June 01, 2009
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Treatment for gestational diabetes: Is oral therapy better?

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A recent study in the New England Journal of Medicine showed that treatment with metformin when compared with treatment with insulin was not associated with increased perinatal complications in women with gestational diabetes. Women in the study also preferred metformin.

“The results are encouraging,” said James Lenhard, MD, medical director of Christiana Care Health System’s Diabetes & Metabolic Disease Center, Wilmington, Del. “However, the results of one study, even a well-done study such as this one, are not sufficient to prove that metformin use during pregnancy does not cause long-term effects in the neonate.”

The Metformin in Gestational Diabetes (MiG) Trial randomly assigned 751 women with gestational diabetes at 20 to 33 weeks gestation to open treatment with metformin (with supplemental insulin if required) or to insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, five-minute Apgar score <7 or prematurity.

The trial was designed to rule out a 33% increase (from 30% to 40%) in this composite outcome in infants of women treated with metformin compared with those treated with insulin. The results showed that 92.6% of the 363 women assigned metformin continued to receive the drug until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32% in the group assigned metformin and 32.2% in the group assigned insulin.

James Lenhard, MD
James Lenhard, MD, said study results of oral agents in gestational diabetes are promising but long-term data are lacking.

Photo by: Sam Trasatti

More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P<.001). The rates of other secondary outcomes did not differ between the two groups.

Rates of neonatal hypoglycemia, one component of the composite end point, were similar in the two groups, but severe hypoglycemia occurred significantly less often in the infants whose mothers had been assigned metformin.

Most importantly, researchers found no significant increase in a composite measure of neonatal complications among women with gestational diabetes who were randomly assigned metformin vs. those who were assigned insulin.

Supplemental insulin

“It is interesting to me that almost half of the women treated with metformin still required supplemental insulin to control their blood sugar level,” said Lois Jovanovic, MD, CEO and chief science officer at the Sansum Diabetes Research Institute in Santa Barbara, Calif.

Jovanovic was quick to point out that even though the study results showed the efficacy of oral treatment without affecting the placenta — a result repeated in previous trials — she was not surprised that women preferred metformin over insulin.

Lois Jovanovic, MD
Lois Jovanovic

“Women would prefer not to get injections; this is not rocket science,” Jovanovic said. She noted that when the treatment failed with metformin, participants were then assigned treatment with insulin.

“You are delaying treatment to the baby while you are trying this medication,” said Jovanovic, a member of Endocrine Today’s Editorial Board.

Lenhard said the lack of perinatal complications associated with metformin was a welcome finding.

“However, I suspect that most endocrinologists would be satisfied and comfortable with one or two additional studies that follow the offspring beyond the newborn period,” he said.

Gestational diabetes occurs in about 4% of all pregnancies, with about 135,000 cases each year in the United States, according to the American Diabetes Association. For the past decade, there has been increasing interest in using oral diabetes medications for the treatment of gestational diabetes.

Although treatment begins with dietary adjustments and scheduled physical activity, insulin is often needed as well. While effective, the use of insulin is not without its difficulties. Its use has long been associated with hypoglycemia and weight gain, and patients must be informed about how to administer it safely.

One study conducted in Denmark showed increased rates of perinatal loss and preeclampsia with metformin use in gestational diabetes, but most outcomes have been favorable. Metformin has long been a controversial option because it crosses the placenta and could directly affect fetal physiology. Another oral medication — glyburide — has also been shown to provide a relatively safe alternative to insulin therapy.

Fast Facts

Underpowered study

Baiju Shah, MD, PhD, assistant professor in the department of medicine at the University of Toronto, said the results of the MiG Trial suggest that metformin is as safe as insulin, but he questioned the power of the results.

“The primary outcome of the study was driven mostly by neonatal hypoglycemia, which is more related to treatment during labor than what necessarily went on in the weeks and months before delivery,” said Shah, also an endocrinologist at Sunnybrook Health Sciences Centre in Toronto.

He said the study was underpowered to detect those differences and not large enough to detect any signal of birth defects or other complications related to possible teratogenicity of metformin.

“Nonetheless, there have been other studies of metformin in pregnancy. I think it’s being used more and more, but I would personally still restrict its use to those women for whom insulin is not possible for social, financial or other personal reasons. Insulin is the treatment of choice, but metformin is better than nothing,” Shah said.

“The use of oral agents, especially metformin, has gained some scientific credence recently, said Robert G. Moses, MD, director of the Illawarra Diabetes Services, Wollongong, New South Wales, Australia. “These appear safe as far as the pregnancy outcomes are concerned, and logically they are unlikely to cause any long-term harm, but this aspect is less well known,” Moses said.

According to Dace Trence, MD, director of the Diabetes Care Center at University of Washington Medical Center in Seattle, the standard treatment is insulin, even though more research is showing that non-insulin treatments can achieve glycemic control.

“A significant problem during pregnancy is resistance to insulin, so oral agents are just not able to keep glucose at the levels known to decrease fetal complications and decrease fetal macrosomia,” Trence said.

There are little data on the long-term effects of these agents on fetal exposure, according to Trence. “In animal models, yolk sac vasculopathy and failure of endocardial cushion epithelial-mesenchymal transformation occurs in hyperglycemic conditions,” Trence said.

“These cardiovascular abnormalities are associated with changes in expression and phosphorylation state of adhesion molecules such as platelet endothelial growth factor-1 and expression of growth factors such as vascular endothelial growth factor,” Trence added.

“In vitro, a high-glucose concentration causes embryonic dysmorphogenesis by generation of free oxygen radicals. An enhanced production of such radicals in embryonic tissues may be directly related to an increased risk of congenital malformations in diabetic pregnancy, but it is also possible that these could have effects on developing organs that might only be seen later in life,” Trence said.

The clinical experience with glyburide treatment of gestational diabetes “has moved ahead of the science,” Thomas R. Moore, MD, wrote in Diabetes Care.

Moore contended that glyburide treatment can provide a safe alternative to insulin therapy. Several retrospective trials have shown that up to 20% of women with gestational diabetes, especially those with substation pretreatment hyperglycemia, are likely to require adjunctive or alternative therapy with insulin.

Moore said that trials have also demonstrated that glyburide treatment, compared with insulin, results in lower mean glucose values and a higher percentage of excellent glycemic control with fewer hypoglycemic episodes.

Glyburide as an option

Lenhard said that the Diabetes & Metabolic Disease Center at Christiana Care Health System has seen a startling increase in the number of women treated for gestational diabetes over the last few years, from about 300 to 700 women per year. His institution does not routinely use oral therapy.

“There have been a number of studies showing successful outcomes with glyburide when compared to women with gestational diabetes treated with insulin,” Lenhard said. “There are a number of reasons that we have not started the routine use of glyburide, however.

“First, the failure rate with glyburide is estimated at 15% to 19%. This is too high. In a research trial, women with inadequate glycemic control are switched to insulin. In the real world, it is often difficult to convince women to start injections, especially if they have only a few weeks left in their pregnancy,” Lenhard said.

“Second, while glyburide in medium doses does not seem to cross the placenta, there is still the question of whether glyburide can be passed through breast milk. Our practice has observed a number of women treated with glyburide during pregnancy who have neonates with hypoglycemia that only stops after they interrupt breast-feeding and then returns when they resume breast-feeding.

“Third, glyburide is harder to titrate than insulin. Everyone is anxiously awaiting international guidelines to be issued based on the results of the HAPO trial,” Lenhard said.

Irene O’Shaughnessy, MD, medical director of the Froedtert & Medical College of Wisconsin Metabolic Syndrome Clinic, referenced a trial published in NEJM in 2000.

Irene O’Shaughnessy, MD
Irene O’Shaughnessy

In that trial, conducted at maternal health clinics in San Antonio, Texas, glyburide was compared to insulin for the treatment of gestational diabetes and seen as a clinically effective alternative. The investigators found no evidence that glyburide passes through the placenta to the baby, and like the metformin study, there was no difference in the cesarean section rate in the two groups.

“It appears that oral medications, specifically metformin and glyburide, may be effective alternatives to insulin for the treatment of gestational diabetes in some women,” O’Shaughnessy said.

Treatment with diet

According to Lenhard, the hallmark of gestational diabetes treatment remains lifestyle changes, as well as self-monitoring of blood glucose levels.

Jovanovic agreed and said that a well-managed diet alone works as the best treatment option in 75% of the cases.

“Many women can successfully control their gestational diabetes by altering their diet, adding daily exercise, and monitoring their blood glucose levels,” Lenhard said. He said there is great variability in the treatment of gestational diabetes in the United States.

At his institution, all women are told to test their blood glucose before breakfast and one hour after each meal. Patients are also asked to report those glucose measurements to the institution by phone, fax or email twice per week.

There, the targets used are premeal blood glucose between 60mg/dL and 90 mg/dL, and a one-hour postmeal value <130 mg/dL, according to Lenhard. All women enrolled in Lenhard’s program are trained by a certified diabetes educator and see an endocrinologist and a nurse practitioner every three to four weeks throughout their pregnancy.

“Working with a registered dietician is also extremely important,” O’Shaughnessy said. “For many women, it is their first exposure to understanding the concept of carbohydrates and their role in blood sugar management. For many ethnic groups, meals are rich in carbohydrates such as rice, bread and potatoes, and the change in diet required to control blood sugars can be very challenging,” she said.

“It is absolutely essential to follow women closely with gestational diabetes, to treat them using a multidisciplinary team, to make communication with these women a top priority and to adjust treatment plans swiftly, with the primary goal of keeping blood sugars within their target range,” O’Shaughnessy said.

Trence stressed the need for “excellent communication between the endocrinologist and the obstetrician regarding pregnancy progress and issues relating to fetal development and monitoring.”

Chart: Metformin in Gestational Diabetes Trial Results

Future research

“Gestational diabetes is a window into the future. We must make women aware that if you do not become fit after pregnancy, your risk of developing type 2 diabetes is much greater,” Jovanovic said.

Shah said that more research is needed. “For example, we still don’t have any strong evidence that intensive glucose control during pregnancy reduces the risk of complications. We assume it does, but I don’t think the evidence is very strong.

“We also don’t yet know what thresholds to diagnose gestational diabetes are the most predictive of future complications and we don’t know what treatment targets to aim for.

“And, finally, we need to better understand the long-term consequences for women and children after gestational diabetes pregnancies and whether these are influenced by its treatment during the pregnancy,” Shah said. – by Angelo Milone

POINT/COUNTER
What are the difficulties in treating gestational diabetes?

For more information:

  • Hellmuth E. Diabet Med. 2000;17:507-511.
  • Moore TR. Diabetes Care. 2007;30:2209-2213.
  • Rowan JA. N Engl J Med. 2008;358:2003-2015.