Type II diabetes, an epidemic fuelled by an unrelenting rise in obesity and sedentary behaviors, is a major risk factor for both micro- and macrovascular disease. An array of new treatments have recently come to trial with the aim of improving glycemic control and reducing disease complications. But lingering doubts remain regarding the cardiovascular implications of several of these agents, with FDA mandated studies now taking place to establish their safety.  Injectable liraglutide, a glucagon-like peptide 1 analogue,  improves HbA1c levels and also leads to weight loss but its cardiovascular effects are unknown.  In this post-approval double-blind study, 9340 patients with type 2 diabetes and at least one other major cardiovascular risk factor, were randomly allocated 1:1 to liraglutide or matching placebo, as well as usual care.  Patients were followed up for a median of 3.8 years with a primary composite study end-point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.  Designed as a non-inferiority study, liraglutide demonstrated statistically significant and clinically meaningful reductions in the primary end-point (13.0% vs. 14.9%, HR, 0.87; 95% CI, 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority) with reductions in both cardiovascular death (P=0.007) and all cause mortality (P=0.02).  Liraglutide also demonstrated a good safety profile with numerically lower rates of heart failure hospitalisations and no increase in rates of pancreatitis, a previous concern.  At 36 months HbA1c was 0.4 lower in the liraglutide group. Of note, significant differences in blood pressure (1.2 mmHg lower) and weight reduction (2.3 kg better) were observed in the trial group.  The NNT to prevent one primary end-point event was 66 and the NNT for all cause mortality 98.

Conclusions

After decades of disappointing results in improving macrovascular outcomes in patients with type II diabetes, liraglutide is the second drug in recent times (after empaglifozin) to report significant reductions in cardiovascular event rates and death.  While the mechanistic action of these effects remains debatable, and may not pertain to glycemic control as such, they herald a new therapeutic era which may at least temporarily arrest the tidal wave of cardiovascular disease foreshadowed by the spread of diabetes.

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jun 13.

Authors: Hussain Contractor, James M. McCabe