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埼玉医科大学　総合医療センター　内分泌・糖尿病内科埼玉医科大学　総合医療センター　内分泌・糖尿病内科Department of Endocrinology and Diabetes, Department of Endocrinology and Diabetes,

Saitama Medical Center, Saitama Medical UniversitySaitama Medical Center, Saitama Medical University

松田　昌文松田　昌文Matsuda, MasafumiMatsuda, Masafumi

20092009 年年 1111 月月 55 日　日　 8:30-8:558:30-8:55８階　医局８階　医局

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.

● 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 ReaserachDREAM ： Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications

Primary Prevention of Type 2 Diabetes Mellitus

Prevention of Diabetes Mellitus

ONTARGET 2008 4.7 ARB 399 8542 10.0 ACEI 366 8576 9.2ONTARGET 2008 4.7 ARB+ACEI 323 8502 8.1 ACEI 366 8576 9.2TRANSCEND 2008 4.7 ARB 319 2954 26.4 placebo 395 2972 28.8Kyoto 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. 　

糖尿病予防効果

松田昌文： DREAM study 内分泌・糖尿病科 26(1):35-41, 2008. 　

ACTNOW 2008 4.0 Pioglitazone 10 303 8.3 Placebo 45 299 37.6

Lancet 2008; 371: 1783–89

58%less

31%less

糖尿病予防研究　（米糖尿病予防研究　（米国）国）

各群約各群約 10001000 人人

41%less

17%less

糖尿病予防研究　（米糖尿病予防研究　（米国）国）

各群約各群約 500500 人人

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

1515

6060

4545

3030

累積

発症

率累

積発

症率

Reduction in incidence of type 2 diabetes in IGT patients receiving acarbose vs placebo

Primary endpoint – time to develop diabetes ITT

Average treatment duration 3.3 years Chiasson JL et al. Lancet 2002

Based on onepositive OGTT

Based on two consecutive positive OGTTs

24.8%

(p=0.0015)

35.8%

(p=0.0017)

Placebo t.i.d. (n=715)

Acarbose 100mg t.i.d. (n=714)

–1 0 366 12 18 24 30 Months

1 2 3 4 5 6 7 8 9 1011 1213 14 visits

Pla

cebo

n=

1,4

29

Pla

ceb

o

60

3 m

ont

hs

pla

ceb

o

STOP-NIDDM

Figure 2: Effect of voglibose and placebo on the cumulative probability of individuals developing type 2 diabetes (Kaplan–Meier method)

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 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) (A)At most two risk factors. (B)At least three risk factors.

Voglibose was associated with a 39 ・3% risk reduction (HR 0 ・ 607, 95% CI 0 ・ 428–0 ・ 863; p=0 ・ 0053)

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).

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

プラセボ群（ TRIPOD ）

トログリタゾン群（ TRIPOD ）

ピオグリタゾン群（ PIPOD ）年間発症率： 4.6%/ 年

累積糖尿病発症率20

40

60（ %）

観察期間0 1 2 3 54 （年）

0

アクトスの糖尿病発症予防効果（ PIPOD Study ）

Buchanan T. et al.: 65th ADA Scientific Sessions,2005.

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。

スクリーニング（ 1,850 例）

IFG/IGT （ 407 例）

IGT* （ 602 例）

Isolated IGT （ 195 例）

ACTos NOW Study for the Prevention of Diabetes （ ACT NOW ） Study

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.

試験対象者の内訳

ACT NOW ～インスリン感受性への影響～

0

6

8

10

4

2

投与前投与後投与前投与後

Matsuda （ 0-120 ） index

p<0.001

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

FSIVGTT による S Ｉ


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。

1

4

5

2

投与前投与後投与前投与後プラセボピオグリタゾ

ン

（ %/ 分）

3

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～

0

3

4

5

6

2

1


I/G x Matsuda （ 0-120 ）

p<0.005

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

AIR x S Ｉ



0

800

1200

400


p<0.005

プラセボピオグリタゾン

症例数プラセボ 299 215ピオグリタゾン 303 220

観察期間10 20 40 50

0.3

0.25

0.2

0.15

0.10

0

300

ACT NOW ～糖尿病発症抑制～

（ヵ月）

累積ハ

ザー

ド

プラセボ

6.8%/ 年

1.5%/ 年

ハザード比 0.19

95%CI 0.09,0.39p 値 0.00001

アクトスの効能･効果は 2 型糖尿病です



NNT （ 1 年間）＝3.5

0.05ピオグリタゾン

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

Background and AimIn 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).

MethodAll 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.

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.

Figure 1: Trial profile

Table 2: Characteristics at DPPOS baseline examination


5 mmol/L = 90 mg/dl


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.

Figure 2: Mean weight changes

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.

all

aged 25–44

Figure 2: Mean weight changes

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.

45–59 years

60 years and older

Figure 3: Cumulative frequency of diabetes

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.

all

aged 25–44

Figure 3: Cumulative frequency of diabetes

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.

45–59 years

60 years and older

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.

ResultsDuring 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.

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.

Message

糖尿病予防も早期介入がよい！

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.

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

MethodIn this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea 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.

Figure 1. Enrollment and Outcomes.

N Engl J Med 2009;361:1736-47

Glycaemic targets and Insulin Injections

Fasting and pre-meal: 4.0-5.5 mmol/l (72-99 mg/dl)

Two-hours post meal: 5.0-7.0 mmol/l (90-126 mg/dl)

6 6 1212 624186 6 1212 624186 6 1212 62418

Biphasic

Basal

Prandial*

* Twice a day if required

N Engl J Med 2009;361:1736-47

Transition to a Complex Insulin Regimen

* Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia

708 T2DMon dual

oral agents

Add biphasic insulin*twice a day

Add prandial insulin*three times a day

R

First Phase

Add basal insulin*once (or twice) daily

Add prandial insulinat midday

Add basal insulinbefore bed

Second Phase

Add prandial insulinthree times a day

From one year onwards, if HbA1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added

N Engl J Med 2009;361:1736-47

Complex Insulin Regimens

Proportion eligible for a second type of insulin per protocol

Proportion taking two types of insulin

Figure 2. Primary and Secondary Outcomes at 3 Years.Panel A shows median levels of glycated hemoglobin in the three study groups, with a kernel-density plot of the distribution of values for patients in each group at 3 years, as compared with the distribution of values for all patients at baseline, shown in Panel B. Panel C shows mean body weight, with a kernel-density plot of the distribution of values for patients in each group at 3 years, as compared with the distribution of values for all patients at baseline, shown in Panel D. Panel E shows median insulin doses. Panel F shows the proportions of patients in the three study groups reporting grade 2 or grade 3 hypoglycemic events over time. The I bars indicate 95% confidence intervals.

Figure 3. Changes from Baseline to 3 Years in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight and the Rate of Hypoglycemia.

Panel A shows the mean (±SE) percentage changes in key outcome measures, with P values adjusted for baseline values (except hypoglycemia), study center, baseline glycated hemoglobin level, and type of oral antidiabetic therapy, where appropriate. Missing data were imputed with the use of a multiple-imputation technique.10 To convert values for glucose to millimoles per liter, multiply by 0.05551. Panel B shows the median number of hypoglycemic events per patient per year in the three groups. The I bars indicate 95% confidence intervals.

•The listed serious adverse events occurred in more than 1% of patients in any study group. Listed adverse events occurred in more than 10% of patients in any study group.

•NA denotes not applicable. † P values are for all comparisons.

N Engl J Med 2009;361:1736-47

Adverse Events

BiphasicN=235

PrandialN=239

BasalN=234

pvalue

Any serious event 105(44.7%)

79(33.1%)

78(33.3%)

0.011

Death from any cause 7(3.0%)

9(3.8%)

4(1.7%)

0.23

Cardiovascular death 4(1.7%)

9(3.8%)

1(0.4%)

0.002

Any adverse event 228(97.0%)

235(98.3%)

227(97.0%)

0.58

No significant differences were seen between groups in:

Serious adverse events occurring in more than 1% in any group

Non-serious adverse events occurring in more than 10% in any group

N Engl J Med 2009;361:1736-47

EQ-5D Quality of Life Scores at 3 Years

Biphasic: 0.76 (0.71 to 0.80)

Prandial: 0.77 (0.73 to 0.81)

Basal: 0.80 (0.77 to 0.83)

p=0.73

p=0.86

p=0.86

Winzorized mean±95% confidence interval

N Engl J Med 2009;361:1736-47

Overview of Main Results

Biphasic Prandial Basal

Median HbA1c level achieved + + +

HbA1c targets achieved + ++ ++

Mean SMBG level achieved + ++ ++

Fewer hypoglycaemic episodes ++ + +++

Less weight gain + + ++

Less increase in waist circumference

+ + ++

N Engl J Med 2009;361:1736-47

Summary

Three quarters of patients added a second insulin

Those commencing therapy with a basal or prandial insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin

Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain

These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding

a mealtime insulin if glycaemic targets are not met

ResultsMedian glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P = 0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P = 0.006) or in the basal group (43.2%, P = 0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P = 0.002). Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups.

Conclusion

Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin.

Message

基礎インスリン補充から。でも　結局　強化療法　４～５回打ちが　２型糖尿病でもよいはず。　ただし、強化療法を最初からガイドラインにどう入れるかはまだ慎重にという感じ。

この研究は NOVO 社がスポンサーなので他の社のインスリンでどうかは？

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