CMHC is more than halfway through, with day #2 headlined by Dr. Julio Rosenstock’s passionate argument for a metformin + SGLT-2 +/- GLP-1 combo therapy at diagnosis. With more than half of people with diabetes still above their A1c targets, Dr. Rosenstock placed some blame on sequential therapy, rather than more aggressive combination therapy, at time of diagnosis.
Renowned researcher Dr. Dan Drucker delivered a keynote on GLP-1 usage and potential their potential mechanisms of action.
- Longtime diabetes expert Joslin’s Dr. Edward Horton gave his final talk, with an overview of major studies on lifestyle interventions, and closing with a lengthy Q&A session.
- Elsewhere, the seemingly omnipresent Dr. Anne Peters shared some advice for helping providers interpret metrics beyond A1c (e.g. time-in-range), while Dr. Irl Hirsch called for a renewed emphasis on insulin use in type 2s.
We are in Chicago – Carl Sandberg’s “City of the Big Shoulders” – and the learnings from CMHC 2019 aren’t letting up. See below for our top highlights from Day #2.
- Top Seven Highlights
- 1. Dr. Julio Rosenstock Argues for Simultaneous Combo Therapy of Metformin + SGLT-2 +/- Oral GLP-1 At Diagnosis; Says that potentially 90% of Type 2 Diabetes Patients Can Reach Goals with One Pill (SGLT-2/Metformin) and One Shot (Fixed Ratio GLP-1/Basal Insulin)
- 2. Dr. Daniel Drucker Provides Comprehensive Look at GLP-1 Usage and Mechanisms; Calls Finding GLP-1 Receptors the “Where’s Waldo” of His Research
- 3. Dr. Anne Peters on “Moving Beyond A1c: Diabetes Devices, and their Clinical Use”
- 4. Dr. Jay Skyler Overviews CVOTs of the Past Year + Contrasts Renal Protective Benefits of SGLT-2s and GLP-1s
- 5. Joslin’s Dr. Edward Horton Gives His Final Talk: Evidence on Lifestyle Intervention to Prevent Diabetes and Tips From 60 Years of Experience
- 6. Dr. Robert Eckel Highlights New JAMA Study on MACE Outcomes w/ Metabolic Surgery and Teases Future Randomized CVOT of Surgery vs. Medical Management in Patients with ASCVD History or High Risk for CVD Events
- 7. Dr. Irl Hirsch’s Call-to-Action: “We Can’t We Can’t Under-Emphasize the Role of Insulin in Today’s World of CVOTs”; Asks for Reclassification
Top Seven Highlights
In an engaging talk on initial simultaneous combo therapy vs. sequential therapy, Dr. Julio Rosenstock passionately argued for the former and outlined his vision of initial metformin + SGLT-2 inhibitor +/- Oral GLP-1 RA combo therapy in newly diagnosed type 2 patients regardless of baseline A1c. Dr. Rosenstock pointed out that despite the vast treatment options in the diabetes therapy armamentarium, too many patients are still not reaching A1c targets (>50%). He posited that an over-reliance on sequential therapy, rather than more aggressive and personalized combination therapy at the start of treatment, is likely contributing to this phenomenon. See below for some of the top takeaways from Dr. Rosenstock’s powerhouse talk, which covered over 70 slides in just under 45 minutes!
Dr. Rosenstock closed his presentation by offering up his future vision for prescriptive algorithms in type 2 diabetes. See picture below for the full algorithm. Most notably, Dr. Rosenstock envisions fixed-dose combos of metformin/SGLT-2s being used at diagnosis, followed by either oral sema, weekly GLP-1s, DPP-4s, or a basal insulin/GLP-1 combo based on tailored considerations for each patient. Justifying his stance on the aggressive use of initial combo therapies, Dr. Rosenstock pointed to recently presented results from the VERIFY study, which for the first time provided robust evidence of durable glycemic control with initial combo therapy. As a reminder, results from VERIFY (presented at EASD 2019) showed that early combination therapy of metformin and Novartis’ DDP-4 inhibitor Galvus (vildagliptin) doubled the time to initial treatment failure vs. metformin monotherapy. We imagine that results would have been even more robust with usage of an SGLT-2 or GLP-1, though they would have had different tolerability profiles.
Dr. Rosenstock somewhat downplayed the slight controversy surrounding new ESC guidelines that recommend SGLT-2/GLP-1 first-line usage over metformin in patients at high risk for or with existing CVD. He commented that some in the diabetes community were up in arms about the change (“How dare the cardiologists tell us to start with SGLT-2s and GLP-1s, don’t they know we should start with metformin?”), but noted that in reality this change is not so dramatic. He emphasized, to get rid of this controversy, because obviously metformin has been helpful to patients: “…We can just start with metformin together with SGLT-2s and GLP-1s at the same time.” We appreciate Dr. Rosenstock’s focus on trying to have as many patients as possible access these highly efficacious therapy classes at earlier timepoints during the progression of type 2 diabetes and to leave less opportunity for “inertia”.
Dr. Rosenstock characterized oral semaglutide “Rybelsus” a “game changer” for patients, and with the understandable caveat that its impact will certainly depend on access and cost. Reviewing results from the ten trial PIONEER program for oral semaglutide, Dr. Rosenstock asserted that he’s “never seen a diabetes pill before that gives you 1-1.5% A1c reductions with four to five kgs of weight loss. And I’ve been doing this for over 30 years.” Enthusiasm is high for Rybelsus following its approval last month (check out KOL commentary here), and we note that access and affordability parameters are still in the works (Novo Nordisk has announced that it will set the list price for the therapy on par with once-weekly Ozempic rather than at the same level as other oral agents). We’ll be eager to here further updates on the launch and uptake of Rybelsus on Novo Nordisk’s 3Q19 update.
Toronto expert Dr. Daniel Drucker delivered a punchy keynote address on GLP-1s, documenting benefits of the class compared to DPP-4 inhibitors and SGLT-2s, as well as potential mechanisms of action. Throughout Dr. Drucker’s talk, one central theme was clear – GLP-1s share a strong and unified class benefit (MACE, particularly all-cause mortality, etc.), but the mechanism behind these effects is complex and not well understood. During the talk’s introduction, we also learned that Dr. Drucker is the 2019 laureate for the Harold Hamm Prize for Biomedical Research in Diabetes (a very important and major prize in the world of diabetes), so a huge congratulations to Dr. Drucker and his impressive body of research! See here for more details on when this will be presented in Oklahoma City. And, read on for our top themes from the presentation.
Despite the fact that GLP-1s have a more profound effect on A1c, cause weight loss, and have proven cardioprotection, DPP-4 inhibitors are still far more widely prescribed. Dr. Drucker opened his talk by discussing pragmatically why DPP-4 inhibitors continue to dominate in dollar volume over GLP-1s, citing easier use in the primary care setting – for example, prescribing DPP-4 inhibitors require no follow-up calls nor discussions about dose estimation. In addition, Dr. Drucker noted that the large number of GLP-1s currently on the market can also add to clinician confusion and burden. For a busy clinician, figuring out which GLP-1 is best to use for each patient is a more cumbersome process than prescribing a GLP-1. Many are also cheaper.
Dr. Drucker stated that he would be “cautious about using [GLP-1s] in those with heart failure with reduced ejection fraction or Class IV heart failure,” compared to SGLT-2s. While GLP-1s have not been shown to increase hospitalization of heart failure, SGLT-2s clearly have a profound benefit on the outcome. Dr. Drucker also quipped that, for the time being, SGLT-2s are the drug of choice for treating chronic kidney disease. As to date, there is no solid evidence that supports GLP-1s having an effect on renal outcomes, though the FLOW trial on GLP-1 semaglutide and CKD is currently in progress.
A plethora of hypotheses exist explaining why GLP-1s provide cardiovascular benefit, but a full picture is still unknown. Dr. Drucker floated a handful of options including (i) a gradual lessening of atherosclerosis, which would explain the ~12-16 months GLP-1s need to generate an effect on MACE; (ii) flattening of postprandial lipemia; (iii) GLP-1 anti-inflammatory effects; or (iv) or kidney-centric mechanisms. Fundamentally, Dr. Drucker emphasized that the cardiovascular benefits are most likely independent of A1c because even though albiglutide only produced subtle changes to A1c in the HARMONY CVOT, the drug conferred an impressive 22% risk reduction in MACE outcomes.
Dr. Drucker also emphasized that while animal models can provide a great deal of information, it is important to remember that they do not fully replicate human studies. As an example, Dr. Drucker pointed out that in mice, rats, and monkeys, GLP-1 receptors are only found in the atrium when looking at the heart. Crucially, this finding is not replicated in humans, as GLP-1 receptors are expressed in all four chambers of the heart.
In terms of what’s on the horizon for GLP-1s, Dr. Drucker mentioned the phase 3 GLP/GIP dual agonist (tirzepatide) trial, as well as other GLP-1 multi-agonists coming down the pipeline. Dr. Drucker seemed particularly interested in how adding a GIP affects cardiovascular biology, and we would be eager to see the findings from such research.
3. Dr. Anne Peters on “Moving Beyond A1c: Diabetes Devices, and their Clinical Use”
In this talk, Dr. Peters led a wide-ranging discussion on interpreting A1c with the benefit of time-in-range data; she also made several references to automated insulin delivery that showed what a game-changer this has been for some of her patients that have been lucky enough to get it. Her discussion underscored how fast work on “time-in-range” has all moved – experts only met at ATTD in Berlin earlier in 2019 to determine goals for patients and then ensuing work was synthesized that was published in Diabetes Care in June 2019: “Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range.” Although there are not official programs that we know of to spread education on time in range with HCPs and patients, we were very intrigued by Dr. Peters’ discussion on Ambulatory Glucose Profile and moving toward a greater time in range and how patients see it. She also discussed at some length how patients from different socioeconomic means used various devices and pointed out deficiencies in A1c in certain ethnic groups.
On A1c and Its Limitations
“No one’s ever going to take away A1c as a population-based tool for diabetes outcomes, because we have data that shows diabetes outcomes – microvascular outcomes, retinopathy, nephropathy, neuropathy – are all improved by reducing A1c. Cardiologists always get annoyed, saying, ‘Well, that doesn’t reduce cardiovascular disease risk.’ I know that, but people don’t want to be blind or have neuropathy or be on dialysis, that just isn’t fun. You have to ask how to reduce cardiovascular disease risk and microvascular complications.”
“[A1c] is an average. Does it tell you have to manage a patient? No. It doesn’t tell you whether they’re going low, whether they’re going high, whether to inject, add medications … We have the population level data, and [A1c] is useful for assessing trends and wellness in populations.”
“[With A1c], you don’t get specific point information about things like hypoglycemia. In African Americans, it may underrepresent the burden of hyperglycemia.”
On Interpreting Time-in-Range and AGPs
“My patients love this tool (Ambulatory Glucose Profile) … because they love the notion of time-in-range. This is sort of like what kids learn when they’re young playing video games. They want to hit the target. They want to be ‘in-range.’ Basically, we want our patients to have a time-in-range of 70% or more.
“I always look at the best days. In every patient’s life, there are best days – days that they didn’t eat the cupcake, days that they exercised, days that they did all those things that ‘good’ [people with diabetes] do. By the way, never use ‘good’ or ‘bad.’”
“I use GMI (Glucose Management Indicator) to say to patients, ‘Your measured A1c is 7.6%, but your GMI is 6.8%, so it shows that your last two weeks were better and you’re trending in the right direction.’ With [diabetes devices], we get data. Then, we have to interpret that data to ourselves, and more importantly, to our patients to help them change behavior and reach the targets.’”
On Disparity in Outcomes
“In my clinic on the west side, the wealthier side, of Los Angeles, my patients with type 1 diabetes have become boring. They come in, their A1cs are in the low 6s, they’re doing amazingly. No longer are they struggling to get their A1cs down, because they’re using technology; they’re using do-it-yourself hybrid closed loop systems, and I’ve just never seen anything like it in the past year. It’s literally in the past year that I’ve seen my patients who work hard at their diabetes do well.”
“I see my patients in east Los Angeles who don’t have access to this diabetes technology only get worse. That’s where I see patients in their 20s and 30s go blind, go on dialysis – horrible outcomes. When I talk, I always talk about my optimism, because with the right patient, the right tools are incredibly helpful. I think no matter what we do, when we look at data from these devices, we have to understand that the users benefit. There are lot of people who won’t use these [devices], who can’t use these. Have you ever looked at an insulin pump manual? It’s written at an 11th grade level. We just got a grant from the Helmsley Charitable Trust to write manuals for devices that are simple, low-literacy, and in English and Spanish.” (Note: these manuals are available for free here and early results were presented at AADE 2019.)
Dr. Jay Skyler provided a very systematic, robust, and valuable overview of diabetes CVOTs and outcomes studies that have read out since CMHC 2018 – five major studies including CAROLINA, CREDENCE, DECLARE, PIONEER 6, and REWIND. In the process, we heard some notable points of commentary from Dr. Skyler on these trials and general trends in the field. Notably, we were excited to hear Dr. Skyler differentiate renal outcomes seen in trials for SGLT-2 inhibitors and GLP-1 agonists – a topic we’ve heard increasing commentary on following landmark CREDENCE results presented in April 2019. In reviewing results from the REWIND CVOT of Lilly’s once-weekly GLP-1 Trulicity (dulaglutide) which read out at ADA 2019, Dr. Skyler commented on secondary endpoints in the trial that focused on renal-related outcomes: “I don’t put as much faith in [these endpoints], since a lot of it is new macroalbuminuria. I think that’s a softer endpoint that was used. As a result, I don’t put as much personal ‘credence’ in it as the CREDENCE study, which had much harder endpoints used.”
As a reminder, results from REWIND showed that 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).
By contrast, CREDENCE showed a 30% relative risk reduction (95% CI: 0.59-0.82, p=0.00001!) on the primary renal endpoint of ESKD, doubling of serum creatinine, and renal or CV death. Our sense from broader KOL discussion of renal endpoints with these two therapy classes is that the impact SGLT-2 inhibitors have had on “hard” renal endpoints (such as reducing eGFR decline) that are more clinically relevant have inspired more confidence in their utility in practice. Dr. Skyler’s comments nicely align with other recent KOL commentary we’ve heard on the subject, including that from Drs. David Cherney, Per-Henrik Groop, and Hiddo Heerspink at EASD 2019, where each of these luminaries made similar points to Dr. Skyler.
Looking ahead, Novo Nordisk’s renal outcomes trial of Ozempic (injectable semaglutide), called FLOW, will help to further flesh out the conversation surrounding GLP-1s and renal protection. As a reminder, the FLOW trial was initiated in June 2019 and will enroll 3,160 patients with type 2 diabetes and CKD (eGFR 25-75 ml/min/1.73 m2) for up to five years. Expected completion is August 2024, and the primary endpoint is a composite of persistent eGFR decline of ≥50%, reaching ESRD, and CV or renal death. Traditional MACE endpoints will also be measured. This is a highly notable, first-ever renal outcomes trial among GLP-1s, and it’s clear that enthusiasm is high for the trial’s potential in further informing renal benefits of the GLP-1 class. We’ve sensed optimism from Novo Nordisk that more efficacious GLP-1s (such as semaglutide) may be able to compete in the future with renal outcomes data from the SGLT-2 class, along with providing the additional benefit of not losing their glucose lowering abilities in patients with a lower eGFR.
For more on this area, see our full SGLT Inhibitors and GLP-1 Agonists in CKD Landscape here. Multiple manufacturers are working on kidney disease trials: Lilly/BI are investigating Jardiance (empagliflozin) in the EMPA-KIDNEY renal outcomes trial (n=5,000, with or without type 2, and including type 1) and AZ is investigating Farxiga (dapagliflozin) in the Dapa-CKD trial (n=4,000, with or without type 2, excluding type 1) – the company received fast-track status from FDA last month. Expected completion dates are June 2022 and November 2020, respectively.
Longtime diabetes expert Dr. Edward Horton (Joslin Diabetes Center) gave a wonderfully organized talk on evidence in lifestyle interventions to prevent diabetes and the metabolic syndrome, ending with a lengthy and enlightening Q&A with Dr. Horton’s recommendations based on his 60 years of experience in the field. At the end of the Q&A session, the former president of the ADA casually announced, “That was my last talk,” prompting rousing cheers and applause from the audience. His full 63-slide presentation is available here, and well worth close examination.
Dr. Horton began by painting a dire picture of the “epidemic of diabetes,” both in the US and globally. For people born in 2000, their lifetime risk of developing diabetes is 33% for men and 39% for women. Dr. Horton called diabetes and obesity a “dual epidemic” with metabolic syndrome as a risk factor for both. Ultimately, the goal of diabetes treatment is to prevent micro- and macrovascular complications and Dr. Horton emphasized the need for interventions to treat all aspects of the metabolic syndrome (i.e. triglyceride levels, HDL-cholesterol, blood pressure, fasting glucose, and waist circumference).
Dr. Horton walked through the results of three major diabetes prevention studies, DPP (1996-2001), DPP Outcomes Study (2002-2015), and Look AHEAD (2003-2013). The three widely-cited studies all demonstrated effectiveness of intense lifestyle interventions at reducing diabetes incidence and improving nearly all aspects of the metabolic syndrome compared to placebo, and at levels similar to, or better than, metformin. With most outcomes, a huge improvement was seen with lifestyle intervention at the first year, with some regression over the following years. Still, diabetes incidence and weight change were all significantly better with lifestyle intervention compared to placebo as far as 15 years out (in the DPPOS study). The studies did not give extensive recommendations for how to prompt action to take on the lifestyle interventions. In Q&A, Dr. Horton suggested greater support of diabetes educators.
Figure 1. Three-year outcomes from DPP
Selected Questions and Answers
Q: I have trouble convincing my patients to do change their lifestyle. Do you have any secrets for that?
A: You’re not alone – this is a major, major problem: how do we work with our patients to adopt and maintain a lifestyle program? This is where our diabetes educators are great; they see people frequently. Work with your diabetes educators, have patients come back and review things with them. It is very, very difficult, my patients are busy - they’ve got tons of things on their minds … I just try to build exercise into their daily activities, but it is a challenge.
Q: I was wondering about the dietary advice in the studies - they happened in the 1990s and early 2000s. Specifically, with regard to advice on carbohydrates, e.g. simple vs. complex, and types of fats: any thoughts?
A: There’s a ton of stuff going on now about what the proper dietary composition is. I think we’ve always recommended a good, adequate source of fiber. I think for people with diabetes, we tend to reduce the carbohydrates, or at least really emphasize complex carbohydrates over sugars, just to avoid post-prandial spikes. What the proper diet is will vary from one person to another, but the biggest thing to me is cutting calories – reducing between-meal snacks, nighttime snacks. I’m much more interested in reducing total caloric intake as part of the diet. One of the biggest problems we’ve had is with sweetened beverages, with high sugar content. I generally tell patients to avoid saturated fats in their diet, reduce calories, and make sure they’re getting enough whole grains and fiber.
Q: I’ve heard that high intensity, interval training improves glycemia and metabolic risk. I tell my patients, “Less is more” and “failure is success”: less time, but higher intensity – to muscle failure. Can you comment on walking vs. short, high intensity workouts?
A: Again, every patient’s a little different in what they tend to do and what they like to do. Stretching exercises, maintaining mobility is big for our aging patients. I think strength training, resistance, exercises are very important for maintaining muscle mass, but cardiovascular-wise, I think walking and cycling. I think you have to consider both types of exercise.
Q: What is your opinion on group sessions and group exercise trainings?
A: I think many people find that participating in a group is very helpful, because they interact with people and it’s easier for them to be involved in group sessions. It’s also good motivation.
In a talk on notable recent studies within the obesity landscape, Dr. Robert Eckel directed the audience’s attention to a recent study published in JAMA, “Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity.” The retrospective cohort analysis looked at 287,438 type 2 patients in the Cleveland Clinic Health System between 1998-2017, with 2,287 patients who had metabolic surgery matched 1:5 to 11,435 nonsurgical patients with type 2 and obesity. The objective of the study was to investigate the relationship between metabolic surgery and incident major adverse CV events (a 6-point MACE was used that included all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, or atrial fibrillation). Results were highly favorable for the surgical group, with a 39% RRR compared to nonsurgical controls on the primary composite endpoint (consistent across each of the individual components of the composite endpoint), and with highly significant secondary endpoints as well (see figure below).
Results were also highly consistent across various subgroups, with no heterogeneity based on sex, age, BMI, baseline A1c level, eGFR, or use of insulin, sulfonylureas, or lipid lowering medications. The study’s authors postulate that the mechanisms driving beneficial effects on MACE with surgery may be related to substantial and sustained weight loss, along with improvements in metabolic, structural, hemodynamic, and neurohormonal abnormalities. Moreover, they also posit that “some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss” – we’re extremely curious to learn more about these weight-independent effects that may be contributing to improvements in MACE outcomes. Of course it’s crucial to acknowledge that these results, while encouraging, are only hypothesis-generating given the study’s observational nature and lack of randomization.
Dr. Eckel also divulged that he, along with Dr. Steven Nissen and colleagues, are currently working on designing a randomized CVOT in patients with ASCVD history or at high risk for CVD events that will compare metabolic surgery vs. medical management. We’re highly intrigued by the potential of such a trial and are curious as to what medications might be prioritized in the medical management group (will SGLT-2 inhibitors and GLP-1 agonists be primarily used?). Our sense is that the field has reached a consensus on the important benefits of metabolic surgery, but concerns about cost and limited generalizability remain that have hampered the broader use of these interventions. Given the current need for further evidence regarding weight loss linked to hard outcomes such as MACE, we’re thrilled to see such a trial in the works.
With his signature enthusiasm, University of Washington’s Dr. Irl Hirsch gave a most valuable presentation on what he characterized as an often-overlooked role of insulin in the management of type 2 diabetes. In the US, 13% of patients with type 2 diabetes use insulin with other agents, and 14% use it alone, coming in at a substantial seven million individuals on top of the 1.5 million with type 1 diabetes. As an exercise, Dr. Hirsch polled the audience, asking “why is there so much excitement for type 2 therapies in 2019?” Overwhelmingly, the audience voted for “positive CVOTs with GLP-1s and SGLT-2s” over other options such as “cheap insulin analogues,” “pending approval of glucose-responsive insulins, [editor’s note – there are none of these that we know of that are close to approval]” or “generic GLP-1s and SGLT-2s.” The crowd’s choice led Dr. Hirsch to reinforce his point further that the potential benefits of insulin treatment should not be overlooked, especially for those whose insurance does not cover either GLP-1 or SGLT-2 inhibitors. As his own modification to the ADA/EASD treatment algorithm, Dr. Hirsch added that following metformin treatment and lifestyle education, he would at least consider basal insulin for any patient with an A1c >9%. Importantly, Dr. Hirsch emphasized keeping any insulin regimens he provides simple for his patients – creating a protocol for “small, medium, or large” meals.
To end his presentation, Dr. Hirsch asked for a change in the type 1 vs. type 2 classification paradigm. Dr. Hirsch noted that such a change would be more for practical reasons rather than academic one, as he is often unable to prescribe certain agents for different patients due to strict health insurance strict delineations. For example, although 1/3 of patients with type 1 diabetes have obesity, Dr. Hirsch is unable to provide them with traditionally “type 2” agents that would be extremely beneficial for them, and similarly, he cannot prescribe CGM for his patients with type 2 except those on Medicare.
--by Albert Cai, Rhea Teng, Martin Kurian, and Kelly Close