Metformin for Diabetes in Pregnancy Do the Cons
Metformin for Diabetes in Pregnancy Do the Cons Outweigh the Pros? N Wah Cheung Clinical Associate Professor, University of Sydney Director, Diabetes & Endocrinology, Westmead Hospital VMO Endocrinologist, Nepean Hospital
Metformin: Mechanism of Anti-Hyperglycaemic Effect • Reduced hepatic gluconeogenesis • Reduced insulin resistance • Increased GLP-1 • Reduced glucose absorption • Improved lipids • Reduced appetite? Central role of AMP Activated Protein-Kinase
Pregestational Diabetes: Guidelines
Pregestational Diabetes: Cochrane Review
Metformin and Pregnancy Observational Data Early reports of use from South Africa (Coetzee) Retrospective review of 118 women with T 2 DM or GDM 1966 -1991 But metformin subjects more obese Results not adjusted for Hb. A 1 c or reason for therapy Hellmuth, Diab Med 2000
Metformin and Pregnancy First Trimester Exposure and Major Malformations Meta-analysis • 32 treatment studies excluded • 8 studies analysed, 172 subjects • Includes PCOS studies Gilbert, Fert Steril 2006
Metformin and Pregnancy More Observational Data Retrospective review of 93 women with type 2 diabetes treated with metformin Hughes Diab Med 2006
Metformin and Pregnancy More Observational Data Retrospective review of 93 women with type 2 diabetes Protocol Metformin if obese, Glibenclamide if not. Combined Met/Glib, then conversion to insulin if glucose not controlled. Direct to insulin if FPG ≥ 8 mmol/L Ekpebegh Diab Med 2007
Metformin in Pregnancy GDM: Mi. G Study 733 women with GDM Randomised 363 Metformin 370 Insulin Up to 2500 mg daily Median 50 units/day 195 (54%) Metformin Alone 168 (46%) Supplementary Insulin Median 42 units/day 18 stopped 9 stopped 4 stopped 39 (11%) GI Side Effects Rowan, NEJM 2008
Metformin in Pregnancy GDM: Mi. G Study Rowan, NEJM 2008
Metformin in Pregnancy PCOS: Preg. Met Study 257 women with PCOS Randomised First trimester 136 Metformin 138 Placebo 2000 mg daily Primary Endpoints Neonatal Outcomes BW (kg) Caesarean Section Perinatal death 3550 (568) 3527 (615) 0. 75 21% 19% 0. 94 1 1 Vanky, JCEM 2010
Metformin and B 12 in Pregancy METFORMIN Median (IQR) NO METFORMIN Media (IQR) p -value Vitamin B 12 level in Pregnancy (pmol/L) 180 (130. 3 – 272. 3) 274. 5 (173. 3 – 352. 0) 0. 02 Time of measurement (weeks gestation) 15. 3 (7. 13 – 23. 0) 13. 5 (8. 75 – 21. 25) 0. 98 METFORMIN NO METFORMIN p -value 12/52 (23. 1%) 3/42 (7. 1%) 0. 037 Low B 12 Levels <130 pmol/L B 12 levels lower in women on Metformin prior to pregnancy Christie-David, ADS 2012
Metformin in Pregnancy Transplacental Passage Vanky, Fert Steril 2005
Implantation and Placentation
Pregnancy Medications Found to have Adverse Consequences 1970 s Indomethacin for threatened preterm labour • Clinical trials demonstrated effectiveness • 1993 NEJM: Increased patent ductus arteriosus, intracranial haemorrhage and necrotising eneterocolitis with indomethacin in very premature babies 1940 -1970 s Diethylstilboestrol to reduce adverse pregnancy outcomes • 1950 Clinical trial demonstrated ineffective but use continued • 1971 NEJM: Association between prenatal exposure to DES and vaginal clear cell carcinoma Could Metformin have long term effects on the offspring?
Metformin and Offspring PCOS Data All births Term births No difference in growth or motor-social development over 18 months Glueck, Hum Rep 2004
Metformin and Offspring MIG-TOFU Study – Follow-up of 318 mothers and offspring Maternal Data at 2 years post-partum Metformin Insulin p value Weight (kg) 87. 7± 26 82. 6± 24 0. 07 BMI 32. 6± 8. 5 31. 4± 8. 2 0. 19 Waist (cms) 102± 18 99. 4± 18 0. 22 Although women gained less weight with metformin during pregnancy, any weight benefit was lost by 2 years post-partum Rowan, Diabetes Care 2011
Metformin and Offspring MIG-TOFU Study Offspring Data at 2 years Metformin Insulin p value Weight (kg) 14. 3± 2. 1 14. 0± 2. 2 0. 18 Waist (cms) 50. 5± 3. 5 50. 1± 4. 0 0. 33 Upper arm circ (cms) 17. 2± 1. 5 16. 7± 1. 5 0. 002 Triceps skinfold (cms) 10. 1± 2. 0 9. 9± 2. 4 0. 5 Subscapular skinfold (cms) 6. 3± 1. 9 6. 0± 1. 7 0. 02 Biceps skinfold (cms) 6. 0± 1. 9 5. 6± 1. 7 0. 04 DEXA total fat (g) 2421± 1002 2274± 711 0. 37 Abdominal fat (g) 132± 73 131± 60 0. 92 Offspring had higher s. c. fat, no difference in central fat Rowan, Diabetes Care 2011
Metformin and Offspring Metformin Treatment in Pregnant PCOS Women Study RCT, randomised to Metforim 1 g bd vs placebo Follow-up at one year N=199 Maternal FU Data Metformin Placebo p value BMI 30. 6± 8. 1 27. 6± 6. 1 0. 004 BMI change from end of pregnancy -2. 1± 3. 6 -4. 1± 4. 9 0. 03 Metformin Placebo p value 10. 2± 1. 2 9. 7± 1. 1 0. 003 Offspring FU Data Weight (kgs) Metformin offspring heavier Carlsen, Pediatrics 2012
Metformin and Offspring Follow-up of RCT of Metformin for PCOS pregnancy 850 mg bd vs placebo, first trimester to delivery 25/37 children studied at age 7 -9 Metformin (N=11 -12) Placebo (N=11 -13) p value Weight (SDS) 1. 15± 0. 87 1. 10± 0. 56 0. 79 Height (SDS) 0. 75± 0. 77 0. 65± 0. 56 0. 89 Fat Mass (%) 26. 9± 5. 5 30. 7± 6. 7 0. 14 106± 6 101± 7 0. 05 Fasting glucose (mmol/L) 4. 93± 0. 31 4. 60± 0. 35 0. 04 HOMA-IR 0. 82± 0. 58 0. 61± 0. 63 0. 12 HOMA-β 51. 8± 30. 2 54. 6± 51. 2 0. 44 LDL-cholesterol (mmol/L) 2. 42± 0. 69 2. 99± 0. 46 0. 07 Systolic BP (mm. Hg) Bo, Scand J Clin Lab Inv 2012
Stimulation of AMP Kinase has Anti-proliferative Effects Viollet, Clin Sci 2012
Metformin and Cancer
AMP Activated Protein Kinase and Embryopathy Metformin ? ? Hyperglycaemia Oxidative Stress ↑AMPK ↓Pax-3 Cell Cycle Inhibition Apoptosis Neural Tube Defect Zabiha Birth Def Res 2010; Wu, Diabetologia 2012
Tartarin, Hum Repro 2012
Fetal Origins Hypothesis Normal Undernutrition Stress ↑IR ↓β-cell mass Glucose shunting to brain Predictive Adaptive Response A d u l t h o o d Normal w i t h Insulin Resistance Central Obesity Diabetes Phenotype Metformin Diabetes ↑β-cell mass ↓IR ↑Adiposity Fuel-mediated Teratogenesis n u t r i t i o n a l e x c e s s Defective Insulin Response What is the Diabetes Phenotype Predictive Adaptive Response? ?
Pros/Cons of Metformin vs Insulin Metformin Insulin Oral Injection Favourable weight effect during pregnancy Weight gain during pregnancy Weight benefit lost post-partum No hypoglycaemia as sole therapy Risk of hypoglycaemia Likelihood of needing insulin anyway Nausea/diarrhoea Cheap More expensive (equipment, training) Transplacental transfer Negligible transplacental transfer Fetal programming effect? Fetal programming unlikely Patient acceptability?
Patient Acceptability: Mi. G Study Rowan, NEJM 2008
Pregnancy and use of Metformin Abrupt deterioration of glycaemic control, particularly in the first trimester, is clearly associated with adverse fetal outcomes. To date evidence is that Metformin does not result in immediate adverse pregnancy outcomes. However there is exposure early in pregnancy and it crosses the placenta. Its potential long-term effect on the offspring is unknown. FIRST DO NO HARM. Metformin does not necessarily remove the need for insulin, and insulin is generally acceptable to patients
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