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

Jan 28, 2026JAMA network open

Use of Glucagon-Like Peptide-1 Drugs and Past Serious Limb Problems in People with Diabetes

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Abstract

Among 17,288 patients, the use of GLP-1 receptor agonists was associated with a lower risk of major adverse limb events compared to DPP-4 inhibitors.

GLP-1 receptor agonists were linked to a reduced risk of major adverse limb events (MALEs) with a subdistribution hazard ratio of 0.90.
A significant reduction in amputation risk was observed, with a subdistribution hazard ratio of 0.86.
The use of GLP-1 receptor agonists was also associated with a decreased risk of major adverse cardiovascular events (MACEs), having a hazard ratio of 0.62.
Cardiovascular death risk was lower in patients using GLP-1 receptor agonists, indicated by a hazard ratio of 0.57.
All-cause mortality was reduced with GLP-1 receptor agonist treatment, as shown by a hazard ratio of 0.63.
Progression to long-term dialysis was less likely in patients treated with GLP-1 receptor agonists, with a subdistribution hazard ratio of 0.61.

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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.