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

Circulation. 2018 Dec 18;138(25):2908-2918. doi: 10.1161/CIRCULATIONAHA.118.036418.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / mortality
  • Double-Blind Method
  • Female
  • Humans
  • Hypoglycemic Agents
  • Liraglutide
  • Male
  • Middle Aged
  • Myocardial Infarction / epidemiology*
  • Myocardial Infarction / mortality
  • Placebos
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / epidemiology
  • Renal Insufficiency, Chronic / mortality
  • Stroke / epidemiology*
  • Stroke / mortality
  • Survival Analysis
  • United Kingdom / epidemiology


  • Hypoglycemic Agents
  • Placebos
  • Liraglutide

Associated data

  • ClinicalTrials.gov/NCT01179048