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