Gestational diabetes and oral hypoglycemic agents: A fresh look at the safety profile
Although insulin has been the treatment of choice when dietary measures fail, oral hypoglycemic drugs are increasingly recognized as safe and effective.
The varying success rates are not surprising. Rather, they reflect varying quality of care and patient education, as well as different patient populations, compliance levels, and cultural preferences.
Metformin. Coetzee et al12,13 studied the effect of metformin as single or combination therapy in pregnancy, demonstrating a significant mean decline in plasma glucose concentrations. In one study, the failure of metformin to achieve the targeted level of glycemic control was 53.8% in women with established diabetes and 28.6% in women with gestational diabetes.13
Apart from a high incidence of neonatal jaundice requiring phototherapy, infant morbidity in the metformin group was low. The rates of large-for-gestational-age infants were comparable in the metformin-treated and insulin-treated groups (20%). The 3 fetal anomalies in this study involved women in the metformin group who initiated therapy in the third trimester.
Another study by Coetzee et al19 involved patients treated with dietary therapy alone, metformin or glibenclamide (glyburide) alone, or, when that failed, a combination of diet, metformin, and glibenclamide. Insulin was given when diet and oral therapy failed to achieve glycemic control. The incidence of large-for-gestational-age neonates was 15% in the metformin group, 27% among the glibenclamide users, 33% for combined therapy, and 41% for insulin. These varying rates can be explained by differences in disease severity. Still, it is notable that subjects treated with metformin had the lowest rate.
Metformin is a popular drug in the treatment of polycystic ovary syndrome (PCOS). When these women become pregnant, the fetus is exposed to the drug during the first trimester. Thus, the physician is faced with 2 dilemmas: Should patients on metformin conceive while on the drug? When they do conceive, should the drug be halted during pregnancy?
In a study by Glueck et al,20 women with PCOS received metformin to reduce the occurrence of gestational diabetes. Researchers found no evidence that the drug was teratogenic. Moreover, metformin reduced the likelihood of first-trimester abortion by a factor of 10.
In addition, use of the drug in the preconception period reduced the incidence of gestational diabetes from 31% to 3%—a rate comparable to that found in the general population. No major fetal malformations or fetal hypoglycemic episodes occurred in the 34 live births, thus supporting Coetzee’s findings.
However, in a study of 118 women with preexisting diabetes, Hellmuth et al21 found an incidence of preeclampsia of 32% in women treated with metformin, compared with 7% in the sulfonylurea group. Perinatal mortality was 11.6% and 1.3%, respectively.
The findings of this study were not replicated by other researchers. This can be partially explained by the relatively small number of patients in each arm of the study (metformin, insulin, diet, and sulfonylurea). The data also suggest that these patients were not maintaining optimal glucose control, since similar rates of macrosomia (35%) were found in all treatment groups.
In a study of women with PCOS, metformin therapy decreased the rate of early pregnancy loss to 11%, compared with a rate of 58% among untreated women.22
Although recent trials showed no adverse effect of metformin in terms of anomalies, no current study has evaluated pregnancy outcomes when patients were treated with the drug throughout gestation. Metformin and many other hypoglycemic and antihyperglycemic agents may, in the future, offer alternatives to glyburide with comparable or greater efficacy. However, current research has not provided the evidence for their safe use in pregnancy. Thus, glyburide is the only drug that can be safely recommended at this time (TABLE 2).
TABLE 2
Safety profile of oral hypoglycemic agents in pregnancy28,29
| DRUG | CLASS | FDA PREGNANCY CATEGORY | SAFETY PROFILE |
|---|---|---|---|
| Tolbutamide | Sulfonylurea | C | Risk cannot be ruled out |
| Glyburide | Sulfonylurea | B | No evidence of risk in humans |
| Metformin | Biguanide | B | No evidence of risk in humans |
| Repaglinide | Meglitinide | C | Risk cannot be ruled out |
Clinical management
The different oral hypoglycemic and antihyperglycemic agents have varying mechanisms of action. When properly selected, these drugs offer a more physiologic approach to the treatment of gestational and type 2 diabetes. Thus, several questions should be addressed when contemplating the use of insulin secretagogues or antihyperglycemic agents in pregnancy:
- Can glycemic control be achieved using the optimal dose?
- Can serious postprandial and fasting hypoglycemia be minimized in comparison with insulin therapy?
- Are there maternal or fetal side effects that mitigate the beneficial effects?
The data suggest that glyburide and possibly metformin can be safely and effectively used to manage gestational diabetes (TABLE 3). Medical therapy with oral agents should be reserved for patients in whom diet therapy fails (ie, those with fasting plasma glucose levels above 95 mg/dL or postprandial levels above 120 mg/dL) (FIGURE) or who are not appropriate candidates for diet therapy alone. For optimal results with oral agents, women must adhere to a diabetic diet and maintain the targeted level of glycemic control; compliance to therapy also is important.
