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Editorial Diabetes Lessons From LEADER – All-round Leadership Sanjay Kalra Department of Endocrinology, Bharti Hospital, Karnal, India T he large multinational, randomised, double-blind LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation) trial recently reported the cardiovascular (CV) benefits achieved with liraglutide therapy in type 2 diabetes mellitus (T2DM). This editorial analyses the primary and secondary CV outcomes (CVO) results of the LEADER trial, and discusses the impact these will have on clinical practice of diabetes in specific, and medicine in general. It delves into the evolution of clinical and biochemical outcomes used in diabetes, and discusses the role of liraglutide in shaping future outcomes. The editorial describes the potential role of liraglutide in primary, secondary and tertiary prevention of CV disease (CVD), and suggests exaptation of this molecule for use in cardiology, nephrology and neurology. Keywords Cardiovascular outcomes, diabetes, empagliflozin, LEADER, liraglutide, lixisenatide, prevention Disclosure: Sanjay Kalra has been a Principal Investigator in the LEADER trial. No funding was received for the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 3 July 2016 Published Online: 18 August 2016 Citation: European Endocrinology, 2016;12(2):76–8 Corresponding Author: Sanjay Kalra, Department of Endocrinology, Bharti Hospital, Karnal, Haryana 132001, India. E: brideknl@gmail.com The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation) trial recently reported the cardiovascular (CV) benefits achieved with liraglutide therapy in type 2 diabetes mellitus (T2DM). In a multinational, randomised, double- blind trial involving 9340 participants, with a median follow-up of 3.8 years, various primary and secondary CV outcomes (CVO) were assessed. This editorial analyses the results of the LEADER trial, and discusses the impact these will have on clinical practice of diabetes in specific, and medicine in general. Study design While the primary outcome of this time-to-event analysis was first occurrence of death from CV causes, nonfatal (including silent) myocardial infarction (MI), or nonfatal stroke, the trial also listed pre-specified exploratory outcomes. This included an expanded composite CV outcome (the three endpoints listed in the primary composite end point, coronary revascularisation, or hospitalisation for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal micro vascular  outcome, neoplasms, and pancreatitis. The composite micro vascular outcome included nephropathy and retinopathy. Nephropathy was defined as the new onset of macro albuminuria, or doubling of serum creatinine level and an estimated glomerular filtration rate (eGFR) of ≤45 ml/minute /1.73m 2 , the need for continuous renal replacement therapy, or death from renal disease. Retinopathy was defined as the need for retinal photo coagulation or treatment with intra-vitreous agents, vitreous haemorrhage, or the onset of diabetes-related blindness. 1 Primary outcome The primary composite outcome (first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke) occurred in significantly fewer participants in the liraglutide group (608/4668; 13.0%) than in the placebo arm (694/4672; 14.9%) (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.78–0.97; p=0.01 for superiority). The major determinant of this benefit was the lower incidence of death from CV causes in the liraglutide group (219/4668; 4.7%) than in the placebo arm (278/4672; 6.0%) (HR 0.78; 95% CI 0.66-0.93; p=0.007). All-cause mortality was also lower in the liraglutide group (381/4668; 8.2%) than in the placebo arm (447/4672; 9.6%) (HR 0.85; 95% CI 0.74–0.97; p=0.02) (Table 1). 1 Secondary macrovascular outcome While the incidence of nonfatal MI and nonfatal stroke was numerically lower in the liraglutide arm of the LEADER trial, as compared to the placebo group, the difference did not reach statistical significance. Nonfatal MI was reported  in 281 out of 4668 liraglutide users (6.0%) as compared to 317 out of 4672 persons on placebo (6.8%) (HR 0.88; 95%CI 0.75-1.03; p=0.11). Similarly, nonfatal stroke occurred in 159 liraglutide users (3.4%) and 177 placebo-users (3.8%) (HR 0.89; 95% 0.72–1.11; p=0.30). 1 There was no difference in the liraglutide and placebo arms with respect to hospitalisation for heart failure (HR 0.87; 95% CI 0.73–1.05; p=0.14). 76 TOU C H ME D ICA L ME D IA