Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial
Last edited 02/2020 and last reviewed 10/2023
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)
- 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
- were 13 patients with pancreatic cancer in the liraglutide group
and 5 in the placebo group
- 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
- 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:
SUSTAIN-6 - subcutaneous semaglutide and cardiovascular outcomes in type 2 Diabetes