Randomized Clinical Trial of Quick-Release Bromocriptine Among Patients With Type 2 Diabetes on Overall Safety and Cardiovascular Outcomes

OBJECTIVE

Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patient''s usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin). The all-cause–safety end point was the occurrence of any serious adverse event (SAE), with a hazard ratio (HR) noninferiority margin of 1.5. In a prespecified analysis, the frequency of cardiovascular disease (CVD) events defined as a composite of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure was evaluated using modified intent-to-treat analysis (clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00377676","term_id":"NCT00377676"}}NCT00377676).

RESULTS

In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98 (9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respecively) (HR 0.60 [95% two-sided CI 0.35–0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group.

CONCLUSIONS

The frequency of SAEs was comparable between the treatment arms. Compared with patients in the placebo arm, fewer patients taking bromocriptine-QR experienced a cardiovascular end point.Type 2 diabetes is a growing global pandemic that is estimated to afflict approximately 350 million people by the year 2030 (1,2). This growing threat to human health requires medical interventions to lessen the morbidity associated with type 2 diabetes. Results from several recent clinical trials have raised concerns about the cardiovascular safety of current therapies and therapeutic strategies (3–10). Therefore, the U.S. Food and Drug Administration has established cardiovascular safety standards that must be met for type 2 diabetes therapies prior to their marketing approval. The Cycloset Safety Trial was designed to assess the overall safety and specifically address cardiovascular safety for a novel treatment for type 2 diabetes, quick-release bromocriptine (bromocriptine-QR) (11).Bromocriptine is a dopamine D2 receptor agonist, and bromocriptine-QR was designed to provide a short duration pulse of this dopamine agonist to centers in the brain (12,13) that regulate peripheral fuel metabolism (14). Bromocriptine-QR is administered in the morning, within 2 h of waking, to effectuate an increase in central dopaminergic tone at the time of day it normally peaks in healthy individuals (15). This circadian peak in central dopaminergic tone has been linked to preservation and/or induction of normal insulin sensitivity and glucose metabolism in several preclinical studies (14). Although bromocriptine-QR had demonstrated improvements in various metabolic parameters in patients with type 2 diabetes as well as improvements in many surrogate markers of cardiovascular disease, (16,17) data from these previous clinical studies were insufficiently powered to adequately assess cardiovascular safety. This article reports the results of a 1-year, double-blind, placebo-controlled, randomized clinical trial where the overall safety and specifically cardiovascular safety of bromocriptine-QR was the primary outcome.