Transcript PowerPoint プレゼンテーション - 埼玉医科大学総合医療センター 内分泌

Journal Club
Gaziano JM, Cincotta AH, O'Connor CM, Ezrokhi M, Rutty D, Ma ZJ,
Scranton RE.
Randomized Clinical Trial of Quick Release-Bromocriptine among Patients
with Type 2 Diabetes on Overall Safety and Cardiovascular Outcomes.
Diabetes Care. 2010 Mar 23. [Epub ahead of print]
A.H. Cincotta; J.M. Gaziano; M. Ezrokhi; R. Scranton
Cycloset (Quick-Release Bromocriptine Mesylate), a Novel Centrally Acting
Treatment for Type 2 Diabetes
EASD 2009
2010年５月13日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
Background
Quick release-bromocriptine
(bromocriptine-QR), a D2 dopamine
receptor agonist, is indicated as a
treatment for type 2 diabetes. The
Cycloset Safety Trial, a 52 week,
randomized, double-blind, multicenter
trial, evaluated the overall safety and
cardiovascular (CVD) safety of this
novel therapy for type 2 diabetes.
Methods
3,095 patients with type 2 diabetes were randomized 2:1
to bromocriptine-QR or placebo in conjunction with the
patient’s usual diabetes therapy (diet controlled only or
up to two anti-diabetes medications, including insulin).
The all cause safety endpoint was the occurrence of any
serious adverse event (SAE), with a hazard ratio (HR)
noninferiority margin of 1.5. In a pre-specified analysis,
the frequency of cardiovascular (CVD) events defined as
a composite of myocardial infarction, stroke, coronary
revascularization, hospitalization for angina or
congestive heart failure was evaluated using modified
intent-to-treat analysis. (clinical trials.gov NCT00377676)
End points
1)assessment of overall safety of
bromocriptine- QR by measuring
the frequency of serious adverse
events (SAEs) among patients
taking bromocriptine-QR and
placebo
2)
cardiovascular safety
assessed by determining the
frequency of major cardiovascular
events, defined as a composite of
first myocardial infarction, stroke,
coronary revascularization or
hospitalization for angina or
congestive heart failure that
occurred after randomization.
*Deaths:
Bromocriptine-QR - 9 deaths (4 deaths
while on treatment and 5 after
treatment had stopped);
Placebo- 3 deaths (2 deaths while on
treatment and one death after
treatment had stopped)
Figure 1- Kaplan-Meier curve of the occurrence of the pre-specified composite cardiovascular endpoint among
patients randomized to bromocriptine-QR (solid line) or placebo (dashed line). The composite cardiovascular
endpoint consisted of the time to first myocardial infarction, stroke, coronary revascularization, hospitalization for
unstable angina, or hospitalization for congestive heart failure that occurred after randomization. All cardiovascular
events were independently adjudicated. The hazard ratio of bromocriptine-QR versus placebo for the occurrence
of the composite cardiovascular endpoint was 0.60 (95% CI 0.37-0.96). The effect of treatment was estimated
from the unadjusted Cox proportional-hazard model that used all the available data.
Baseline and change from baseline laboratory and blood pressure data in patients
with Type 2 Diabetes
The peripheral cardiometabolic effects of bromocriptine-QR on
cardiovascular risk may be in part the consequence of its
attenuation of CNS/hypothalamic functions potentiating
sympathetic nervous system over-activity to the vasculature,
visceral adipose, and liver as well as attenuation of increased
hypothalamic-pituitary-adrenal axis activity, which are known to
increase CVD risk if overactive .
Improvements in post prandial hyperglycemia and hyperlipidemia
have been observed with this treatment and may have contributed
to the CVD event reduction in this trial.
Moreover, recent studies in animal models of insulin resistance
have demonstrated marked improvements in both liver
inflammatory pathways potentiating vascular damage and
endothelial dysfunction during treatment with a parental
formulation of bromocriptine (Cincotta AC, unpublished data).
Results
176 (8.6%) people in the bromocriptine-QR
group reported SAEs compared to 98
(9.6%) in the placebo group; HR 1.02, 96%
one-sided CI, 1.27. Fewer people reported
a CVD endpoint in the bromocriptine-QR
group 37 (1.8%) versus placebo 32 (3.2%);
HR of 0.60; 95% two-sided CI: 0.35 - 0.96.
Nausea was the most commonly reported
adverse event in the bromocriptine-QR
group.
Conclusion
The frequency of SAEs was
comparable between the treatment
arms.
Compared to patients in the placebo
arm, fewer patients taking
bromocriptine-QR experienced a
cardiovascular endpoint.
Message
Bromocriptineは心血管障害に対してもよい影
響があるらしい！
⇒ FDAの方針はどうやって知ったのか？だが
血糖管理はそこその群での比較で若干副作用は
ただし多そう。
Cycloset (Quick-Release Bromocriptine
Mesylate), a Novel Centrally Acting
Treatment for Type 2 Diabetes
1
2
1
3
A.H. Cincotta; J.M. Gaziano; M. Ezrokhi; R. Scranton
1 Research, VeroScience, Tiverton, RI, United States
2 Medicine, Harvard Medical School, Boston, MA, United States
3 Medical Affairs, VeroScience, Tiverton, RI, United States
All Subjects
Only Subjects
that did NOT
Change Diabetes
Medication Regimen
Overall Safety and Tolerability of Cycloset from the
Cycloset Safety Trial
All-Cause SAEs
HR 1.02; 96%CI (-,1.27)
Balanced among SOCs for
events occurring at ≥2%
Placebo-subtracted
Discontinuation due to AEs
occurring at a frequency ≥5%
Nausea
7.7%
Dizziness
2.6%
Headache
1.9%
Fatigue
2.6%
Cycloset Safety Trial
Composite Cardiovascular Outcome By Treatment
(MI, stroke, hospitalization for unstable angina, CHF, or revascularization surgery)
ITT Analysis; N = 3070
HR 0.58 (95% CI 0.35 – 0.96)
Placebo
Bromocriptine- QR
Months
Summary
Timed daily administration of bromocriptine acts centrally to improve postprandial
insulin responsiveness in insulin resistant animal models.
Daily morning pulsatile delivery of bromocriptine via the Cycloset formulation to type
2 diabetes subjects failing a variety of peripherally acting OHA therapies improves
glycemic control after 24 weeks of therapy (0.6 - 0.9 HbA1c reduction).
Daily morning pulsatile delivery of Cycloset is associated with a 42% reduction in rate
of adverse cardiovascular events ( MI, stroke, hospitalization for CHF, unstable
angina or revascularization surgery).
Morning Cycloset Therapy for type 2 diabetes represents a potential new approach in
treating the microvascular and macrovascular complications of this disease.