Oral antidiabetic agents in gestational diabetes: a narrative review of current evidence

Abstract

Gestational diabetes mellitus (GDM) classically occurs when maternal glucose metabolism is unable to compensate the progressive development of insulin resistance that arises from the continuously rising diabetogenic placental hormones. Although most women can be treated satisfactorily with diet alone, some require more intensive treatment. Insulin has been the most reliable treatment strategy in GDM over several decades. Although a long time has passed since the publication of two randomized controlled trials suggesting comparable efficacy and safety of metformin and glibenclamide, international bodies have not yet approved these oral agents. However, with the consistently emerging efficacy and safety data of these two drugs in the past decade, they may perhaps open a rather new door. The aim of this narrative review is to critically evaluate the existing evidence regarding safety and efficacy of oral drugs in GDM accumulated since the first publication in year 2000, suggesting clinical equivalency of glibenclamide (glyburide).

Keywords:

• acarbose
• gestational diabetes
• glibenclamide
• hypoglycemia
• maternal outcome
• metformin
• neonatal outcome
• teratogenicity

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Prevalence of gestational diabetes mellitus is increasing with the global rise of diabetes. Insulin is the gold standard and universally accepted modality of treatment in gestational diabetes mellitus since several decades when maternal nutritional therapy fails. Some newer insulin analogs such as lispro, aspart and detemir have also been currently upgraded to category B drug and may be a valuable addition.

• Nevertheless, insulin therapy has some potential perceived issues. Difficulties of storage in developing countries, proper education about its administration, multiple daily injections, potential for hypoglycemia and weight gain in mothers are some of the limiting factors and may be cumbersome for many pregnant patients.

• Glibenclamide is the only sulfonylurea which is currently placed under category B drug. It does not appear to cross the placenta on conventional dosage and therefore least likely to alter direct fetal-related outcomes. Several randomized controlled studies as well as observational studies suggested comparable maternal and neonatal outcomes to insulin. However, some studies hinted at higher macrosomia and higher neonatal hypoglycemia. These issues need to be further evaluated before glibenclamide can be considered as a safe alternative. Nonetheless, this agent would still play a significant role in some situations where insulin therapy has several logistic, social and financial issues.

• Metformin has emerged as a potential contender, owing to its clear advantage in terms of lower maternal weight gain and lower maternal hypoglycemia. Knowing the adverse impact of maternal weight gain to macrosomia and other neonatal outcomes, metformin use in GDM may have a clear edge. Moreover, its use from preconception until delivery in PCOS pregnancy yielding no teratogenic effect also reenforces its further safety. With the emerging safety and efficacy data, it appears that metformin could be a potential contender to insulin in the near future. However, it should be noted that failure rate with metformin is substantially higher, as seen across the studies, and the time lag until the start of insulin could possibly be hazardous for the fetus with a period of unintended hyperglycemia.