GLP-1s Reduce Limb and Cardiac Events in Peripheral Artery Disease

On the heels of STRIDE, one of the first trials to show glucagon-like peptide-1 (GLP-1) receptor agonists can help patients with PAD, a retrospective study of more than 100,000 patients provides more evidence of for a potential vascular benefit.

At 1 year, rates of major adverse limb events (MALE), major adverse cardiac events (MACE), and hospitalizations all were lower in patients on a GLP-1 in the new analysis.

The data fit with those of the recent STRIDE study showing that weekly semaglutide (Wegovy; Novo Nordisk), compared with placebo, was associated with a 13% improvement in mean walking distance and an 11% improvement in pain-free walking ability for patients with mild PAD. Approximately 65% of the GLP-1 use in the new study also was semaglutide.

“I don’t know if it’s entirely weight loss and I don’t think it’s entirely glycemic control, because we did find that patients that did not have diabetes or who had normal A1cs that were on this medication also benefited from GLP-1 treatment,” said Catherine Go, MD (Charleston Area Medical Center, WV), who presented the findings last week at the Society for Vascular Surgery’s 2025 annual meeting.

As in the STRIDE study, the average weight loss observed by Go and colleagues over the study period wasn’t much, averaging about 7 pounds in the GLP-1 group and 3 pounds in the control group.

Go said it seems unlikely that such small weight loss would be enough to move the needle in terms of CV and limb events, suggesting a more complicated interplay between the GLP-1 and the vasculature.

Some have theorized that the benefit may come from the anti-inflammatory properties of GLP-1s. There also have been suggestions in studies like FLOW that semaglutide may improve vascular function, in addition to the broad cardiometabolic benefits seen in nondiabetic patients in trials like SELECT.

Anahita Dua, MD (Massachusetts General Hospital, Boston, MA), who commented on the study for TCTMD, said while it makes sense that GLP-1 medications would be useful in peripheral vascular disease as they are in cardiovascular disease, there’s still little data available to help clinicians identify PAD patients who might benefit most.

“It is exciting because we don’t have many medical therapies that are effective for PAD, but as we saw with STRIDE, there is still room for confounding. It’s not at all clear that every patient with mild claudication, for example, should get a GLP-1,” she said. “It is possible that there’s a signal there, but we will have to weigh the risks and benefits for each patient. I’m not convinced that we’re there yet.”

Teasing Out Who Will Benefit

The researchers used the TriNetX research network to identify patients with moderate PAD, with a mean ankle-brachial index (ABI) between 0.4 and 0.9. Those who were and were not started on a GLP-1 were propensity-score matched into groups of 55,041 each (mean age 62 years; 54% women).

Approximately 75% of patients in each group had diabetes. CAD was present in 42%, hypertension in about one-third, and smoking history in one-third. Statin use was nearly 100% in both groups. In addition to semaglutide, other GLP-1 medications taken were tirzepatide (Zepbound; Eli Lilly) in about 12% and liraglutide in 10%. Much smaller percentages of patients were on dulaglutide, exenatide, or lixisenatide.

The rate of MALE at 1 year was 0.8% in the GLP-1 group and 1.46% in the non-GLP-1 group (HR 0.57; 9% CI 0.51-0.64), while the rate of MACE was 1.7% and 4.4%, respectively (HR 0.41; 95% CI 0.38-0.44). Similarly, hospital admission rates were 17.9% and 26.8%, respectively (HR 0.64; 95% CI 0.62-0.66).

Go noted that the improvements in the GLP-1 group occurred despite them having higher overall LDL and HbA1c levels at baseline than the those not on a GLP-1.

A comparison of men and women suggested slightly more benefit of the GLP-1 on MACE and MALE events in men, but the numbers are too small to definitively ascribe a benefit, say researchers.

To TCTMD, Go said the emerging data are at least enough to justify having a conversation with PAD patients about GLP-1 therapy if they also have diabetes. If they don’t have diabetes, she said, it may still be something for them to discuss with their primary care physician, bearing in mind that there are no randomized data in PAD patients outside of the STRIDE trial.

“If you’re a purist right now, you want to see a randomized trial of best medical therapy alone versus GLP-1 medications—semaglutide and tirzepatide most likely—plus best medical therapy,” Go said. “One of the problems with an observational trial is we don’t know the doses of various medications that people were on to where we can say they were on best medical therapy, so that is something that needs to be clarified in future trials.”

Among the big questions that remain in the GLP-1 space in general is how long patients should remain on the medication. Patients in Go’s study who had diabetes saw increasingly greater improvements in their HbA1c with a GLP-1 over the 1-year period.

“That does make me wonder if it’s supportive of those people staying on the medication long-term,” Go noted. “We just don’t know enough yet, but maybe we need to work toward finding a maintenance dose for that group that gives them the most benefit from the GLP-1.”

For Dua, zeroing in on the extra benefits over time that the medication provides for patients with PAD, and in which categories and constellation of PAD symptoms, will be among the key questions going forward.

“I would need a bit more data to really show me there’s a worthwhile difference in giving someone these medications. If you tell me that functionally 3 years down the line, patients in both groups really had no difference, then it’s not worth it. But, if you find that patients are more likely to adhere to their programs of walking because they have the GLP-1 added and that their ABIs are higher, I can get behind that,” she said.

“We also have to look at how, if at all, adding a GLP-1 changes the overall trajectory of the peripheral vascular disease,” Dua added. “Will it change the conversion rate so that patients are less likely to progress to [chronic limb threatening ischemia]?  Does starting a GLP-1 increase survival benefit down the line? It would be wonderful if it did, but these are still things we need to tease out.”