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

## TL;DR

GLP-1 receptor agonists may reduce limb and cardiovascular risks in diabetic patients with prior limb issues compared to DPP-4 inhibitors.

## Contribution

This study provides evidence that GLP-1 RAs offer better secondary prevention outcomes than DPP-4 inhibitors in high-risk diabetic patients.

## Key findings

- GLP-1 RAs were associated with lower risks of limb events, amputation, and cardiovascular events.
- Use of GLP-1 RAs reduced all-cause mortality and progression to dialysis.
- Findings suggest GLP-1 RAs should be preferred in secondary prevention for high-risk diabetes patients.

## Abstract

This cohort study analyzes associations of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with risk of recurrent major adverse limb events in patients with diabetes.

Are glucagon-like peptide-1 receptor agonists (GLP-1 RAs) associated with improved limb, cardiovascular, and kidney outcomes compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetes and prior major adverse limb events?

In this cohort study of 17 288 patients, the use of GLP-1 RAs was associated with significantly lower risks of limb events, amputation, cardiovascular events, progression to dialysis, and all-cause mortality compared with DPP-4 inhibitors.

These findings suggest that GLP-1 RAs may offer important protective benefits for high-risk patients with diabetes and prior limb events, supporting their preferential use in secondary prevention.

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.

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.

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.

Initiation of GLP-1 RAs (liraglutide, dulaglutide, or semaglutide) vs DPP-4 inhibitors.

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.

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).

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.