Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin

ABSTRACT

Objectives: Type 2 diabetes mellitus (T2DM) is associated with a substantially increased risk of cardiovascular disease (CVD). Bromocriptine-QR (B-QR), a quick release sympatholytic dopamine D₂ receptor agonist, is a FDA-approved therapy for T2DM which may provide CVD risk reduction. Metformin is considered to be an agent with a potential cardioprotective benefit. This large placebo controlled clinical study assessed the impact of B-QR addition to existing metformin therapy on CVD outcomes in T2DM subjects.

Methods: 1791 subjects (1208 B-QR; 583 placebo) on metformin ± another anti-diabetes therapy at baseline derived from the Cycloset Safety Trial, a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were included in this study. The primary CVD endpoint evaluated was treatment impact on CVD event rate, prespecified as a composite of time to first myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina/congestive heart failure. Impact on glycemic control was evaluated as a secondary analysis.

Results: The composite CVD end point occurred in 16/1208 B-QR treated (1.3%) and 18/583 placebo treated (3.1%) subjects resulting in a 55% CVD hazard risk reduction (intention-to-treat, Cox regression analysis; HR: 0.45 [0.23–0.88], p = 0.028). Kaplan-Meier curves demonstrated a significantly lower cumulative incidence rate of the CVD endpoint in the B-QR treatment group (Log-Rank p = 0.017). In subjects with poor glycemic control (HbA1c ≥ 7.5) at baseline, B-QR therapy relative to placebo resulted in a significant mean %HbA1c reduction of −0.59 at week 12 and −0.51 at week 52 respectively (p < 0.001 for both) and a 10 fold higher percent of subjects achieving HbA1c goal of ≤7% by week 52 (B-QR 30%, placebo 3%; p = 0.003).

Conclusion: These findings suggest that in T2DM subjects on metformin, BQR therapy may represent an effective strategy for reducing CVD risk.

Cycloset Safety Trial registration: ClinicalTrials.gov Identifier: NCT00377676.

KEYWORDS:

• Bromocriptine
• cardiovascular
• circadian
• diabetes
• dopamine

Declaration of interest

B Chamarthi and D Rutty have been consultants for VeroScience. AH Cincotta is President and Chief Science Officer for VeroScience. M Ezrokhi is an employee of VeroScience. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The funding sources for this study were VeroScience, LLC and S2 Therapeutics, Inc.