Transcript Metformin and Pregnancy

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
T2DM or GDM
1966-1991
But metformin subjects more obese
Results not adjusted for HbA1c 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 ≥8mmol/L
Ekpebegh Diab Med 2007
Metformin in Pregnancy
GDM: MiG 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: MiG Study
Rowan, NEJM 2008
Metformin in Pregnancy
PCOS: PregMet 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 B12 in Pregancy
METFORMIN
Median (IQR)
NO METFORMIN
Media (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
12/52
(23.1%)
3/42
(7.1%)
0.037
Low B12 Levels
<130 pmol/L
B12 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
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 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 1g 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 (mmHg)
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?
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