GLP-1 receptor agonists for people with type 2 diabetes and peripheral artery disease: reducing uncertainty in clinical practice.

Peripheral artery disease (PAD) may be the most frequent first manifestation of cardiovascular disease (CVD) in type 2 diabetes (T2D). Management of PAD in T2D aims to improve symptoms and lower the high risk of major adverse cardiovascular (MACE) and limb (MALE) events. Drugs commonly used are lipid-lowering and antihypertensive medicines, antithrombotic and antihyperglycemic agents. The ADA recommends both GLP-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as the first-line therapy to reduce the cardio-renal risk in people with T2D, including those with PAD. Meta-analyses of randomized controlled trials (RCTs) show that semaglutide is better than placebo in reducing by 30% PAD events in people with T2D (with or without PAD at baseline), although no RCT was designed to investigate PAD-related hard outcomes as a primary endpoint; however, both liraglutide and semaglutide may increase walking distance by approximately 25-30 m at six months in people with T2D and PAD. Cohort studies also confirm that GLP-1RA use is better than non-use in reducing by 28% the risk of MALE in individuals with T2D and PAD, although their retrospective design might introduce residual confounding and under-ascertainment of outcomes. Dedicated RCTs will obtain more direct evidence for the promising lower limb benefits of GLP-1RAs, but the scientific outlook of specific RCTs on hard limb events is empty. In the meantime, clinicians should choose a GLP-1RA of proven efficacy in subjects with T2D and PAD to improve their cardio-nephro-metabolic outlook, as well as their walking capacity, limited at present to liraglutide and semaglutide.