SURPASS-CVOT and the Case for Dual Incretin Therapy

Podcast Transcript

Announcer:

Welcome to Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic. This podcast will explore the latest innovations, medical and surgical treatments, diagnostic testing, research, technology and practice improvements.

Luke Laffin, MD:

Hi, I'm Dr. Luke Laffin, and I'm here with Dr. Steven Nissen, the Chief Academic Officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic. Here we're going to discuss your fascinating research that was just presented at the American College of Cardiology Scientific Sessions, the SURPASS-CVOT trial and an important secondary analysis of that.

Dr. Nissen, can you tell us a little bit about SURPASS-CVOT, why it's important?

Steven Nissen, MD:

Well, first of all, it's important for everybody to understand that the use of these drugs, these GLP-1 (glucagon-like peptide-1) and GLP/GIP (glucose-dependent insulinotropic polypeptide) drugs is really exploding. The numbers of patients being treated are huge. We've progressed from what we call monoagonists, which is something like the traditional drug, semaglutide, which treats GLP-1. It's an agonist for GLP-1, versus a newer class of drugs. Tirzepatide is the example that targets both GLP-1 and GIP.

The first question that was asked, and the one that was asked was SURPASS-CVOT, is a dual-treating drug as good as a single treatment? And the answer is, in SURPASS-CVOT, it was. The agent that was studied was tirzepatide as the active agent, and the control drug was dulaglutide, a first-generation GLP-1 agonist. It was non-inferior, but it wasn't superior.

But in that trial, it was necessary to use a very narrow endpoint. The reason is that dulaglutide was studied in the REWIND trial using the narrow endpoint of cardiovascular death, stroke or myocardial infarction (MI). But we've learned over the last few years that obesity has a lot more effects than simply death, stroke and MI. It affects heart failure, it affects kidney disease, it affects the need for revascularization, stenting, or bypass surgery.

Well, we collected all that information in SURPASS-CVOT, and we actually adjudicated those endpoints here at Cleveland Clinic. We were very much involved. I proposed that we look at the broad effects of these drugs on all of the bad things that obesity does to patients. The analysis that we did had six components to the composite endpoint. We looked at not cardiovascular death, but all-cause mortality, and more about that later, stroke, myocardial infarction, revascularization, heart failure and kidney failure.

The idea was to look at the totality of the effects. Now, before we get into the results, let me say, why did we study all-cause mortality? It turns out that obesity does more than increase cardiovascular death. It increases death due to cancer. It increases death due to infectious causes. In a lot of the contemporary trials, including one that you and I are involved with together, we're studying using all-cause mortality. We included all-cause mortality in the secondary analysis that I performed.

What we found was a very striking difference. The newer generation, the dual agonists that target GLP-1 and GIP, had a very statistically strong benefit compared with dulaglutide, the monoagonist. In fact, there was an additional 16% reduction in the composite, so a hazard ratio of 0.84 with a P value of less than 001.

Unequivocally, I think it shows, albeit in a secondary analysis, that targeting both of these hormones, both GLP-1 and GIP, very likely produces incremental benefits over a simple GLP-1 drug, such as the drugs that are now very widely popular. Some of them are going to go generic relatively soon.

Luke Laffin, MD:

Right, right, right. Now, do you think these post-hoc analysis findings are enough to change one's clinical practice if you're choosing to prescribe for your patients with diabetes and things like that?

Steven Nissen, MD:

It's a very good question. I can tell you based upon historical precedent, it's not enough to change the labeling with the regulators. The FDA requires that you study one pre-specified endpoint that's controlled for type 1 error, and they will give a label claim.

But what we do as clinicians is not necessarily what is entirely dictated by regulatory action. I found the information sufficiently convincing that I think I would say to colleagues, if you really have a patient at risk – particularly if they have a level of obesity that is more severe – and they have diabetes and they have high risk for heart disease events, that the dual agonist, tirzepatide, is a better choice.

Is it the best choice for everybody? Maybe not, but certainly given the morbidity and mortality associated with obesity in patients with diabetes and high cardiovascular risk, we need every bit of help that we can get. It's already been shown that tirzepatide does produce substantially more weight loss than the first-generation drugs like semaglutide, liraglutide and dulaglutide. That we already knew.

One thing we did do to make sure we were making the right call here is we did what's generally known as a sensitivity analysis. We said, okay, well, let's look at the six components, but then let's take out the kidney benefits and look at five.

Luke Laffin, MD:

Gotcha.

Steven Nissen, MD:

P-value less than 0.01 for benefit, about the same benefit. Now let's take out the heart failure component. Same thing.

Luke Laffin, MD:

Same idea.

Steven Nissen, MD:

Same degree of benefit. Then let's just look at the three components, but use all-cause mortality rather than cardiovascular death. There's still a statistically significant benefit. It's really kind of bombproof. It's hard to find any evidence that it's not a superior strategy. For clinicians, I would say it's pretty convincing.

Luke Laffin, MD:

Well, and for patients too, they don't really care if they get a cardiovascular death or how they die. We want them not to die.

Steven Nissen, MD:

Well, death is not a good thing no matter how it happens.

Luke Laffin, MD:

However, it happens. Exactly.

Steven Nissen, MD:

The other thing about all-cause mortality is that it's the gold standard.

Luke Laffin, MD:

Exactly.

Steven Nissen, MD:

In clinical trials, whenever you can show a benefit on all-cause mortality, no adjudication required, no ifs, ands or buts, you either survive or you don't survive. In fact, in our study, all-cause mortality alone was statistically significant, even without any of the other components, and that's pretty convincing.

Luke Laffin, MD:

So, beyond this trial of SURPASS-CVOT, can we extrapolate that to other lower-risk patient populations, those patients without diabetes?

Steven Nissen, MD:

Well, you and I are going to find that out. We're doing a trial known as SURMOUNT-MMO. It's fully enrolled. It's 15,000 patients, and it's studying substantially lower-risk patients. These are people that don't have diabetes, so that automatically puts them in a low-risk category. Some of them have never had any cardiovascular event of any kind. They're primary prevention patients, albeit high-risk primary prevention.

That study is moving along and within the next couple of years, we're going to get an answer about whether people that are at lower risk will benefit by a strategy that attacks both GLP-1 and GIP. Those of you that watch the literature carefully should know that there's a three-component drug in advanced stages of development that targets both GLP-1, GIP and glucagon, likely to be approved within the next year. You are one of the people studying an oral drug.

Luke Laffin, MD:

Yeah, exactly. Orforglipron, yeah.

Steven Nissen, MD:

Orforglipron. This whole area – we call these incretin-based drugs – is just absolutely a huge turn of events. I've been around long enough to have watched the failure of one after another obesity therapy. Now, for the first time in history, this devastating epidemic, we are making progress and we're making progress very quickly, doing good quality studies, following these patients carefully, and I'm very optimistic about the future.

Luke Laffin, MD:

Well, that's wonderful. Thanks so much for that information on your wonderful research, Dr. Nissen.

Steven Nissen, MD:

Thank you.

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