Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial

• double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo
  • primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
  • primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome
    
    
• total of 9340 patients underwent randomization
  • with type 2 diabetes who had a glycated hemoglobin level of 7.0% or more were eligible if they either had not received drugs for this condition previously or had been treated with one or more oral antihyperglycaemic agents or insulin or a combination of these agents
    • major inclusion criteria were the following: an age of 50 years or more with at least one cardiovascular coexisting condition (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease of stage 3 or greater, or chronic heart failure of New York Heart Association class II or III) or an age of 60 years or more with at least one cardiovascular risk factor, as determined by the investigator (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle–brachial index [the ratio of the systolic blood pressure at the ankle to the systolic blood pressure in the arm] of less than 0.9)
      
      
  • median follow-up was 3.8 years
    
    
  • primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P = 0.01 for superiority)
    • fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P = 0.007)
    • rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P = 0.02)
    • rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group
    • most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events
      
      
  • overall rates of benign or malignant neoplasms were higher in the liraglutide group than in the placebo group, but the difference was not significant
    • were 13 patients with pancreatic cancer in the liraglutide group and 5 in the placebo group
      
      
• in the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
  • number of patients who would need to be treated to prevent one event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause

Notes:

• microvascular Outcomes
  • incidence of a composite outcome of renal or retinal microvascular events was lower in the liraglutide group than in the placebo group (hazard ratio, 0.84; 95% CI, 0.73 to 0.97; P = 0.02), a difference that was driven by a lower rate of nephropathy events in the liraglutide group (1.5 vs. 1.9 events per 100 patient-years of observation; hazard ratio, 0.78; 95% CI, 0.67 to 0.92; P = 0.003)
  • incidence of retinopathy events was nonsignificantly higher in the liraglutide group than in the placebo group (0.6 vs. 0.5 events per 100 patient-years; hazard ratio, 1.15; 95% CI, 0.87 to 1.52; P = 0.33)
• glycaemic control
  • prespecified analysis at 36 months showed a mean difference between the liraglutide group and the placebo group of -0.40 percentage points (95% CI, -0.45 to -0.34)
• many patients in each group were treated with sulfonylureas or insulin at baseline, but fewer patients in the liraglutide group than in the placebo group added insulin during the trial
• in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, the GLP-1-receptor agonist lixisenatide, which is shorter-acting than and structurally dissimilar to liraglutide, did not show any cardiovascular benefit in patients with diabetes and a recent acute coronary syndrome

Reference:

• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.N Engl J Med. 2016 Jun 13