In patients with type 2 diabetes and high CV risk, liraglutide reduced a composite CV outcome at a median 3.8 y

Question In patients with type 2 diabetes and high cardiovascular (CV) risk, is liraglutide noninferior to placebo for CV events? Methods Design Randomized, placebo-controlled, noninferiority trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER] trial). ClinicalTrials.gov NCT01179048. Allocation {Concealed}*. Blinding Blinded (patients, event adjudication committee, {health care providers, data collectors, data analysts, and manuscript writers}*). Follow-up period Median 3.8 years. Setting 410 centers in 32 countries. Patients 9340 patients (mean age 64 y, 64% men, mean glycated hemoglobin [Hb] level 8.7%) who had type 2 diabetes, glycated Hb level 7%, and age 50 years with 1 CV condition or 60 years with 1 CV risk factor. Exclusion criteria included type 1 diabetes; previous multiple endocrine neoplasia type 2 or medullary thyroid cancer or family history of conditions; acute coronary or cerebrovascular event in the past 14 days; or use of glucagon-like peptide-1 (GLP-1)receptor agonists, dipeptidyl peptidase-4 inhibitors, pramlintide, or rapid-acting insulin. Intervention Liraglutide, 1.8 mg or maximum tolerated dose in a daily subcutaneous injection (n =4668), or placebo (n =4672). All patients received standard care. Outcomes Primary outcome was a composite of CV events (CV death, nonfatal myocardial infarction, or nonfatal stroke). Other outcomes included all-cause mortality, an expanded CV composite (primary composite components and coronary revascularization or hospitalization due to heart failure or unstable angina), and a composite microvascular outcome (nephropathy or retinopathy). Patient follow-up 97% completed the trial {intention-to-treat analysis}*. Main results The main results are in the Table. Conclusion In patients with type 2 diabetes and high cardiovascular risk, liraglutide reduced a composite cardiovascular outcome at a median 3.8 years. Liraglutide vs placebo in patients with type 2 diabetes and high CV risk Outcomes Event rates At a median 3.8 y Liraglutide Placebo RRR (95% CI) NNT (CI) Primary CV composite 13% 15% 12% (3 to 21) 56 (33 to 243) CV death 4.7% 6.0% 21% (7 to 33) 78 (51 to 246) Nonfatal myocardial infarction 6.0% 6.8% 12% (3 to 24) NS Nonfatal stroke 3.4% 3.8% 11% (11 to 28) NS Expanded CV composite 20% 23% 11% (4 to 17) 42 (26 to 125) All-cause mortality 8.2% 9.6% 14% (3 to 25) 73 (42 to 365) Composite microvascular outcome 7.6% 8.9% 15% (3 to 26) 74 (44 to 392) CV = cardiovascular; NS = not significant; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from placebo event rates and hazard ratios in article. CV death, nonfatal myocardial infarction, or nonfatal stroke. Primary CV composite components and coronary revascularization (8.7% vs 9.4%, P =0.18) or hospitalization for either heart failure (4.7% vs 5.3%, P =0.14) or unstable angina (2.6% vs 2.7%, P =0.87). Retinopathy (2.3% vs 2.0%, P =0.33) or nephropathy (5.7% vs 7.2%, P =0.003). Commentary 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 (1). 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 subgrouptreatment 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 (2). 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.