Glucagon-Like Peptide-1 Receptor Agonists and Prior Major Adverse Limb Events in Patients With Diabetes

Abstract

Importance Patients with diabetes and a history of major adverse limb events (MALEs) are at an increased risk of cardiovascular and limb-related complications; however, effective glucose-lowering therapies for secondary prevention in this population are limited. Objective To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with reduced risk of MALEs and major adverse cardiovascular events (MACE) compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetes and prior MALEs. Design, Setting, and Participants This retrospective, nationwide cohort study used data from the Taiwan National Health Insurance Research Database from October 2012 to December 2023. Patients with diabetes and a history of MALE who initiated GLP-1 RAs or DPP-4 inhibitors were included. MALEs were defined as chronic limb-threatening ischemia, lower limb revascularization, or nontraumatic minor and major amputation. Exposures Initiation of GLP-1 RAs (liraglutide, dulaglutide, or semaglutide) vs DPP-4 inhibitors. Main Outcomes and Measures The primary outcome was a composite of lower limb revascularization and nontraumatic major and minor amputation. The secondary outcomes were MACEs (cardiovascular death, ischemic stroke, and myocardial infarction), all-cause mortality, and progression to long-term dialysis. A new-user, active-comparator design with inverse probability of treatment weighting was employed. Results Among 17 288 patients (mean [SD] age, 70.7 [12.0] years; 10 010 male [57.9%]), 1583 initiated GLP-1 RAs and 15 705 initiated DPP-4 inhibitors. After weighting, the use of GLP-1 RAs was associated with a lower risk of MALEs (subdistribution hazard ratio [SHR], 0.90; 95% CI, 0.83-0.97), primarily due to a marked reduction in amputation (SHR, 0.86; 95% CI, 0.75-0.98). GLP-1 RAs were also associated with reduced risks of MACEs (HR, 0.62; 95% CI, 0.58-0.65), cardiovascular death (HR, 0.57; 95% CI, 0.53-0.61), all-cause mortality (HR 0.63; 95% CI, 0.60-0.66), and progression to dialysis (SHR, 0.61; 95% CI, 0.54-0.70). Conclusions and Relevance In this nationwide cohort study of patients with diabetes and prior MALEs, treatment with GLP-1 RAs was associated with significantly lower risks of recurrent limb events, cardiovascular events, all-cause mortality, and kidney disease progression compared with DPP-4 inhibitors. These findings support the preferential use of GLP-1 RAs for secondary prevention in this high-risk population.