A randomized trial of patients with pre-existing cardiovascular (CV) disease or high CV risk found that liraglutide was associated with a reduction in CV events compared to placebo. The study's primary composite outcome was first occurrence of death from CV causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke. Mortality from CV causes or any cause was also lower in the liraglutide group, according to the study, which was funded by Novo Nordisk and the National Institutes of Health.
The study was published in the July 28 New England Journal of Medicine and summarized in the July ACP Diabetes Monthly. The following commentary by Michal Mazurek, MD, and Gregory Y.H. Lip, MD, was published in the ACP Journal Club section of the Oct. 18 Annals of Internal Medicine.
Liraglutide, one of the GLP-1 analogues, is currently a second-line therapy for patients with type 2 diabetes in whom glycemic control cannot be achieved despite lifestyle modification and initial therapy with metformin. The main advantage of GLP-1 analogues is low risk for hypoglycemia and modest weight loss; drawbacks are subcutaneous injection, gastrointestinal side effects, and high price.
The LEADER trial found that adding liraglutide to standard care improved survival and reduced CV outcomes and microvascular events, namely nephropathy. The trial was well-designed and conducted, and reported outcomes were robust. Liraglutide was superior to intensified standard care in the placebo group, irrespective of antihyperglycemic medications used (P=0.73 for subgroup–treatment interaction).
Unfortunately, the reasons for such a benefit remain unclear. Was it weight loss, lower incidence of hypoglycemia, lower systolic blood pressure, modestly decreased glycated Hb level, or other reasons on which we can only speculate? Another GLP-1 receptor agonist, lixisenatide, did not show any CV benefit in the ELIXA trial.
Moreover, safety requires further assessment over a much longer perspective given that patients will probably be prescribed the drug for long-term, if not lifelong, use. For example, although there was no significant between-group difference in the overall incidence of neoplasia, rates of pancreatic cancer were higher with liraglutide than placebo, whereas the opposite was observed for leukemia and prostate cancer.
Does this change our daily practice? Indeed, there is now evidence to discuss with eligible patients and consider for use of liraglutide as the first-option drug in second-line therapy of poorly controlled diabetes.