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 2009 年 11 月 12 日 8:30-8:55 ８階 医局 Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; the TREAT Investigators. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. N Engl J Med Oct 30. [Epub ahead of print] Scranton RE, Gaziano JM, Rutty D, Ezrokhi M, Cincotta A. A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset or placebo. BMC Endocr Disord Jun 25;7:3.

/nejmoa nejm.org From the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School (M.A.P., E.F.L., A.K.S., S.D.S.); and the Division of Nephrology, Tufts Medical Center (A.S.L.) — both in Boston; Hospital de Base, Faculdade de Medicina de Sao Jose do Rio Preto, Sao Jose do Rio Preto, Brazil (E.A.B.); Global Biostatistics and Epidemiology and Global Clinical Development, Amgen, Thousand Oaks, CA (C.-Y.C., R.K.); Baker Heart Research Institute, Melbourne, VIC, Australia (M.E.C.); the Division of Clinical Pharmacology, University Medical Center, Groningen, the Netherlands (D.Z.); the Department of Nephrology and Hypertension, University of Erlangen- Nuremberg, Erlangen, Germany (K.-U.E.); the Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (J.M.F.); the Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (P.I.); the Department of Medicine, Washington University School of Medicine, St. Louis (J.B.M.); the Department of Cardiology, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, United Kingdom (J.J.V.M.); the Division of Nephrology, Health Sciences Centre, St. John’s, NF, Canada (P.P.); the Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, and Faculty of Health Science, Aarhus University, Aarhus (H.-H.P.) — both in Denmark; Mario Negri Institute for Pharmacological Research, Bergamo, Italy (G.R.); and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas (R.T.).

Background and Aim Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. This study is registered with ClinicalTrials.gov, number NCT

Method In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.

Enrollment by country was as follows (numbers of patients are in parentheses): Argentina (84), Australia (58), Austria (3), Brazil (190), Bulgaria (28), Canada (176), Chile (14), Czech Republic (96), Denmark (10), Estonia (16), France (11), Germany (135), Hungary (70), Italy (87), Latvia (51), Mexico (150), Poland (213), Portugal (17), Romania (47), Russia (117), Slovakia (65), Slovenia (12), United Kingdom (49), United States (2339).

Results Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P = 0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P = 0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient- reported fatigue in the darbepoetin alfa group as compared with the placebo group.

Conclusion The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. The trial was sponsored by Amgen and designed in collaboration with an academic executive committee.

Message 糖尿病性腎症の治療でエリスロポイエチン製剤 を用いるのには注意が必要。

Scranton, R. et al. 20th World Diabet Congr (Oct 18-22, Montreal) 2009, Abst D-0770

Quick release bromocriptine (Cycloset™) a novel treatment for type 2 diabetes also demonstrates improvements in blood pressure

Background Cycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of oncedaily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points. Trial registration: clinical trials.gov NCT

Method 3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.

Results (to be available) This study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alphaglucosidase inhibitors and exogenous insulin regimens.

A 52 week, double-blind safety trial of 3,000 patients treated with Cycloset did not show an increase in pre-specified and independently adjudicated adverse cardiovascular outcomes-a composite of myocardial infarction, stroke, hospitalization for unstable angina, congestive heart failure, and revascularization surgery-compared to patients taking a placebo (HR 0.58; CI ).

Message 米国では 2009 年５月に ブロモクリプチン が２型糖尿病治療薬として認可された。 FDA が「心血管障害についても問題ないことが 承認の前提」としてから 最初に認可された薬 物！ ところで、 先端巨大症に 使っているのは ２型糖尿病の治療になっている？