LEADER post hoc analysis: Mechanism behind liraglutide’s cardioprotective effects unclear

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

Dr. Richard Pratley

Liraglutide also reduced cardiovascular events to about the same extent regardless of whether patients later started insulin, sulfonylureas, or thiazolidinediones or developed severe hypoglycemia.

Such findings signal a fundamental shift in diabetes care, commented Steven Nissen, MD, chair of the department of cardiovascular medicine, at the Cleveland Clinic, Cleveland, Ohio. For decades, patients and clinicians lacked diabetes outcomes trials, and “it took three successive shockwaves to awaken the medical community from its 50-year slumber.”

The wake-up call started when Dr. Nissen and his associates linked muraglitazar (JAMA. 2005 Nov 23;294[20]:2581-6) and rosiglitazone (N Engl J Med 2007; 356:2457-71) to an increased risk of major adverse cardiovascular events. This continued when researchers found that targeting glycated hemoglobin levels below 6.0% increased the risk of death in patients with type 2 diabetes, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N Engl J Med 2008; 358:2545-59).

In response, the Food and Drug Administration began requiring cardiovascular outcomes trials before and after approving new diabetes drugs. “The result has been a new era of research” that has revealed uneven outcomes and a lack of uniform class effects, Dr. Nissen said.

For example, lixisenatide and long-acting exenatide are GLP-1 receptor agonists like liraglutide, but neither of these two drugs were found to prevent cardiovascular outcomes compared with placebo. In addition, the DPP-4 inhibitors “provide no meaningful outcome benefits, minimal glucose lowering, and potential harm at a high cost of about $400 per month,” he said.

This class has suffered “three disappointments,” he added. He referred to findings that alogliptin and sitagliptin did not reduce cardiovascular events compared with placebo in the EXAMINE trial (N Engl J Med 2013; 369:1327-35) and TECOS trial (N Engl J Med 2015; 373:232-42), respectively, while the SAVOR-TIMI 53 trial linked saxagliptin to an increased risk of hospitalization for heart failure (HR, 1.27; 95% CI, 1.07 to 1.51).

In contrast, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin reduced the rate of cardiovascular death, stroke, and MI by about 14% in the EMPA-REG trial (N Engl J Med 2015;373:2117-28).

Dr. Steven Nissen

Based on the LEADER results, the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee voted 17-2 supporting a new cardiovascular indication for liraglutide in type 2 diabetes, at a meeting in June 2017.

“After 60 years of stagnation, we are now witnessing a new era in the pharmacological management of type 2 diabetes, which is allowing a choice of therapies based on actual clinical outcomes – risks and benefits – rather than a surrogate biochemical marker like glucose levels,” Dr. Nissen said.

But current ADA recommendations “only weakly reflect contemporary knowledge,” he added. Although these guidelines do recommend considering empagliflozin or liraglutide for patients with atherosclerotic cardiovascular disease and “long-standing, suboptimally controlled type 2 diabetes,” their guidance on dual therapy does not reflect diverse cardiovascular outcomes data within and between classes, he said. “Just as we observed with statins, adoption of pivotal results is often just too slow.”

Integrating knowledge into practice will require close collaboration between cardiovascular and diabetes practitioners and “leadership from ADA to overcome residual inertia from decades of complacency,” he commented.

Dr. Pratley disclosed ties to AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Nissen disclosed research support from Novo Nordisk, Abbvie, Eli Lilly, and several other pharmaceutical companies, and travel support from Novo Nordisk.