PAD and GLP-1 drugs: the 2026 evidence

A review published in the European Heart Journal on 17 July 2026 by Garagoli, Slipczuk, Shapiro, Bonaca, and Bhatt sets out where medical therapy for peripheral artery disease now stands^[1]. The headline message is direct: PAD remains underdiagnosed and undertreated despite clear evidence for treatments that cut both cardiovascular events and limb-related outcomes. Among those treatments, semaglutide is singled out as the only anti-obesity medicine currently shown to reduce cardiovascular events in high-risk patients with overweight or obesity in the absence of diabetes^[1].

Peripheral artery disease is atherosclerosis of the leg arteries. It is associated with elevated risk of both major adverse cardiovascular events (MACE: heart attack, stroke, cardiovascular death) and major adverse limb events (amputation, acute limb ischaemia). The review uses a phenotype-driven framework, meaning it sorts patients by their dominant risk driver, metabolic, lipid-related, inflammatory, or thrombotic, and maps treatments to that profile rather than applying one protocol to everyone.

Where semaglutide fits in PAD care

GLP-1 receptor agonists, including semaglutide, are now positioned in the review as agents that confer cardiovascular and kidney benefits independent of blood-glucose control^[1]. That framing matters for PAD patients because many of them do not have diabetes; the question has been whether the cardiovascular signal holds in a non-diabetic population.

The SELECT trial answered that question for semaglutide. In 17,604 adults with established cardiovascular disease and a BMI of 27 or above, but without diabetes, semaglutide 2.4 mg weekly reduced MACE by 20% compared with placebo over a mean follow-up of 39.8 months (hazard ratio 0.80, 95% CI 0.72 to 0.90, P less than 0.001)^[2]. SELECT did not enrol PAD patients exclusively, but a substantial share of the participants had pre-existing atherosclerotic disease and the effect held across the population.

A 2022 analysis of GLP-1 receptor agonist trials by Verma and colleagues looked specifically at the PAD subgroup within LEADER (liraglutide) and SUSTAIN-6 (semaglutide). In patients with PAD and type-2 diabetes, semaglutide produced an estimated hazard ratio for MACE of 0.61 (95% CI 0.33 to 1.13), with an absolute risk reduction of 4.63 percentage points, compared with 1.90 percentage points in patients without PAD. The direction favoured treatment in both groups; the larger absolute benefit in the PAD population reflects the higher baseline event rate in that group.

Walking capacity: the STRIDE trial

A separate question from cardiovascular events is functional capacity: can patients with PAD and intermittent claudication walk further on semaglutide? The STRIDE trial answered this. Published in the Lancet in May 2025^[3], STRIDE randomised 792 adults with symptomatic PAD and type-2 diabetes to semaglutide or placebo for 52 weeks. The primary endpoint was maximum walking distance ratio at week 52 on constant-load treadmill testing. The semaglutide group achieved a median ratio of 1.21 versus 1.08 for placebo, an estimated treatment ratio of 1.13 (95% CI 1.06 to 1.21, P equals 0.0004). The trial enrolled patients with type-2 diabetes and symptomatic disease; whether the walking benefit extends to PAD patients without diabetes is still being studied.

The rest of the medical therapy toolkit

The Garagoli 2026 review covers more than GLP-1 agonists. On anticoagulation, dual pathway therapy combining low-dose rivaroxaban with aspirin has emerged as the superior strategy for patients with high ischaemic risk and non-high bleeding risk, cutting both cardiovascular and limb events. On lipids, statins are the first-line treatment for all PAD patients, with ezetimibe, bempedoic acid, and PCSK9 inhibitors added if LDL cholesterol targets are not reached on maximally tolerated statin doses. The review also covers SGLT2 inhibitors as a second drug class with cardiovascular and kidney benefits independent of glycaemic control.

What we do not yet know

The 2026 review notes that emerging data suggests GLP-1 receptor agonists may also reduce limb events, not just cardiovascular events, in PAD patients^[1]. That signal is preliminary; the trial datasets large enough to characterise limb-event rates as a primary endpoint are not yet available. STRIDE covered walking capacity but was not powered for hard limb outcomes such as amputation or acute limb ischaemia.

A second open question is whether the cardiovascular and functional benefits of semaglutide in PAD patients without diabetes are as clear as those seen in the SELECT population or the STRIDE population with T2D. The review calls for further research in that direction.

Where this sits on the site

Semaglutide's place in cardiovascular medicine has been building since SELECT reported in 2023. PAD is one more disease setting where the evidence base is accumulating for a drug originally licensed to treat type-2 diabetes and obesity. The semaglutide page covers the full evidence base including SELECT, STEP-1, SUSTAIN-6, and FLOW, as well as the prescription-only regulatory status in each country we track. If you are a patient or carer reading about PAD and GLP-1 therapy, the decision about whether semaglutide is appropriate belongs with the prescribing clinician who knows your cardiovascular history, kidney function, and current medications. See the semaglutide regulatory overview for country-specific access information.