The Impact of Liraglutide on Diabetes-Related Foot Ulceration and Associated Complications in Patients With Type 2 Diabetes at High Risk for Cardiovascular Events: Results From the LEADER Trial

Abstract

Objective: Diabetes-related foot ulcers (DFUs) and their sequelae result in large patient and societal burdens. Long-term data determining the efficacy of individual glucose-lowering agents on DFUs are lacking. Using existing data from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, we conducted post hoc analyses assessing the impact of liraglutide versus placebo in people with type 2 diabetes and at high risk of cardiovascular (CV) events on the incidence of DFUs and their sequelae.

Research design and methods: The LEADER trial (NCT01179048) was a randomized, double-blind, multicenter, CV outcomes trial assessing liraglutide (1.8 mg/day) versus placebo, in addition to standard of care, for up to 5 years. Information on DFUs was collected systematically during the trial, and DFU complications were assessed post hoc through reviewing case narratives.

Results: During a median of 3.8 years' follow-up, similar proportions of patients reported at least one episode of DFU in the liraglutide and placebo groups (3.8% [176/4,668] versus 4.1% [191/4,672], respectively; hazard ratio [HR] 0.92 [95% CI 0.75, 1.13; P = 0.41]). Analysis of DFU-related complications demonstrated a significant reduction in amputations with liraglutide versus placebo (HR 0.65 [95% CI 0.45, 0.95; P = 0.03]). However, no differences were found for foot infections, involvement of underlying structures, or peripheral revascularization in the main analysis.

Conclusions: Treatment with liraglutide in patients with type 2 diabetes and at high risk of CV events in the LEADER trial did not increase the risk of DFU events and was associated with a significantly lower risk of DFU-related amputations compared with placebo. This association, possibly due to chance, needs further investigation.

© 2018 by the American Diabetes Association.

Figures

Figure 1

Cumulative incidence plot of time to first DFU event among all patients in the LEADER trial. Aalen-Johansen plot, with death as a competing risk factor. This figure includes data from the first DFU events in 176 liraglutide-treated and 191 placebo-treated patients.

Figure 2

Cumulative incidence plot of time to first DFU-related complication among patients treated with liraglutide vs. placebo in the LEADER trial. A: Amputation (44 first DFU events in the liraglutide group and 67 first DFU events in the placebo group). B: Infection (107 and 131 first DFU events in liraglutide and placebo groups, respectively). C: Involvement of underlying structures (64 and 80 first DFU events in liraglutide and placebo groups, respectively). D: Peripheral revascularization (20 and 23 first DFU events in liraglutide and placebo groups, respectively).