Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin.
OBJECTIVE
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 D2receptor 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).


CONCLUSIONS
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.
a VeroScience, LLC , Tiverton , RI , USA.|b Division of Endocrinology, Diabetes and Hypertension , Brigham and Women's Hospital , Boston , MA , USA.|c Department of Medicine , Harvard Medical School , Boston , MA , USA.
Bindu
B
Chamarthi
a VeroScience, LLC , Tiverton , RI , USA.
Michael
M
Ezrokhi
d Statistical Operations , Everest Clinical Research Services Inc , Markham , Canada.
Dean
D
Rutty
a VeroScience, LLC , Tiverton , RI , USA.
Anthony H
AH
Cincotta
D000368:Aged; D001786:Blood Glucose; D001971:Bromocriptine / Q000008:administration & dosage*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D018491:Dopamine Agonists / Q000008:administration & dosage*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D012307:Risk Factors
D001786:Blood Glucose; D001971:Bromocriptine; D018491:Dopamine Agonists; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin
Bromocriptine; cardiovascular; circadian; diabetes; dopamine