For the millions of patients with type 2 diabetes and peripheral artery disease — a potentially debilitating but often ignored condition where less blood flows to the legs — limited treatment options have left many with a worsening condition that can result in being unable to walk without pain.
Now, new international research led by a University of Colorado Department of Medicine faculty member has shown that semaglutide, a popular weight loss medication, can improve these patients’ ability to walk and their overall quality of life.
“Peripheral artery disease is actually very common, but it’s under recognized and under diagnosed. It’s been 25 years since we’ve had a new therapy approved for it,” says lead investigator Marc Bonaca, MD, a CU professor of cardiology, director of vascular research at the CU Anschutz Medical Campus, and executive director of CPC Clinical Research, an academic research organization.
“Knowing how important this was, we had tremendous excitement when we started to see the results — that semaglutide was improving everything we were looking at,” he adds. “This is an opportunity for people to become more aware of this disease, because knowing if you have peripheral artery disease matters — especially since we now have a new treatment.”
The dangers of peripheral artery disease
Even though it is estimated that more than 12 million Americans and 230 million people across the globe have peripheral artery disease, many people are unaware of what it is, Bonaca explains.
“Peripheral artery disease is often caused by atherosclerosis,” he says. “Atherosclerosis is a condition where the blood vessels get diseased over time as a result of risk factors like smoking, diabetes, and high cholesterol. You develop cholesterol plaque that clogs up the arteries, so the arteries and some of the small vessels that deliver blood to the tissues don’t function normally.”
Atherosclerosis can manifest in different ways, such as the clogging of arteries in the heart or the brain, leading to a heart attack or stroke. The peripheral arteries, however, are outside of the brain and the heart, carrying blood to other parts of the body like the legs and arms.
“When we talk about peripheral artery disease, we generally mean leg artery disease,” Bonaca says. “Beyond a high risk of heart attack and stroke, it means that the blood to your legs is reduced and that you can’t walk well. You have severely impaired function, and at later stages of disease, you can develop things like amputations and limb loss.”
The two strongest risk factors for the development of peripheral artery disease are smoking and diabetes, and the risk increases as people age.
“It is highly likely that someone you know has peripheral artery disease and they don’t know it,” he says. “Talk to your doctor. We can do a very easy test called an ankle-brachial index, where we determine the blood pressure on the arms and on the legs to determine if you have it.”
How people experience peripheral artery disease is highly variable, Bonaca notes. Some struggle with walking long distances or experience a feeling of heaviness in their legs. Others develop pain in their muscles, such as having cramps in their calves. Many people dismiss their symptoms, thinking that they are walking slower because they are older, their legs are tired, or they are out of shape.
“One of the dangers of this disease is that it comes on slowly and it progresses slowly, so people never have that aha moment that they've got a blockage. They just say, ‘I’m not walking as well anymore,’” he says. “We have historically used the term symptomatic and asymptomatic, but the truth is that no one is asymptomatic. If you study people with this condition, they all have severe functional limitations whether they recognize it or not.”
‘We can do better’
Although there are many medical therapies and interventions to reduce the risk of a heart attack or stroke, such as by lowering a person’s cholesterol, identifying a good treatment specifically for the legs “has been really difficult,” Bonaca explains.
“We have one drug called cilostazol that was approved 25 years ago, and the guidelines recommend prescribing it to help these patients walk better. However, it has a lot of side effects and doesn’t always work very well, so it’s used in probably less than 10% of patients,” he says. “Other than that, we have supervised exercise therapy, which does help patients but is broadly underutilized because it’s hard for many people to get to a gym three days a week to do supervised exercise.”
Procedures and surgery are also uncommon to treat peripheral artery disease, as these operations are often expensive and can have complications.
“Sometimes we don’t recognize, as clinicians, how much these patients suffer. And some have said that this condition can’t be fixed, saying it is too complicated or the patients are too sick,” he says. “We can do better.”
Passionate about finding better treatments for patients with peripheral artery disease, Bonaca and his mentor William Hiatt, MD, former president of CPC Clinical Research, first proposed conducting research into the viability of semaglutide about six years ago.
“We hoped that we might develop a new treatment for patients with peripheral artery disease who are in the early stage of symptoms, to prevent the disease from progressing,” he says.
A step in the right direction
Bonaca’s research — funded by the pharmaceutical company Novo Nordisk, manufacturers of Ozempic and Wegovy — involved 112 outpatient clinical trial sites in 20 countries in North America, Asia, and Europe. There were 792 participants, all of whom were adults with type 2 diabetes and symptomatic early-stage peripheral artery disease, meaning they could only typically walk roughly one-tenth of a mile until they needed to stop.
“And they could only walk about half of that distance without symptoms or pain. Think of how debilitating that is,” Bonaca says.
Half of the participants were randomly assigned to get a weekly 1-milligram dose of semaglutide for a year, while the other half received a placebo. The study was double blind, meaning the research participants and the investigators did not know who was receiving what until the end of the study.
“The drug itself is an incretin therapy, a glucagon-like peptide-1 (GLP-1) agonist, which is a hormone that we have in our bodies already. It’s a way of increasing the concentration of it, and it has a multitude of benefits,” he says of semaglutide. “Research suggests it lowers blood pressure, lowers blood sugar, leads to weight loss, helps with sleep apnea, and reduces inflammation, which is a key driver of risk in peripheral artery disease, and that’s why we’re so excited about it.”
At the end of 52 weeks, the investigators assessed how far the patients could walk, when they experienced pain while walking, and their legs’ blood pressure and blood flow. They also assessed participants’ quality of life (using validated questionnaires) and monitored other outcomes such as the participant having to get a surgery or amputation.
“We learned that the patients who got semaglutide had significant improvement in their walking function — around 40 meters of an increase on average relative to those who got the placebo,” he says. “The baseline was walking 180 meters, so this was a big increase.”
The investigators also found that, overall, patients who got semaglutide reported a clinically meaningful improvement in their walking function and were able to walk longer distances without experiencing pain or other symptoms.
There were also statistically significant increases in the participants’ quality of life when they got semaglutide, and the blood pressure and blood flow in their legs also improved. Over the course of the year, the investigators also looked at the likelihood that a participant would progress to needing a procedure on their legs, have an amputation, or die. The investigators found that there was a significantly lower rate of that happening among those who got semaglutide.
“These results are immediately applicable because this drug is available. Today, when clinicians see patients with type 2 diabetes and peripheral artery disease, they should prioritize this treatment option for them, because it can really help,” Bonaca says. “When somebody says they can't walk and their legs hurt, we now have something that will not just make them feel better and walk better but will also reduce the likelihood of disease progression.”
‘Not the end of the story’
Something that stood out to Bonaca was that the study’s positive results were independent of weight loss, indicating that semaglutide may be a beneficial treatment for all patients with peripheral artery disease — regardless if they have type 2 diabetes.
“I was initially worried that if the only benefit was weight loss and the participants experienced walking improvements only because of the weight loss, then this might be a neutral trial,” he says. “But this population we studied was not obese, and we found positive results in patients regardless of their body weight.
“That was the most exciting part — we didn’t just have a successful treatment, but it was clearly treating the underlying problem of this vascular disease and was not just a band aid,” he adds.
Given the results, Bonaca suspects that semaglutide may be a useful treatment for all patients with peripheral artery disease, as the data suggests the drug has anti-inflammatory properties; however, this would need to be proven through additional research, he notes. Further research is also needed to determine exactly how semaglutide interacts with the body.
“Understanding the mechanisms unlocks the door to new, novel therapies that could be more effective and better tolerated,” he says. “Secondly, we need to also see if semaglutide benefits patients who have more severe forms of peripheral artery disease.”
Moving forward, Bonaca hopes other clinicians will inquire more about what their patients with peripheral artery disease are experiencing and take the proper steps to treat them, whether it be through supervised exercise, lowering cholesterol, or offering semaglutide if they also have type 2 diabetes.
“We can’t just talk about it. We need to implement better care,” he says. “This finding on semaglutide is a huge advance, but it’s not the end of the story.”
