GLP-1 drugs like Ozempic and Wegovy are already known for treating type 2 diabetes and helping with weight loss. Now, a new study suggests they may also improve some of the most difficult complications to treat in type 2 diabetes.
Diabetics are especially vulnerable to developing peripheral artery disease (PAD), when narrowed arteries, most often in the legs, lead to reduced blood flow. In severe cases, PAD can cause tissue damage and ulcers that make amputation a real risk.
Cleveland Clinic researchers analyzed electronic health records from adults with both type 2 diabetes and PAD to see whether the treatment they were prescribed made a difference to long-term outcomes.
“We observed fewer amputations, fewer revascularizations, and fewer hospitalizations – outcomes that reflect worsening limb ischemia and disease progression,” study authors Akiva Rosenzveig and Aravinda Nanjundappa told Refractor. “These improvements may ultimately translate into better survival, even if rates of myocardial infarction and stroke remain similar. It’s an interesting finding that deserves further investigation in prospective trials.”
The researchers compared people prescribed GLP-1 receptor agonists (GLP-1RAs) with a matched group who were not prescribed these drugs and instead had repeated prescriptions for metformin, one of the most commonly used type 2 diabetes medications.
After matching, the main PAD analysis included 2,133 people in each group. At five years, GLP-1RA use was associated with a 26% lower risk of death from any cause, a 13% lower risk of hospitalization, a 36% lower risk of revascularization procedures, a 48% lower risk of major amputation, and a 37% lower risk of minor amputation.
Rates of heart attack, stroke, major adverse cardiovascular events, and major adverse kidney events were similar between groups. Revascularization procedures are medical treatments to restore blood flow to a part of the body.
“[C]linicians should consider prescribing GLP-1s because peripheral artery disease, also known as PAD, has limited treatment options,” said Nanjundappa, an interventional cardiologist at the Cleveland Clinic, Cleveland. “Our findings indicate these medications may improve long-term health for people with PAD, in addition to managing blood sugar and weight loss.”
The findings arrive soon after the STRIDE trial, which found that semaglutide improved walking capacity, symptoms and quality of life with symptomatic PAD and type 2 diabetes. That trial was important because PAD is not only a blood-vessel disease; it is also a disease that changes daily life. Walking to the mailbox, getting around a supermarket, or making it through a day without leg pain can become a genuine achievement.
But STRIDE was not designed to answer whether GLP-1 drugs reduce harder outcomes such as amputation, revascularization, or death. That’s where the new study fits in.
“The two studies are highly complementary,” Rosenzveig and Nanjundappa said. “STRIDE demonstrated that GLP-1 receptor agonists improve how patients with PAD feel and function by increasing walking capacity and quality of life. Our study extends those observations by showing that GLP-1RA use was also associated with lower rates of clinically important outcomes, including mortality, hospitalization, revascularization, and amputation.
“Together, these findings suggest that the functional improvements seen in STRIDE may reflect broader vascular benefits, although randomized trials powered for hard clinical endpoints are still needed to confirm this.”
In plain language: one trial suggests people may walk better and feel better; this new real-world analysis suggests they may also have fewer catastrophic limb-related outcomes. But because the new study was observational, it can’t prove the drugs caused those improvements.
GLP-1RAs work by mimicking glucagon-like peptide 1, a hormone involved in blood sugar control, appetite and digestion. They help the body release insulin when blood sugar is high, slow stomach emptying and reduce appetite. That is why drugs in this class, including semaglutide and liraglutide, have become central players in diabetes and obesity treatment.
But the benefits seen in the new study may not be explained by weight loss and glucose control alone.
“It’s likely a combination of both,” said the researchers. “Better glycemic control and weight loss undoubtedly contribute to improved outcomes, but accumulating evidence suggests GLP-1 receptor agonists also have direct vascular effects.”
That may help explain why the strongest signal appeared in people with chronic limb-threatening ischemia, the most severe form of PAD. In that subgroup, GLP-1RA use was linked to lower mortality, hospitalization, revascularization, and major and minor amputation. The benefits were particularly notable in people with obesity.
The study also produced an interesting split. Limb outcomes improved, hospitalizations fell, and survival appeared better, but heart attack and stroke rates did not significantly differ between the GLP-1 and comparison groups.
“That pattern suggests GLP-1 receptor agonists may have their greatest impact on the progression of peripheral artery disease itself rather than on acute atherothrombotic events,” the researchers told New Atlas.
In other words, these drugs may be doing something especially useful in the diseased blood vessels of the legs, rather than simply reducing all cardiovascular events across the board. That’s the kind of finding that makes researchers lean forward in their chairs, but it also needs testing in a proper randomized trial before anyone starts rewriting treatment guidelines.
The researchers are upfront about the study’s limitations. This was a retrospective study using electronic health records, not a randomized clinical trial. The researchers used propensity score matching to balance the groups across many factors, including age, sex, race, other diagnoses and medications, but medical records can’t capture everything.
“The most important limitation is that observational studies cannot establish causation,” Rosenzveig and Nanjundappa said. “Although we carefully balanced the treatment groups using propensity score matching, unmeasured confounding always remains possible.”
The next step, according to the researchers, should be a large, multicenter randomized trial enrolling people with symptomatic PAD, including a substantial number with chronic limb-threatening ischemia. Semaglutide would be a logical drug to test, given the STRIDE trial results. The endpoint that matters most, they said, should be major adverse limb events, including major amputation and peripheral revascularization, with death and hospitalization as secondary outcomes.
“Demonstrating improvements in those hard clinical endpoints would have the greatest potential to change clinical practice,” they said.
For now, the study adds to the sense that GLP-1 drugs are not just diabetes or weight-loss medications. They are increasingly looking like broader cardiometabolic drugs, with effects that may extend into blood vessels, inflammation and organ protection. In people with diabetes and PAD – a group with a high risk of pain, disability, hospitalization and limb loss – that could matter a great deal.
The study was published in the Journal of the American Heart Association.
Source: American Heart Association
Fact-checked by Mike McRae
