Metformin versus Insulin for the Treatment of Gestational Diabetes Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D. N Engl J Med 2008;358:2003-15. R2 Jang Jeong Yoon / Prof. Jun Suck N Engl J Med 2008;358:2003-15

Background Gestatianl DM : about 5% complication of pregnancies If maternal hyperglycemia persists, treatment with additional insulin have been shown to improve perinatal outcomes. - Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477-86. Use insulin : associated with hypoglycemia, weight gain How about oral agent ? N Engl J Med 2008;358:2003-15

Background Metformin : improves insulin sensitivity, probably by activating AMP kinase, and is not associated with weight gain or hypoglycemia. Reported favorable outcomes: -Coetzee EJ, Jackson WP. Pregnancy in established non-insulin-dependent diabetics. S Afr Med J 1980;58:795-802. Hughes RCE, Rowan JA. Pregnancy in women with Type 2 diabetes: who takes metformin and what is the outcome? Diabet Med 2006;23:318-22. increased rates of perinatal loss and preeclampsia as compared with insulin treatment. - Hellmuth et al. Oral hypoglycaemic agents in 118 diabetic pregnancies Diabet Med 2000;17: 507-11. retrograde cohort study N Engl J Med 2008;358:2003-15

Purpose assess the efficacy and safety of metformin versus insulin use for GDM N Engl J Med 2008;358:2003-15

Method- Design and Subjects Study Design : randomized, open-label trial comparing metformin with insulin treatment in 10 New Zealand and Australian urban obstetrical hospitals Study Subjects : 18 and 45 years of age ** Gestational diabetes mellitus : the criteria of the Australasian Diabetes in Pregnancy Society (ADIPS) - pregnant with a single fetus , 20 ~ 33 weeks of gestation age - usual criteria for starting insulin treatment, and, after lifestyle modification more than one capillary blood glucose > 5.4 mmol /L (97.2 mg /dL ) after an overnight fast > 6.7 mmol /L (120.6 mg /dL ) after 2-hour postprandial N Engl J Med 2008;358:2003-15

Method- Design and Subjects Exclusion criteria prepregnancy diagnosis of diabetes a contraindication to metformin a fetal anomaly gestational hypertension, preeclampsia fetal growth restriction, and ruptured membranes. the capillary glucose levels recommended by the ADIPS level after an overnight fast < 99mg/dL 2-hour postprandial level < 126 mg /dL Metformin or Diaformin 500mg  2500mg daily

Method-Data collection Demographic and clinical data Laboratory findings : liver, kidney function , Hb A1C, glucose glucose : fast , 2 -hours postprandial (MediSense meter ) At 36 to 37 weeks of gestation, after an overnight fast At delivery, complications of pregnancy, the indication for delivery, the mode of delivery, and neonatal complications were recorded. After the umbilical cord had been clamped, cord blood was collected for Serum insulin concentration N Engl J Med 2008;358:2003-15

Methods -Study Outcomes primary outcome was a composite of neonatal complications : maternal hyperglycemia , directly influenced by the passage of metformin across the placenta - Neonatal hypoglycemia . - respiratory distress , need for phototherapy, birth trauma , - 5-minute Apgar score < 7 , premature birth (<37 weeks of gestation) Maternal hypertensive complications Birth-weight percentiles Neonatal anthropometric measurements : crown–heel length, abdominal circumference,etc. N Engl J Med 2008;358:2003-15

Methods -Study Outcomes Secondary outcome : maternal and neonatal body composition maternal glycemic control maternal hypertensive complications maternal glucose tolerance at 6 to 8 weeks post partum acceptability of treatment N Engl J Med 2008;358:2003-15

Results- Study Subjects

Metformin or Diaformin 500mg 2500mg 1-2 weeks 46.3% stopped metformin before delivery : 27 (7.4%) N Engl J Med 2008;358:2003-15 11

The baseline characteristics of the two groups were similar

Results- Study Subjects The median daily dose of metformin : 2500 mg supplemental insulin, the median maximum daily dose of insulin was 42 units : lower than the maximum daily dose in those assigned to insulin (50 units) (P = 0.002). Supplemental insulin was started at a median of 20.4 days

Results- Study Outcomes < ccording to indication for preterm birth, the frequency of iatrogenic preterm births was similar in both treatment groups, but there was a trend toward more spontaneous preterm births (spontaneous labor or preterm ruptured membranes) in the metformin group There was a statistically significant but clinically small difference in the mean gestational age at delivery between the metformin group (38.3 weeks) and the insulin group (38.5 weeks, P = 0.02). >

> < There was a statistically significant but clinically small difference in the mean gestational age at delivery between the metformin group (38.3 weeks) and the insulin group (38.5 weeks, P = 0.02). There were no significant differences between the groups in neonatal anthropometric measures or measurements of umbilical-cord serum insulin concentrations. > <

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Reaults- Metformin Treatment and Supplemental insulin As compared with metformin alone group, women requiring supplemental insulin had a higher BMI and had higher baseline glucose levels The rates of the primary outcome did not differ between women treated with metformin alone and those treated with supplemental insulin (29.7% and 34.5%, respectively; P = 0.33).

Conclusions Metformin, alone or with supplemental insulin, is not associated with increased perinatal complications as compared with insulin an effective and safe treatment option for women with gestational diabetes mellitus who meet the usual criteria for starting insulin, and that metformin is more acceptable to women with gestational diabetes mellitus than is insulin.

Metformin stop stopped in 27 women (7.4%) before delivery - 11 (accordance with the protocol )  9 obsterical Complication 1 sepsis 1 worsening of LFT - 7 women (1.9%) because of gastrointestinal side effects - 5 women chose to stop metformin - 4 women were advised to stop by other health professionals who were not involved in the trial. doses were reduced because of gastrointestinal side effects in 32 women (8.8%); all but 1 of these women were able to maintain a dose of at least 1000 mg per day.

Universal versus selective screening by blood test ADIPS ACOG   Universal versus selective screening by blood test Universal unless low GDM incidence or resources limited No recommendation. States that "many physicians elect to screen all pregnant patients as a practical matter" Differences in definition of low risk for GDM Age < 30 years, obesity, family history of diabetes Age < 25 years, body mass index < 25 kg/m2. No known diabetes in first-degree relative Oral glucose tolerance test used 75 g, 2-hour, 2-point blood sampling 100 g, 3-hour, 4-point blood sampling Criteria for diagnosis of GDM Plasma glucose level: Fasting, ≥ 5.5 mmol/L (99mg/dL) and/or 2-hour, ≥ 8.0 mmol/L (144mg/dL) Plasma glucose level: Fasting, ≥ 5.3 mmol/L; 1-hour, ≥ 10.0 mmol/L 2-hour, ≥ 8.6 mmol/L; 3-hour, ≥ 7.8 mmol/L; (2 or more time points need to elevated) Insulin therapy commenced after medical–nutrition therapy and/or 1-hour postprandial, ≥ 8.0 mmol/L (144mg/dL) and/or 2-hour postprandial, ≥7.0 mmol/L (126mg/dL) Plasma glucose level: Fasting, ≥ 5.3 mmol/L and/or 1-hour postprandial, ≥ 7.2–7.8 mmol/L and/or 2-hour postprandial, ≥ 6.7 mmol/L

: neonates were monitored for hypoglycemia by measuring blood glucose levels within 2 hours after birth and before each feed feeding until consecutive glucose values < 2.6 mmol/L (46.8 mg /dL )