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Randomized Controlled Trial
. 2016 Jul 28;375(4):311-22.
doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Steven P Marso  1 , Gilbert H Daniels  1 , Kirstine Brown-Frandsen  1 , Peter Kristensen  1 , Johannes F E Mann  1 , Michael A Nauck  1 , Steven E Nissen  1 , Stuart Pocock  1 , Neil R Poulter  1 , Lasse S Ravn  1 , William M Steinberg  1 , Mette Stockner  1 , Bernard Zinman  1 , Richard M Bergenstal  1 , John B Buse  1 ; LEADER Steering Committee; LEADER Trial Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Steven P Marso et al. N Engl J Med. .

Abstract

Background: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.

Methods: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes.

Results: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The 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). The 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). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.

Conclusions: 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. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

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Figures

Figure 1
Figure 1. Primary and Exploratory Outcomes
The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. The insets show the same data on an enlarged y axis.
Figure 2
Figure 2. Primary Composite Outcomes in Various Demographic and Clinical Subgroups
Prespecified Cox proportional-hazard regression analyses were performed for subgroups of patients with respect to the primary outcome (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). P values signify tests of homogeneity for between-group differences with no adjustment for multiple testing. The percentages of patients with a first primary outcome between the randomization date and the date of last follow-up are shown. Race and ethnic group were self-reported. There were missing data for the body-mass index (the weight in kilograms divided by the square of the height in meters) in 5 patients in the liraglutide group and 4 in the placebo group and for the duration of diabetes in 11 patients in the liraglutide group and 8 in the placebo group. Renal function was assessed by means of the estimated glomerular filtration rate, as calculated by the Modification of Diet in Renal Disease equation. CVD denotes cardiovascular disease.
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References

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