Peripheral artery disease (PAD) is a prevalent, but underrecognized, macrovascular atherosclerotic complication associated with type 2 diabetes.

The Saturday, June 21, symposium, Diabetes and Peripheral Artery Disease—Evolving Role of GLP-1 RA and New Insights from the STRIDE Trial, highlighted the epidemiology and burden of PAD in individuals living with type 2 diabetes, and the findings and implications of the STRIDE trial.

“PAD remains a recalcitrant problem in people living with diabetes, for which we have very few solutions,” said Subodh Verma, MD, PhD, FRCSC, Cardiac Surgeon-Scientist and Professor at St. Michael’s Hospital and the University of Toronto, Canada. He reviewed the study rationale and results at the 85^th Scientific Sessions.

The key question in STRIDE was whether semaglutide can change the trajectory of disease in individuals with type 2 diabetes and PAD who are identified at the earliest symptomatic stage of PAD. The answer appears to be a resounding yes.

“Semaglutide is the first therapy to decrease MACE (major cardiovascular events), improve cardiometabolic and kidney outcomes, and improve walking capacity and related quality of life and disease progression in patients with PAD and type 2 diabetes in 25 years,” he said.

STRIDE was a phase 3b double-blind randomized study of semaglutide in people with comorbid type 2 diabetes and PAD. Key inclusion criteria included: A1C ≤10%, early-stage symptomatic PAD (Fontaine stage IIa), pain-free walking distance (PFWD) ≥200 m, minimal walking distance (MWD) ≤600 m, and an ankle-brachial index (ABI) ≤0.9 or toe-brachial index (TBI) ≤0.7.

Semaglutide significantly improved MWD, which translated to a clinically meaningful change, as well as PFWD. Notably, functional improvements were maintained five weeks after cessation of semaglutide. Semaglutide also improved patient-reported symptoms, quality of life, and disease progression based on composite outcomes of rescue therapy initiation, all-cause death, or major adverse limb events.

Dr. Verma said that the improvement in the ABI within the 52-week study period was an unexpected finding that proves the therapy is truly a vascular medication. Further, STRIDE adds to the growing totality of evidence for the use of GLP-1 receptor agonists (GLP-1 RAs) in individuals living with type 2 diabetes and other comorbidities.

“We already have a million and one reasons to be using GLP-1 receptor agonists in individuals living with type 2 diabetes,” said Alice Y.Y. Cheng, MD, FRCPC, Endocrinologist and Associate Professor at the University of Toronto. “What STRIDE does is remind us of these other important things to take away and the importance of PAD in this population.”

The improvement in functional PAD outcomes with semaglutide may be most meaningful to those living with the disease, Dr. Cheng said. She explained that the daily life of an individual living with PAD and type 2 diabetes can be significantly impacted by being able to walk longer distances, pain-free, while “hard outcomes,” like stroke, heart attacks, and even death, may seem more abstract.

Dr. Cheng discussed the implications of STRIDE findings for endocrinologists, highlighting the “atypical” study population compared to previous studies of GLP-1 RAs in people with type 2 diabetes. In STRIDE, patients had a mean A1C of about 7% and a mean body mass index (BMI) of 28.7 (semaglutide arm) or 28.5 (placebo arm). Most enrolled patients had a BMI <30.

She said clinicians must remember to screen people with type 2 diabetes for PAD, as PAD onset is often insidious and gradual, and patients may not always present with or complain about symptoms. Dr. Cheng also said that clinicians need to know where to refer patients for appropriate ABI assessments. Additionally, although concerns around potential concomitant sarcopenia in people with GLP-1 RA-mediated weight loss exist, STRIDE data do not demonstrate a sarcopenia safety signal.

Neda Rasouli, MD, Director of the Diabetes and Endocrinology Clinical Trial Program and Professor of Medicine at the University of Colorado, called attention to the importance of early diagnosis and intervention in individuals with type 2 diabetes and PAD.

“That is why the ADA Diabetes Standards of Care in Diabetes now recommends screening asymptomatic patients for PAD, for those who are at risk,” she noted.

Dr. Rasouli shared new subgroup analyses of STRIDE, stratified by diabetes characteristics, BMI, and use of concomitant medication, either sodium-glucose cotransporter 2 (SGLT2) inhibitors or insulin.

The post hoc subgroup analyses showed that the benefits of semaglutide were independent of baseline diabetes duration, A1C levels, BMI status, or concomitant use of SGLT2 inhibitors or insulin. These findings were published simultaneously in Diabetes Care.

The functional benefits of semaglutide did not correlate with weight loss or glycemic improvement. Benefits were seen in people without obesity or with well-controlled glycemia.

Zaina Albalawi, MD, MSc, FRCPC, Clinical Assistant Professor of Medicine, Memorial University of Newfoundland, Canada, reviewed epidemiologic evidence and meta-analyses examining the intersection of PAD and type 2 diabetes.

Concomitant PAD and type 2 diabetes are associated with higher morbidity and mortality, compared to when each occurs alone. Notably, individuals with comorbid PAD and type 2 diabetes are at higher risk of lower limb amputations. The contribution of type 2 diabetes is highest for the PAD-associated outcome of non-traumatic lower limb amputations (70% annually).

“Ultimately, the most feared complication for people living with diabetes is amputation,” Dr. Albalawi said.

Dr. Verma said that individuals with comorbid type 2 diabetes and PAD tend to have more distal, rather than proximal disease, making PAD in this population less amenable to traditional revascularization modalities.

Drs. Cheng and Verma both emphasized that larger, randomized studies of GLP-1 RAs, including in PAD, are necessary.

On-demand access to recorded presentations from the 85^th Scientific Session will be available to registered participants following the conclusion of the meeting in Chicago, from June 25–August 25.