Liraglutide and Glycaemic Outcomes in the LEADER Trial

Abstract

Introduction: The LEADER trial was a cardiovascular (CV) outcomes trial in patients with type 2 diabetes at high CV risk that compared liraglutide (n = 4668) with placebo (n = 4672) using a primary composite endpoint of 3-point major adverse CV events. The objective of this post hoc analysis was to investigate glycaemic outcomes across both treatment groups.

Methods: Glycated haemoglobin (HbA1c) was measured at randomisation, month 3, month 6 and every 6 months thereafter. Cox regression was used to analyse time to a composite endpoint of glycaemic deterioration, defined as a specified change in HbA1c or a substantial intensification of insulin or oral antihyperglycaemic drug (OAD). The individual components of the composite were also analysed.

Results: Baseline characteristics, including insulin and OAD use, were balanced between treatment groups. HbA1c decreased from baseline in both groups, but the reduction was greater with liraglutide [estimated treatment difference at month 36: - 0.40%; 95% confidence interval (CI) - 0.45, - 0.34] despite the addition of more OADs and higher insulin use in the placebo group. Fewer of the patients treated with liraglutide (n = 3202, 68.6%) experienced glycaemic deterioration compared with those administered the placebo (n = 3988, 85.4%; average hazard ratio: 0.50; 95% CI 0.48, 0.53; p < 0.001). Analysis of the individual components showed similar results (both p < 0.001).

Conclusions: Type 2 diabetes patients at high risk of CV events who were treated with liraglutide achieved greater reductions in HbA1c, had a lower risk of hypoglycaemia and presented less glycaemic deterioration than similar patients who received the placebo. Nonetheless, progressive loss of glycaemic control occurred in both groups.

Trial registration: ClinicalTrials.gov, NCT01179048.

Funding: Novo Nordisk. Plain language summary available for this article.

Keywords: GLP-1 agonist; Glycaemic control; Incretin therapy.

Figures

Fig. 1

Cumulative incidence plot of time to HbA1c ≥ 8% and reduction < 0.5% since previous visit or substantial intensification* in insulin or OAD treatment. Aalen–Johansen plot, with death as a competing risk factor. *Substantial intensification of insulin or OAD defined as: start of new OAD; start of insulin; increase in insulin dose ≥ 10 units; or addition of mealtime bolus insulin to basal insulin or a shift from basal insulin to premixed insulin. HbA1c glycated haemoglobin, OAD oral antihyperglycaemic drug

Fig. 2i–ii

Cumulative incidence plots for both parts of the composite endpoint. i Time to HbA1c ≥ 8% and reduction < 0.5% since previous visit. ii Time to substantial intensification* of insulin or OAD treatment. Aalen–Johansen plots, with death as a competing risk factor. *Substantial intensification of insulin or OAD defined as: start of new OAD; start of insulin; increase in insulin dose ≥ 10 units; or addition of mealtime bolus insulin to basal insulin or a shift from basal insulin to premixed insulin. HbA1c glycated haemoglobin, OAD oral antihyperglycaemic drug