drug can lower A1c significantly and fasting plasma glucose significantly and it didn’t bring more people to normoglycemia in this group.

A: That’s a function of patient distribution and how well we measured those parameters. In the future, we’re going to assess this rigorously. More work will be done on this for sure.

Oral Presentations: Innovations in Insulin Therapy

DUAL VIII: Significantly Longer Time to Treatment Intensification with Insulin Degludec/Liraglutide (IDegLira) vs. Insulin Glargine (IGlar U100) in a 104-Week (Wk) Randomized Trial Mirroring Clinical Practice

Vanita Aroda, MD (Brigham and Women’s Hospital, Boston, MA)

Brigham and Women’s Dr. Vanita Aroda revealed full 104-week results from the DUAL VIII trial (n=1,012 insulin-naïve people with type 2 diabetes), which found significantly greater durability of treatment effect alongside vast improvements in insulin dose, weight, and hypoglycemia with Novo Nordisk’s GLP-1/basal insulin combo therapy Xultophy (liraglutide/insulin degludec) vs. Sanofi’s basal insulin Lantus (insulin glargine) – full results and an accompanying editorial were simultaneously published in Lancet Diabetes and Endocrinology. At the end of the 104-week study period, just 37.4% of those taking Xultophy met the requirements for treatment intensification (defined as back-to-back A1c measurements ≥7.0%) compared to 66.2% of those on Lantus (p<0.0001), though both values were steadily rising. Among those reaching the 104-week mark with an A1c <7.0%, 51.8% on Xultophy did it with no hypoglycemia vs. 25.5% with Lantus (p<0.0001), 20.9% on Xultophy did it with no weight gain vs. 6.3% on Lantus (p<0.0001), and 20.0 % on Xultophy did it with no hypoglycemia or weight gain vs. 6.1% on Lantus. Daily insulin dose was cut down by almost 30% in those taking Xultophy (37 units/day vs. 52 units per day), and Xultophy also conferred half as much weight gain vs. Lantus (1.7 kg vs. 3.4 kg, p<0.0001). Very impressively, there was a 56% lower rate of severe or blood glucose-confirmed symptomatic hypoglycemia with Xultophy compared to Lantus (ERR=0.44, 95% CI: 0.33-0.60, p<0.0001). Altogether, these results paint a stunning picture of the sheer power of GLP-1/basal combinations, particularly Xultophy, as first-line injectables (as a reminder, Dr. John Buse has previously called these agents, “without a doubt the most powerful glucose-lowering agents on the planet”). While it may not have been a fair fight from the get-go – pitting two highly efficacious agents in combination vs. a single, first-gen basal insulin – we do believe these results make a strong case for earlier and more aggressive treatment with GLP-1/basal combinations. As a reminder, FDA earlier this year removed the label restriction requiring that patients already be taking basal insulin or liraglutide before starting Xultophy, meaning that first-line treatment with this agent is just now possible in the US (this restriction never applied OUS). It’s great from our view that this label is gone, though memories are long.

• We continue to be impressed by the clinical performance of Xultophy and other GLP-1/basal insulin combinations but note that commercial uptake has lagged significantly behind. Building on optimal clinical outcomes, a DUAL VII post-hoc analysis at EASD 2018 found 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. Yet, despite these multifactorial benefits, neither Xultophy or Soliqua has truly taken off in the market, particularly in the US. In a conversation with our team, Novo Nordisk CMO in North America Dr. Todd Hobbs confessed his belief that it “might be too late in the US to rebound … once you have a tough product launch, it can be difficult to bounce back.” That said, Xultophy is doing quite well in several countries in the EU, such as France, where reimbursement is strong and clinical algorithms are different.

• In Q&A, after complimenting the researchers on a job well done, the venerable Dr. Julio Rosenstock noted that this study does not answer a key remaining question: Does simultaneous administration of GLP-1/basal insulin outperform sequential administration? This issue was also brought up in the paper’s accompanying editorial (which we highly recommend), though it is not a new concept. In fact, Dr. Rosenstock has previously contributed to formal debates on the subject, with consensus being that a dedicated RCT will be needed to draw a final conclusion. Perhaps such a study would also improve the commercial outlook for the class (provided simultaneous outperforms sequential), as it is our understanding that many providers are more comfortable prescribing and titrating each agent separately, rather than in a fixed-ratio.

• Given that its primary purpose was to measure durability, DUAL VIII was designed to mirror clinical practice. Clinic visits occurred just once every 12-14 weeks, vs. the standard 4-6 week visits present in most RCTs, perhaps giving the study greater generalizability to a real-world setting.

LixiLan-G: A Randomized Trial Assessing Switching to iGlarLixi vs. Continuation of Daily or Weekly GLP-1RA in T2D Inadequately Controlled by a GLP-1RA and OAD(s)

Lawrence Blonde, MD (Oschner Medical Center, New Orleans, LA)

Dr. Lawrence Blonde presented results from LixiLan-G, Sanofi’s randomized, open-label study of switching to the basal insulin/GLP-1 receptor agonist [GLP-1RA] fixed ratio combination [FRC] of insulin glargine/lixisenatide [iGlarLixi; Soliqua] vs. continuation of the maximum tolerated dose of daily or weekly GLP-1RA (n=514). At study entry, 52.5 and 56.4% of participants were taking once-daily liraglutide (Novo Nordisk’s Victoza), 7.0% and 3.5% were on exenatide BID [Byetta] and 40% were receiving once-weekly dulaglutide [~20% and 21% of participants], exenatide XR [17.5% and 18.7% of participants], or albiglutide (Lilly’s Trulicity, AZ’s Bydureon, or GSK’s Tanzeum). All patients were also being treated with metformin, ± pioglitazone, ± SGLT-2 inhibitor. At 26 weeks, Soliqua was associated with a 0.6% greater reduction in A1c from baseline compared to continuation of GLP-1RA (-1.0% vs.  -0.4%, 95% CI: -0.8, -0.5, p<0.0001), resulting in end of study A1C values of 6.7% and 7.4% respectively from a baseline of 7.8%. An impressive 62% of participants randomized to Soliqua achieved an A1c target of <7% and 41% achieved the target of ≤6.5%, compared to 26% and 10% continuing on GLP-1RA (p<0.0001 for both). Moreover, 2-hour postprandial glucose and 2-hr PPG excursions were significantly improved with Soliqua; treatment differences were -51 mg/dl and -18 mg/dl, respectively (p<0.0001 for both). On the other hand, as would be expected when initiating an insulin containing therapy, those on Soliqua gained 1.9 kg (4.2 lbs) over 26 weeks, compared to 1.1 kg (2.4 lbs) of weight loss with GLP-1 alone, and the treatment difference of 3.0 kg was significant (95% CI: 2.4-3.6). The modest increase in body weight seen with FRC therapy in this patient population receiving GLP-1 RA therapy on study entry is in contrast to the small weight loss or weight neutrality experienced by participants on oral agents or basal insulin whose therapy was intensified with FRC.  Additionally, 9% [24 participants] of the Soliqua group experienced documented symptomatic hypoglycemia <54 mg/dl, compared to only 0.4% (one participant) on GLP-1RA alone, However, events per patient year were low in both groups [0.25 vs. <0.01 respectively] and 54% of those receiving Soliqua achieved the composite target of A1c <7% without documented symptomatic hypoglycemia (<54 mg/dl), compared to 25% on GLP-1RA alone. 64% of the Soliqua group had an adverse event compared to 47% of the GLP-1RA group. The Soliqua group actually had more GI events (22% of participants) vs. continued, unchanged GLP-1RA alone (10%). This might be linked to the comparison of initiation of a different type of GLP-1 RA (lixisenatide) versus continuation of a GLP-1 RA regimen that had been stable for at least 3-6 months. The study also shows the impact of adherence – an additional 0.4% A1c drop from GLP-1RA that participants were already taking is impressive, particularly given the only variable that changed was enrollment in a clinical trial.

Oral Presentations: New Insights in Diabetic Kidney Disease—Clinical and Experimental Studies (With State-of-the-Art Lecture and ADA Presidents' Select Abstract Presentation)

Chronic Kidney Disease (CKD) Outcomes with Dulaglutide (DU) vs. Insulin Glargine (IG) in Type 2 Diabetes (T2D) and Moderate-to-Severe CKD by Albuminuria Status: AWARD-7

Katherine Tuttle, MD (University of Washington, Seattle, WA)

Dr. Katherine Tuttle presented a post-hoc analysis of the AWARD-7 trial, demonstrating that 1.5 mg dulaglutide significantly reduced risk of a composite renal endpoint of (i) >40% eGFR decline and (ii) ESRD when compared to insulin glargine, and that this was driven primarily by the macroalbuminuria subgroup. In a time-to-first-event analysis of the primary composite endpoint, 1.5 mg dulaglutide was shown to significantly reduce risk (HR=0.45, 95% CI: 0.20-0.97, p=0.04) while the lower 0.75 mg dose dulaglutide did not reach significance (HR=0.79, 95% CI: 0.41-1.5, p=0.47) – see the survival curve below. These results were primarily driven by participants in the macroalbuminuria subgroup, as event rates in the microalbuminuria and no albuminuria subgroups were much lower (see table below). Of course, this is somewhat expected given the short duration of follow-up; we would expect that longer follow-up would help glean insights into potential effects in the microalbuminuria subgroup as well (Dr. Tuttle said as much during the ensuing Q&A session). These results join renal findings from the REWIND CVOT for Trulicity presented at ADA 2019; at present, Lilly has no plans to initiate a renal outcomes trial.

• As a reminder, initial results from the AWARD-7 trial showed that decline in eGFR was significantly reduced with both doses of dulaglutide when compared to glargine at both 26 and 52 weeks. While eGFR declined by an average of 1.9 units in the insulin glargine group at 26 weeks, eGFR only declined by 0.1 and 0.4 units in the 1.5 mg and 0.75 mg groups, respectively. Baseline eGFR was around 38 ml/min/1,73 m² in all three treatment arms.

• A related post-hoc on AWARD-7 was just published in DOM (also led by Dr. Tuttle) showing that the lesser decline in eGFR associated with dulaglutide treatment was not influenced by body weight loss.

Primary Outcome Results

Oral Presentations: Diabetes Management and Macrovascular Outcomes

Do GLP-1RA and SGLT2i Reduce Cardiovascular Mortality in African-American Patients with Type 2 Diabetes? A Meta-Analysis

Basem Mishriky, MD (East Carolina University, Greenville, NC)

An unsettling meta-analysis of recent CVOTs found no cardioprotective benefit for GLP-1 agonists or SGLT-2 inhibitors in black and African American people with type 2 diabetes. Across major GLP-1 agonist and SGLT-2 inhibitor CVOTs, these next-gen therapies delivered no significant relative risk reduction (RR=0.93, 95% CI: 0.70-1.23) in black study participants. This held true for GLP-1 agonists alone (RR=0.96, 95% CI: 0.61-1.53) and SGLT-2 inhibitors alone (RR=0.93, 95% CI: 0.47-2.14). This study included seven CVOTs: On the SGLT-2 inhibitor front EMPA-REG OUTCOME (empagliflozin) and CANVAS (canagliflozin), and on the GLP-1 agonist front LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), HARMONY (albiglutide), and – very impressively – REWIND (dulaglutide), which was released only at ADA 2019. Major thanks to Dr. Mishriky for updating these results so quickly. The DECLARE trial (dapagliflozin) was not included because outcomes were not reported by race in the published results. We are not sure, however, the strength of this finding given that there have been significantly fewer than ideal black and African American people included in these trials in the first place.

• Indeed, Dr. Mishriky was careful to underscore that this meta-analysis has limitations – namely a small population of black participants enrolled in CVOTs (only ~5% of the study population in most CVOTs), a correspondingly low number of events in black participants (ranging from 106 events [LEADER] to just 12 events [SUSTAIN-6] across the included trials), variation in trial design and population between different CVOTs, and, notably, the fact that the trials were not powered to specifically examine racial differences. In this way, the results can be interpreted less as an announcement or admonition that the cardioprotective benefits of GLP-1 agonists and SGLT-2 inhibitors don’t extend to the black population, and more as a call for dedicated trials to assess whether they do.

• We couldn’t agree more with Dr. Mishriky’s conclusion that there is an “urgent need” for additional studies evaluating new diabetes therapies in the black population specifically – however, this same conclusion has been made for countless years based on a broader commentary for greater diversity having nothing to do with actual trial results. During subsequent Q&A, Dr. Mishriky issued an important reminder on the epidemiological front that black people with type 2 diabetes have an especially high need for therapies that reduce cardiovascular risk. This population is at higher risk for developing cardiovascular disease than the general diabetes population, and the black population in the US has experienced some of the most modest improvements in cardiovascular mortality over recent decades compared to other groups. To say nothing of population-level differences in socioeconomic status and healthcare access, there are also physiological differences that may disadvantage black individuals when it comes to diabetes outcomes – Dr. Mishriky pointed out that the sickle cell trait confers additional risk of CV and kidney disease, for instance. Dr. Mishriky pointed out that it is well understood that certain cardiovascular therapies such as ACE inhibitors are less effective in black individuals, and it would be extremely unfortunate from a public health perspective if the same was true for the next generation of GLP-1 agonists and SGLT-2 inhibitors. We hope this meta-analysis causes manufacturers to reconsider the designs of future CVOTs to more directly assess this important question – we are not particularly confident this will be done, however, since there has already been a similar call for this for many years. We hope this startling announcement prompts far more investment and action on this front to enroll more racially diverse clinical trials. Although these trials were not powered to examine racial differences, we are curious about what was seen in other ethnic sub-groups.

Product Theaters

Is GLP-1 Activity Insufficient in T2D? (Sponsored by Novo Nordisk)

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

In this Novo Nordisk product theater, Dr. Vivian Fonseca reviewed the pathophysiology of type 2 diabetes and argued that GLP-1 agonists are a logical way to address the mechanisms that go awry in this disease state. He acknowledged that obesity is a major risk factor for T2D, but pointed out that diabetes occurs in only 20% of people with obesity. Beta cell dysfunction is what differentiates those who progress to diabetes from the 80% who do not. Dr. Fonseca described how obesity promotes insulin resistance, which puts pressure on beta cells – if these islets can’t compensate, they start to deteriorate, and people diagnosed with prediabetes have usually already lost measurable beta cell mass. Dr. Fonseca drew attention to the role of endogenous GLP-1, which is secreted immediately upon eating and prevents beta cell apoptosis (spontaneous death) in those individuals who don’t develop type 2. Studies in rodents and humans have revealed that diabetes dampens the body’s natural GLP-1 response. When a subject with diabetes is given a GLP-1 infusion alongside a meal, their insulin level rises and their glucose and glucagon levels dramatically fall, emulating physiologic pancreatic function. Based on this underlying biology, it makes sense that prescribing a DPP-4 inhibitor (to prevent the rapid breakdown of endogenous GLP-1) or a GLP-1 agonist is an effective way to treat diabetes. Dr. Fonseca endorsed both these therapy classes, though he touted the non-glycemic benefits of GLP-1s as well, listing neural action that suppresses appetite, slowed gastric emptying, weight loss, and cardioprotection in patients with atherosclerosis. No products were mentioned by name during his talk, but during Q&A, audience members inquired about Novo Nordisk’s two GLP-1 offerings: once-daily Victoza (liraglutide) and once-weekly Ozempic (semaglutide). The company has also developed oral semaglutide for type 2 diabetes – the first non-injectable GLP-1 – and an FDA decision is coming up in September.

• “The property of GLP-1 I like the most is that it’s glucose-dependent, unlike an SU, which causes hypoglycemia.” Dr. Fonseca railed against persistently high use of sulfonylureas in real-world diabetes care (though of course, low cost is the primary reason for this). He shared his hope that GLP-1 agonists become standard of care in the not-too-far future, pointing to ADA’s 2019 Standards of Care which recommend treatment with a GLP-1 agonist when diabetes is comorbid with CV disease. “When you consider blood sugar, obesity, CV risk, hypoglycemia ­– all signs point to GLP-1 as an ideal drug class.”

Getting to Goal – Treatment Options for T2DM Patients with Very High A1c (Sponsored by Sanofi)

Steve Edelman, MD (UCSD, San Diego, CA)

Dr. Steve Edelman positioned Sanofi’s Soliqua (a fixed-ratio combination of basal insulin glargine + short-acting GLP-1 agonist lixisenatide) as an ideal therapeutic option for type 2 diabetes patients in need of aggressive A1c-lowering. According to ADA’s 2019 Standards of Care – “excellent” guidelines, in Dr. Edelman’s view – patients with A1c ≥2% above target should be prescribed basal insulin and a GLP-1 simultaneously. Soliqua makes this recommended combination therapy more convenient; patients face one co-pay instead of two, one daily injection instead of two. As part of the product theater, Dr. Edelman summarized key findings from pivotal trials LixiLan-O and LixiLan-L. He particularly highlighted data from the subgroup of participants with baseline A1c ≥9%: In LixiLan-O, these patients on Soliqua (n=49) experienced a mean 2.9% A1c reduction over 30 weeks, ending the study with an A1c <6.5% (incredible!). In comparison, patients with A1c ≥9% on lixisenatide alone (n=29) experienced a 1.7% mean A1c drop (p<0.0001 in favor of Soliqua) and those on Lantus alone (n=55) experienced a 2.5% mean A1c drop (p=0.03 in favor of Soliqua). In LixiLan-L, average A1c fell from 9.45% to 6.97% among Soliqua-treated patients vs. from 9.45% to 7.6% (still above goal) among Lantus-treated patients over 30 weeks. Dr. Edelman emphasized that regardless of baseline A1c, Soliqua can effectively and efficiently get type 2s to meet glycemic targets, though HCPs should especially consider the fixed-ratio combination for their patients with very high A1c.

• Dr. Edelman advocated that any HCP should be prescribing Soliqua – endos and PCPs alike. He again alluded to the convenience factor, saying “endocrinologists are crazy busy. I like anything that’s easy.” Primary care doctors who treat type 2 diabetes are already accustomed to initiating and titrating basal insulin, and he argued that a fixed-ratio combo product like Soliqua only simplifies that process. He acknowledged that PCPs are even busier than endos, and to this end, Soliqua is extremely effective and easy to prescribe. We’d love to see a diversity of providers use Soliqua and Xultophy (Novo Nordisk’s product in the same class, insulin degludec/liraglutide) in type 2 diabetes care. It’s been hard to watch the slow commercial uptake of these products since their launch in early 2017, especially because they were (and still are) highly praised by thought leaders – who have not thought through why they may not be more popular among patients and HCPs. Given the sheer numbers of real-world patients not at goal (~30% of type 2s in the US have A1c above 9%, according to Dr. Edelman – that’s more than nine million individuals, to say nothing of all those with A1cs above 7%), it’s very troubling that more people aren’t accessing this medicine known to accelerate progress toward glucose targets.

• Turning to safety, Dr. Edelman underscored that neither component therapy in Soliqua is “new,” meaning there are no new adverse event concerns. In fact, Soliqua boasts a milder side-effect profile compared to basal insulin monotherapy or GLP-1 monotherapy. In pivotal trials, 24% of participants randomized to lixisenatide alone experienced nausea vs. only 9.6% of participants taking Soliqua. Dr. Edelman explained that the reduced GI symptoms result from a lower dose of lixisenatide as well as smoother up-titration. He did warn that since Soliqua delays gastric emptying (through its GLP-1 component), there may be adverse drug interactions with any agent that must be absorbed within a limited time window.

GLP-1 Agonist Poster Highlights

SGLT Inhibitors

Symposium: DECLARE-TIMI 58 Trial

Renal Outcomes

Ofri Mosenzon, MD (Hadassah Hebrew University Hospital, Jerusalem, Israel)

Dr. Ofri Mosenzon presented very positive in-depth renal outcomes from the DECLARE CVOT (n=17,160) for AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin 10 mg), detailing their potential in CKD prevention and treatment – see the full publication in The Lancet Diabetes & Endocrinology. Results with Farxiga for the full cohort are as follows:

Because DECLARE met only one of its co-primary endpoints, these analyses are considered exploratory. Dr. Mosenzon also paid particular attention to the impact of Farxiga on UACR, which was not included in DECLARE’s two main renal outcomes – unlike in CANVAS and EMPA-REG. Farxiga conferred (i) greater improvements in UACR and (ii) lower rates of UACR deterioration vs. placebo. On the improvement component, Farxiga conferred a 46% increased risk (95% CI: 1.31-1.62) of moving from micro- to normoalbuminuria, an 82% increased risk (95% CI: 1.51-2.2) of moving from macro- to normo/microalbuminuria, a 54% increased risk (95% CI: 1.4-1.69) of moving from macro- to normo/micro- or micro- to normoalbuminuria, and a 41% increased risk (95% CI: 1.27-1.56) of moving from micro/macro- to normoalbuminuria. On the other side of the coin (preventing deterioration), those on the SGLT-2 had a 46% reduced risk (HR=0.54, 95% CI: 0.45-0.65) for moving from normo/microalbuminuria to macroalbuminuria, a 21% reduced risk (HR=0.79, 95% CI: 0.72-0.87) for normo- to micro/macroalbuminuria, and a 27% reduced risk (HR=0.73, 95% CI: 0.67-0.79) for normo- to micro/macro- or micro to macroalbuminuria. That is, in all categories of UACR, dapagliflozin conferred an improvement. To reinforce the importance of impacting both components of renal pathophysiology (eGFR and albuminuria), Dr. Mosenzon showed the cardiorenal and renal-specific event rates across the array of UACR and eGFR categories – see how both contribute to risk below.

• We also very much appreciated Dr. Mosenzon’s emphasis on the importance of early identification and intervention in renal disease. Given the still-staggering incidence and prevalence of CKD and the contribution of diabetes to this epidemiology, SGLT-2s doubtless represent a huge opportunity area through earlier intervention. Of course, this argument aligns well with the data from DECLARE: Given the study’s large primary prevention population (59% of participants) and labeling restrictions at the time of design, the study had a higher mean eGFR of 85 ml/min/1.73 m² than other SGLT-2 trials, including CANVAS (77 ml/min/1.73 m²), EMPA-REG OUTCOME (74 ml/min/1.73 m²), and CREDENCE (56 ml/min/1.73 m²). In DECLARE, 48% had an eGFR ≥90, 45% an eGFR 60 to <90, and only 7% <60 (a function of the equation used – this eGFR was technically excluded). Additionally, 69% had a UACR <30 mg/g, 24% ≥30-≤300 mg/g, and only 7% >300 mg/g.

• AZ’s renal outcomes trial for Farxiga, Dapa-CKD (n=4,000 with CKD, with or without diabetes), is already well underway and expected to complete in November 2020. Given consistently strong evidence around SGLT-2s and renal outcomes, including the recently-reported and groundbreaking CREDENCE trial, Dapa-CKD is very much expected to be positive.

Symposium: CREDENCE and CARMELINA—Results from Two Major Clinical Trials in Kidney and Cardiovascular Disease in Diabetes

CREDENCE–Cardiovascular and Renal Outcomes by Baseline Cardiovascular Disease

Kenneth Mahaffey, MD, PhD (Stanford Center for Clinical Research, Palo Alto, CA)

Dr. Kenneth Mahaffey presented an exciting new CREDENCE analysis of outcomes by baseline CVD presence, showing consistent CV and renal outcomes in both primary and secondary prevention groups. On three-point MACE, canagliflozin treatment was associated with a 32% RRR (HR=0.68, 95% CI: 0.49-0.94) in the primary prevention group and a 15% RRR (HR=0.85, 95% CI: 0.69-1.06) in the secondary prevention group. This trend toward greater CV benefit in the primary prevention group is highly interesting and represents the first SGLT-2 inhibitor CVOT to show a nominally significant trend toward MACE benefit in such a patient population (CANVAS showed a HR=0.98 and DECLARE showed a HR=1.01 in their respective primary prevention subgroups). On the composite endpoint of CV death or hospitalization for heart failure, canagliflozin treatment was associated with a 26% RRR (HR=0.74, 95% CI: 0.54-1.03) in the primary prevention group and a 34% RRR (HR=0.66, 95% CI: 0.52-0.83) in the secondary prevention group. Renal outcomes were similarly consistent across primary and secondary prevention groups (see second image below).

• Very notably, the overall rates of the primary composite renal outcome were nearly identical between the primary and secondary prevention groups. This is in stark contrast to MACE, where events were obviously elevated in the secondary prevention group. Dr. Mahaffey highlighted this finding, and we note how this further justifies the earlier use of canagliflozin to achieve similar absolute risk reductions for renal outcomes in those with and without CVD. The risk/benefit profile of using canagliflozin in primary prevention groups (both for reducing CV and renal risk) appears to be highly favorable.

Symposium: Cardiovascular and Renal Protection in Diabetes—Emphasis on SGLT-2 Inhibitors and GLP-1 Receptor Agonists

Cardiovascular Effects of GLP-1 Receptor Agonists—From Basic Mechanisms to Clinical Data

Jens Holst, MD (University of Copenhagen, Denmark)

In a talk on CV effects of novel therapies, University of Copenhagen’s Dr. Jens Holst picked out an intriguing recent study suggesting that A1c lowering in CVOTs may have a more profound effect on CV outcomes than previously thought. Despite CVOTs being designed for glycemic equipoise (i.e., both arms achieving the same A1c to assess CV effects independent of glucose lowering), they often fail to achieve balance due to the strong efficacy of novel therapies (SGLT-2s, GLP-1s) vs. “placebo” (or, rather, standard care). To this end, Second University of Naples’ Professor Dario Giugliano conducted a meta-analysis for all completed CVOTs for DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists, finding a significant relationship between achieved A1c and the hazard ratio reduction for MACE (p=0.002). Notably, this relationship explained nearly all (94.1%) of between-study variance. Per the analysis, lowering A1c by 0.5% conferred a significant risk reduction of 20% (95% CI: 4%-33%) on MACE. By component, there was no relationship between achieved A1c and the risk ratio for nonfatal MI or CV death, but there was a significant correlation with nonfatal stroke (p=0.002). Together, these results suggest that the cardioprotection found in many of the recent CVOTs may by partly related to A1c lowering, rather than an independent cardiometabolic effect. That said, we note that DPP-4 inhibitors were very neutral across the board, regardless of A1c lowering (though no trial breached the 0.5% difference mark), meaning that the trend was carried heavily by SGLT-2 inhibitors and GLP-1 agonists. Indeed, there isn’t a huge diversity of data feeding into this analysis, and, to our understanding, trials of intensive glucose lowering have also generally struggled to show an impact on CV risk (though this is another question in and of itself). Of course, weight change is also prominent with these agents, and we’d love to see an analysis which takes this variable into account.

• Notably, the three CVOTs which read out at ADA – REWIND for GLP-1 agonist Trulicity, CAROLINA for DPP-4 inhibitor Tradjenta vs. sulfonylurea glimepiride, and PIONEER 6 for GLP-1 oral semaglutide – all fit well into this model. REWIND achieved an A1c difference of 0.61% with Trulicity and conferred a significant 12% reduction on 3-point MACE, placing it solidly in the far right bin of the below figure. CAROLINA had an A1c difference of <0.1% and a HR of 0.98 on MACE, placing it in the far left bin, and PIONEER 6 had an A1c difference of 0.7% and a MACE HR of 0.79, placing it in the far right bin.

Mini-Symposium: Cardiovascular Disease in Patients with Diabetes

Controversies in Clinical Implementation—Should the Use of Novel Therapies Be Conditional on Background Metformin and Baseline A1C? Extended to Lower Risk Patients? Those with Chronic Kidney Disease?

Jean-François Yale MD (McGill University, Canada)

In a comprehensive talk reviewing the clinical implementation of SGLT2 inhibitors and GLP-1 agonists, Dr. Jean-François-Yale urged clinicians to leverage price equivalence of higher doses into lower patient costs. After a thorough rundown of clinical trial data that has illuminated the impressive effects SGLT2i and GLP-1RAs on A1c, weight, and cardio and renal protection, Dr. Jean-François Yale turned to what he views as the last hurdle for these therapy classes: cost. Very few people with diabetes are actually on either of these classes (see this 2017 Diabetes Care article), a fact he attributed to often-prohibitive costs that makes their broad scale use as a first- or second-line therapy challenging. Dr. Jean-François Yale highlighted this barrier by contrasting the patient cost of a “classical” treatment approach that does not involve newer drug classes (i.e. using metformin, a sulfonylurea, and a DPP-4) against costs with an “innovative” approach using newer drug classes (i.e. metformin, an SGLT2i, and a GLP-1RA). The total daily cost of the classical approach in the US would be ~$16.60/day compared to ~$43.60/day for the innovative approach (and we note that even the classical approach is cost-prohibitive for many!); to our understanding, this doesn’t account for reimbursement. How might clinicians work around this barrier? Dr. Jean-François Yale detailed a strategy described as “simple yet novel” that he uses in practice that can make a dramatic difference for patients: Costs for low and high doses of SGLT2i pills are currently identical, and this price equivalence can be uniquely leveraged to help patients reduce the costs of SGLT2 inhibitors, especially if they only require a lower dose. Dr. Jean-François Yale recommended that clinicians prescribe the higher dose of the pill, and then have patients cut the pills in half and take them separately – effectively halving the price of their medication (see slide below) while still getting the full lower dose; this assumes the potency of the lower dose will work for everyone.

Of course, we can imagine several barriers that might limit the effectiveness of this strategy: Will patients view pill-splitting as too much of a burden? Could there be potential for over-dosing if a patient forgets to split? An alternative is to use an SGLT2i-metformin combination pill of the higher dose but only 1 pill a day effectively giving a low-dose SGLT2i at a low cost with half of the daily metformin. We’re intrigued by the approach and curious about how widespread its adoption could be – for the right patients, it certainly could work. Even more encouragingly, Dr. Jean-François Yale pointed out that a similar approach can also be taken with semaglutide, for which the high dose (1.0 mg/week) pens are priced the same as low dose (0.5 mg/week) pens. Adding both of these “hacks” to the equation, the cost of the innovative treatment approach can be lowered to $14.90/day – actually lower than the $16.60/day for the classical approach, though still far more expensive than those outside the US are paying (or their systems are paying.

Oral Presentations: Effective Diabetes Care—At What Cost?

Renal Outcomes from the DECLARE-TIMI 58 Trial: Quantifying the Health-Care Implications

Philip McEwan, PhD (Health Economics and Outcomes Research Ltd., Cardiff, UK)

Using renal outcomes data from the DECLARE trial (see a deeper dive from Dr. Ofri Mosenzon above), an AZ economic modeling study suggests dramatic renal-related healthcare savings with the SGLT-2 inhibitor dapagliflozin (Farxiga) – to the tune of $2.8 billion (or $285 per patient) over four years. These numbers were derived by projecting the risk reduction for renal outcomes with dapagliflozin to all 10.8 million people in the US with diabetes and CKD. As presented at AHA 2018, Farxiga drove a 47% relative risk reduction (95% CI: 0.43-0.66) on a composite renal endpoint of  40% decrease in eGFR to <60, end-stage renal disease, or renal death. The presenter, Dr. Phil McEwan (University of Swansea, Wales, UK) elaborated that on standard therapy the cost of treating 1,000 people with diabetes and CKD for four years is $460,277 vs. just $174,833 with dapagliflozin (a 62% reduction). Specifically the model projects a 46% reduction in costs associated with worsening CKD and a 67% reduction in ESRD-related costs with dapagliflozin therapy. Dr. McEwan further elaborated that this avoidance of end-stage renal disease and related healthcare usage would prevent 15,614 new ESRD cases and an incredible 30,184 person-years’ worth of dialysis over the course of four years – an enormous win for quality of life. To contextualize, in addition to being one of the most prevalent complications of diabetes (affecting 36% of people with diabetes in the US), CKD is also one of the most costly, accounting for 29% of diabetes-associated medical expenditures. In total CKD is associated with an average of $10,165  per person in yearly healthcare costs; this ranges from ~$2,000/year for milder stage 1 and 2 CKD, but skyrockets to >$82,000/year for stage 5 CKD, which involves renal replacement therapy (either in the form of dialysis or kidney transplantation). The renal outcomes trial for Farxiga, Dapa-CKD, is expected to complete in November 2020.

• During Q&A, an audience member correctly pointed out that the cost of four years of dapagliflozin therapy would likely outweigh the $285 in healthcare savings across that time period. Dr. McEwan agreed, but contended that Farxiga is likely cost-effective when considering the healthcare savings associated with its positive effects on glycemic control, weight loss, and heart failure in addition to CKD.

Oral Presentations: Expanding Horizons on SGLT Inhibition

Empagliflozin and Cardiorenal Outcomes in Patients with Nonproteinuric Kidney Disease in the EMPA-REG OUTCOME Trial

Silvio Inzucchi, MD (Yale School of Medicine, New Haven, CT)

Yale’s Dr. Silvio Inzucchi provided an intriguing post-hoc of the EMPA-REG CVOT, suggesting that the CV and renal benefits with SGLT-2 inhibitor Jardiance are maintained in those with CVD and nonproteinuric DKD. Results were simultaneously announced by both Lilly and BI. Specifically, no significant p-values for interaction were found between the sub-population with eGFR <60 mL/min/1.73m² and UACR ≤300, and the rest of participants. The only intriguing trend, as highlighted by Dr. Inzucchi, was on CV death, which trended less in favor of Jardiance than in other EMPA-REG patients. No new safety concerns were raised with empagliflozin in this population. In total, 1,290 (18%) people in the study qualified for the post-hoc, and the cohort was older, had a longer time since diagnosis, and was more female than other EMPA-REG enrollees (all p<0.0001). For context, the cohort represented here is more substantial in real life. According to Lilly’s press release, more than 500 million people globally have CKD, up to 40% comorbid with diabetes, the majority of which is nonproteinuric (~100 million people worldwide, by our calculations).

• Prior to the sub-analysis, Dr. Inzucchi briefly compared EMPA-REG to the landmark CREDENCE trial, which has thrust SGLT-2 inhibitors into the CKD prevention and treatment spotlight of late. Including only those subjects who would have been eligible for CREDENCE, he pointed out that the (very rough) comparison between the two suggests strong renal protection with Jardiance (and as a class effect, we might add) in this higher-risk renal population (eGFR between 30 and 90, UACR >300). However, we will need full results from the CREDENCE-equivalent EMPA-KIDNEY trial to draw definite conclusions. Dr. Inzucchi reminded the audience that this trial is enrolling a broad CKD population, including both proteinuric and nonproteinuric CKD as well as people without diabetes (and also those with type 1!), to give a more complete picture of the renal protection conferred by Jardiance.