1. Journal Club 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 2010 年５月 13 日 8:30-8:55 ８階 医局 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

4. 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.

5. 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) Methods

6. *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) 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.

9. 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.

10. Baseline and change from baseline laboratory and blood pressure data in patients with Type 2 Diabetes

11. 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).

12. 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.

13. 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.

14. 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。

16. Cycloset (Quick-Release Bromocriptine Mesylate), a Novel Centrally Acting Treatment for Type 2 Diabetes A.H. Cincotta; J.M. Gaziano; M. Ezrokhi; R. Scranton 12 1 3 1 Research, VeroScience, Tiverton, RI, United States 2 Medicine, Harvard Medical School, Boston, MA, United States 3 Medical Affairs, VeroScience, Tiverton, RI, United States

65. Only Subjects that did NOT Change Diabetes Medication Regimen All Subjects

67. Overall Safety and Tolerability of Cycloset from the Cycloset Safety Trial All-Cause SAEs Placebo-subtracted Discontinuation due to AEs occurring at a frequency ≥5% Nausea7.7% Dizziness2.6% Headache1.9% Fatigue2.6% HR 1.02; 96%CI (-,1.27) Balanced among SOCs for events occurring at ≥2%

68. Placebo Bromocriptine- QR ITT Analysis; N = 3070 HR 0.58 (95% CI 0.35 – 0.96) Months Cycloset Safety Trial Composite Cardiovascular Outcome By Treatment (MI, stroke, hospitalization for unstable angina, CHF, or revascularization surgery)

69. 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.