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Is Liraglutide A Wonder Drug Against Cardiovascular Death?

LEADER showed liraglutide reduces risk of cardiovascular death, but latest study shows no benefit to high-risk patients.

Liraglutide is a human glucagon-like peptide receptor analog. It is an incretin hormone produced in the gut and secreted in response to food consumption. The main pharmacological effects of GLP-1 are its stimulation of endogenous insulin in response to elevated glucose, suppression of raised glucagon and regulation of appetite. It reduces both body weight and blood pressure. It is approved for use in type 2 diabetes mellitus. The glucose lowering efficacy of liraglutide has been established. Its use results in hemoglobin A1C reductions of 1.0 to 1.5%. Diabetes mellitus affects nearly 350 million people worldwide including 26 million patients in the United States. The prevalence is growing and is a chronic disease connected with long term vascular complications. It is also independently linked to adverse cardiovascular outcomes including coronary heart disease (CHD), stroke and cardiovascular death. Ways to decrease the occurrence of microvascular complications are the foundations for managing patients with diabetes. Various previous studies have stated that associated mechanisms are unknown and its effect is often dismissed as clinically unimportant.

The purpose of this study was to investigate whether liraglutide reduces risk of cardiovascular death in type 2 diabetes. A study called the LEADER trial was used to compare liraglutide to a placebo based on the incidence of cardiovascular events. It is a multicenter, international randomized, double blind placebo controlled clinical trial with a long term follow up. Type 2 diabetic patients who were either naïve or were on antidiabetic drugs, either an oral hyperglycemic agent or on insulin were included in this study. Patients with prior CVD were ≥ 50 years whilst those without CVD were ≥ 60 years old. A total of 400 patients had 30-59 ml/min per 1.73m2 and 200 patients with severe <30ml /min per 1.73m2 reduction in baseline. Subjects were randomized in a 1:1 manner to receive a double blind once daily maximum dose of liraglutide 1.8mg or an equivalent placebo, added to their standard of care management. Liraglutide was administered at 0.6 mg daily for 1 week, 1.2 mg for an additional week and afterwards a potential maximum dosage of 1.8mg. A 20% insulin dosage reduction is recommended when initiating randomization for patients with an HbA1c ≤ 8%. The primary end point were cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke in adult patients with type 2 diabetes mellitus. The primary analysis done was the noninferiority testing. The secondary endpoints include the first occurrence of an expanded composite cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, hospitalization for unstable angina or hospitalization for chronic heart failure. Other endpoints were also recorded. Safety endpoints like hypoglycemia were also assessed. Calcitonin was monitored and any value ≥ 20 ng/L is reported to calcitonin monitoring committee for further analysis and diagnosis. Cox regression model was used to estimate the hazard ratio of liraglutide to placebo and a 2-sided 95% confidence interval. Safety is however recognized if the two sided 95% confidence limit is less than the prespecified upper bound of 1.3.

The effect of sex, age, body mass index, HbA1c, duration of diabetes, region, race, cardiovascular risk, chronic heart failure, severe chronic renal failure, severe to moderate chronic renal failure and use of concomitant glucose medication and insulin on the primary composite end point was explored separately as a main effect and interaction with treatment by adding each to the original model. A decrease in systolic blood pressure of 2.1 mm Hg with liraglutide 1.2 mg and 3.6 mm Hg with 1.8mg. Together, there was a sustained weight loss of approximately 2 kg. There was no adverse impact of liraglutide treatment on lipid profiles concerning cardiovascular risk and favorable changes in triglycerides and free fatty acids.

A decrease in levels of cardiovascular risk markers such as plasminogen-activator inhibitor-1 and B-natriuretic peptide after treatment have been reported. Liraglutide is still linked with an estimated 1-2 beats/min in heart rate. Study is still ongoing and we hope a better conclusion comes out soon as to its risk on cardiovascular outcomes. The weakness of this study is that it is funded by Novo Nordisk, which stands to benefit when claims are approved, and also it was compared to a placebo and not to another antidiabetic drug.

Practice Pearls:

  • Study reports a decrease in systolic blood pressure of 2.1 mm Hg with liraglutide 1.2 mg and 3.6 mm Hg with 1.8mg.


  • A decrease in levels of cardiovascular risk markers such as plasminogen-activator inhibitor-1 and B-natriuretic peptide after treatment has been reported.


  • Liraglutide is  linked with an estimated reduction of 1-2 beats/min in heart rate.


UPDATE: FIGHT Study Proves Type-2 Diabetes Therapy Ineffective in the Treatment of High-Risk Heart Failure Patients.  In an attempt to correct defects in the energy generation that contribute to poor pump function among heart failure patients, researchers examined whether the diabetes drug liraglutide could improve the condition of patients with advanced heart failure. Despite improvements in blood sugar control, the therapy did not improve the clinical stability or pumping action of the heart in patients with advanced heart failure.  Published August 2nd 2016 in JAMA.



Robinson, Louise E et al. “Effects of Exenatide and Liraglutide on Heart Rate, Blood Pressure and Body Weight: Systematic Review and Meta-Analysis.” BMJ Open 3.1 (2013): e001986. PMC. Web. 26 June 2016.

Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2009; 32:193–203. Web. 26 June 2016

Marso Steven P, MD et al. “Design of liraglutide effect and action in diabetes: Evaluation of cardiovascular outcome results (LEADER) trial”. American Heart Journal. Vol 166 (5) 823-83025. Web. 26 June 2016

Danaei G, et al. “National, regional and global trends in fasting plasma glucose and diabetes prevalence: systemic analysis of health examination surveys and epidemiological studies” Web June 26th 2016