How GLP-1 Drugs and SGLT2 Inhibitors Affect Heart and Limb Outcomes in Peripheral Artery Disease | Research

The takeaway

GLP-1 receptor agonists and SGLT2 inhibitors reduce cardiovascular events in diabetes, but their effects specifically on peripheral artery disease and limb complications remain poorly studied.

PAD underrepresented
Despite high cardiovascular and amputation risk, peripheral artery disease patients have been consistently underrepresented in the major GLP-1 RA and SGLT2i clinical trials

What the researchers found

Both SGLT2 inhibitors and GLP-1 receptor agonists have shown significant reductions in major adverse cardiovascular events (MACE) in type 2 diabetes patients with cardiovascular risk. However, patients with peripheral artery disease (PAD) have been consistently underrepresented in these trials. Notably, one major canagliflozin trial showed a signal of increased amputation risk, raising specific concerns for the PAD population.

The review found that while cardiovascular benefits appear to extend to PAD patients based on limited subgroup analyses, dedicated PAD-focused trial data for both drug classes remains scarce.

Why it matters

Peripheral artery disease affects millions of people with diabetes and carries high risks of amputation, heart attack, and death. GLP-1 receptor agonists represent one of the most promising drug classes for reducing cardiovascular events in diabetic patients, but their specific effects on limb outcomes in PAD are poorly understood. The amputation signal with canagliflozin has created uncertainty about SGLT2 inhibitor safety in this population, making GLP-1 RAs potentially more relevant for PAD patients.

The numbers in context

2 drug classes reviewed (SGLT2i, GLP1-RA) · MACE reduction demonstrated · PAD patients underrepresented in trials · Amputation signal with canagliflozin flagged

How the study worked

This was a narrative literature review summarizing published clinical trials, subgroup analyses, and societal guideline recommendations for SGLT2 inhibitors and GLP-1 receptor agonists in patients with cardiovascular disease, with a focus on data available for the peripheral artery disease subpopulation.

Who was studied

Review of type 2 diabetes patients with cardiovascular disease, with focus on the peripheral artery disease subpopulation

What this study cannot tell us

As a narrative review, no systematic search or meta-analysis was conducted. The main limitation acknowledged by the authors is the lack of dedicated PAD-focused trials for either drug class — most conclusions about PAD patients are drawn from subgroup analyses of larger cardiovascular outcome trials, which may be underpowered. The amputation signal with canagliflozin has not been definitively linked to the drug mechanism.

How to read the evidence

This is a narrative literature review synthesizing results from multiple randomized trials and guideline recommendations. It does not present new data or use systematic review methodology.

When this study was published

Published in 2023, this review captures a period of rapid expansion in incretin-based therapy research. Some of the evidence gaps identified may have been partially addressed by newer studies published since.

The bigger picture

As GLP-1 peptide drugs expand their indications beyond blood sugar control, understanding their effects on vascular disease in the limbs becomes critical. Peripheral artery disease is one of the most disabling complications of diabetes, and the lack of dedicated trial data in this population represents a significant evidence gap. GLP-1 RAs, with their anti-inflammatory and antiatherosclerotic properties, may offer particular promise for PAD, but this needs to be confirmed.

Questions still open

Do GLP-1 receptor agonists specifically reduce limb amputation risk in patients with peripheral artery disease?
Is the canagliflozin amputation signal a class effect of SGLT2 inhibitors or specific to that drug?
Should PAD patients preferentially receive GLP-1 RAs over SGLT2 inhibitors given the amputation concern?

Common questions

What is peripheral artery disease and why is it concerning for diabetic patients?

Peripheral artery disease (PAD) occurs when fatty deposits narrow the arteries supplying blood to the legs and feet. In diabetic patients, PAD is particularly dangerous because it can lead to non-healing wounds, gangrene, and amputation. People with both diabetes and PAD also have much higher rates of heart attack, stroke, and death.

Should diabetic PAD patients avoid SGLT2 inhibitors due to amputation risk?

One major trial of canagliflozin (an SGLT2 inhibitor) showed a possible increase in amputations, but this signal has not been consistently seen with other SGLT2 inhibitors. Current guidelines generally still recommend these drugs for cardiovascular benefit in diabetes, but the review suggests PAD patients may warrant additional monitoring. GLP-1 receptor agonists may be an alternative for patients concerned about limb safety.

Read the original research

Effects of SGLT2 inhibitors and GLP1-receptor agonists on cardiovascular and limb events in peripheral artery disease: A review.

Vascular medicine (London, England), 28(1), 62-76

View on PubMed ↗Publisher’s paper ↗

Citation

Skeik, Nedaa; Elejla, Sewar A; Sethi, Anish; Manunga, Jesse; Mirza, Aleem. (2023). Effects of SGLT2 inhibitors and GLP1-receptor agonists on cardiovascular and limb events in peripheral artery disease: A review.. Vascular medicine (London, England), 28(1), 62-76. https://doi.org/10.1177/1358863X221143811