1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2006 年 10 月 12 日 8:20-8:50 B 棟８階 カンファレンス室

2. Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study

3. ● 生活習慣改善による 2 型糖尿病一次予防 ・ Malmö feasibility study(Eriksson, 1991) ・ Malmö Prfevention Trial(Eriksson, 1998) ・ DaQing IGT and Diabetes Study(Pan, 1997) ・ Finnish Diabetes Prevnetion Study(Tuomilehto, 2001) ・ Japan Diabetes Prevention Study( 葛谷英嗣, 進行中 ) ・ Stockholm Diabetes Prevention Program(Bjärås, 進行中 ) ● 薬物介入による 2 型糖尿病一次予防試験 ・ Diabetes Prevention Program(DPP Research Group, 2002) ・ STOP-NIDDM(Chiasson, 2002) ・ TRIPOD(Buchanan, 2001) ・ EDIT(Holman, 進行中 ) ・ NAVIGATOR( 進行中 ) ・ DREAM( 進行中 ) STOP-NIDDM ： Study To Prevent NDDM, TRIPOD ： Troglitazone In Prevention of Diabetes EDIT ： Early Diabetes Intervention Trial, NAVIGATOR ： Natglinide and Valsartan in Impaired Glucose Tolerance Outcome Reaserach DREAM ： Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications Primary Prevention of Type 2 Diabetes Mellitus

10. 58%less 31%less

13. PIProf. R. Holman, Univ. of Oxford PopulationIFG/IGT subjects; n= 631 (6 years follow-up) EndpointOnset of diabetes (OGTT or FPG) Treatment:Metformin 500 mg tds, Acarbose 50 mg tds Early Diabetes Intervention Trial Acarbose + Metformin N=315 N=159N=160 N=157 N=312 N=319 N=155 N=316 MetforminPlacebo Glucobay Acarbose reduces the risk of developing type 2 diabetes in IGT by 34 % in the ITT analysis versus no effect of Metformin

14. Pravastatin therapy also remained a significant predictor with a multivariate hazard ratio of 0.70 (95% CI 0.50 to 0.99, P=0.042). Pravastatin and the Development of Diabetes Mellitus (Circulation. 2001;103:357-362.)

15. P110 PI 3-kinase P-Ser- -Tyr-P P-Ser- AⅡAⅡ AT-R P-Ser- -Tyr-P α β Insulin Receptor IRS-1 P85 Diagram of A Ⅱ signaling interactions with the insulin receptor, IRS-1, and PI 3 kinase in RASMC

16. ARB の種類と糖尿病の発症 （２型糖尿病治療における ARB の意義） 名称投与薬糖尿病の発症リスク比較対照薬 VALUEARB Ca 拮抗薬 LIFEARB  遮断薬 SCOPEARB通常薬 SHEP利尿薬偽薬 CAPPP ACE 阻害薬 利尿薬 /  遮断薬 HOPE ACE 阻害薬 偽薬 INSIGHT Ca 拮抗薬 配合利尿薬 (%) (2001) (2004) (2002) (2005) (2004) (2003) VALUE, LIFE, SCOPE, CHARM のメタ解析の発症リスクは -23% NAVIGATOR, ONTARGET, TRANSCEND が進行中

17. Background Several trials involving people with hypertension or cardiovascular disease have suggested that agents that block or inhibit the renin–angiotensin system may also prevent diabetes. The Heart Outcomes Prevention Evaluation (HOPE) study showed that, in a population at high risk for cardiovascular events, the use of ramipril reduced cardiovascular events by 22% and diabetes by 34%, as compared with placebo. However, the presence of diabetes was ascertained by self report in the HOPE study and was not a prespecified outcome. Other studies reported similar findings in people with cardiovascular disease or hypertension.

18. AIM We conducted a prospective trial, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study, to evaluate whether ramipril reduces the risk of diabetes in people who have impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance but who are at low risk for cardiovascular events.

19. Study Design Ramipril: 1.25, 2.5, 5, 10 mg capsules 2.5~20mg/day Rosiglitazone: 1, 2, 4 mg tablets 4~8mg/day Cf. dose for clinical use Study Subjects Diabetes mellitus will be diagnosed if: (i) any diagnostic plasma glucose threshold is reached or exceeded on any two consecutive occasions, on two different days, in a 3-month period (i.e. the locally measured FPG is ≥7 mmol/l, or the local 2-h plasma glucose is ≥11.1 mmol/l); or (ii) a diagnosis has been made by a participant’s physician, an oral hypoglycaemic agent has been prescribed, and evidence of a confirmatory glucose concentration can be obtained (FPG ≥7 mmol/l, or any glucose ≥11.1 mmol/l). Those aged 30 or over with IGT or IFG and no diabetes (i.e. a fasting plasma glucose [FPG] ≥6.1 mmol/l and <7.0 mmol/l, and a 2-h plasma glucose <11.1 mmol/l after a 75-g OGTT). Exclusion criteria are listed in Table 1 and included evidence of previous ischaemic CVD, heart failure or low ejection fraction, previous intolerance to ACE inhibitors and/or TZDs, and previous diabetes mellitus.

20. Rosiglitazone Part Lancet 368:1096-1105, 2006 Published Online September 15, 2006

21. Study Subjects -8.2/-4.3 -3.9/-1.6

24. Figure 1. Kaplan–Meier Estimates of Death or Diabetes (Panel A) and Regression to Normoglycemia (Panel B). The 2-hour post-load plasma glucose levels were first routinely measured at 2 years; therefore, in Panel B, results are presented from that time onward. The hazard rate is the cumulative daily risk of having an outcome.

25. Figure 1. Kaplan–Meier Estimates of Death or Diabetes (Panel A) and Regression to Normoglycemia (Panel B). The 2-hour post-load plasma glucose levels were first routinely measured at 2 years; therefore, in Panel B, results are presented from that time onward. The hazard rate is the cumulative daily risk of having an outcome.

26. Figure 2. Participants with Diabetes, Any Impaired Fasting Glucose Level (IFG) or Impaired Glucose Tolerance (IGT), or Normoglycemia (Normal Fasting Plasma Glucose Level and Normal Response to the Oral Glucose- Tolerance Test) at the End of the Study. The P value for the likelihood that the proportions among the glycemic categories would have occurred by chance alone was 0.006. N=1116 N=1012 HR=1.16, CI 1.07-1.27, P=0.001

27. Figure 3. Median Fasting Plasma Glucose Levels (Panel A) and 2-Hour Post- Load Glucose Levels (Panel B) over Time. To convert values for plasma glucose to milligrams per deciliter, divide by 0.05551.

28. Figure 3. Median Fasting Plasma Glucose Levels (Panel A) and 2-Hour Post- Load Glucose Levels (Panel B) over Time. To convert values for plasma glucose to milligrams per deciliter, divide by 0.05551.

30. CONCLUSION Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia.

32. Oral renin inhibitors Jan A Staessen, Yan Li, Tom Richart Review Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of cardiovascular and renal disorders. The idea of blocking the renin system at its origin by inhibition of renin has existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak blood-pressure- lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development. This Review summarises the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren. Lancet Published online September 26, 2006

33. Figure 1: The renin-angiotensin-aldosterone system Black arrows show stimulation and red arrows show inhibition. Dotted lines show alternative pathways mainly documented in experimental studies. β blockers, renin inhibitors, inhibitors of angiotensin-converting enzyme (ACE) and angiotensin II type-1 receptor blockers (ARB) reduce the activity of the renin-angiotensin system (RAS). AT-R=angiotensin receptor; EP=endopeptidases; EC=endothelial cells.

35. Figure 2: Chemical structure of orally active renin inhibitors

36. Aliskiren is not metabolised by cytochrome P450, does not interfere with the action of warfarin, and shows no clinically relevant pharmacokinetic interactions with lovastatin, atenolol, celecoxib, or cimetidine.

38. Figure 3: The 24-hour systolic pressure at baseline and after inhibition of the renin system with either aliskiren or losartan Aliskiren and losartan were given for 4 weeks in once daily doses. of 150 mg (n=41), 300 mg (n=40) and 100 mg (n=36), respectively. Adapted from reference 50 with permission from Lippincott Williams and Wilkins.

40. Effects on intermediate markers of target-organ damage the Aliskiren in Left-Ventricular Hypertrophy trial (ALLAY, registration number [http://clinicaltrial.gov] NCT00219141) the Aliskiren Observation of Heart Failure Treatment trial (ALOFT, NCT00219011) The Aliskiren in the Evaluation of Proteinuria In Diabetes trial (AVOID, NCT00219206)

41. For almost 20 years, the development of oral renin inhibitors met huge problems. The clinical development of aliskiren signifies a breakthrough. However, the search for agents with improved oral bioavailability, specificity for human renin, and efficacy will continue CONCLUSION