Therapy for gestational diabetes mellitus—time for a change? Peter Damm and Elisabeth R. Mathiesen Refers to Balsells, M. et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ doi:10.1136/bmj.h102

For >30 years, insulin has been the drug of choice for the medical treatment of gestational diabetes mellitus. However, the use of oral hypoglycaemic agents has increased during the past 1–2 decades, so a recent comparison of treatment with glibenclamide, metformin or insulin in women with gestational diabetes mellitus is highly relevant. The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide and affects 1–28% of all pregnancies depending on the ethnic and geographic populations studied and the diagnostic criteria used.1 In a new and carefully performed systematic review and meta-analysis,2 Balsells and coworkers investigated the short-term effects of the two most commonly used oral hypoglycaemic agents (OHA)—g­libenclamide and metformin—as well as insulin, in women with GDM. They concluded that glibenclamide is inferior to both metformin and insulin, whereas metformin (often with added insulin) performs slightly better than insulin alone. Hyperglycaemia in pregnancy is associated with maternal, fetal and neonatal morbidity 3 and treatment of GDM is feasible, efficient and necessary.4,5 The first step in treatment is lifestyle counselling that includes advice on diet and physical activity. However, medical treatment is necessary in ~10–30% of women with GDM, depending on the population and treatment goals. Traditionally, insulin has been the drug of choice for these patients, as it has been used safely and effectively for many years in pregnant women with pre-existing diabetes mellitus and does not normally cross the placen­tal barrier. Using OHA to treat women with GDM has gained a lot of interest in the past 1–2 decades as these drugs are inexpensive, easy to use and more patient-friendly than insulin. That the short-term effects of three different initial medical treatment strategies have been compared in the systematic

review and meta-analysis by Balsells and colleagues is therefore highly interesting.2 The study is based on a thorough literature search that only included randomized controlled trials. Three different comparisons were made: glibenclamide versus insulin; metformin versus insulin; and metformin versus glibenclamide. The review, based on 15 randomized controlled trials, highlights our current knowledge of treating women with GDM, as well as the gaps in this understanding. Seven studies on glibenclamide versus insulin, including ~400 women in each treatment group, showed that treatment with glibenclamide was associated with increased birth weight (average ~109.0 g), a more than twofold increased risk of macro­ somia (birth weight >4.0 kg) and a more than twofold increased risk of neonatal

hypoglycaemia compared with initial treatment with insulin (Table 1). Additional adverse effects were reported in 6% of the women receiving glibenclamide and 6% of the women in this treatment group needed supplementary insulin treatment. Six studies on metformin versus insulin included ~680 women in each treatment group. Compared with insulin, treatment with metformin resulted in lower gestational weight gain (average 1.14 kg), lower gestational age at delivery (by an average 0.16  weeks) and 50% increased risk of preterm deliveries; however, birth weights were similar. Additional adverse effects, mainly gastrointestinal discomfort, were reported in 2–46% of the women receiving metformin and 34% needed supplementary insulin. For secondary outcomes, the metformin group had slightly lower postprandial blood levels of glucose (average difference of 0.14 mmol/l), a 50% reduced risk of pregnancy-induced hypertension and a 40% reduced risk of severe neonatal hypoglycaemia compared with the insulin treatment group. Women treated with metformin had a higher prepregnancy BMI than women who received insulin (average difference of 0.78 kg/m2). This observation indicates that if the two groups had had similar BMIs, the differences in some outcomes (such as birth weight and hypertensive complications) between the two groups might have been more in favour of the metformin group. However, gestational weight gain is known to decrease with increasing BMI so

Table 1 | Main results from Balsells et al.2 Treatment comparison


Difference between treatments

Glibenclamide versus insulin

Birth weight (g)

+109.0 (35.9–181.0)

Macrosomia (birth weight >4 kg)

RR 2.62 (1.35–5.08)

Neonatal hypoglycaemia

RR 2.04 (1.30–3.20)

Gestational weight gain (kg)

–1.14 (–2.22 to –0.06)

Birth weight (g)

–31.4 (–86.5 to 23.6)

Gestational age at delivery (weeks)

–0.16 (–0.30 to –0.02)

Preterm delivery

RR 1.50 (1.04–2.16)

Gestational weight gain (kg)

–2.06 (–3.98 to –0.14)

Birth weight (g)

–209 (–314 to –104)

Macrosomia (birth weight >4 kg)

RR 0.33 (0.13–0.81)

Metformin versus insulin

Metformin versus glibenclamide

Pooled mean difference or pooled risk ratios between treatments are given with 95% confidence intervals.


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NEWS & VIEWS the effect of metformin might have been overestimated with respect to this outcome. The analysis only included two studies that compared metformin with gliben­ clamide, with ~175 women in each treatment group. Metformin treatment was associated with lower gestational weight gain (average difference of 2.06 kg), lower birth weight (average difference of 209.0 g) and fewer neonates with macrosomia than treatment with glibenclamide. The need for supplementary insulin treatment was reported in 27% on the women who received metformin and 24% of the women in the glibenclamide group.


…very little is known about the long-term consequences of using OHA in pregnancy...


The study by Balsells et al.2 is well performed and updates our knowledge in the field—time will show if the results will change clinical practice in favour of OHA. In our experience, the choice of glibenclamide, metformin or insulin as treatment for GDM is partly based on tradition, economic considerations, ease of access to insulin, patient compliance and concerns about unknown long-term consequences. Consequently, as far as we know, OHA are used frequently in some centres and countries and almost not at all in others. The use of OHA, particularly metformin, is convenient, patient-friendly and has short-term perinatal outcomes that seem to be largely similar to those of insulin treat­ ment. Deciding which outcomes are most important might be difficult (that is, reduced maternal gestational weight gain versus more preterm births) or which adverse effects are most tolerable (maternal gastrointestinal discomfort versus increased risk of neonatal hypoglycaemia). The fact that approximately one-third of women treated with OHA will need supplemental insulin can also influence the decision of whether or not to use OHA. Furthermore, very little is known about the long-term consequences of using OHA

in pregnancy, for the offspring in particular but also for the mother. Currently, when we are very aware of the long-term adverse effects of intrauterine exposure to various substances, such as glucose, 6 we have to be concerned about the effect of potent drugs passing through the placental bar­ rier. Metformin is easily transferred across the placen­tal barrier, which results in fetal concentrations close to the maternal level, and although the transplacental passage of glibenclamide has previously been considered negligible, this viewpoint has been questioned in the past few years.2 Both OHA drugs are potent and might induce epi­ genetic changes in the fetus that could lead to obesity or diabetes mellitus later in life. In a 2‑year follow-up of offspring from the Metformin in Gestational Diabetes Trial,7 children of mothers treated with metfor­min had more subcutaneous fat on the shoulder and upper arm regions than off­spring of mothers who only received insulin.8 A 1‑year follow-up of women and their offspring from a randomized controlled trial of women with polycystic ovary syndrome treated with or with­out metformin during pregnancy9 found that although individuals in the metfor­min group gained less weight during pregnancy, they had a higher BMI 1 year postpartum than those who did not receive metformin. Furthermore, at 1 year old, the offspring in the metformin group were considerably heavier than those in the no metformin group (average differ­ ence of 0.5 kg). In another similar, but smaller, study from the same authors, fast­ ing levels of glucose were increased (aver­ age 0.33 mmol/l) in 8‑year-old offspring of women treated with metformin.10 On the basis of the present evidence on possible short-term and long-term consequences of using OHA to treat women with GDM, we do not recommend routine use of OHA in these women. However, as always in medicine, the doctor and the patient should, in close collaboration, choose the best available treatment taking the many pros and cons into consideration.


Center for Pregnant Women with Diabetes 4001, Departments of Obstetrics and Endocrinology, Rigshospitalet, The Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, DK‑2100 Copenhagen, Denmark (P.D., E.R.M.). Correspondence to: P.D. [email protected] doi:10.1038/nrendo.2015.54 Published online 7 April 2015 Competing interests P.D. and E.R.M. are participating in a multicentre, multinational observational study of the use of injectable hypoglycaemic agents in pregnant women with type 1 diabetes mellitus and type 2 diabetes mellitus in collaboration with Novo Nordisk. P.D. has received fees for giving talks for Novo Nordisk. E.R.M. has received fees for giving talks for Novo Nordisk, Sanofi-Aventis and Eli Lilly, E.R.M. has received a research grant from The Novo Nordisk Foundation. 1.

Jiwani, A. et al. Gestational diabetes mellitus: results from a survey of country prevalence and practices. J. Matern. Fetal Neonatal Med. 25, 600–610 (2012). 2. Balsells, M. et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 3. HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N. Engl. J. Med. 358, 1991–2002 (2008). 4. Crowther, C. A. et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N. Engl. J. Med. 352, 2477–2486 (2005). 5. Landon, M. B. et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N. Engl. J. Med. 361, 1339–1348 (2009). 6. Clausen, T. D. et al. High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 31, 340–346 (2008). 7. Rowan, J. A. et al. Metformin versus insulin for the treatment of gestational diabetes. N. Engl. J. Med. 358, 2003–2015 (2008). 8. Rowan, J. A. et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34, 2279–2284 (2011). 9. Carlsen, S. M., Martinussen, M. P. & Vanky, E. Metformin’s effect on first-year weight gain: a follow-up study. Pediatrics 130, e1222–e1226 (2012). 10. Rø, T. B., Ludvigsen, H. V., Carlsen, S. M. & Vanky, E. Growth, body composition and metabolic profile of 8‑year‑old children exposed to metformin in utero. Scand. J. Clin. Lab Invest. 72, 570–575 (2012). © 2015 Macmillan Publishers Limited. All rights reserved

Diabetes: Therapy for gestational diabetes mellitus--time for a change?

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