Type 2 Diabetes Podcast

A Brave New World in Type 2 Diabetes Treatment and Beyond

Silvio Inzucchi, MD; Mikhail Kosiborod, MD

Disclosures

March 22, 2022

This transcript has been edited for clarity.

Silvio Inzucchi, MD: Welcome to Medscape InDiscussion. I'm your host, Dr Silvio Inzucchi from Yale School of Medicine. Today we're talking about cardiovascular effects of type 2 diabetes medications and we'll get to that shortly. First, I'd like to introduce today's guest. He is Dr Mikhail Kosiborod, a cardiologist and vice president of research at St. Luke's Health System in Kansas City, Missouri. There he's also director of cardiometabolic research at the St. Luke's Mid America Heart Institute, as well as professor of medicine at the University of Missouri, Kansas City. Mikhail is an international expert in the field of diabetes and cardiovascular disease, cardiometabolic syndromes, and cardiorenal syndromes. Welcome today Mikhail.

Mikhail Kosiborod, MD: Thanks so much, Silvio, for your kind introduction. It's a real pleasure to be with you, as always.

Inzucchi: Let's start with just a personal question before we get to the meat of our discussion today. What would you be if you were not a physician?

Kosiborod: That's a great question. I had a choice to make when I was a teenager because there were two things I was really passionate about. I grew up in a very medical family. My dad's a physician. My mom was a dentist. My brother is a physician, and medicine was always one of the things that I was extremely interested in and was one of the top things for consideration. But the other one was music. I played violin very seriously when I was a child. That went on all the way through my teenage years. The city where I grew up is in the former Soviet Union and had a high concentration of very talented violin teachers. Some of the best violin players in the world ultimately came from the music school I used to go to. I was very much involved in classical music and violin.

Inzucchi: Maybe at the end of the discussion, you can close us out with a little symphony. Mikhail, both you and I have been very interested in this notion of use of diabetes medication specifically for cardiovascular risk reduction, and we are clearly moving from an era of what we call glucose-centricity in diabetes care. In other words, super focused just on the hemoglobin A1c to a more, shall we say, a broader, more inclusive approach which involves close attention to cardiovascular risk reduction. Can you take us through the last few years in this area?

Kosiborod: It's really been an unbelievable ride. You may recall, and I know you make that point frequently, that if you look at the circa 2015 International Diabetes Guidelines, it was all about hemoglobin A1c management. As important as glycemic control is, it's not what the laboratory value looks like, right? I mean, typically patients don't come into the office complaining that the A1c is too low or too high, or that they have a problem with A1c. They know what it means, but at the end of the day, what really matters in clinical practice, what we really want to achieve and accomplish in the goal of management is to make patients live longer and feel better. And the way you get there with diabetes or any other chronic disease is by reducing complication rates. And the two most common morbid complications of the disease are cardiovascular and kidney disease.

How do we make patients live longer and feel better? We reduce the risk for cardiovascular and kidney complications. And of course, in 2015 we didn't have the data yet, but now we do. And so seeing what happened just in the last 6 years and how the field has been completely transformed by these large-scale cardiovascular outcome trials and how this kind of intersection of diabetes and cardiovascular disease, what we call cardiometabolic medicine today, went from being one of the least evidence based fields in medicine to one of the best evidence-based is just remarkable and incredibly rewarding because many of us were hoping that that's exactly what's going to happen. But of course, back in 2015, we didn't know it was going to happen. It's a remarkable chapter in the history of medicine.

Inzucchi: I fully agree. It's always been a bit of a conundrum that treating the most common metabolic abnormality of diabetes — obviously, hyperglycemia — has had very little impact on the most common reason for morbidity and mortality in diabetes, which is cardiovascular disease.

Kosiborod: I'm going to add to that just a little bit: Look at where things are going today. As a cardiologist who has been interested in this for so long, I'm looking at the most promising developments for new medications for treating cardiovascular disease, both atherosclerotic cardiovascular disease (ASCVD) and heart failure. And the most promising developments are coming from the field of metabolism. I mean, not all of it, but lots of it is. These developments really have fostered a renaissance of this intermix between, first of all, seeing the whole patient, not just seeing a laboratory abnormality or an organ system, but thinking of the patient as a whole and the understanding that it's the same disease process affecting multiple organ systems. And also, collaboration between different specialties. In the last 7 or 8 years, I've seen more endocrinologists and befriended more endocrinologists than I probably have in the previous 35.

Inzucchi: We're not bad, folks, are we?

Kosiborod: And it's not just endocrinologists, right? It's nephrologists and also, there is a growing area developing kind of between the cardiometabolic field and oncology. I mean, there is just so much going on.

Inzucchi: It reminds me of the fable of the five blind men who are feeling a big elephant and everyone is feeling a different aspect of the elephant. And that's what diabetes and cardiometabolic diseases have been, right? I'm focused on the glucose; you're focused on the heart; then, a nephrologist is focused on the kidney — but all within the same patient. And collaboration is terrific. But it's interesting, as you pointed out, that just in the last 6 years we have solid data from large-scale clinical trials which have shown us the way in terms of which drugs to prefer and for which individuals.

So obviously, we're talking about the two newer drug classes: the glucagon-like peptide 1 (GLP-1) agonists, which are for the most part injectables, but there is an oral formulation available now, and the sodium-glucose cotransporter 2 (SGLT2) inhibitors and they work very differently in terms of reducing glucose and also have a sort of unique thumbprint, if you will, on the types of cardiovascular events that they improve and also their impact on renal function. So the question for you now is that obviously these drugs have pervasive benefits on cardiovascular risk; are they used solely in patients with established cardiovascular disease? What about those of us who see patients who are at high cardiovascular risk but haven't had events yet?

Kosiborod: Our good friend Darren McGuire and I had a debate at the American Diabetes Association back in 2020 over this very question. We know from cardiovascular outcomes trials that patients who already have established disease clearly benefit from these two types of therapies. And as you said, for different reasons, they work differently. They have a different impact on a variety of outcomes. They both have cardiovascular benefits clearly in people who already have established disease.

But what happens to the people who haven't yet developed established cardiovascular disease? Should we be using them in that population as well? Of course, this is a very difficult question to definitively answer, because the lower the risk of the patient populations that you study, the lower is what we call in clinical trials "event rates," right? That is, the rates at which patients are going to have things like myocardial infarction (MI), stroke, hospitalization for heart failure, and cardiovascular death. Studying that population becomes much more difficult because you need to enroll very large populations of patients and follow them for a very long period of time, which is not only very expensive, but also from a practical standpoint, it becomes very difficult in terms of trial mechanics. It's very difficult to keep people in clinical trials for a very, very long period of time.

So how do you do that? Generally speaking, what we try to do is enroll some patients, in between those two groups — those who maybe have lots of risk factors that haven't yet been diagnosed, as has been done with both classes of agents. The REWIND trial of the GLP-1 receptor agonist (RA) dulaglutide had a majority of patients that had not yet been diagnosed with established vascular disease. And the DECLARE trial with [the SGLT2 inhibitor] dapagliflozin also included a majority of patients that didn't have established cardiovascular disease.

What did those trials show? They essentially showed that when it comes to prevention of heart failure, for example for SGLT2 inhibitors, the effects are very much in terms of relative risk reduction, almost precisely the same as what we see in people with established disease. And the same can be said about major adverse cardiovascular events (MACE), prevention, things like MI, stroke, and death from vascular disease with dulaglutide in the REWIND trial with GLP-1 RA.

So what does that mean? Generally speaking, if the drugs are really effective in working in the high-risk patient populations, they typically, in most cases, would also be similarly effective from a relative risk reduction standpoint in low-risk populations. But it's just much more difficult to prove. At this point, given the data we have, it's pretty safe to say that they will work in a similarly effective fashion, even in low-risk populations, but the absolute benefits are going to be less because absolute risk is less, and therefore you need a longer period of time to observe that benefit. But again, the horizon over which we're looking to get benefits may be much longer in those low-risk populations.

If you see a patient with diabetes at the age of 40 and they don't have any known complications, the lifespan of that patient could be 30 or 40 years vs seeing somebody who has had an MI — chances are that patient may not live as long. What you're really trying to do is prevent things in a much shorter period of time. And that's exactly what these agents are also going to be effective in doing because the absolute benefits are so much greater in that very high-risk patient population.

That's my take on it. Of course, the one thing that ultimately becomes important in these decisions is not just medical or clinical effectiveness, but also cost. And from a cost-effectiveness standpoint, the lower the risk of the population, the less cost effective the medications are, assuming that the medications themselves have a cost premium. Now, as they become generic of course, the population of patients for whom it becomes cost-effective dramatically expands.

Inzucchi: Like we've seen with the statins and the angiotensin-converting enzyme (ACE) inhibitors from 10 or 15 years ago, it's the same approach. We spoke earlier about the different effects of these medications on cardiovascular risk, saying that there appears to be maybe more of an antiatherosclerotic effect from the GLP-1 agonists. And what we're seeing with the SGLT2 inhibitors — particularly with the heart failure outcomes, which are quite striking, and also the renal benefits, which are certainly stronger than we see with the GLP-1s — is that we're talking more about a hemodynamic effect. Can you tease those out for us?

Kosiborod: That's a million-dollar question of what the true mechanisms are. It's safe to say that these two classes of medicines work differently. If you look at the main benefits of SGLT2 inhibitors, the most robust benefits (which, if you take a historic view on medications in cardiovascular disease, are quite impressive) and that has to do with heart failure prevention or treatment as well as prevention or treatment of chronic kidney disease. And that, by the way, extends to people with or without diabetes. That's where the SGLT2 inhibitors really shine.

Now there is some hemodynamic effect, meaning that we know these medications, SGLT2 inhibitors, cause at least a transient osmotic diuresis and a transient increase in a fractional excretion of sodium, even though that increase in the fractional excretion of sodium is quite modest and relatively short-lived. So it's possible that there is some contribution of that, but it's very, very clear, especially in heart failure trials that have been done, that you cannot explain all of the heart failure prevention or treatment benefit just by those effects. There is something else going on and that something else may be actually much more important than the diuretic effect.

And that's the key question: What is that something else? There are lots of different theories. There definitely appears to be some positive remodeling effect on the myocardium, including positive effects on left ventricular hypertrophy, probably because of preload and afterload, possibly because of other factors.

There are some metabolic effects that are really important. I know there was a ketone hypothesis that was offered by Ele Ferrannini and others, but it's unclear at this point whether it's actually the ketones themselves that have a positive effect or whether it's things that lead to the greater production of ketones that do that. And there is an enormous amount of research still ongoing to try to better understand that. But it’s definitely not just one mechanism; we can safely say that with SGLT2 inhibition.

Inzucchi: What about with the GLP-1s?

Kosiborod: GLP-1 RAs are another class of agents that really have numerous complex effects. What we see with the GLP-1 RAs are mostly [reductions in] atherothrombotic events, like MI and stroke, where the effects appear to be especially large as well as reductions in cardiovascular and total mortality that are a bit more modest but definitely there and definitely significant.

And so, the question is what mediates that? Of course, we know these medications lower A1c, especially potent long-acting agents — they produce a substantial amount of weight loss, and weight loss certainly could be an important contributor. We know that improving weight can improve lots of different cardiovascular risk factors. There is improvement in lipids and blood pressure that happens with these agents.

The question is, what exactly is mediating that? It's interesting because if you look at certain trials with GLP-1 RAs — like HARMONY, which used albiglutide, an agent that has relatively mild effects on hemoglobin A1c and very little effect on weight — you see substantial improvements in MACE despite all of that. And what that tells you is that once again, it's not just weight and blood pressure and hemoglobin A1c effects. It's got to be something else.

The best way I can describe current thinking is that something else may well be reducing inflammation because these agents clearly have a relatively potent effect on at least broad markers of inflammation, such as high-sensitivity C-reactive protein (CRP), and that may be one of the pathways. This story is probably more complex than we typically make it to be.

Inzucchi: I fully agree. Any insights so far on the possibility of an added benefit between these two classes, or even synergism? We talk about synergism and diabetes all the time. But do we have any data here?

Kosiborod: Until recently, the data that we had were really on surrogate markers of cardiovascular health, things like blood pressure and weight and hemoglobin A1c. There were a couple of studies that looked at that with combination therapy and what they really showed is that there is an additive effect on weight and there appears to be an additive effect on some other surrogates. For hemoglobin A1c, it's a little bit less of an additive effect. For blood pressure, there does appear to be an additive effect. So there are definitely those types of data.

The question all this time is, what about cardiovascular outcomes? For right now, there is no trial that has been completed that tested combination therapy vs one drug alone. What we do have, and probably the closest we get to it is the AMPLITUDE-O trial, which was the trial of efpeglenatide, an exendin-based, long-acting GLP-1 RA. That's the first GLP-1 RA trial that had a reasonable proportion of patients on the background of SGLT2 inhibitors, and they also stratified randomization by baseline SGLT2 inhibitor use, meaning that this was a kind of a key stratification factor.

What they observed in that trial overall is that efpeglenatide reduced the risk for MACE. Interestingly, it also actually reduced the risk for heart failure as well as kidney endpoints, so it was beneficial on multiple fronts. But what's important and very interesting is that the MACE benefit, which we already know exists with GLP-1 RAs, was independent of whether patients were on SGLT2 inhibitors at baseline or not. This suggests indirectly that because the mechanisms of action are different and nonoverlapping, that there is certainly very high likelihood that combination therapy may be better than either drug alone — even though, once again, it's not a direct evidence of that hypothesis.

Inzucchi: It would be nice to have a trial, three arms: one with SGLT2, a second with GLP-1 RA, and then a combination. But it's going to be hard to power that study because all the drugs have beneficial effects on cardiovascular risk.

Kosiborod: And it's also going to become increasingly difficult assigning somebody to one drug or the other drug. It may become more and more problematic.

Inzucchi: I agree. In terms of the guidelines, we're now focused mainly on the American Diabetes Association guidelines in endocrinology, and still, metformin is, for the most part, considered to be the foundation therapy, although in the most recent guidelines there's nuance suggesting that you might be able to go with one of these more evidence-based strategies first. But the first question that's asked as to drug number two would be, "What is the comorbidity of that patient?" If it's ASCVD, then either a GLP-1 or an SGLT2. If there's heart failure, an SGLT2. If there is chronic kidney disease (CKD) — not severe CKD where the drugs may not be beneficial — but at least down to a glomerular filtration rate (GFR) of 30 or maybe even 25, then [at that non severe GFR threshold of 30-25] an SGLT2 inhibitor.

These drugs have gotten a lot of attention from both the cardiovascular and the nephrology communities. Do you want to highlight what we know about these studies that have been conducted in both diabetic and nondiabetic individuals?

Kosiborod: What we've seen over the past few years is now a transition of these medicines, both SGLT2 inhibitors and GLP-1 RAs, from a diabetes sphere to being cardiovascular and kidney drugs. We have multiple trials with SGLT2 inhibitors showing heart failure benefits (in both reduced and preserved ejection fraction (EF) heart failure) regardless of diabetes. There are kidney benefits, regardless of diabetes.

Now, GLP-1 RAs are being studied for MACE prevention in nondiabetic individuals with obesity on established ASCVD, and we're doing trials now with GLP-1 RAs and obesity-related heart failure with preserved EF, regardless of diabetes.

We're in a brave new world now where we started with these medicines being thought of as diabetes medications. They’re now cardiovascular and kidney drugs being studied or already having established benefits. There is, of course, so much more. GLP-1 RAs are being evaluated in nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), and there is a lot more going on in that regard. But these are no longer diabetes medicines, that's for sure.

Inzucchi: I know I always tease you, Mikhail, about the fact that cardiologists are always stealing the endocrinologist drugs.

Kosiborod: They're not just diabetes medications. We laugh about it, but drugs don't belong to certain specialties when they have multiple effects — numerous complex effects. They belong to the patients. We've got to treat the whole patient.

Inzucchi: We're just about out of time. I do want to pick your brain about one last topic before I let you go: screening for cardiovascular disease in asymptomatic patients with diabetes. What's the state of the art?

Kosiborod: There is one imaging test that one should consider in people with diabetes who are above a certain age. I wouldn't do it on 30-year-olds for example, but in those of an age wherein ASCVD is prevalent and you have diabetes, a coronary calcium score is probably not unreasonable. It definitely has high discrimination power for identifying high-risk individuals and may potentially impact clinical care in terms of preventive efforts. That would probably be one that I would highlight if [patients] are asymptomatic. And it's inexpensive, so it can be done without a big financial burden on a patient. For symptomatic individuals, that's an entirely different story.

Inzucchi: Thanks so much for sharing your insights today, Mikhail. Thanks for joining us.

Kosiborod: My pleasure. Always wonderful to be with you.

Inzucchi: It is a brave new world in diabetes management. We're more focused on comorbidities in our patients, particularly cardiovascular and kidney comorbidities, and selecting proper glucose-lowering medications to decrease event rates in our patients while not being as gluco-centric. Thanks for listening. Dr Silvio Inzucchi for Medscape InDiscussion.

Resources

New ACC Guidance on CVD Risk Reduction in Diabetes

Type 2 Diabetes in Adults: Management

Type 2 Diabetes and Causes of Sudden Cardiac Death: A Systematic Review

Cardiometabolic Medicine – the US Perspective on a New Subspecialty

Antidiabetics, Glucagon-like Peptide-1 Agonists

Antidiabetics, SGLT2 Inhibitors

Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): A Double-Blind, Randomised Placebo-Controlled Trial

Mechanistic Insights Regarding the Role of SGLT2 Inhibitors and GLP1 Agonist Drugs on Cardiovascular Disease in Diabetes

SGLT2 Inhibitors for Primary and Secondary Prevention of Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Systematic Review and Meta-analysis of Cardiovascular Outcome Trials

Cardiologists Debate use of Glucose-lowering Drugs for Primary CVD Prevention

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care

Worldwide Inertia to the Use of Cardiorenal Protective Glucose-Lowering Drugs (SGLT2i and GLP-1 RA) in High-Risk Patients With Type 2 Diabetes

Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease (Harmony Outcomes): A Double-Blind, Randomised Placebo-Controlled Trial

High-Sensitivity C-Reactive Protein

Optimal Use of SGLT2 Inhibitors and GLP-1 Agonists: 5 Things to Know

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes

Coronary Artery Calcification on CT Scanning

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