Effects of Liraglutide Versus Placebo on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease

Abstract

Background: LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results) results demonstrated cardiovascular benefits for patients with type 2 diabetes mellitus at high cardiovascular risk on standard of care randomized to liraglutide versus placebo. The effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus and chronic kidney disease is unknown. Liraglutide's treatment effects in patients with and without kidney disease were analyzed post hoc.

Methods: Patients were randomized (1:1) to liraglutide or placebo, both in addition to standard of care. These analyses assessed outcomes stratified by baseline estimated glomerular filtration rate (eGFR; <60 versus ≥60 mL/min/1.73 m²) and baseline albuminuria. The primary outcome (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and secondary outcomes, including all-cause mortality and individual components of the primary composite outcome, were analyzed using Cox regression.

Results: Overall, 2158 and 7182 patients had baseline eGFR <60 or ≥60 mL/min/1.73 m², respectively. In patients with eGFR <60 mL/min/1.73 m², risk reduction for the primary composite cardiovascular outcome with liraglutide was greater (hazard ratio [HR], 0.69; 95% CI, 0.57-0.85) versus those with eGFR ≥60 mL/min/1.73 m² (HR, 0.94; 95% CI, 0.83-1.07; interaction P=0.01). There was no consistent effect modification with liraglutide across finer eGFR subgroups (interaction P=0.13) and when analyzing eGFR as a continuous variable (interaction P=0.61). Risk reductions in those with eGFR <60 versus ≥60 mL/min/1.73 m² were as follows: for nonfatal myocardial infarction, HR, 0.74; 95% CI, 0.55-0.99 versus HR, 0.93; 95% CI, 0.77-1.13; for nonfatal stroke, HR, 0.51; 95% CI, 0.33-0.80 versus HR, 1.07; 95% CI, 0.84-1.37; for cardiovascular death, HR, 0.67; 95% CI, 0.50-0.90 versus HR, 0.84; 95% CI, 0.67-1.05; for all-cause mortality, HR, 0.74; 95% CI, 0.60-0.92 versus HR, 0.90; 95% CI, 0.75-1.07. Risk reduction for the primary composite cardiovascular outcome was not different for those with versus without baseline albuminuria (HR, 0.83; 95% CI, 0.71-0.97; and HR, 0.92; 95% CI, 0.79-1.07, respectively; interaction P=0.36).

Conclusions: Liraglutide added to standard of care reduced the risk for major cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus and chronic kidney disease. These results appear to apply across the chronic kidney disease spectrum enrolled.

Clinical trial registration: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT01179048.

Keywords: LEADER; cardiovascular outcomes; diabetic kidney disease; liraglutide; type 2 diabetes mellitus.

Figure 1.

Hazard ratios between treatment groups for primary and key secondary outcomes by baseline eGFR and albuminuria groups. Time-to-event analyses applied a Cox proportional-hazards model with treatment as a covariate. Primary composite CV outcome was a composite of nonfatal stroke, nonfatal MI, or CV death. The expanded composite CV outcome was the same as the primary composite CV outcome plus coronary revascularization or hospitalization for unstable AP or heart failure. AP indicates angina pectoris; CV, cardiovascular; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; N, number of patients with an event; and %, proportion of patients with an event.

Figure 2.

Hazard ratios between treatment groups for the primary composite CV outcome by baseline eGFR subgroups in all patients. Time to first event is analyzed using Cox proportional hazards model with treatment, subgroup, and the interaction between treatment and subgroup as factors. *P value is from the test statistic for testing the interaction between treatment and baseline eGFR-MDRD group. The primary composite CV outcome includes CV death, nonfatal myocardial infarction, or nonfatal stroke. CV indicates cardiovascular; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; and N (%), number of patients with an event (proportion of patients within the subgroup with an event).

Figure 3.

Change in HbA1c (A), body weight (B), SBP (C), and LDL cholesterol (D) at 36 months. Interaction P between treatment and eGFR/albuminuria status at baseline was not significant, except for eGFR and weight (P=0.012). Changes are presented at 36 months (the last visit when all participants had their annual analysis of all laboratory results). eGFR indicates estimated glomerular filtration rate; ETD, estimated treatment difference; HbA_1c, glycohemoglobin; LDL, low-density lipoprotein; Micro/macro, microalbuminuria/macroalbuminuria; Normo, normalbuminuria; and SBP, systolic blood pressure.