Quick-Release Agent Cuts CV Events in Patients with Diabetes

First CNS-Based Antidiabetic Drug Controls Metabolic Abnormalities

By Jill Stein

CHICAGO—A quick-release formulation of the investigative centrally-acting dopamine D₂ receptor agonist bromocriptine mesylate (Cycloset; Wythe Therapeutics/VeroScience), given as adjunctive therapy, reduces the rateof major cardiovascular (CV) events by 43% in patients with type 2 diabetes compared with placebo, accordingto new data reported at the American Diabetes Association (ADA) annual meeting.

Quick-release bromocriptine, which has received an approvable letter from the FDA, acts centrally in the brain to "reset" neuroendocrine signaling when given as a single, timed, morning dose of up to 4.8 mg. If approved, the agent will be a "first-in-its-class" treatment for type 2 diabetes, using a central nervous system (CNS) mode of action."The antidiabetic drugs we havenow address blood sugar, which isonly one aspect of diabetes," J. Michael Gaziano, MD, a cardiologist andepidemiologist at Brigham and Women's Hospital and Veteran Affairs Boston Healthcare System, Boston, pointed out.

"While decreased hypothalamic dopaminergic tone may contributeto insulin resistance, treatment with centrally acting dopamine agonistslike quick-release bromocriptine improves the metabolic abnormalities that are often associated with insulin resistance, like obesity and increased triglyceride levels."

There have been no large trials to date that have convincingly shown that normalizing blood glucose levels will prevent myocardial infarction (MI) and stroke, he added. "This is unfortunate, given that diabetics have about twice the rate of cardiovascular events as nondiabetics, and female diabetics have twice the risk of cardiovascular events as male diabetics," he said.

Dr Gaziano presented results in 3070 patients randomized in a 2:1 ratio to 52 weeks of treatment with placebo or quick-release bromocriptine (titrated from 1.6 mg/d to a maximum tolerated dose up to 4.8 mg/d). Participants were already being treated with diet alone; up to 2 hypoglycemic agents; or insulin, with or without 1 additional oral agent.

The primary goals of the study were to determine the safety of quick-release bromocriptine in patients with type 2 diabetes and to identify any potential positive CV benefits.

Previous clinical studies had shown that the drug improves glucose tolerance, insulin resistance, glycemiccontrol, and dyslipidemia in obese patients with insulin resistance or with type 2 diabetes.

Participants ranged in age from 30 to 80 years; hemoglobin (Hb) A_1c level was ≤10.0% and body mass index was ≤43 kg/m². All had been diagnosed with diabetes at least 6 months earlier.

Results showed that the rate of serious adverse events was similar in the 2 treatment groups, but the rate of serious CV events differed significantly. Twice as many serious CV events occurred in the 1106 patients in the placebo group than in the 2054 patients in the quick-release bromocriptine group (3.0% vs 1.5%, respectively). The difference between the 2 groups was significant for each component of the CV composite, which included MI, stroke, coronary revascularization, hospitalization for angina, and hospitalization for heart failure.

The investigators also evaluated HbA_1c levels after 24 weeks of therapy in a subgroup of 121 patients who had a baseline HbA1c ≥7.5% despite treatment with metformin (Glucophage) and a sulfonylurea.

The addition of bromocriptine resulted in a mean HbA_1c reduction of 0.69% compared with placebo (P= .002) and of 0.67% compared with baseline.In addition, 39% of the quick-release bromocriptine group achieved theADA HbA_1c target of 7.0% compared with only 11% of the placebo group(P= .004).

"We need more data before we can say whether such factors as disease stage or type of background treatment, among others, affect response to this drug," Dr Graziano said. "However, in the long run I will be using a drug that not only lowers blood sugar but also prevents heart attacks and strokes. And my hope is that this agent will someday be first-line treatment."