We’re saying our goodbyes to the Windy City, as another wonderful edition of CMHC has come to a close.
On Day #1, we heard a very valuable talk from Stanford’s Dr. Mintu Turakhia on early results from the massive (n=419,297), fully-virtual Apple Heart Study (ClinicalTrials.gov) evaluating whether data from Apple Watch could be used to detect atrial fibrillation (irregular heartbeat). The trial completed in February and first read out at ACC 2019, but Dr. Turakhia’s CMHC talk remained very relevant, hitting several points related to the FDA’s recently released draft guidance on “Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations.” Although details are not included in this report because of Dr. Turakhia’s preference not to disclose them more broadly right now, we look very forward to hearing more in the future. We also heard from Dr. Joshua Stolker during a Novo Nordisk sponsored lunch symposium on SGLT-2s being a gateway drug for cardiologists into diabetes, Dr. Lawrence Blonde commenting on the potential of a pragmatic real world study of SGLT-2s/GLP-1s in type 1 diabetes, and Dr. Eric Peterson providing a comprehensive overview of the state of big data in healthcare.
Day #2 was 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. Elsewhere, the seemingly omnipresent Dr. Anne Peters shared some advice for helping providers interpret metrics beyond A1c (e.g. time-in-range).
Finishing out the conference, Dr. Javed Butler delivered a sweeping overview of heart failure and type 2 diabetes, most notably expressing strong support for GLP-1 efficacy in HFpEF, advocating for broader studies of SGLT-2 inhibitors in all parts of the CV spectrum, and calling for next-gen outcomes trials with SGLT-2/GLP-1 combination therapy. We are very excited to hear advocacy for such a trial, since we have heard so much positive anecdotal evidence. Dr. George Bakris gave a valuable deep dive on CREDENCE and SGLT-2 inhibitors in kidney disease, concluding his talk by arguing that SGLT-2 inhibitors are “cardiorenal risk reducing agents with glucose lowering as a side effect.” Mechanistically, Dr. Bakris advanced the idea that SGLT-2 inhibitors’ cardiorenal risk reducing effects might be attributable to both hemodynamics and anti-inflammatory mechanisms. Dr. Irl Hirsch led a valuable workshop on navigating insulin access and costs, and notably directed his focus toward the pharmaceutical industry’s lobbying efforts as an under-analyzed reason for high insulin costs.
We’re also bringing coverage of the intimate exhibit hall here at CMHC. See below for details on six exhibits in diabetes therapy, including booths from Amarin, AZ, Amgen, BI, Novo Nordisk, and Merck.
Greetings from Chicago, IL, where CMHC 2019 took place! See below for our top highlights in (i) Diabetes Therapy; (ii) Diabetes Technology; (iii) Big Picture; and (iv) Obesity.
- Top Therapy Highlights
- 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)
- Dr. Javed Butler Optimistic on GLP-1 in HFpEF; Sees “Endless Opportunity” for SGLT-2s Across Diabetes Spectrum; Hopes to See Future Outcomes Trials of SGLT-2/GLP-1 Combination Therapy
- Novo Nordisk Lunch Symposium: Dr. Joshua Stolker Reviews GLP-1 CVOT Data, Calls SGLT-2s the "Gateway Drug" for Cardiologists into Diabetes"
- Dr. Daniel Drucker Provides Comprehensive Look at GLP-1 Usage and Mechanisms; Calls Finding GLP-1 Receptors the “Where’s Waldo” of His Research
- Dr. George Bakris: SGLT-2 Inhibitors are Cardiorenal Risk Reducing Agents with Glucose Lowering Side Effects; Mechanisms May Include Both Hemodynamic and Anti-Inflammatory Effects
- Dr. Jay Skyler Overviews CVOTs of the Past Year + Contrasts Renal Protective Benefits of SGLT-2s and GLP-1s
- Dr. Lawrence Blonde Suggests Utility of Pragmatic Real World Studies in Determining CV/Renal Benefits of SGLT-2s/GLP-1s in Type 1 Diabetes
- 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 Technology Highlights
- Top Big Picture Highlights
- Dr. Irl Hirsch: Hundreds of Millions of Dollars are Spent on Healthcare Lobbying, “It’s Bi-Partisan,” and “Nobody Talks About This”; Tips for Using Affordable Insulin
- Joslin’s Dr. Edward Horton Gives His Final Talk: Evidence on Lifestyle Intervention to Prevent Diabetes and Tips From 60 Years of Experience
- Polygenic Risk Score Measured at Birth Could Predict Coronary Artery Disease Better Than Any Other Traditional Risk Factor (e.g. LDL-C, Triglycerides, etc.)
- Dr. Eric Peterson Talks Big Data: “Big Data is the New Oil”; Documents the Upcoming Innovations in Healthcare
- Dr. Elizabeth McNally Unveils the Emerging Field of “Cardiogenetics”; Documents the When and Where of Genetic Testing in Cardiometabolic Medicine
- Top Obesity Highlights
- 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
- The Biology Behind Metabolic Surgery: Dr. Lee Kaplan Talks Surgery vs. Calorie Restriction; The Role of Pharmacological Treatment Post-Op
- Exhibit Hall
Top Therapy 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.
In what one audience member referred to as “the best talk of the entire weekend,” Dr. Javed Butler (University of Mississippi) delivered a sweeping overview of heart failure and type 2 diabetes, along with a handful of personal hypotheses regarding the field. Considering Dr. Butler’s expertise, we especially enjoyed hearing his personal premonitions and “gut feelings” – a rare treat at conferences. Similar to his presentation at EASD 2019, Dr. Butler began by explaining that when it comes to patients with diabetes, the distinction between preventing heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) “doesn’t really matter,” as once the patient develops either condition, the mortality rate is extremely high. Therefore, if any treatment options to prevent HF exist, they should be utilized, as “chasing patients” once they have developed HF is an exceedingly challenging task.
Current mechanistic models of heart failure are widely “vasculature-centric”; however, a 2018 study published in NEJM has shown that even when vasculature-related risk factors (elevated A1c, BP, LDL-C, albuminuria, tobacco use) are not present or within guideline ranges in patients with type 2 diabetes, a 45% increase in risk of hospitalization for heart failure (hHF) still remains. This means that although atherosclerosis clearly contributes to heart failure, other factors also exist. Moreover, results from SGLT-2 inhibitor CVOTs have elucidated the potential renal contribution to heart failure. As Dr. Butler puts it, “if you start preserving renal function, perhaps we shouldn’t be surprised that you’re preventing heart failure. You’re not developing the fluid overload challenge, which might prevent development of the HF syndrome.”
- Moving on to current drugs available in the heart failure field, Dr. Butler expressed strong personal support for GLP-1s as a treatment for HFpEF but “significant concerns” with the class as a treatment for HFrEF. He stated, “I have my strong bias that HFpEF is predominantly a disease of obesity and maladaptive aging of the heart, so it makes sense that GLP-1s would be a good treatment for HFpEF. That’s entirely my bias. I have significant concerns with using GLP-1 in HFrEF.” To summarize his thoughts on GLP-1s in HF, he commented, “HF prevention? Neither good nor bad. HF treatment? We don’t have data. HFpEF? I’m bullish. HFrEF? I’m [incredulous].” Notably, we’ve heard similar chatter from representatives at Novo Nordisk, who are similarly bullish on the idea of GLP-1 in HFpEF for similar reasons to Dr. Butler. Our sense is that future trials may investigate semaglutide in HFpEF to further elucidate any potential benefits here.
- In his commentary on the EMPA-REG trial, Dr. Butler described himself as “very comfortable” in 2015 saying that empagliflozin prevented HF in patients with type 2 diabetes, but needed more data then to determine if the drug also treats HF. While about a 35% reduction in hHF was seen in both trial participants with and without a history of heart failure, a substantial ~6,300 patients contributed to the pool of patients without a history, while only ~700 patients made up those with a history. Data from the 700 patients gives Dr. Butler a “good sense” that the drug may treat heart failure, but he emphasized the need for a dedicated trial to fully answer this question. Of course, results from DAPA-HF now helps answer this question, as dapagliflozin was shown to be a highly efficacious treatment for patients with existing HFrEF. Whether this is a class effect remains to be seen, although our sense from the field is that a class effect is likely. More data on HFpEF are needed.
- Dr. Butler sees “endless opportunity to now study [SGLT-2 inhibitors] across the spectrum of patients with cardiovascular disease.” Pointing to results from the DAPA-HF trial, which showed equal benefit in patients with or without diabetes, Dr. Butler stated that he believes both “more sick” (i.e. someone post-MI) and “less sick” (i.e. individuals with pre-diabetes) patients may benefit from SGLT-2 inhibitors. He then pointed to ACE inhibitors and statins as drugs that are not classified as treatments for specific conditions (whether angina, hypertension, CKD, etc.), but more so as all-encompassing drugs; his “personal bias” being that SGLT-2s may follow suit as drugs that influence a whole suite of conditions.
- Looking to the future, Dr. Butler hopes for next generation trials with combination GLP-1/SGLT-2 treatment in order to see if incremental benefit on cardiovascular outcomes or HF can be achieved. Dr. Butler voiced his skepticism towards the argument that GLP-1s are an ASCVD treatment, while SGLT-2s are a HF drug, as detailed in the ADA/EASD treatment algorithm. Instead, he described the two drugs’ mechanisms as “parallel pathways,” and urged for greater investigation into possible synergistic benefits. Dr. Butler noted that in his clinical practice, it’s extremely difficult to parse out whether patients have CKD or HF or ASCVD, and to what extent each disease is affecting the patient, which would again make combination GLP-1/SGLT-2 therapy a practical consideration.
Dr. Joshua Stolker gave an engaging presentation on GLP-1s and cardiovascular safety data in a Novo Nordisk sponsored lunch symposium, highlighted by a Q&A session that touched on the dynamics of cardiologists using GLP-1s and SGLT-2s in practice. In one of the more intriguing points of the session, Dr. Stolker—a cardiologist himself—noted that from his personal experience, he considers SGLT-2s as the “gateway drug” for cardiologists into the diabetes field. He explained that cardiologists tend to feel more comfortable with SGLT-2s at first because of their more easily understood mechanism of action, easier nature of prescription and use as an oral medication, and impressive outcomes data on endpoints important to cardiologists (such as heart failure). In his experience, Dr. Stolker said that it took him a year of really using SGLT-2 inhibitors as his first diabetes-adjacent drug before moving outside of the class and starting to use injectable GLP-1s. Dr. Stolker noted that even today, there’s significant inertia within the community in terms of using injectable therapies, and we note that prescription data from various specialties back this up – cardiologists continue to display much lower prescriptions rates of GLP-1s when compared to other specialties, even in light of the positive outcomes data that have emerged for the class. Looking ahead, we’re immensely curious about how just-approved Rybelsus (oral semaglutide) will shake up this picture. Will we see increased adoption of the GLP-1 class by cardiologists due to Rybelsus? Only time will tell, but we imagine it would be very positive for the field if oral semaglutide can similarly serve as a “gateway” therapy for the GLP-1 class into the cardiology community.
- Regarding potential additive cardioprotective benefits of SGLT-2s and GLP-1-1s, Dr. Stolker pointed to the lack of evidence from trials investigating these combinations but noted that he has a “suspicion” of such benefits. Dr. Stolker is one of many thought leaders who we have heard from that have speculated about potential complementary cardio and renal-benefits with these two therapy classes. At AACE 2019, Dr. Richard Pratley reviewed potential mechanisms of actions for cardioprotective benefits with both therapy classes, and noted that because of their probably distinct mechanisms of benefit, it would be likely that the two classes would have complementary and additive benefits. While we are tremendously excited about the potential of these two classes in tandem and hope to see outcomes trials cementing their additive benefits, it’s important to note that the majority of patients don’t yet have access to even one of these therapies. Only a fraction of those with type 2 diabetes are taking either of these agents, and serious work remains to be done in ensuring broader access, reimbursement, and affordability of these agents (nearly half of all type 2 diabetes prescriptions are still for sulfonylureas!)
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.
In reviewing results from the landmark CREDENCE trial, Dr. George Bakris (University of Chicago) concluded by arguing that SGLT-2 inhibitors are “cardiorenal risk reducing agents with glucose lowering as a side effect.” Dr. Bakris pointed to an online published an invited editorial perspective in the American Journal of Kidney Disease where he argues this point in a broader push to better educate physicians about extra-glucose effects of SGLT-2 inhibitors. To be sure, recent events in the field, including landmark CREDENCE and DAPA-HF results, have further cemented the idea of SGLT-2 inhibitors as potent therapies for reducing cardiorenal risk, regardless of glucose lowering effects. However, our sense is that much still needs to be done in educating physicians (especially those outside of endocrinology) about these extra-glucose effects of SGLT-2 inhibition (some attribute low prescription rates in specialties outside of endocrinology to this low awareness and appreciation of extra-glucose effects). On this front, we’re thrilled to see luminaries such as Dr. Bakris hammer home this point to audiences.
- Mechanistically, Dr. Bakris also broke some new ground in his talk, advancing the idea that SGLT-2 inhibitors’ cardiorenal risk reducing effects might be attributable to both hemodynamics and anti-inflammatory mechanisms. While we’ve certainly heard much discussion about potential hemodynamics effects with the class, we’re highly intrigued about anti-inflammatory effects of SGLT-2 inhibition that may modulate cardiorenal risk.
- Dr. Bakris also highlighted the absence of an amputation signal in CREDENCE and emphasized the importance of proper foot care and education. He noted that 5% of the CREDENCE population had prior amputations (2.5 times higher than in the CANVAS trial), making it a much higher risk population. Despite this higher risk group, no signal for amputation was seen during the trial. Dr. Bakris commented that the lack of an amputation signal was due to a “miracle,” with that miracle simply being the proper use of foot exams and education. As a reminder, FDA originally added a blackbox warning to Invokana’s label after the near-doubling of amputation risk with canagliflozin vs. placebo in CANVAS (HR= 1.97, 95% CI: 1.41-2.75, p<0.001 – there were 10,142 people in this trial). However, results from CREDENCE (n=4,401) painted a more reassuring safety profile, demonstrating no significant imbalance in amputations (HR=1.11, 95% CI: 0.79-1.56). It appears that the updated label for Invokana following its new renal indication also reflects the added safety data from CREDENCE reflecting the similar rates of amputations between placebo and Invokana groups.
- Regarding the upcoming FLOW trial of semaglutide in CKD, Dr. Bakris noted that the trial is designed very similarly to CREDENCE, partly because multiple steering committee members are the same for both trials. Importantly, our general sense is that although CREDENCE was designed with a clear hypothesis in mind regarding a potential renal-protective effect with SGLT-2 inhibition, such a hypothesis does not currently exist for GLP-1 agonism. Nonetheless, we’ll have to wait and see for full results from FLOW (expected in ~2024), especially in light of some positive signals for reducing macroalbuminuria and eGFR decline in various GLP-1 CVOTs.
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.
Answering a question during Q&A on the usage of SGLT-2s/GLP-1 in type 1 patients for cardio and renal protective purposes, Dr. Lawrence Blonde noted that “this may be an area where pragmatic real world studies could get us information more efficiently.” Dr. Blonde’s point of a pragmatic type 1 CVOT echoes a similar call from Dr. Julio Rosenstock at EASD 2018, where he also noted: “If there was ever a need for a pragmatic CVOT, this is it – SGLT inhibitors in people with type 1 diabetes at high risk for CV disease.” We’re glad to see Dr. Blonde express optimism about the utility of a pragmatic real world study in this situation (given the clearly large unmet need) and wonder how such a study would work in practice. Where would funding come from (pharmaceutical industry or philanthropy?), and how would enrollment work? Looking ahead, we expect to get a small glimpse into the potential effects of SGLT-2s specifically through ongoing studies of these agents that aren’t excluding patients with type 1 diabetes, including Lilly/BI’s EMPA-KIDNEY and EMPEROR-HF studies of Jardiance in CKD and heart failure, respectively. To be sure, challenges of funding, enrollment, and trial design present sizable challenges to a potential type 1 CVOT, but the insight to be gained through such a study would is immensely important. Mechanistically, there’s reason to believe these effects of SGLT inhibition could play out similarly in type 1. However, hard evidence in the way of a completed CVOT is surely needed to promote broad use of these agents for reducing risk. In our view, fully fleshing out these potential benefits is crucial to any discussion of these two therapy classes as adjunct treatments for type 1 diabetes, in order to fully understand the risk/benefit profiles of such treatment.
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.
Top Technology Highlights
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.)
A Look at the Future of Wearables: Stanford’s Dr. Mintu Turakhia, the Fully-Virtual Apple Heart Study (n=419,297) and Use of Apple Watch to Detect Atrial Fibrillation
Closing out Thursday’s sessions, Dr. Mintu Turakhia (Stanford University) discussed the origin story of wearables, the use cases, machine learning, artificial intelligence, and telehealth – a tour de force showing the power of wearables moving ahead, particularly related to conditions like heart arrhthmias. Dr. Turakhia illustrated these points by presenting previously presented data from the massive (n=419,297), fully-virtual Apple Heart Study (ClinicalTrials.gov) evaluating whether data from Apple Watch could be used to detect atrial fibrillation (irregular heartbeat). The trial completed in February and first read out at ACC 2019, and we very much appreciated his further discussion of this high-profile study. Dr. Turakhia’s CMHC talk was among the most relevant of the day in terms of where clinical trials may head, hitting several points related to the FDA’s recently released draft guidance on “Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations.” As a reminder, the single-arm Apple Health study was able to enroll an incredible 419,297 participants, including ~20,000 people with diabetes and ~160,000 people with obesity, in just eight months. We look forward to learning more on these sub-populations in particular; we’ll be back with more on this once published. For those interested in hearing more insights from Dr. Turakhia on the Apple Health Study itself, please see this video interview with Dr. Turakhia and ACC from last March as well as the full slideset from ACC and the Apple Health Study, in addition to Close Concerns’ coverage from ACC on this talk.
Top Big Picture Highlights
Dr. Irl Hirsch (University of Washington) hosted a valuable workshop, “Navigating Insulin Access and Cost,” that directed ire for rising insulin costs on a group that he says “nobody talks about”: lobbyists. While a lot of focus in the insulin affordability movement has understandably been placed on pharmaceutical companies and PBMs, Dr. Hirsch pointed out that the public has, so far, ignored the role of money in politics. According to the Center for Responsive Politics’ website OpenSecrets.org, the entire pharmaceutical/healthcare industry spends ~$30 million/year on lobbying. Dr. Hirsch compared that number to the NRA’s ~$3 million/year in lobbying spending, and then asked the rhetorical question, “Now, do you understand why our lawmakers struggle to make insulin affordable?”
- Early on, Dr. Hirsch underscored the scale of the problem, citing Dr. Kasia Lipska’s (Yale University) study that found one in four Americans ration insulin because of affordability concerns. He presented a graph of the price of insulin per unit from 1960 to 2017, showing a tripling in insulin prices from 2002-2013. Using the graph, Dr. Hirsch noted a jump in price from 0.4¢/U in 1975 to 2¢/U in 1983, with the advent of human insulin in 1982 and another jump from 2¢/U in 1983 to 3¢/U in 1996 with the first insulin analogs. From 2005 to 2017, the price for regular insulin nearly quintupled to 15¢/U, while analog insulin prices hit 29¢/U.
- Given the high costs of most insulins, Dr. Hirsch called Walmart’s ReliOn brand human insulin, priced at $25/vial (1000 U), “literally a lifesaver.” Looking at human insulins more broadly, Dr. Hirsch pointed at a 2018 real-world study (n=25,489 type 2s) comparing hypo-related emergency department visits and hospital admissions between patients starting NPH vs. analog basal insulin therapy. That study found numerically fewer hypoglycemic events in those using NPH insulin compared to those using analog insulin, though this difference missed statistical significance (11.9 vs. 8.8 events/1000 person-years; p=0.07). Additionally, one-year after initiating insulin therapy, the NPH users saw a greater reduction in A1c (from 9.4% to 7.9%) compared to analog insulin users (from 9.4% to 8.2%); though this difference was statistically significant, and Dr. Hirsh noted that it was not clinically meaningful.
- Dr. Hirsch concluded that in type 2s, it was “okay” to use regular insulins, but that many had been “brainwashed” to put patients on analog insulin. Even as the price of insulin has increased, human insulins are making a smaller percentage of insulin prescriptions. Dr. Hirsch did concede that human insulin was only available in vials and that he’d rather use analog insulin, but for many, the cost is simply unaffordable.
- For the HCPs in the room, Dr. Hirsch shared a few pearls for using NPH and regular human insulins. Due to the kinetics of NPH insulin, it can act as a prandial and basal insulin. This could mean twice-daily injections for people with higher insulin deficiencies and the need for strategic snacking. For regular human insulin, the timing of pre-meal injection is critical, though this may be less important for type 2s. Additionally, injection site (abdomen vs. thigh vs. hips) becomes more important and risk of nighttime hypoglycemia is increased with large dinner doses.
- Dr. Hirsch, a self-described “baseball nut,” also presented a patient case study, calling a mean glucose of 200 mg/dl the “Mendoza Line.” The term comes from former baseball infielder Mario Mendoza, whose poor batting average is used to define the threshold of minimum acceptability for a major league player. In baseball, the Mendoza line is generally said to be 0.200.
- Dr. Hirsch pointed workshop attendees to a few ways to obtain analog insulin that “doesn’t cost more than a house mortgage.” Earlier this year, Lilly launched its “generic” lispro at $137/vial. Unfortunately, the product has seen slow market adoption, with Express Scripts declining to include the drug on its formulary in April. All three major insulin manufacturers have assistance programs (Lilly, Novo Nordisk, Sanofi), which Dr. Hirsch emphasized are all much easier to use (i.e. less hassle) than they were just two to three years ago. He also advised providers to check whether their organizations were 340B Health Care Organizations, which would allow organizations to receive covered drugs at significantly reduced prices. Additionally, Sanofi introduced a “$99/month” insulin program (up to five vials, any insulin brand) last year and Novo Nordisk introduced a “$99/month” insulin program (up to three vials, any insulin brand) last summer. Lastly, Dr. Hirsch noted that “20%” of his patients get insulin from Canada, where insulin can be purchased for ~$30/vial or $50 for a box of pens.
- Ultimately, Dr. Hirsch noted the fundamental issue at question was whether having access to insulin was a privilege or a right. He expressed his disappointment that insulin access had become a political issue, and we’d certainly agree that no one should ever have to ration insulin. Early on in his presentation, Dr. Hirsch showed a powerful picture with Ms. Nicole Smith-Holt looking down at the death certificate of her son, Alec Smith, who died in 2017 due to insulin rationing. He did not apparently know about any patient access programs – as long as there is any rationing in insulin, more investment in awareness would be fantastic to see. During Q&A, when asked if there was anything that could be done to change the issue, Dr. Hirsch answered with one word: vote.
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.
Cardiologist Dr. Amit V. Khera (Massachusetts General Hospital) gave a valuable look at the potential of genomic medicine in preventing cardiometabolic disease and presented data showing that a polygenetic risk score was a stronger predictor of coronary artery disease than any other traditional risk factor (e.g. LDL-C, triglycerides) by itself. Dr. Khera’s group compared the genomes of ~60,000 people who experienced a myocardial infarction (MI) at a young age (<55 years) and ~120,000 controls. Looking at 6.6 million genetic variants, a computational algorithm integrated all variants into a single risk-score metric. When testing the polygenic score in 300,000 additional people, they found normally distributed scores in the population. For the top 5% of scores, risk of MI was over three times higher. Notably, carriers of a high-risk score couldn’t be identified by most traditional risk factors (i.e. higher risk score was not strongly associated with LDL-C, type 2 diabetes, BMI, etc.). In 300,000 individuals from the UK Biobank followed for eight years, there were 7,000 incident cases of coronary artery disease (CAD). The researchers found the polygenic risk score, combined with age and sex, was a stronger predictor of CAD than any other traditional risk factor; additionally, unlike other risk factors, polygenic risk scores could be calculated from birth, potentially empowering patients to take action on their predisposition to cardiometabolic disease well before symptoms begin to appear.
- Underscoring one major advantage of using genetic risk scores, which can be evaluated at birth, favorable lifestyle was linked to a 50% lower rate of coronary events. For high polygenic risk individuals with an unfavorable lifestyle, standardized 10-year coronary event rate was 10.7%; for this with a favorable lifestyle, the rate was reduced to 5.1%. It’s unclear what the study size and population for this analysis was. Favorable lifestyle was determined based on four factors: current smoking status, BMI <30 kg/m2, regular exercise, and healthy diet. Those who met 3-4 factors had a “favorable lifestyle,” those who met 2 factors had an “intermediate lifestyle,” while those with 0-1 factors had an “unfavorable lifestyle.”
In the first session of CMHC 2019, Dr. Eric Peterson (Duke Clinical Research Institute) gave a comprehensive overview of the state of big data, highlighting inadequacies in the current electronic health record (EHR) system and future goals for the field. See below for some of the main takeaways from his excellent overview:
- Creating new medicines is too expensive, too slow, and non-representative of the general population. Dr. Peterson began his talk by pointing out the barriers between basic research and approved medicines that big data can seek to address. The cost to develop a drug through FDA approval is currently more than $2.5 billion, takes an average of 17 years, and only 3% of eligible patients actually participate in clinical trials, making results widely inapplicable to what’s seen in routine clinical practice. Furthermore, actual adoption of drugs once they are approved is still quite poor and persistence on evidence-based medications is low – a 2017 study published in American Health & Drug Benefits revealed that only 61% of patients initiated on SGLT-2 inhibitors continue on treatment. According to Dr. Peterson, however, “big data will solve all of that for you.”
- Learning health networks have the potential to revolutionize healthcare. Historically, EHRs have struggled to fulfill their potential promise. Currently, EHRs are largely focused on billing, lack in data completeness and quality, and the ROI in terms of helping research or decision support remains unclear. To counter these inadequacies, the vision for learning health networks of the future is to (i) integrate multiple EHR systems and registries; (ii) facilitate randomized clinical trials by harmonizing a data stream; (iii) help in decision support and clinician feedback; and (iv) provide patient education.
- Big data is not just a pipe dream. Though successfully utilizing big data may seem like a lofty goal, Dr. Peterson emphasized that several studies have successfully implemented such systems. For example, the ADAPTABLE study aims to use patient reported outcomes to determine whether the 325 mg dose or 81 mg dose of aspirin is most effective. The nearly completed study will enroll a total of 15,000 patients across multiple health networks and only require 1/10th the average cost of a traditional trial.
- Using clinical data to transform practice remains a goal. While Dr. Peterson’s own work creating a system that generates HCP feedback for the Duke Cardiology Clinics documenting blood pressure control has had minimal success in changing outcomes, he continues to advocate for the use of clinical data in pushing clinical practice forward. Dr. Peterson jokingly surmised that perhaps the best course of action is to work directly with patients rather than providers to create change and highlighted medical mobile apps as an exciting area of innovation.
Northwestern Center for Genetic Medicine’s Dr. Elizabeth McNally painted an engaging portrait of genetic testing and its potential in cardiometabolic medicine, calling the human genome “the biggest data set anyone of us has.” Dr. McNally opened her presentation by sharing an impressive statistic with the audience: about five million genetic differences exist between any two people. And with companies like 23andMe and Ancestry.com becoming increasingly mainstream, there is a growing interest in harnessing these genetic differences in a meaningful way. In the case of medicine, genetic differences can help elucidate why certain treatments work well for some but not for others.
- Medically actionable genetic testing is more specific than genetic risk score testing. Dr. McNally spent a fair amount of her presentation differentiating rare genetic variations and common genetic variations. Common genetic variation contributes to about 15% of the total variation in the human genome, while 85% of genetic variation is rare. As much as 10%, and perhaps more, of the human populations has a rare disease. Genetic risk score testing only assesses common genetic variation but sums up large swaths of data into a cumulative and more meaningful risk score. Medically actionable genetic testing instead pinpoints specific genes that can inform HCPs on medical care decisions.
- Genetic risk scores are of less or unproven value in diverse populations. Dr. McNally emphasized that the vast majority of risk score research has been performed on those of Caucasian and European descent – an extremely narrow genetic group considering the wide diversity from other ethnicities. More research is needed to know how well genetic risk scores perform in diverse populations.
- Prospective gene sequencing of medically actionable genes could significantly impact current cardiometabolic care. Currently, there are a number of gene panels available for cardiomyopathies, arrhythmias, familial hypercholesterolemia, neuromuscular disease, aortopathies, and other CV diseases. As an example of gene panels in action, the Electronic Medical Records & Genomics Network (EMERGE) has a project that is sequencing 109 actionable genes in a cohort of 25,000 patients. The database is available to the public, and in theory, will allow prediction of phenotype from the genetic information given. Astoundingly, ~5% of the population may have an actionable finding using gene panel testing, which could markedly change current paradigms of treatment.
Top Obesity Highlights
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.
Dr. Lee Kaplan (Director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital) presented a captivating explanation of the physiological changes driving weight loss from metabolic surgery, noting a complex mechanism that goes far beyond malabsorption. The crux of Dr. Kaplan’s argument is that metabolic surgery not only decreases food absorption, but more fundamentally, alters the fat mass set point to which a person’s body equilibrates to, leading the body to “defend a new body fat mass.” Clinical evidence supporting mechanisms beyond a reduction in caloric intake following metabolic surgery include: (i) dramatic effects on hunger and satiety (i.e. patients become more quickly satiated after a meal); (ii) few patients become underweight after surgery, which would be the case if consistent malabsorption were driving weight loss; (iii) little or no weight loss is seen in thin patients or thin animals, suggesting a “floor” weight or lipid content underscoring the physiology; and (iv) women who receive bariatric surgery and later become pregnant experience a transient weight gain during pregnancy, which would not be possible if surgery prevented nutrient absorption – or in Dr. Kaplan’s words, “the physiology of pregnancy trumps the physiology of obesity.” To cause this change in set point, surgeries like Roux-en-Y Gastric Bypass decrease appetite drive, alter food preference, modify hormone signaling, affect the microbiota, and vastly alter metabolism, along with a plethora of other mechanisms.
Compared to calorie restriction, other lifestyle modifiers like a change in diet content, exercise, stress, or the use of anti-obesity medication, will similarly alter the metabolic set point. Interestingly, Dr. Kaplan commented that the only difference between surgery and drugs or lifestyle is that surgery is more powerful.
Dr. Kaplan also highlighted pharmacological treatment after completion of surgical weight loss as the most promising strategy to combat inadequate weight change. More specifically, a stepwise treatment pattern should be used, only adding new medications after a stable response to the previous one has been established. Dr. Kaplan encouraged the audience to seek out the “highly responsive subgroup” for all therapy options, as currently, no good predictors exist to help decide the “right” treatment for an individual. GRAVITAS, the first randomized clinical trial for an anti-obesity drug following inadequate response to bariatric surgery in patients with type 2 diabetes, showed a substantial drop in bodyweight (-5.26 kg; 95% CI: -6.15 to -4.38, p<0.0001) in participants treated with GLP-1 liraglutide following metabolic surgery compared to those treated with placebo, hinting at the potential success of other surgery and medication combinations.
Amgen brought one of the largest booths to this year’s exhibit hall, with one section dedicated to PCSK9 inhibitor Repatha (evolocumab) and the other to a mapping campaign asking, “do you know the cholesterol levels in your area?” Each side of the booth sported its own podium and salesperson, making the area open and inviting to exhibit hall goers. The large advertisement for Repatha, which made up the backdrop of one section, asked onlookers to “take action” with the drug “to prevent MI or stroke,” boosted by data from the FOURIER clinical trial. On the other side, the mapping campaign overtly lacked advertisements and instead consisted of an interactive screen in which onlookers could examine LDL-C statistics across America. Altogether, the booth created cohesive support for Repatha’s LDL-C lowering benefits and was one of the most engaging options at this year’s CMHC.
AZ’s modest booth featured a table with standing posters primarily for SGLT-2 inhibitor Farxiga (dapagliflozin) and GLP-1 Bydureon (exenatide). As part of the Farxiga campaign, other smaller posters displayed facts on Xigduo XR (dapagliflozin/metformin) and Qtern (dapagliflozin/saxagliptin) with the slogan “stay in the Farxiga family.” Though informational pamphlets were aplenty, our associates were a bit underwhelmed with the booth’s offerings overall, especially compared to AZ’s usual robust presence on the exhibit hall floor.
Amarin brought a small booth to CMHC to promote Vascepa (icosapent ethyl). As usual, the main focus of the company’s presentation were REDUCE-IT results showing the impressive 25% RRR of Vascepa treatment on MACE, along with an important post-hoc showing a 30% RRR on total CV events over the length of the trial. Notably, FDA is set to hold an Advisory Committee on November 14 to discuss a potential label expansion for Vascepa. The PDUFA date for an FDA decision on the label expansion has been moved back to late December 2019 from an initial date of September 28, 2019
BI had a cozy booth with a few posters of promotional materials for SGLT-2 inhibitor Jardiance. The booth’s lone representative was naturally concentrated on discussing Jardiance’s CV death indication in the US, which was granted based on an impressive 38% relative risk reduction vs. placebo in EMPA-REG OUTCOME. There was no mention of DPP-4 Tradjenta at the booth, despite the relatively recent readout of the CARMELINA CVOT at EASD 2018. Given that the trial demonstrated only CV safety, and not CV superiority, vs. placebo (as was expected), we find it unsurprising that Lilly/BI prioritized their cardioprotective agent in this display.
Novo Nordisk brought two separate booths to Chicago – one each to separately promote Saxenda (obesity grade liraglutide) and Ozempic (injectable semaglutide). Our team found the Saxenda booth particularly engaging, as representatives offered each passerby the chance to try on a 20-lb vest and try sitting down and standing up in order to simulate the average amount of weight that Saxenda treatment is associated with. The difference in experience with and without the vest was truly remarkable and speaks to the efficacy of Saxenda in promoting weight loss. Novo Nordisk’s separate booth for Ozempic contained familiar advertising of results from the SUSTAIN program. Representatives were unable to further discuss the upcoming launch of Rybelsus (oral semaglutide) but were able to provide handouts of prescribing information for the therapy.
Merck’s midsized booth went all out for SGLT-2 inhibitor Steglatro (ertugliflozin), the center piece of the operation being an upright, interactive television screen featuring data on the product perched atop a table. In addition, informational pamphlets were plentiful, so passersby could take learnings to go. Merck and Pfizer’s primary treatment for diabetes is the DPP-4 inhibitor Januvia, and we were not surprised that this table emphasized its SGLT-2 inhibitor.
--by Rhea Teng, Albert Cai, Martin Kurian, and Kelly Close