Oral glucose lowering agents in gestational diabetes. Yes: E. Sobngwi (Cameroon) No: A. Vambergue (France)

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1 Oral glucose lowering agents in gestational diabetes Yes: E. Sobngwi (Cameroon) No: A. Vambergue (France)

2 CONTROVERSIES Oral glucose lowering agents in gestational diabetes «NO» Pr Anne VAMBERGUE Department of Diabetology and Endocrinology, Claude Huriez Hospital Department of Obstetric, Jeanne de Flandre Hospital CHRU Lille, FRANCE

3 BACKGROUND Subcutaneous insulin therapy has been the mainstay of treatment of women with GDM not controlled by diet modification, but it is expensive and inconvenient. Several authoritative randomized clinical trials (RCTs) and reviews show that oral antidiabetic drugs (OADs) are as effective as insulin in terms of controlling hyperglycemia in patients with GDM, with similar maternal and neonatal outcomes, including studies on glyburide, metformin, and acarbose.

4 BACKGROUND Some previous traditional meta-analysis (TMA) has performed to compare the effects of OADs with insulin in achieving glycemic control. Zeng YC et al. Adv Med Sci. 2014;59(1): Su DF, Wang XY. Diabetes Res Clin Pr. 2014;104(3): Nevertheless, the effects of any of these OADs compared with another in management of GDM remains inconclusive due to lack of evidence from head-to-head RCTs.

5 Meta-analysis of 5 randomized controlled trials: 1270 patients Results: Average weight gains after enrollement were much lower in the metformin group (p=0.003) Incidence of pregnancy Induced hypertension was significantly less in the metformin group (p=0.02) but no significant reduction for the rate of preeclampsia. BUT : Average gestational ages at delivery were lower in the metformin group (p=0.02) Incidence of preterm birth was significantly more in metformin group (p=0.01, OR=1.74, 95%CI [ ] Incidence of requiring additional insulin to achieve euglycemia in metformin group : 46.3% Conclusions: Metformin is comparable to insulin in glycemic control. But metformin might have an unrecognized effet on the labor process in GDM Gui J, Liu Q, Feng L. PLoS One. 2013;8(5):e64585.

6 15 ARTICLES AND 2509 SUBJECTS Randomized controlled trials Women with GDM requiring drug treatment Information on one or more maternal and fetal outcome Published as a full paper

7 Forest plots of birth weight in the meta-analysis comparing glibenclamide and metformin with insulin or with each other in women with GDM Macrosomia: X2 Glibenclamide versus insulin: birthweight: mean difference 109g 95%CI [ ] Macrosomia: RR=2.62 ( ) Metformin versus glibenclamide: birthweight: mean difference -209 [-314 to -104] Macrosomia: RR=0.33 ( ) LGA : RR =0.44 ( 0.21 to 0.92)

8 Forest plots of any neonatal hypoglycaemia in the meta-analysis comparing glibenclamide and metformin with insulin or with each other in women with GDM Neonatal hypoglycaemia:x2 Glibenclamide versus insulin: Neonatal hypoglycaemia RR=2.04 ( )

9 Other primary outcomes in the meta-analysis comparing glibenclamide and metformin with insulin or with each other in women with GDM In metformin versus insulin, significance was reached for maternal weight gain (mean difference 1.14 kg ( 2.22 to 0.06)), gestational age at delivery (mean difference 0.16 weeks ( 0.30 to 0.02)), and preterm birth (risk ratio 1.50 (1.04 to 2.16)). In metformin versus glibenclamide, significance was reached for maternal weight gain (mean difference 2.06 kg ( 3.98 to 0.14). Treatment failure was higher with metformin than with glibenclamide.

10 Records identified through database searching (n=461) Not randomised controlled trials removed (n=121) Records screened (n=121) Full-text articles assessed for eligibility (n=25) 96 of records excluded based on abstract review: Review, irrelevant interventions, nonhuman studies Full-text articles excluded with reasons: 2 inappropriate interventions 4 meta-analysis 3 included no GDM population Studies included in quantitative synthesis (meta-analysis) (n=18)

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12 Glibenclamide is clearly inferior to both insulin and metformin whereas metformin (plus insulin when required) performs slightly better than insulin.

13 GLYBURIDE: PLACENTAL TRANSPORT AND TERATOGENICITY The maternal-to-fetal transport of second generation sulfonylureas (glyburide) is significantly lower than the first-generation drugs (chlorpropamide and tolbutamide). (a method with a detection limit 10 ng/ml). Elliott BD et al. Am J Obstet Gynecol. 1994;171: BUT. Umbilical cord plasma glyburide concentrations averaged 70% of maternal concentrations. Diverging results to the use of a method with a detection limit of 0.25 ng/ml. Hebert MF et al. Clin Pharmacol Ther. 2009;85: Glibenclamide taken during pregnancy takes longer to reach peak concentration and is metabolized more rapidly than glibenclamide taken in the non-pregnant state. Earlier administration in relation to a meal, alteration in dosing, and pre-meal rather than once a day dosing may enhance the performance of this drug. Caritis SN et al. Obstet Gynecol 2013;121: We can speculate that maternal to fetal transfer of glibenclamide is the most likely explanation for the higher birth weight and risk ratios of macrosomia and neonatal hypoglycaemia observed in the glibenclamide group.

14 METFORMIN: PLACENTAL TRANSPORT Metformin has been shown to pass freely across the placenta. Two in vivo studies measured maternal and cord blood samples in women taking metformin throughout pregnancy (850 mg twice daily in 15 women and 2,000 mg/day in 8 women). The results of these trials showed that the fetus is exposed to concentrations as high or higher than those seen in the mother. Vanky E et al. Fertil Steril 2005;83: Charles B et al. Ther Drug Monit 2006;28:67-72

15 METFORMIN: TERATOGENICITY Little randomized evidence is available evaluating the use of OAAs in women with pre-existing diabetes mellitus/impaired glucose tolerance. So, regarding teratogenicity, data is available from non-randomized studies primarily from two groups of women during pregnancy: pregnant women with polycystic ovary syndrome and pregnant women with diabetes, both pre-gestational and gestational diabetes. The development of congenital anomalies that did occur in these studies was attributed to the presence of hyperglycemia during organogenesis and not to metformin itself. Therefore, metformin is not considered teratogenic. BUT.. Refuerzo JS. Clin North Am 2011;38:

16 Aim of this study: Investigation of the effect of metformin administered during pregnancy on the development and function of the fetal testis. Methods: a dual approach in vitro and in vivo using human and mouse models was chosen. Cultures of human and murine organotypic testes were made and in vivo embryonic testes were analysed after oral administration of metformin to pregnant mice. Results: In human and mouse organotypic cultures in vitro, Metformin decreased testosterone secretion Metformin decreased mrna expression of the main factors involved in steroid production. Human Reproduction, Vol.27, No.11 pp , 2012

17 RESULTS IN VIVO A reduction of the testicule size of the fetal and neonatal testes. A reduction of Sertoli cells in both period (fetal and neonatal period) A reduction of the nurse cells of germ cells in both period (fetal and neonatal period) A reduction of the Leydig population (which produce androgens) and the testosterone content in the fetal period.

18 Aim of this study: Investigation of the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice. Methods: Metformin or vehicule was administrated orally to dams during the gestation. Body weight development and several metabolic parameters were monitored both during regular diet and hight fat diet. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Glut4 mrna and Insig-1 (hepatic gene) expression were analysed in liver and fat tissue. Plos One, 2013

19 Results: Metformin exposed fetuses were lighter at birth Metformin exposed offspring gained more body weight and mesenteric fat during the high fat diet. The male offspring had impaired glucose tolerance and elevated fasting glucose during the high fat diet. The expression of GLUT4 mrna was down regulated in epididymal fat in male offspring prenatally exposed to metformin. The expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Prenatal exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice Plos One, 2013

20 CONCLUSIONS Oral agents are increasingly used to treat GDM, and current guidelines consider their use even though information on their safety is limited. BUT.. For maternal and neonatal outcome: Glibenclamide is clearly inferior to both insulin and metformin. Metformin is associated with a higher rate of preterm delivery. The providers should communicate to the women that there are no data available on the longterm health of the offspring s exposure to glyburide or metformin, as the safety aspects of these oral hypoglycemic drugs are limited to the prenatal period. We therefore need more randomized control trials to provide more information on the longterm follow up on neonatal function, metabolic syndrome and cognitive development.

21 Thank you for your attention