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 2008 年５月 22 日 8:20-8:50 B 棟８階 カンファレンス室

3. Original Article Hyperglycemia and Adverse Pregnancy Outcomes The HAPO Study Cooperative Research Group Boyd E. Metzger, M.D., Lynn P. Lowe, Ph.D., Alan R. Dyer, Ph.D., Northwestern University Feinberg School of Medicine, Chicago; Elisabeth R. Trimble, M.D., Queen’s University Belfast, Belfast, Northern Ireland; Udom Chaovarindr, M.D., Rajavithi Hospital, Bangkok, Thailand; Donald R. Coustan, M.D., Women and Infants’ Hospital of Rhode Island–Brown University Medical School, Providence, RI; David R. Hadden, M.D., David R. McCance, M.D., Royal Jubilee Maternity Hospital, Belfast, Northern Ireland; Moshe Hod, M.D., Helen Schneider Hospital for Women, Rabin Medical Center–Sackler Faculty of Medicine, Tel-Aviv University, Petah- Tiqva, Israel; Harold David McIntyre, M.B., B.S., Jeremy J.N. Oats, M.D., Mater Misericordiae Mothers’ Hospital–University of Queensland, Brisbane, Australia; Bengt Persson, M.D., Ph.D., Karolinska Institute, Stockholm, Sweden; Michael S. Rogers, M.D., Prince of Wales Hospital–Chinese University of Hong Kong, Hong Kong; and David A. Sacks, M.D., Kaiser Foundation Hospital, Bellflower, CA N Engl J Med Volume 358(19):1991-2002 May 8, 2008

4. Gestational diabetes is also diagnosed based on plasma glucose values measured during the OGTT. Blood glucose levels are checked four times during the test. If your blood glucose levels are above normal at least twice during the test, you have gestational diabetes. Table shows the above-normal results for the OGTT for gestational diabetes. Table Gestational Diabetes: Above-Normal Results for the Oral Glucose Tolerance Test WhenPlasma Glucose Result (mg/dL) Fasting95 or higher At 1 hour180 or higher At 2 hours155 or higher At 3 hours140 or higher Gestational diabetes is also diagnosed based on plasma glucose values measured during the OGTT. Blood glucose levels are checked four times during the test. If your blood glucose levels are above normal at least twice during the test, you have gestational diabetes. Table 3 shows the above-normal results for the OGTT for gestational diabetes. Table 3. Gestational Diabetes: Above-Normal Results for the Oral Glucose Tolerance Test

5. Objective It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. We conducted the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study to clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than that in overt diabetes mellitus.

6. Characteristics of the Study Participants and Their Newborns and Frequency of Outcomes The HAPO Study Cooperative Research Group. N Engl J Med 2008;358:1991-2002 July 2000- April 2006 Screening n=53295 (15 centers in nine countries) 75g OGTT at 24-43 wks n=25505 On study: FPG <105mg/dl 2hPG < 200mg/dl n=23316 White: 48.3% Black: 11.6% Hispanic: 8.5% Asian: 2.6%

7. Frequency of Primary Outcomes across the Glucose Categories The HAPO Study Cooperative Research Group. N Engl J Med 2008;358:1991-2002 Category1234567 FPG74 or less 7984899499100 or more 1hPG105 or less132155171193211212 or more 2hPG90 or less108125139157177178 or more (mg/dl)

8. Adjusted Odds Ratios for Associations between Maternal Glucose as a Categorical Variable and Primary Outcomes The HAPO Study Cooperative Research Group. N Engl J Med 2008;358:1991-2002

9. Adjusted Odds Ratios for Associations between Maternal Glycemia as a Continuous Variable and Primary and Secondary Perinatal Outcomes The HAPO Study Cooperative Research Group. N Engl J Med 2008;358:1991-2002

10. Study Overview In this large, multinational study, glucose levels that were increased during pregnancy but were below levels diagnostic of diabetes were significantly associated with increased risks of birth weight above the 90th percentile and C-peptide levels above the 90th percentile, as well as with other adverse pregnancy outcomes These results indicate the need to reconsider current thresholds for diagnosing and treating hyperglycemia during pregnancy

11. Conclusion Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels

12. Editorial Until trials show clinical benefits from expanding expanding the diagnostic criteria for “gestational diabetes,” we would not favor any change.

14. Original Article Metformin versus Insulin for the Treatment of Gestational Diabetes Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D., Wanzhen Gao, Ph.D., Malcolm R. Battin, M.B., Ch.B., M. Peter Moore, M.B., Ch.B., for the MiG Trial Investigators N Engl J Med Volume 358(19):2003-2015 May 8, 2008

15. Background and Aim Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking. This open-label trial compared insulin with metformin (with supplemental insulin if required) for the treatment of gestational diabetes mellitus.

16. Enrollment of Subjects

17. Maternal Characteristics at Baseline

18. Primary Outcome and Additional Neonatal Complications

19. Secondary Outcomes and Additional Measurements

21. Adverse Events

22. Study Overview This open-label trial compared insulin with metformin (with supplemental insulin if required) for the treatment of gestational diabetes mellitus The rates of neonatal complications were similar in the two groups, and more women in the metformin group than in the insulin group reported that they would choose their assigned treatment again These results provide support for the use of metformin as initial treatment for gestational diabetes in women who require pharmacologic therapy

23. Conclusion In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin The women preferred metformin to insulin treatment

24. Editorial This noninferiority trial of 751 women showed that infants of mothers in the metformin group fared no worse than those in the insulin group. Unfortunately, maternal outcomes such as cesarean delivery were not reported, but birth weights were similar in the two groups. Not surprisingly, patients preferred pills to shots. The main question now is whether metformin is better or worse than glyburide, an acceptable alternative pill. Although the two oral agents have not been directly compared in trials, it is notable that in the Metformin in Gestational Diabetes Trial, 46% of subjects in the metformin group required supplemental insulin, whereas in the previous trial, only 4% of women treated with glyburide needed insulin.