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 2009 年 12 月 10 日 8:30-8:55 ８階 医局 Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 32:1924-9, 2009. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 25:2361-71, 2009.

2. スタチン介入大規模臨床試験における LDL-C と冠動脈疾患イベント発症率の関係 Fisher M:Heart,90(3),336-340(2004) Mean LDL cholesterol ( mmol / l ) (mg/dl) CARE DM (placebo) 4S DM (placebo) LIPID DM (placebo) 4S DM (simvastatin) CARE DM (pravastatin) LIPID DM (pravastatin) 4S (placebo) LIPID (placebo) CARE (pravastatin) LIPID (pravastatin) CARE (placebo) AFCAPS (lovastatin ) AFCAPS (placebo) WOSCOPS (pravastatin) WOSCOPS (placebo) Patient with CHD event (mean%) Diabetes secondary Secondary prevention Primary prevention 1.52.02.53.03.54.04.55.05.5 0 5 10 15 20 30 4S (simvastatin) 5877 116 154 193

3. 糖尿病予防効果 (1) ONTARGET20084.7 ARB399854210.0ACEI36685769.2 ONTARGET20084.7 ARB+ACEI3238502 8.1ACEI36685769.2 TRANSCEND 2008 4.7 ARB 319 2954 26.4 placebo 395 2972 28.8 Kyoto Heart20093.3ARB58111615.6CCB86110823.2 松田昌文： DREAM study 内分泌・糖尿病科 26(1):35-41, 2008.

4. 糖尿病予防効果 (2)

5. the 1Department of Epidemiology and Population Health and Department of Medicine, Albert Einstein College of Medicine, New York, New York; the 2Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio; and the 3Center for Cardiovascular Disease Prevention and Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Diabetes Care 32:1924–1929, 2009

6. Background and Aim Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesistesting trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.

7. Method A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis- testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I 2 statistic.

9. Table 1—Randomized controlled trials evaluating the effect of statin use risk of incident type 2 diabetes

11. Figure 2—Meta-analysis of clinical trials evaluating the effects of statins on diabetes risk

12. One possible explanation is that statin therapy may interfere with normal glucose metabolism (11). In this regard, both in vitro and in vivo data suggest that atorvastatin decreases adipocyte maturation and results in a decline in expression of GLUT4 and upregulation of GLUT1 in cultured preadipocytes and in mice (12). This results in a marked reduction in insulin-mediated cellular glucose uptake caused by decreased insulin sensitivity, which may possibly result in exacerbation of glucose intolerance (13). It is also possible that statin-induced insulin resistance may result from inhibition of isoprenoid biosynthesis, an intermediate product in cholesterol formation, becausee these effects can be reversed by the isoprenoid precursor mevalonate (12,14). Furthermore, in addition to inducing insulin resistance, statin therapy may also directly affect insulin secretion. From this perspective, the most relevant experimental data in rats have demonstrated that when pancreatic beta-cells are incubated with statins, insulin secretion is reduced due to inhibition of glucose stimulated increase in free cytoplasmic Ca 2+ and L- type Ca 2+ channels (15). Similar findings were also reported in another study using a beta-cell line, MIN6 cells, where investigators demonstrated that high doses of lipophilic but not hydrophilic statins decrease insulin secretion, either due to hydroxymethylglutaryl- CoA inhibition or cytotoxicity (16).

13. Results In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03–1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis- generating trial WOSCOPS was included (1.06 [0.93–1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P < 0.03, I 2 = 57.7%).

14. Conclusion Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.

15. Message スタチンで糖尿病の頻度が増えるかどうか？ ⇒ メタ解析では増えそう。 もしかしたらスタチンにより差があるかもしれ ない。

18. Background To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD)

19. Method In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted. Main outcome measures: The primary efficacy endpoint was change in HbA1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG ≧ 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia.

27. Results Least squares (LS) mean change in HbA1c was significantly ( p ≦ 0.001) greater for alogliptin 12.5 mg ( － 0.66%) or 25 mg ( － 0.80%) than for placebo ( － 0.19%). A significantly (p ≦ 0.016) larger proportion of patients achieved HbA1c ≦ 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p ≦ 0.003) greater with alogliptin 12.5 mg ( － 19.7 mg/dL [ － 1.09 mmol/L]) or 25 mg ( － 19.9 mg/dL [ － 1.10 mmol/L]) than with placebo ( － 5.7 mg/dL [ － 0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p ≦ 0.001) lower for alogliptin ( － 25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

28. Conclusion Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

29. Message 新しい治療薬が加わり、併用治療について有効性と安 全性の確認が重要である。