Metformin plus Cycloset shows significant CVD risk reduction for type 2 diabetes patients in trial….
It is well known that type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease (CVD). Of the currently available therapies for T2DM, none have been conclusively shown to reduce CVD risk. However, there is some limited data suggesting that metformin may do so. There is also evidence suggesting that bromocriptine-QR (Cycloset), a quick release sympatholytic dopamine agonist that is a FDA-approved therapy for T2DM, has the potential to decrease cardiovascular events in patients with diabetes.
At the American Heart Association (AHA) Scientific Sessions held in Dallas, Texas in November 2013, Dr. B Chamarthi gave a poster presentation on a post-hoc analysis of the Cycloset Safety Trial (CST). The CST determined that bromocriptine-QR added to standard T2DM care resulted in a 40% hazard rate reduction (HRR) in cardiovascular events. This new analysis of the original CST investigated the impact of adding bromocriptine-QR versus placebo, on CVD outcomes in subjects already on metformin therapy at baseline (N= 1,791 subjects). Bromocriptine-QR was titrated weekly to a max dose of 1.6-4.8 mg/day and was taken once daily with a meal within two hours of waking. Changes to pre-existing anti-diabetes therapy were allowed if necessary but could not include adding medications that exceeded two oral agents or insulin plus an oral agent. The endpoint of the study was a major cardiovascular event including MI, stroke, coronary revascularization, or hospitalization for angina or congestive heart failure. Cox proportional-hazards regression analysis of endpoints was completed and adjusted for baseline covariates such as age, pre-existing CVD, history of stroke and cardiovascular revascularization. The Kaplan-Meier estimate showed 16/1208 subjects experienced an endpoint in the bromocriptine-QR group and 18/583 subjects in the placebo group. This represented a 53% CVD HRR. In addition, subjects on bromocriptine-QR therapy had a significantly higher odds of being in good glycemic control (at HbA1c goal of ≤ 7%) at 52 weeks than the placebo (odds ratio (OR) 1.753, confidence interval 1.310- 2.347, P=0.0002).
Bromocriptine-QR is a quick-release formulation of bromocriptine, which provides a brief daily interval of circulating bromocriptine, which in turn provides a timed pulse of increased dopaminergic activity centrally. The bioavailability and dosing of this quick-release timed formulation of bromocriptine is different from the traditional bromocriptine formulations used for other indications such as Parkinson’s, which deliver higher circulating drug levels throughout the day and as a consequence prolonged dopamine stimulation centrally. The mechanism of cardiovascular event reduction with bromocriptine-QR therapy is yet to be fully determined. According to the poster presented at the AHA, based on available evidence, it is postulated that the restoration of the daily (morning) peak in central circadian dopaminergic neural activities reduces abnormally elevated sympathetic nervous system drive to the vasculature, adipose, and liver and the activity of the hypothalamic-pituitary-adrenal axis, both of which are known to increase CVD risk if overactive, primarily by the induction of endothelial dysfunction.
In conclusion, the findings of this post-hoc analysis of the CST dataset, limited to individuals already on metformin therapy, indicated that in T2DM subjects, addition of bromocriptine QR was associated with a 53% cardiovascular event rate reduction and greater odds (OR: 1.75) of achieving good glycemic control at the end of the 52-week study period.
Chamarthi, B. et al. Bromocriptine-QR: A Potential Novel Strategy for Cardiovascular Risk Reduction in Type 2 Diabetes. American Heart Association 2013 Scientific Session Poster Presentation.