Cardiovascular, limb, and kidney effects of SGLT2 inhibitors in patients with peripheral artery disease: a systematic review and meta-analysis of randomized controlled trial data

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) provide substantial cardiovascular benefits across a broad spectrum of patients at high atherosclerotic risk. However, evidence for their cardiovascular efficacy in patients with peripheral artery disease (PAD) remains limited. Accordingly, we conducted this systematic review and meta-analysis to synthesize available evidence and clarify the cardiovascular, limb, and kidney outcomes of SGLT2i in patients with PAD. PubMed, Embase, and the Cochrane Library were searched from inception to 20 December 2025 for studies evaluating SGLT2i therapy in patients with PAD. The primary outcome was the composite of hospitalization for heart failure (HHF) or cardiovascular death. Secondary outcomes included HHF, cardiovascular death, amputation, composite renal outcomes, all-cause mortality, and major adverse cardiovascular events (MACE). Five studies comprising 7,275 patients with PAD were included. Among patients with PAD, SGLT2i therapy was associated with a lower risk of the composite of HHF or cardiovascular death (HR 0.73; 95% CI 0.64 to 0.83; p < 0.001), HHF (HR 0.63; 95% CI 0.51 to 0.77; p < 0.001), cardiovascular death (HR 0.83; 95% CI 0.69 to 1.00; p = 0.045) and adverse renal outcomes (HR 0.74; 95% CI 0.55 to 0.98; p = 0.038). SGLT2i was not associated with an increased risk of amputation (HR 1.17; 95% CI 0.87 to 1.56; p = 0.293). No significant reductions were observed for all-cause mortality (HR 0.86; 95% CI 0.69 to 1.08; p = 0.192) or MACE (HR 0.89; 95% CI 0.75to 1.06; p = 0.207). There was no evidence of effect modification based on PAD status (all Pinteraction >0.10). However, in exploratory subgroup analyses among patients with PAD, SGLT2i treatment for ≥ 2 years was associated with a numerically greater reduction in cardiovascular death (HR 0.73; 95% CI 0.60–0.90), whereas no clear effect was observed in trials with a duration of < 2 years (Pinteraction = 0.06). SGLT2i-therapy is associated with a reduced risk of composite of cardiovascular and kidney outcomes in patients with PAD, without increasing the risk of amputation. These findings support a potential role of sustained long-term SGLT2i-therapy in this high-risk group.