December 3-6, 2020; Virtual; Day #4 Highlights – Draft

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Day #1 Highlights – Joint Lancet Diabetes & Endocrinology & WCIRDC session on diabetes and COVID-19; AZ symposium on redefining HF and CKD treatment paradigms; Drs. Martha Gulati and Gina Lundberg on heart disease in women; Dr. Ralph DeFronzo on “fatty kidney”

Day #2 Highlights – Day #1 summary panel QQs; Pharmacological and surgical interventions in pediatric obesity; Dr. Jay Skyler on type 1 immunotherapies; Dr. Julio Rosenstock on future insulins; Cancer & metabolic diseases

Day #3 Highlights – Day #2 summary panel QQS; Day #3 summary panel QQs; Dr. Tim Garvey on future obesity pharmacotherapies; Exenatide study calls GLP-1 anti-atherosclerotic hypothesis into question; Joint Metabolism & WCIRDC session

Top Four Highlights

1. Dr. Carolyn Lam Explores Future of HFpEF: Novartis’ Entresto, New Classifications, and SOLOIST-WHF

The ever-engaging Dr. Carolyn Lam (Professor at Duke NUS and CMO/Co-Founder of eko.ai) gave audience members a rapid-fire review of why they should care about heart failure with preserved ejection fraction (HFpEF) and where current diagnostics and treatments stand. While HFrEF (defined as LVEF ≤40%) treatment has experienced a renaissance due to positive results from DAPA-HF for AZ’s dapagliflozin and EMPEROR-Reduced for Lilly/BI’s empagliflozin, to date, a highly efficacious therapy for HFpEF remains elusive. To begin her talk, Dr. Lam shared startling statistics on rising HFpEF prevalence and incidence worldwide: based on data from the Get with the Guidelines-HF registry from 2005-2010, HFpEF (represented in black below) is poised to become the most dominant form of heart failure; furthermore, data from Olmsted County published in JAMA Internal Medicine showed that the incidence of HFpEF, relative to incidence of HFrEF, rose from 48% of incident HF from 2000-20003 to 52% in 2008-2010.

• Importantly for patients with diabetes, Dr. Lam emphasized that ~1/3 of HFpEF patients have diabetes, and obesity and insulin resistance are stronger predictors of HFpEF than HFrEF. Dr. Lam reminded audience members that although those “from the diabetes world” sometimes think of HF as a large event such as myocardial infarction (heart attack) or severely reduced ejection fraction, both HFrEF and HFpEF can be associated with abundant microvascular inflammation as well.  Indeed, data from the prospective PROMIS-HFpEF study showed that 75% of patients with HFpEF have microvascular coronary dysfunction in the absence of macrovascular coronary disease. Notably, these microvascular complications in the heart correlate with microvascular damage across the body. As such, Dr. Lam recommends that HCPs start to think about HFpEF when microvascular dysfunction in other organs is present in patients with diabetes (i.e., retinopathy, nephropathy, peripheral neuropathy). If SGLT-2 inhibitor trials in HFpEF (DELIVER, EMPEROR-Preserved) deliver positive results, we hope that HCPs take this data as a call-to-action to more proactively treat and potentially prevent the disease in patients with diabetes.

• While no treatments have proven to “convincingly reduce morbidity and mortality in patients with HFpEF,” Dr. Lam stated that she believes the totality of data supporting Novartis’ Entresto (sacubitril/valsartan) suggests “some benefit.” As a reminder, Entresto narrowly missed significance in the phase 3 PARAGON-HF trial on the primary composite of CV death/total HF hospitalization. To support how “narrow” this truly was, Dr. Lam presented a number of sensitivity and supportive analyses from PARAGON-HF, which demonstrated that if urgent HF visits or all investigator reported events (vs. only adjudicated events) had been used in the analysis, benefits would have been statistically significant. Dr. Lam also presented other analyses which showed that Entresto delivered the greatest benefit to those at highest risk (i.e., most recently hospitalized, high NTproBNP levels).

• Dr. Lam ended her talk with an important point on HF classification, advocating that heart failure with moderate ejection fraction (typically classified as LVEF in the 40-50% range) be renamed “heart failure with mildly reduced ejection fraction.” Dr. Lam recently published this theory as a “Viewpoint” in the European Heart Journal, in which she argued, “the implications of this new nomenclature are…patients with a mildly reduced EF should be given he benefit of the doubt and considered for treatment with established therapies in HF with more severely reduced EF.” This mindset is of particular importance when treating women, as Dr. Lam postulates that ejection fractions are supposed to be higher in women (women tend to be smaller, so for same stroke volume, ejection fraction is higher in women vs. men). As such, women with LVEFs as high as 55% may benefit from HFrEF therapies.

Select Panel Question & Answer

Dr. Mikhail Kosiborod (Saint Luke’s Health System): I’m going to start with a question from the audience for you, Carolyn. What do you do with mid-range ejection fraction? We always talk about HFrEF and HFpEF, but there is this middle group, which we sometimes call HFmEF – between 40 and 50% is how it’s typically defined. How do we treat those patients? As HFrEF or HFpEF? Or should we get rid of classification altogether?

Dr. Carolyn Lam (Duke NUS): Thanks, Mikhail. Well, I think it’s time we call it “heart failure with mildly reduced ejection fraction.” I truly think that if you see someone with an EF that is reported in that range, we really owe it to them to double check the echo, or whatever modality, look at it yourself and really try to discern whether there is systolic dysfunction – for example, if the ventricle is very small, if there’s mitral regurgitation, in cases like that, you would expect a higher EF, so if it’s already at only 40, that’s clearly reduced, and I would treat as HFrEF.

Just one other element that I didn’t think I had time to mention during the talk is that it matters which direction they were going. A lot of patients in the mid-range are actually in transition between a lower and a higher EF. Those that are transitioning from a clearly lower to higher EF, that’s improved. What we’ve learned now is that you continue to treat them as HFrEF. TRED-HF tells us, “don’t take off those medications,” so that’s what we’ll do for now, and I do think the ESC guidelines which first called it “mid-range” and currently groups its management with HFpEF in that ‘we don’t know what to do,’ I think that’s going to have to change a bit because the totality of evidence shows that these patients may benefit from therapies for HFrEF.

Dr. Kosiborod: Unlike this deluge of efficacious treatments we have for HFrEF, we’ve been striking out time and time again in HFpEF. Every single time we’ve tried to use therapies that’s beneficial in HFrEF, they don’t appear to work in HFpEF, or results are not really definitive, and we don’t really know if they are working or not. With SGLT-2 inhibitors, we probably have the best shot in decades in terms of having something that is disease modifying. In that regard, the SOLOIST-WHF trial with sotagliflozin – a mixed SGLT-1/2 inhibitor – was just presented at AHA 2020 by Dr. Bhatt and published in the NEJM…Among ~1,200 patients the trial, there was a subgroup of ~250 patients with HFpEF, and statistically, there was no heterogeneity in terms of treatment benefit, so overall, sotagliflozin reduced the risk of total events of CV death or worsening HF, without heterogeneity between reduced and preserved EF HF– in fact, numerically, the benefit in HFpEF patients was even better. So, based on these results, can we start treating patients with HFpEF with SGLT-2 inhibitors? Or do we need to wait for large and dedicated trials?

Dr. Lam: I’m almost afraid to comment to jinx the whole situation because we’ve added a few more tombstones to this graveyard with the VITALITY and CAPACITY trials with soluble guanylate cyclase stimulators also being neutral. So yes, the SGLT-1/2 inhibitor trials bring a glimmer of hope. I say trials (plural) because other than SOLOIST, SCORED, which was predominantly a CKD trial, also allowed patients with baseline HF in it, including HFpEF. I remember Dr. Bhatt presented a combined analysis with a total of more than 730 patients from SOLOIST-WHF and SCORED with HFpEF, and it was so tantalizing – I mean you see this huge separation in curves.

But a couple of things – no, I don’t think it’s ready for prime time, unfortunately. First of all, this is an SGLT-1/2 inhibitor. I think everybody is trying to ask, “can we extrapolate this to just the plain SGLT-2 inhibitors?” I’m not so sure because the subgroup analyses from the SGLT-2 inhibitor trials that we have are not so clear regarding baseline HFpEF, so I’m not sure. The other thing, of course, is that SOLOIST and SCORED were both stopped prematurely – events were not adjudicated, although I highly applaud the investigators because what a beautiful report in the end. So, I don’t think we can definitely apply it right now, but I do think it offers a lot of hope to the ongoing trials like DELIVER with dapagliflozin and EMPEROR-Preserved with empagliflozin.

Dr. Kosiborod: Javed, continuing on this topic of SOLOIST. Of course, about half of patients in SOLOIST were in the hospital for decompensated heart failure and were randomized in the hospital, and the other half were randomized soon after discharge. The question that has been raised  many times, is ‘are we ready to start these medications in patients going home after hospitalization with heart failure?’ Do we really need to wait until they’re in the outpatient setting? We know that if started in the hospital, they’re more likely to take it, adhere to it, and be on those medications long term, so do we need additional trials looking at dapagliflozin or empagliflozin being initiated in patients in the hospital? Do we need to wait for those trials? Or are we ready after SOLOIST to start doing it? 

Dr. Javed Butler (University of Mississippi). Well, that’s a three in one question, so let me just quickly answer all three. One question is, “is there efficacy for the drug being started in the hospital?” Remember, the best predictor of a drug being taken in the long run in terms of adherence and filling prescriptions is the drug being started in the hospital. So at the time of discharge, it makes a lot of sense, but also remember that in the large trials – DAPA-HF and EMPEROR-Reduced – a lot of these patients did get admitted but the total and recurrent event rate was even lower, so I don’t think there’s particularly safety concern. More of the registries will show the data, and in terms of the efficacy, it’s the same disease – HFrEF – and if you look at the recurrent event data from DAPA-HF and EMPEROR-Reduced, and now with SOLOIST, it makes perfect sense that in a person stable and ready to go home, that it is started in the hospital. That’s safety and efficacy.

There’s actually a second question for SGLT-2 inhibitors and that is whether or not there is an interaction with loop diuretics in terms of decreasing diuretic resistance, that mechanistic study being done by people like […] have shown that. Having said that, there is an ongoing trial with dapagliflozin looking at urine output and weight loss in the first five days – a much more detailed mechanistic study of about 300 patients – so, I would reserve whether or not we should give it early in the admission to break diuretic resistance; I don’t know the answer to that, but giving it at the time of discharge for long term benefit? Absolutely yes.

2. The Future of Cardiometabolic Care is Patient-Centered, Collaborative, and Includes SGLT-2 Inhibitors and GLP-1s

Drs. Brendan Everett (Harvard Medical School) and Mikhail Kosiborod (Saint Luke’s Health System) outlined how new professional society consensus statements and collaborative care models can improve cardiovascular outcomes for people with and without diabetes. In his presentation of the new 2020 ACC Expert Consensus Decision Pathway, Dr. Everett emphasized that SGLT-2 inhibitors and GLP-1 agonists can revolutionize cardiac care. However, controversy remains on if patients should begin treatment with metformin at baseline instead of one of these new therapies. Currently, the ADA recommends metformin as first-line therapy, while the EASD recommends starting patients with type 2 diabetes on an SGLT-2 inhibitor or GLP-1 if they have or are at high risk for ASCVD. After this presentation, Dr. Kosiborod took to the virtual stage to discuss new methods of cardiometabolic care to go along with new treatment paradigms. He started by outlining the goals of type 2 diabetes care:  prolonging life and improving quality of life, which can best be reached by preventing the common comorbidities of CVD and DKD. SGLT-2 inhibitors and GLP-1 agonists are especially helpful in improving CV outcomes, and focus is shifting away from A1c and toward CV risk reduction. Dr. Kosiborod urged physicians to work along allied health professionals in patient-centered collaborative care models, like those at the Saint Luke’s Cardiometabolic Center Alliance, to take the lead and improve patient outcomes.

Select Panel Question and Answer

Dr. Peter Grant (University of Leeds): A lot of patients will be seeing diabetologists way before cardiologists, so we need to start giving them these new medications early.

Dr. Jorge Plutzky (Harvard Medical School): How do you pick between an SGLT-2 and GLP-1?

Dr. Mikhail Kosiborod (Saint Luke’s Health System): Within a class, in the US, the choice is being made for us by the economics of prescribing these medications. I tell my colleagues and my patients that it’s more important to prescribe a drug within a (cardioprotective) than a choice of a specific agent. Which agent can be argued, but the bottom line is, there are some agents in each of the classes that have better data than others, but that’s less important. For GLP-1s, there are also patient preferences that come into play if medications are injected daily or weekly, or if they are taken orally.

Dr. Plutzky: How often do you find that you end up with patients on both agents, and is that a payer challenge?

Dr. Kosiborod: We use combination therapy quite a bit, and while we don’t have CVOTs on combination therapy, it’s reasonable to assume effects are complimentary, and these two classes are usually well-tolerated together. GLP-1s are effective more in terms of ASCVD, while SGLT-2s are more effective in preventing and treating heart failure and CKD. Regarding insurance coverage, we can’t solve that issue quickly, but physicians have an opportunity to use PAPs, many of which are quite flexible.

Dr. Brendan Everett (Harvard Medical School): Is the SGLT-2 or GLP-1 the right choice for someone with ASCVD? I share optimism about combination therapy, but I have friends who are endocrinologists that believe benefits together are less than additive or synergistic. Weight loss may be less substantial with combination therapy. We should test this in randomized trials.

Dr. Kosiborod: From RCTs, weight loss and blood pressure effects are additive, but A1c is not. I hope we will be able to answer the question definitively someday.

Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles): I think the whole idea of clinical trials is to guide clinical practice. We have three GLP-1s approved for CV benefit, and those are the three that I would choose. Some are also approved for patients without manifest CVD, and I would prefer those to those that have only benefit in patients with established CVD. I’m a stickler for evidence-based medicine, and that’s what I would advocate.

Dr. Plutzky: Has anyone looked at the health economics or have thoughts to add?

Dr. Robert Chilton (UT Health San Antonio): Mikhail’s right, if you ask the companies for help with paying, they give the drugs to patients for free.

Dr. Plutzky: I agree; appeal, and people are willing to pay.

3. Dr. Richard Pratley and Dr. David Nathan Debate the Promises and Pitfalls of SGLT-2 inhibitors and GLP-1s in Type 1 Diabetes

A 2005 NEJM article from DCCT/EDIC established that in patients with type 1, intensive glucose control confers significant reductions in long-term cardiovascular (CV) risk. At 20-years follow-up, the cumulative incidence of any first cardiovascular event was 42% lower for patients with type 1 receiving intensive therapy relative to those receiving standard therapy (95% CI: 0.09-0.63, p=0.02). However, T1D exchange data shows that the number of patients with type 1 achieving recommended A1c targets (<7%) remains low, hovering between 11-30% of patients across age groups. In addition, cardiovascular disease (CVD) and kidney disease remain major causes of mortality in type 1 diabetes, with residual risk increasing with diabetes duration. Given these worrisome trends, interest has grown around the use of adjunctive therapies with established CV benefit in type 1 diabetes patients – specifically SGLT-2 inhibitors and GLP-1 receptor agonists. In a stimulating debate, Drs. Richard Pratley (AdventHealth Diabetes Institute) and David Nathan (Harvard Medical School) discussed whether healthcare professionals should be prescribing these adjunctive therapies to their type 1 patients. In a careful survey of the existing data, Dr. Nathan argued that the risks of SGLT-2 inhibitors and GLP-1s in type 1 diabetes outweigh the potential benefits, while Dr. Pratley offered the counterargument. While Dr. Nathan won the debate by a slim margin – 52% vs. 48% by a viewer poll – both speakers offered novel and expert insight into where the field stands on CV risk reduction in type 1 diabetes. See below for highlights from each presentation.

• Dr. Pratley showed that a meaningful percentage of patients with “type 2 diabetes” in RCTs have some degree of autoimmune diabetes. In one RCT evaluating linagliptin versus glimepiride in patients with type 2, around 6.5% were positive for GAD65 autoantibodies. In the AWARD-2 ,-4, and -5 studies evaluating dulaglutide in type 2, around 7.6% of participants were GAD65 positive, and even those with high GAD65 titers still showed meaningful A1c reductions (around -1%) with treatment. If these observations are extrapolated to large CVOTs in type 2 diabetes – such as those investigating SGLT-2 inhibitors and GLP-1s over long durations – around 14,000 out of 200,000 enrolled patients might have autoimmune diabetes. If “type 2 diabetes” studies include patients with autoimmune diabetes as well, perhaps the cardiorenal benefits seen with SGLT-2 inhibitors and GLP-1s are relevant to patients with type 1 as well.

• Dr. Pratley made the case for GLP-1 receptor agonists and SGLT-2 inhibitors in type 1 by reviewing a number of small-scale clinical studies. In ADJUNCT ONE and ADJUNCT TWO trials, the GLP-1 liraglutide achieved statistically significant reductions in body weight, A1c, and insulin dosing requirements – albeit with an increase in symptomatic hypoglycemia and episodes of hyperglycemia with ketosis, which precluded the GLP-1 from receiving a type 1 indication. SGLT-2 inhibitors, on the other hand, have been shown to confer reductions in weight (although to a lesser extent than GLP-1s) and A1c without increasing symptomatic or severe hypoglycemia – as shown in the EASE trials with empagliflozin, for example. While SGLT-2 inhibitors have consistently been shown to increase the risk of diabetic ketoacidosis (DKA) in type 1 patients, Dr. Pratley emphasized that there were proactive steps patients and providers could take to mitigate risk: avoid low-carb diets, drink adequate fluids, continue insulin therapy, discontinue treatment if nausea or sickness occurs, and use ketone monitoring, to name a few strategies.

• On the opposition, Dr. Nathan argued that the “risks [outweighed] demonstrated benefits” for prescribing SGLT-2 inhibitors and GLP-1 receptor agonists in type 1 diabetes. Citing a network meta-analysis of 23 RCTs investigating insulin alone or in combination with SGLT-2 inhibitors, metformin, or GLP-1 receptor agonists, Dr. Nathan showed that all therapies conferred only modest A1c reductions – which shrunk in magnitude when adjusted for the placebo effect. Further, since all trials were only between 30- and 52-weeks in duration, they were too brief to demonstrate any benefit on long-term complications.

  • While SGLT-inhibitors show some effect on A1c- and weight-lowering in type 1 diabetes, as well as increased time in range, Dr. Nathan emphasized the severely elevated risk of DKA which comes with treatment. Across multiple trials, ~3% of patients treated with an SGLT-inhibitor had a DKA episode they would not have otherwise had. In one particularly striking statistic, dual SGLT-1/2 inhibitor sotagliflozin was associated with between a 5- to 17-fold increased risk of DKA relative to placebo. In addition, SGLT-inhibitors also increase the risk of genital mycotic infections in women. These combined risks, argued Dr. Nathan, far outweighed the potential benefits for this therapy in type 1 diabetes.

• GLP-1 receptor agonists have been shown to confer even less impressive A1c reductions than those associated with SGLT-inhibitors (only 0.1-0.2%) and are also associated with greater nausea in patients with type 1. They also fail to increase time in range (“smoothing” of glycemic control) to the same extent that SGLT-inhibitors do. GLP-1s are associated with significant weight loss in type 1 diabetes, but this benefit is not necessarily associated with CVD risk reduction. In one RCT of exenatide versus placebo in patients with type 1, patients in the treatment arm demonstrated significant reductions in fat and lean body mass without showing improvement in CVD-related biomarkers of oxidation and/or inflammation – hsCRP, IL-2, IL-6, TNF-alpha, and NT-proBNP, to name a few.

4. Day 4 Quotable Quotes: The Future of Cardiometabolic Care and Multidisciplinary Treatment Plans

On the last day of WCIRDC 2020, Drs. Christian Mende, Yehuda Handelsman, Daniel Einhorn, Ralph DeFronzo, and Mikhail Kosiborod discussed the day’s presentation, with implications on the future of cardiometabolic care. Sessions today focused on cardiovascular disease, insulin resistance, contemporary diabetes management, obesity, kidney disease, and heart failure. Summary session conversations focused on moving away from specialists focusing on individual organ systems, broader treatment paradigms, and the importance of insulin resistance in treating type 1 diabetes.

• There were a number of trials that appeared this year. Fidelio DKD is a trial of finerenone in type 2 and DKD. It’s a cardiorenal drug, so what do we now do for patients with DKD or kidney disease in general? Its benefits may extend to people with kidney disease without diabetes. Should that be the new standard of care, should we be thinking about new combination therapy? Dr. Mikhail Kosiborod (Saint Luke’s Health System)

• I think we are entering a new treatment paradigm in managing people. ACC guidelines are narrow and don’t really look at people with diabetes. Stating that people should not take a DPP-4 inhibitor and insulin together doesn’t acknowledge that insulin is a necessity for some to stay alive. I also think we’re going to find ourselves in a new area with medication. ACC will not give recommendations, and neither will ADA. There’s no one med society that takes all of this information from trials and comes out with guidance on how to manage patients with cardiometabolic diseases with established or at high risk for CVD. – Dr. Yehuda Handelsman (The Metabolic Institute of America)

• I agree, this has to leave specialized medical science and enter a group with representation of many people. There’s no med society built around cardiometabolic disease. – Dr. Daniel Einhorn (Scripps)

• We need to get away from the idea that every specialist runs one organ system. That’s outdated. Who is responsible for treating the entire patient? The patients are sometimes lost, they have no idea who’s responsible for what. Unfortunately, there is an avalanche of information coming to PCPs, and they have little time to see patients let alone coordinate all that. Somebody’s got to do it, and that’s what we’re doing for the Cardiometabolic Center Alliance. Most care is likely going to be administered by non-physicians anyway to make sure patients get adequate care.– Dr. Mikhail Kosiborod

• As Mikhail said, every center takes a different approach. It all depends where you are, what resources there are, and who can enter it. – Dr. Yehuda Handelsman
  
• All of my patients get triple therapy. I tend to go against standards, so in my opinion, metformin shouldn’t be first line therapy. It doesn’t give you cardiorenal protection, and after first year, your A1c goes up. We need to be starting with drugs that prevent these problems: GLP-1, SGLT-2, pioglitazone. If you had a patient with a heart attack who is a newly diagnosed diabetic, why would you put them on metformin? These can be used in combination. In diabetes care, combination with liraglutide and canagliflozin gives an additive effect on blood pressure, weight, and A1c reduction. It’s true, we don’t know if we get additive effects for CVD. Would you argue that it is additive? I would say yes. This is a study that needs to be done. – Dr. Ralph DeFronzo
  

• If you treat most patients with type 2 upfront with an SGLT-2, GLP-1, and pioglitazone, an overwhelming majority will not need anything else for years, with glucose control (hypothetically if access is not an issue). – Dr. Mikhail Kosiborod

• There are two probs: insulin resistance and beta cell failure. Insulin resistance is early, and you don’t develop diabetes without beta cell failure. There are only two drugs that save beta cells, TZDz and GLP-1s. If you want to keep A1c down, you need those two beta cell saving drugs and do other good things. Metformin and SGLT-2s do not save beta cells as a primary effect. – Dr. Ralph DeFronzo (UT Health San Antonio)

• The moment you introduce the agents matters so much. We need to identify people. I agree, it’s not an A1c story, and the whole algorithm is being driven by other points. – Dr. Daniel Einhorn

• We as cardiologists are seeing more people with type 1 living longer. But the fact that you have insulin deficiency doesn’t mean you don’t have insulin resistance. There’s reluctance to consider anything other than insulin as a treatment. I understand there are no trials, but from a physiologic standpoint, insulin resistance and obesity often coexist in a patient either relative or absolute insulin deficiency. If you have obesity and insulin resistance, it will produce the same results as in any other patient. There’s a growing recognition that insulin resistance is becoming a bigger issue in type 1. – Dr. Mikhail Kosiborod

--by Ursula Biba, Joseph Bell, Rhea Teng, and Kelly Close