Gestational Diabetes: The Treatment Controversy Rages On

Christine Kilgore

January 31, 2020


WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a "reasonable and safe first-line" alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there's one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that "the primary concern" about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

"The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations]," said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and "the superiority of insulin over oral agents simply remains questionable."

ACOG's 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of "poor trial quality," and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG's committee on practice bulletins, said in an interview. "Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment."

In its 2017 and 2018 bulletins, ACOG said that metformin is a "reasonable alternative choice" for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. "Insurance companies aren't always covering [insulin]," said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. "It's a challenge – no question."

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, "because, in most studies, it does not yield outcomes equivalent to insulin or metformin," Dr. Turrentine emphasized.

Glyburide's role

Dr. Landon took issue with ACOG's stance on the sulfonylurea. "Frankly, I think this [conclusion] is debatable," he said. The trend in the United States – "at least after the 2017 ACOG document came out" – has been toward use of metformin over glyburide when an oral agent is [used], but "I think glyburide has been unfairly trashed. It probably still has a place."

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which "had become the number one agent" after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, "this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous," said Dr. Landon. "There are real problems with this and other meta-analyses."

That increase, Dr. Landon said, was "not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%." The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide's role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient's GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study's principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the "seminal" Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk "was all driven by the Rowan study," Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. "But this is a classic half-full, half-empty [phenomena]," Dr. Landon said. "Some people say this isn't good, but on the other hand, 54% avoided insulin."

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in "more than half" of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society's view, recent meta-analyses and systemic reviews "support the efficacy and safety of oral agents," and "although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited."

The society says that the difference between its statement and the ACOG recommendations is "based on the values placed by different experts and providers on the available evidence," and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is "a little more forgiving" in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. "The professional organizations don't make it easy for [us]," he said. At this point, "insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM."

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have "unknown fetal programming effects," and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are "clearly needed," Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan's MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on "both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects" (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

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