SAN FRANCISCO — An investigational quick-release formulation of bromocriptine mesylate produced a 42% reduction in a prespecified combined end point of myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure or angina in a 52-week study of more than 3,000 patients with type 2 diabetes.
The data come from the Cycloset safety trial, a prospective, randomized, double-blind, placebo-controlled study in which quick-release (QR) bromocriptine was given as add-on therapy to patients already taking one or two oral hypoglycemic agents with or without insulin, as well as cardiovascular medications. The beneficial reduction in the prespecified cardiovascular composite end point was seen even among patients with good glycemic control at baseline, Dr. Richard Scranton reported at the annual scientific sessions of the American Diabetes Association.
Cycloset, developed by VeroScience LLC, is a novel quick-release formulation of the dopamine-2 receptor agonist that is given once daily in the morning. The time of administration is critical, because circadian neuroendocrine rhythms in the hypothalamus are key to the regulation of peripheral metabolism, said Dr. Scranton, chief medical officer of VeroScience.
In animals that undergo marked annual cycles of metabolism, seasonal shifts from the obese, insulin-resistant condition to the lean, insulin-sensitive state are driven by shifts in the circadian phase relations of hypothalamic neurotransmitter levels. By mimicking this neurophysiological shift pharmacologically, it is possible to produce a shift in metabolism. Available evidence suggests that bromocriptine-QR acts centrally to reset hypothalamic centers regulating postprandial insulin-mediated glucose and lipid metabolism, thereby reducing postprandial hyperglycemia and hyperlipidemia.
“The time-of-day-dependent impact of dopamine upon circadian hypothalamic regulation of metabolism is a key component to the drug's mechanism of action,” Dr. Scranton explained.
In three previous phase III clinical trials, Cycloset significantly reduced hyperglycemia among obese individuals with type 2 diabetes (Expert Opin. Investig. Drugs 1999;8:1683-707). Based on those data, the Food and Drug Administration issued an “approvable” letter for the agent for the treatment of type 2 diabetes, conditional in part on the completion of a large, placebo-controlled, randomized trial in patients with type 2 diabetes in order to evaluate drug-related adverse events fully. Those data are provided by the current study, Dr. Scranton said.
A total of 3,095 patients from 74 U.S. centers were randomized 2:1 to receive bromocriptine-QR starting at 0.8 mg and titrating up to 4.8 mg, taken once daily in the morning, or placebo. Concomitant diabetes medications were adjusted to maintain ideal glucose control. The final intent-to-treat analysis included 2,054 patients who received bromocriptine-QR and 1,016 who received placebo.
At baseline, the patients had a mean age of about 60 years, mean hemoglobin A1c (HbA1c) of 7.0%, and mean diabetes duration of 8 years. Most were on at least one oral glucose-lowering agent, about a third were on two oral agents, and about 15% were on insulin. They were typical of type 2 patients, with a mean body mass index of 32 kg/m
The treatment and placebo groups were comparable in all baseline characteristics except history of revascularization surgery, in 10% vs. 13%, respectively.
Discontinuations from any cause were 41% with bromocriptine-QR and 26% on placebo. Discontinuations because of adverse events occurred in 24% with bromocriptine-QR, compared with 10.5% on placebo, including four deaths among those receiving bromocriptine-QR and two in the placebo group (0.2% of each group). Nausea, occurring mainly during the initial dose-escalation phase of the study, was the primary reason for both the increased discontinuations and the adverse event reports in the treatment group. For most patients, the nausea was mild to moderate and lasted less than 2 weeks, Dr. Scranton said in a follow-up interview.
In prespecified analyses of glycemic control, subgroups of patients who failed oral diabetes therapies (HbA1c at or above 7.5%) at baseline experienced on average a 0.7 % reduction in HbA1c in favor of bromocriptine-QR, relative to both placebo and to baseline.
The prespecified composite cardiovascular disease (CVD) end point occurred in 1.6% of the bromocriptine-QR group compared with 3.0% of those on placebo. That 42% relative reduction did not change significantly with adjustment for baseline covariables including stroke, coronary revascularization, or center. Analysis of the individual components of the composite suggested benefit for each one, including a 56% relative reduction in myocardial infarction (0.3% vs. 0.8%) and a 63% relative reduction in stroke (0.2% vs. 0.6%). A 55% relative reduction was seen in the combined end point of myocardial infarction, stroke, or CVD death.