Bromocriptine: A Sympatholytic, D2-dopamine Agonist for the Treatment of Type 2 Diabetes

Ralph A. DeFronzo, MD

Disclosures

Diabetes Care. 2011;34(4):789-794. 

In This Article

All-cause Safety Trial

A large (n = 3,070) 52-week, randomized, placebo-controlled (2:1), double-blind trial evaluated overall and cardiovascular safety of Cycloset in type 2 diabetic patients treated with diet alone, one to two OHAs, or insulin alone or with one OHA.[41] Mean age was 60 years, mean BMI 32.4 kg/m2, and mean HbA1c 8.3%. Fifty-seven percent of subjects were male, and ethnic background was 68% Caucasian and 17% African American. Cycloset therapy was initiated at 0.8 mg/day and titrated to 4.8 mg/day, as tolerated. After 3 months, alteration in other antidiabetic medications was permitted.

Overall, there were 8.6% serious adverse events in the Cycloset group and 9.6% serious adverse events in the placebo group (hazard ratio [HR] 0.89, P = NS). Thirty-two diabetic patients (3.2%) in the Cycloset group compared with 37 patients (1.8%) in the placebo group experienced a prespecified cardiovascular event (myocardial infarction, stroke, hospitalization for angina, hospitalization for congestive heart failure [CHF], coronary revascularization, and death) (HR 0.60, two-sided 95% CI 0.37–0.96, P = 0.036) (Fig. 3). Using the major adverse cardiac events (MACE) end point (myocardial infarction, stroke, and death), the HR was reduced in the Cycloset compared with placebo-treated subjects (HR 0.55, two-sided 95% CI 0.39–0.98, P < 0.05) (Fig. 3). Based on the composite cardiovascular outcome, 79 diabetic patients need to be treated for 1 year to avoid one cardiovascular event.

Adverse events that occurred at a frequency >5% and numerically were greater in the Cycloset group included nausea (32.2 vs. 7.6%), dizziness (14.8 vs. 9.2%), fatigue (13.9 vs. 6.7%), headache (11.4 vs. 8.3%), vomiting (8.1 vs. 3.1%), diarrhea (8.1 vs. 8.0%), and constipation (5.8 vs. 5.1%).

The mechanism(s) via which timed bromocriptine reduces cardiovascular events in type 2 diabetic patients remains to be defined. In the cardiovascular safety trial,[41] bromocriptine reduced HbA1c by 0.6% (P < 0.0001), blood pressure by 2/1 mmHg (P < 0.02), heart rate by 1 bpm (P = 0.02), and plasma triglyceride by 0.08 mmol/L (P = 0.02). However, these changes were modest and seem unlikely to explain the 40% decrease in composite cardiovascular outcome. Although not measured in the safety trial, reductions in postprandial FFA levels have been observed in other trials with bromocriptine.[30,31] In animal studies, bromocriptine has been shown to attenuate the effect of CNS sympathetic overactivity on the vasculature,[44,45] and a direct inhibitory effect of bromocriptine on mitogen-stimulated proliferation of rat vascular muscle cells and human aortic smooth muscle cells has been demonstrated in vitro.[46] In the high fat–fed, spontaneously hypertensive rat (SHR)—an animal model of the insulin resistance syndrome and eNOS uncoupling—bromocriptine reduced pathologically elevated endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) levels.[47] Uncoupled eNOS increases NAD[P]-H oxidase levels, resulting in generation of reactive oxygen species and decreased nitric oxide production, a potent vasodilator and antiatherogenic agent. All of these biochemical abnormalities were reversed in the aorta of bromocriptine-treated SHR, and aortic stiffness was markedly reduced. Thus, a number of biochemical/molecular abnormalities involved in the development of atherosclerosis, as well as multiple circulating cardiovascular risk factors (hyperglycemia, hypertriglyceridemia, and elevated FFA) and hypertension, improve with bromocriptine therapy. At present, it is unclear whether the salutatory effect of bromocriptine to reduce cardiovascular events[41] is related to the drug's beneficial effect on any of these pathologic processes/atherosclerotic risk factors. Further mechanistic studies and a large, long-term prospective study will be required to establish the mechanism of action and cardiovascular protective benefit of bromocriptine therapy.

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