Semaglutide in Atrial Fibrillation

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Featured is the presentation entitled "Semaglutide in Atrial Fibrillation" by Andrea M Russo, MD, FACC, FHRS, FAHA, at the 2024 Western AF Symposium. 

Andrea M Russo, MD, FACC, FHRS, FAHA: Thank you, Nassir, for inviting me to this wonderful meeting. It's amazing that it gets even better and better every year. It has been really great. Thank you.

My disclosure is not really related to this topic. So, we know that there is a relationship between obesity and cardiovascular disease. It can cause an increase in inflammation, which causes an increase in insulin resistance. In addition, there are a lot of other comorbidities, and all these can add up to cardiovascular disease, including an increase in atrial fibrillation (AF).

We do know that weight reduction can significantly reduce cardiovascular risk. These hypoglycemic medications, including semaglutide, have been proven to be effective in weight loss in randomized clinical trials, and have also had cardiovascular outcomes that I will show you in diabetic patients. One study did look at obese and nondiabetic patients.

Here are some of the newer agents. A lot of us are not used to using them and prescribing them on our own. We leave that up to the internist. But for this purpose, we might want to start thinking of it. We have the glucagon-like peptide 1 receptor agonists (GLP-1 receptor agonists), and that includes both injection, semaglutide, as well as the tablet forms. The other important class here will be the sodium-glucose cotransporter-2 (SGLT2) inhibitors, which we have heard a lot about lately as well.

This is very complex, and we know that diabetes is an independent risk factor for AF. It can cause things related to changes in blood constituents. It causes inflammation and a lot of other associated comorbidities. But, importantly, in our respect, it is related to atrial remodeling, atrial structural remodeling, electrical remodeling, and effects on the autonomic nervous system that could eventually put someone into AF and perhaps increase stroke risk.

There are certainly lots of ways that we can have this impact, and these targets are potentially therapeutic targets for these antidiabetic drugs.

So, to mention the studies evaluating overall cardiovascular risk, GLP-1 receptor agonists as well as SGLT2 inhibitors have shown a significant reduction in major adverse cardiovascular events in patients with diabetes. I will show you a meta-analysis. There were multiple studies done, but this is just the GLP-1 receptor agonists in patients with diabetes. These are randomized trials. There were 8 trials. Two of the trials in this class included semaglutide. PIONEER used the PO form and SUSTAIN used the subcutaneous (SQ) form of semaglutide. You can see on the left here that the GLP-1 receptor agonists reduced major adverse cardiovascular events by 14%, reduced all-cause mortality, and also reduced admission for heart failure. Because of that, this got into the prevention guidelines that these drugs may be useful in diabetic patients, not just for glucose control but also in altering diabetic risk and altering cardiovascular risk in diabetic patients. 

So, we know that semaglutide is useful in reducing adverse cardiovascular events. But what about the effect in the absence of diabetes? Meaning, obesity without diabetes. GLP-1 is a gut hormone that is released in response to food intake. It causes satiety and stimulates insulin release, inhibits glucagon secretion, and regulates gastric emptying. It also has an effect on diuresis, reduces blood pressure, and reduces/improves inflammation. Semaglutide is one of these. 

This is the one study in cardiovascular outcomes without diabetes, it's called SELECT. This was presented recently and published in the New England Journal of Medicine last year. It was a multicenter randomized trial of over 17,000 patients who had either pre-existing cardiovascular disease, a large BMI of 27 or more, and no history of diabetes, and they were randomized to either subcutaneous semaglutide or placebo. You can see the primary cardiovascular outcome, which is a measure of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke is shown with a much lower risk of this in the semaglutide group compared to the placebo group. That is overall cardiovascular risk. 

What about AF? What data do we have? Most of that is based on post hoc analysis. So, before even looking at some of those studies, there have been a lot of cohort studies. This was a nationwide cohort in Denmark, Norway, and Sweden, and had propensity score matching, and you can see that this was the use of SGLT2 inhibitors. Compared to the GLP-1 receptor agonists, this was associated with a modestly reduced risk of new-onset AF. So, that is comparing the 2 different diabetic drugs. Similar studies were done in the United States with the Medicare database and in Taiwan with their large database.

What about the GLP-1 receptor agonists in randomized controlled trials? Now, this is just to control those different comparators, not necessarily placebo. Overall, they were looking at adverse events, so no significant increase in adverse events with AF, but there was no decrease either overall, but the subgroup analyses (in the red square) is looking at semaglutide, so that showed that it looks like it might have a favorable effect in reducing AF compared to some of the other drugs which may have the opposite effect. So, this maybe is drug specific, even though you are in the same class of drugs.

If you look at this in randomized trials, the GLP-1 receptor agonists compared to placebo, you can see overall when you look at all the drugs together in the meta-analysis that there was no significant effect. However, you can see with the 2 semaglutide studies, PIONEER and SUSTAIN, either the SQ or PO form, that there could be at least a trend towards a significant reduction in AF.

Now, what about if you take all the semaglutide trials and you do a meta-analysis of those? But it might not just be the placebo, there are other comparators when you do that. In the 2 studies with semaglutide specifically, that particular drug did show that there was a lower risk of developing AF in the large groups when you combine them altogether.

If you look at semaglutide alone, and again, just looking at comparators here, you can see that there were 21 studies on semaglutide, but they are compared to multiple other drugs. If you look at that, that reduces the risk of AF by 31%. So, in a lot of post hoc analyses, there was really nothing with a primary endpoint of AF. 

And just to remind people that, again, we do not use these drugs a lot on our own, but the risk of incident AF, even with some of the earlier drugs like metformin were found to have a reduced risk. So, they may not often be first-line drugs and they may be combined with other drugs. So, that is something to keep in mind when you are looking at this meta-analysis of multiple studies. 

As far as mechanisms, again, we do not really understand this, but we do know that there is a role of epicardial fat in AF, and that these drugs, the GLP-1 agonists as well as the SGLT2 inhibitors, do seem to have an effect on epicardial fat. Maybe that has something to do with why they might work. Who knows?

Then, there were some studies in mice. This is looking at the effect of this strain of mice that has an increased susceptibility to AF and has a prolonged action potential duration. They gave one of these analogs this GLP-1 agonist and showed that you can prevent that effect. In mice, it looked like it was going to be good. In dogs, they looked at AF inducibility. Again, the GLP-1 analog suppressed these electrophysiological changes and prevented that reduction in conduction velocity that was induced with atrial pacing compared to the control group.

So, studies certainly look promising with GLP-1 receptor agonists as well as SGLT2 inhibitors in reducing risk of AF. Certainly, there are many limitations and gaps in evidence. Some of the studies I did not show you were not even randomized, and some that were randomized were comparators and not placebo, and then often not just used as first-line therapy, and these are post hoc analyses to evaluate the impact on AF. Almost all studies were done in diabetic patients. There was only one study in obese patients with cardiovascular outcomes. Mechanisms are unclear and likely very complex. Also, are the benefits related to the drug itself, are they due to concomitant effects of weight loss, or even other healthy lifestyle changes? We do not know that. 

What we need are randomized studies that have a primary endpoint of atrial arrhythmias as prespecified. We do not even have head-to-head comparisons between the different drugs. But we need something that is more powered for AF as an endpoint.

Looking at clinicaltrials.gov, there were 3 trials. Two were not going to happen for some reason or another; someone suggested yesterday that maybe this was due to the supply of the drug. But there was a Dutch study that has not yet started that maybe we will learn more from. Thank you.

The transcripts have been edited for clarity and length.