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 for Diabetes in Pregnancy
Do the Cons Outweigh the Pros?
N Wah Cheung
Clinical Associate Professor, University of SydneyDirector, Diabetes & Endocrinology, Westmead HospitalVMO Endocrinologist, Nepean Hospital
Metformin: Mechanism ofAnti-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 PregnancyObservational Data
Retrospective review of 118 women with T2DM or GDM
1966-1991
But metformin subjects more obeseResults not adjusted for HbA1c or reason for therapy
Hellmuth, Diab Med 2000
Early reports of use from South Africa (Coetzee)
Metformin and PregnancyFirst 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 PregnancyMore Observational Data
Retrospective review of 93 women with type 2 diabetes treated with metformin
Hughes Diab Med 2006
Metformin and PregnancyMore 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 ≥8mmol/L
Ekpebegh Diab Med 2007
Metformin in PregnancyGDM: MiG Study
Randomised
9 stopped 4 stopped
39 (11%) GI Side Effects
Rowan, NEJM 2008
370 InsulinMedian 50 units/day
733 women with GDM
363 MetforminUp to 2500 mg daily
168 (46%)Supplementary Insulin
Median 42 units/day
195 (54%)Metformin Alone
18 stopped
Metformin in PregnancyGDM: MiG Study
Rowan, NEJM 2008
Vanky, JCEM 2010
Randomised
138 Placebo
257 women with PCOS
136 Metformin2000 mg daily
Metformin in PregnancyPCOS: PregMet Study
First trimester
Primary Endpoints
BW (kg) 3550 (568) 3527 (615) 0.75
Caesarean Section 21% 19% 0.94
Perinatal death 1 1
Neonatal Outcomes
Metformin and B12 in Pregancy
METFORMINMedian (IQR)
NO METFORMINMedia (IQR)
p -value
Vitamin B12 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
Low B12 Levels <130 pmol/L
12/52 (23.1%)
3/42 (7.1%)
0.037
B12 levels lower in women on Metformin prior to pregnancy
Christie-David, ADS 2012
Metformin in PregnancyTransplacental Passage
Vanky, Fert Steril 2005
Implantation and Placentation
Pregnancy Medications Found to have Adverse Consequences
1970s 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
1940-1970s 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 OffspringPCOS Data
All births Term births
No difference in growth or motor-social development over 18 monthsGlueck, 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
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
Metformin and Offspring
Offspring had higher s.c. fat, no difference in central fatRowan, Diabetes Care 2011
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
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
Metformin and Offspring
Metformin Treatment in Pregnant PCOS Women Study
RCT, randomised to Metforim 1g bd vs placebo
Follow-up at one year N=199
Maternal FU Data
Offspring 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
Weight (kgs) 10.2±1.2 9.7±1.1 0.003
Metformin offspring heavierCarlsen, Pediatrics 2012
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 and Offspring
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
Systolic BP (mmHg) 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
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
Systolic BP (mmHg) 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
Bo, Scand J Clin Lab Inv 2012
Stimulation of AMP Kinase hasAnti-proliferative Effects
Viollet, Clin Sci 2012
Metformin and Cancer
AMP Activated Protein Kinase and Embryopathy
↑AMPK ↓Pax-3Oxidative StressHyperglycaemia
Zabiha Birth Def Res 2010; Wu, Diabetologia 2012
Cell Cycle Inhibition Apoptosis
Neural Tube Defect
Metformin
??
Tartarin, Hum Repro 2012
Fetal Origins Hypothesis
↑β-cell mass
↑Adiposity
Normal UndernutritionStress
Diabetes Metformin
Normal Insulin ResistanceCentral Obesity
Diabetes Phenotype
A d u l t h o o d w i t h n u t r i t i o n a l e x c e s s
↓IR
Predictive AdaptiveResponse
↑IR
↓β-cell massGlucose shunting to brain
Fuel-mediated Teratogenesis
Defective Insulin ResponseDiabetes Phenotype
What is thePredictive 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?
Patient Acceptability: MiG 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