Effect of Bromocriptine‐QR (a Quick‐Release Formulation of Bromocriptine Mesylate) on Major Adverse Cardiovascular Events in Type 2 Diabetes Subjects
Authors: Gaziano J. Michael , Cincotta Anthony H. , Vinik Aaron , Blonde Lawrence , Bohannon Nancy , Scranton Richard 
Published: May 2013

Background

Bromocriptine‐
QR
(a quick‐release formulation of bromocriptine mesylate), a dopamine D2 receptor agonist, is a
US F
ood and
D
rug
A
dministrration–approved treatment for type 2 diabetes mellitus (
T2DM
). A 3070‐subject randomized trial demonstrated a significant, 40% reduction in relative risk among bromocriptine‐
QR
‐treated subjects in a prespecified composite cardiovascular (
CV
) end point that included ischemic‐related (myocardial infarction and stroke) and nonischemic‐related (hospitalization for unstable angina, congestive heart failure [
CHF
], or revascularization surgery) end points, but did not include cardiovascular death as a component of this composite. The present investigation was undertaken to more critically evaluate the impact of bromocriptine‐
QR
on cardiovascular outcomes in this study subject population by (1) including
CV
death in the above‐described original composite analysis and then stratifying this new analysis on the basis of multiple demographic subgroups and (2) analyzing the influence of this intervention on only the “hard”
CV
end points of myocardial infarction, stroke, and
CV
death (major adverse cardiovascular events [
MACE
s]).

Methods and Results

Three thousand seventy
T2DM
subjects on stable doses of ≤2 antidiabetes medications (including insulin) with
HbA1c
≤10.0 (average baseline
HbA1c
=7.0) were randomized 2:1 to bromocriptine‐
QR
(1.6 to 4.8 mg/day) or placebo for a 52‐week treatment period. Subjects with heart failure (
N
ew
Y
ork
H
eart
C
lasses I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. Study outcomes included time to first event for each of the 2
CV
composite end points described above. The relative risk comparing bromocriptine‐
QR
with the control for the cardiovascular outcomes was estimated as a hazard ratio with 95% confidence interval on the basis of
C
ox proportional hazards regression. The statistical significance of any between‐group difference in the cumulative percentage of
CV
events over time (derived from a
K
aplan–
M
eier curve) was determined by a log‐rank test on the intention‐to‐treat population. Study subjects were in reasonable metabolic control, with an average baseline
HbA1c
of 7.0±1.1, blood pressure of 128/76±14/9, and total and
LDL
cholesterol of 179±42 and 98±32, respectively, with 88%, 77%, and 69% of subjects being treated with antidiabetic, antihypertensive, and antihyperlipidemic agents, respectively. Ninety‐one percent of the expected person‐year outcome ascertainment was obtained in this study. Respecting the
CV
‐inclusive composite cardiovascular end point, there were 39 events (1.9%) among 2054 bromocriptine‐
QR
‐treated subjects versus 33 events (3.2%) among 1016 placebo subjects, yielding a significant, 39% reduction in relative risk in this end point with bromocriptine‐
QR
exposure (
P
=0.0346; log‐rank test) that was not influenced by age, sex, race, body mass index, duration of diabetes, or preexisting cardiovascular disease. In addition, regarding the
MACE
end point, there were 14 events (0.7%) among 2054 bromocriptine‐
QR
‐treated subjects and 15 events (1.5%) among 1016 placebo‐treated subjects, yielding a significant, 52% reduction in relative risk in this end point with bromocriptine‐
QR
exposure (
P
<0.05; log‐rank test).

Conclusions

These findings reaffirm and extend the original observation of relative risk reduction in cardiovascular adverse events among type 2 diabetes subjects treated with bromocriptine‐
QR
and suggest that further investigation into this impact of bromocriptine‐
QR
is warranted.

Clinical Trial Registration

URL:
http://clinicaltrials.gov
. Unique Identifier: NCT00377676