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Journal Club

Journal Club. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009 Oct 28. [Epub ahead of print]

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Journal Club

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  1. Journal Club Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009 Oct 28. [Epub ahead of print] Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009 Oct 29;361(18):1736-47. Epub 2009 Oct 22. 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5日　8:30-8:55 ８階　医局

  2. Primary Prevention of Type 2 Diabetes Mellitus ● Life style modification ・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 (Kuzuya, on going) ・Stockholm Diabetes Prevention Program (Bjärås, on going) ● Drug intervention ・Diabetes Prevention Program (DPP Research Group, 2002) ・STOP-NIDDM (Chiasson, 2002) ・TRIPOD (Buchanan, 2001) ・EDIT (Holman, 2003) ・NAVIGATOR (on going) ・DREAM (Boche, 2006) ・ACT NOW (DeFronzo，2008) ・ONTARGET (ONTARGET group, 2008) 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

  3. Prevention of Diabetes Mellitus ONTARGET 2008 4.7 ARB 399 8542 10.0 ACEI 366 8576 9.2 ONTARGET 2008 4.7 ARB+ACEI 323 8502 8.1 ACEI 366 8576 9.2 TRANSCEND 2008 4.7 ARB 319 2954 26.4 placebo 395 2972 28.8 Kyoto Heart 2009 3.27 ARB+x 58 1116 51.6 x 86 998 76.7 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 ACTNOW 2008 4.0 Pioglitazone 10 303 8.3 Placebo 45 299 37.6 松田昌文：DREAM study 内分泌・糖尿病科 26(1):35-41, 2008.

  5. Lancet 2008; 371: 1783–89

  6. 糖尿病予防研究　（米国） 31%less 58%less 各群約1000人

  7. 糖尿病予防研究　（米国） 追跡期間中におけるメタボリックシンドローム累積発症率 60 17%less 45 41%less 累積発症率 30 15 各群約500人

  8. Months –1 0 6 12 18 24 30 36 60 ITT Placebo t.i.d. (n=715) Placebon=1,429 3 months placebo STOP-NIDDM Placebo Acarbose 100mg t.i.d. (n=714) Primary endpoint – time to develop diabetes 1 2 3 4 5 6 7 8 9 10 11 12 13 14visits Reduction in incidence of type 2 diabetes in IGT patients receiving acarbose vs placebo Based on one positive OGTT Based on two consecutive positive OGTTs 35.8% 24.8% (p=0.0017) (p=0.0015) Average treatment duration 3.3 years Chiasson JL et al. Lancet 2002

  9. The HR was 0・577 (two-sided 95% CI 0・404–0・825; p=0・0026), verifying the efficacy of voglibose compared with placebo and, accordingly, the Independent Data Monitoring Committee made the decision to terminate the study early. The HR was 0・595 (95% CI 0・433–0・818), showing that voglibose-treated individuals had a 40・5% lower risk of developing type 2 diabetes than did placebo-treated individuals (p=0・0014) Figure 2: Effect of voglibose and placebo on the cumulative probability of individuals developing type 2 diabetes (Kaplan–Meier method)

  10. Figure 3: • Effect of voglibose and placebo on the cumulative probability of individuals developing type 2 diabetes based on the number of risk factors (Kaplan–Meier method) • At most two risk factors. • At least three risk factors. the difference was not significant in individuals with at most two risk factors (9 vs 19 cases, 0・544, 0・258–1・147; p=0・1098). Voglibose was associated with a 39・3% risk reduction (HR 0・607, 95% CI 0・428–0・863; p=0・0053)

  11. Kawamori. R. et al. ：Lancel.373：1607, 2009.

  12. アクトスの糖尿病発症予防効果（PIPOD Study） （%） 60 プラセボ群（TRIPOD） 累積糖尿病発症率 40 トログリタゾン群（TRIPOD） 20 ピオグリタゾン群（PIPOD） 年間発症率：4.6%/年 0 0 1 2 3 4 5 （年） 観察期間 妊娠糖尿病既往例におけるトログリタゾンの糖尿病発症予防効果を検討したTRIPOD Studyのうち、試験中止後、糖尿病を発症していなかった89例を対象に3年間にわたるアクトス（45mg/日）の糖尿病発症予防効果をみた。 Buchanan T. et al.: 65th ADA Scientific Sessions,2005.

  13. ACTos NOW Study for the Prevention of Diabetes （ACT NOW） Study 試験対象者の内訳 スクリーニング（1,850例） IGT*（602例） IFG/IGT（407例） Isolated IGT（195例） IGT（ Impaired glucose tolerance）：1回のOGTTにより2時間血糖値が140～199mg/dLを示す アクトスの効能･効果は2型糖尿病です De Fronzo R.A.：ADA 68th Scientific Sessions,2008,San Francisco.

  14. ACT NOW ～インスリン感受性への影響～ FSIVGTTによるSＩ Matsuda（0-120）index （%/分） 10 5 p<0.001 8 4 6 3 4 2 2 0 1 投与前 投与後 投与前 投与後 投与前 投与後 投与前 投与後 プラセボ ピオグリタゾン プラセボ ピオグリタゾン アクトスの効能･効果は2型糖尿病です IGT患者600例をアクトス45mg/日またはプラセボに割り付け、二重盲検下で2型糖尿病の発症を4年にわたり検討した。 De Fronzo R.A.：ADA 68th Scientific Sessions,2008,San Francisco.

  15. ACT NOW ～インスリン抵抗性に対する膵β細胞の代償能への影響～ AIR x SＩ I/G x Matsuda（0-120） p<0.005 6 p<0.005 1200 5 4 800 3 2 400 1 0 0 投与前 投与後 投与前 投与後 投与前 投与後 投与前 投与後 プラセボ ピオグリタゾン プラセボ ピオグリタゾン アクトスの効能･効果は2型糖尿病です IGT患者600例をアクトス45mg/日またはプラセボに割り付け、二重盲検下で2型糖尿病の発症を4年にわたり検討した。 De Fronzo R.A.：ADA 68th Scientific Sessions,2008,San Francisco.

  16. ACT NOW ～糖尿病発症抑制～ 0.3 NNT（1年間）＝3.5 6.8%/年 0.25 累積ハザード 0.2 プラセボ 0.15 0.10 1.5%/年 0.05 ピオグリタゾン 0 0 10 20 30 40 50 （ヵ月） 症例数 プラセボ 299 215 ピオグリタゾン 303 220 観察期間 アクトスの効能･効果は2型糖尿病です IGT患者600例をアクトス45mg/日またはプラセボに割り付け、二重盲検下で2型糖尿病の発症を4年にわたり検討した。 De Fronzo R.A.：ADA 68th Scientific Sessions,2008,San Francisco.

  17. Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852, USA www.thelancet.com Published online October 29, 2009 DOI:10.1016/S0140-6736(09)61457-4

  18. Background and Aim In the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term. Funding National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

  19. Method All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5・7 years (IQR 5・5–5・8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727.

  20. Figure 1: Trial profile Screening and recruitment done in the Diabetes Prevention Program (DPP). OGTT=oral glucose tolerance test. ILS=intensive lifestyle intervention. m=month. *Includes 585 randomised to troglitazone before this treatment group was discontinued. †DPP enrolled participants during 3 years ending June, 1999. Participants had varying durations of DPP follow-up, dependent on their year of enrolment. ‡DPP participants who had not died or withdrawn consent as of Sept 1, 2002, were eligible. §Numbers of those examined in year 6 are lower than are those for the other years because the close of data for analysis occurred before all follow-up examinations were scheduled.

  21. Figure 1: Trial profile

  22. Table 2: Characteristics at DPPOS baseline examination

  23. 5 mmol/L = 90 mg/dl Table 2: Characteristics at DPPOS baseline examination

  24. Data are mean (SD) apart from triglycerides for which data are median (IQR), or number of participants (n). Data from the study baseline examination were stratified by presence of diabetes as of Sept 1, 2002. At enrolment to the Diabetes Prevention Program Outcomes Study (DPPOS), we identified significant differences between treatment groups for fasting plasma glucose, HbA1c, weight (overall and in men only) and body-mass index (BMI; overall and in each sex). We also noted significant differences between treatment groups in those without diabetes for fasting plasma glucose, systolic and diastolic blood pressure, HDL cholesterol, and triglycerides, and in those with diabetes for fasting plasma glucose and HDL cholesterol. Data were missing for 22 enrolled people who had no DPPOS baseline examination. Data were missing for additional people, in varying numbers, for some of the variables. ILS=intensive lifestyle intervention. HbA1c=glycosylated haemoglobin. Table 2: Characteristics at DPPOS baseline examination

  25. all aged 25–44 Weight changes for originally assigned treatment group since Diabetes Prevention Program (DPP) randomisation for (A) all participants, (B) those aged 25–44 years at randomisation, (C) 45–59 years, and (D) 60 years and older; and since enrolment in the present study for (E) all participants, (F) those aged 25–44 years, (G) 45–59 years, and (H) 60 years and older, including participants irrespective of whether they developed diabetes during follow-up. Webappendix p 2 shows numbers of those in every datapoint. Figure 2: Mean weight changes

  26. 45–59 years 60 years and older Weight changes for originally assigned treatment group since Diabetes Prevention Program (DPP) randomisation for (A) all participants, (B) those aged 25–44 years at randomisation, (C) 45–59 years, and (D) 60 years and older; and since enrolment in the present study for (E) all participants, (F) those aged 25–44 years, (G) 45–59 years, and (H) 60 years and older, including participants irrespective of whether they developed diabetes during follow-up. Web appendix p 2 shows numbers of those in every datapoint. Figure 2: Mean weight changes

  27. all aged 25–44 Development of diabetes since Diabetes Prevention Program (DPP) randomisation for (A) all participants, (B) those aged 25–44 years at randomisation, (C) 45–59 years, (D) and 60 years and older; and since enrolment in the DPPOS (Sept 1, 2002) for (E) all participants, (F) those aged 25–44 years at randomisation, (G) 45–59 years, and (H) 60 years and older. Web appendix p 6 shows numbers of participants remaining at risk of diabetes at every datapoint. Figure 3: Cumulative frequency of diabetes

  28. 45–59 years 60 years and older Development of diabetes since Diabetes Prevention Program (DPP) randomisation for (A) all participants, (B) those aged 25–44 years at randomisation, (C) 45–59 years, (D) and 60 years and older; and since enrolment in the DPPOS (Sept 1, 2002) for (E) all participants, (F) those aged 25–44 years at randomisation, (G) 45–59 years, and (H) 60 years and older. Web appendix p 6 shows numbers of participants remaining at risk of diabetes at every datapoint. Figure 3: Cumulative frequency of diabetes

  29. Figure 5: Fasting glucose, glycosylated haemoglobin, and antidiabetic drug use A=fasting glucose in mmol/L. B=HbA1c (%). C=use of antidiabetic drugs (%). All participants were included irrespective of whether they developed diabetes during follow-up. Study-assigned metformin is excluded from antidiabetic drug use. Information for each data point is shown in webappendix p 7.

  30. Results During the 10・0-year (IQR 9・0–10・5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4・8 cases per 100 person-years (95% CI 4・1–5・7) in the intensive lifestyle intervention group, 7・8 (6・8–8・8) in the metformin group, and 11・0 (9・8–12・3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5・9 per 100 person-years (5・1–6・8) for lifestyle, 4・9 (4・2–5・7) for metformin, and 5・6 (4・8–6・5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24–42) in the lifestyle group and 18% (7–28) in the metformin group compared with placebo.

  31. Conclusion During follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years.

  32. Message 糖尿病予防も早期介入がよい！

  33. the Diabetes Trials Unit (R.R.H., J.L.D., J.F.K., S.K.P.), Oxford Centre for Diabetes, Endocrinology and Metabolism (R.R.H., A.J.F., J.C.L., J.L.D., J.F.K., S.K.P.), and the Department of Primary Health Care and National Institute for Health Research School of Primary Care Research (A.J.F.), University of Oxford, Oxford; and the Department of Cardiovascular Sciences, University of Leicester, Leicester (M.J.D.) — both in the United Kingdom. N Engl J Med 2009;361:1736-47.

  34. Background Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited.

  35. Method In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin andsulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. This study is registered with ISRCTN51125379 as Current Controlled Trials.

  36. Figure 1. Enrollment and Outcomes.

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