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.
We reached similar conclusions in a retrospective analysis of 850 women with type 2 diabetes who were exposed to oral hypoglycemic agents, insulin, or diet therapy prior to and during the first trimester of pregnancy.2 Again, it was blood glucose and not the mode of therapy that had the net effect on the rate of anomalies.
In a randomized study in 1971, Notelovitz et al9 compared the efficacies of tolbutamide, chlorpropamide, diet, and insulin in a randomized trial. When glycemic control was good (ie, blood glucose less than 150 mg/dL), there were no significant differences among the groups in perinatal mortality and congenital anomalies.
In a prospective, randomized trial, we also compared the efficacy of glyburide and insulin in 404 women with singleton pregnancies, and found no significant differences in maternal hypoglycemic episodes, preeclampsia, rate of cesarean section—or number of patients achieving the desired level of control.3 As for the neonates, no significant differences were found in the rate of macrosomia; large-for-gestational-age infants; metabolic, respiratory, and hematologic complications; and congenital anomalies.
Interestingly, no glyburide was detected in the arterial cord serum of any infant in the glyburide group, even though fetal insulin levels were comparable between the groups. These results demonstrate that patients with type 2 or gestational diabetes can maintain the desired level of control using oral agents, thereby lowering diabetes-related risks.
To date, no randomized study with an adequate sample size has addressed use of oral hypoglycemic agents during organogenesis. The likelihood of such a study being performed is very small, since most pregnancies are unplanned and we lack the ability to determine the lag time between conception and drug effect. Therefore, the clinical decision to give the drugs should be based on existing data rather than potentially unattainable information (TABLE 1).
TABLE 1
Selected trials using ‘new’-generation oral agents in pregnancy
| AUTHOR | YEAR | NO. OF PATIENTS | DESIGN | DRUG | OUTCOME |
|---|---|---|---|---|---|
| Notelovitz9 | 1971 | 4×52 | Randomized | Tolbutamide | No significant differences in perinatal mortality and congenital anomalies for blood glucose <150 mg/dL |
| Coetzee and Jackson12 | 1980 | 148 | Retrospective | Glibenclamide (glyburide) | Reduced perinatal mortality |
| Coetzee and Jackson11 | 1984 | 171 | Retrospective | Metformin | Drug was deemed safe in first trimester and later pregnancy, if blood glucose control is good |
| Coetzee and Jackson26 | 1986 | 126 | Retrospective | Metformin | Reduced perinatal mortality |
| Langer et al3 | 2000 | 404 | Randomized | Glyburide | No significant differences between the glyburide and insulin groups in large-for-gestational-age and macrosomic infants, hypoglycemia, neonatal intensive care unit admissions, and fetal anomalies |
| Pendsey27 | 2002 | 46 | Randomized | Repaglinide | Same success rate as with insulin therapy |
Success rates of oral agents
Glyburide. In the prospective randomized trial mentioned earlier, we found glyburide to be as effective as insulin, since 82% of the patients receiving glyburide and 88% of those receiving insulin achieved targeted levels of glucose control.3 In the Notelovitz study,9 80% of subjects treated with oral agents or diet maintained blood glucose levels below 150 mg/dL, while only 38% of the insulin-treated patients were able to achieve this goal, probably due to poor compliance. In yet another study, a success rate of 83% was found in glyburide-treated patients, who also claimed complete satisfaction with the mode of therapy.16
Success with oral agents is not universal, however. For example, Kitzmiller17 reported that among 73 women refusing insulin therapy who were assigned to receive glyburide, approximately 47% failed to achieve the targeted glycemic goals after 1 to 9 weeks of treatment. And in a US study of nongravid patients with type 2 diabetes, 62% of those treated with oral therapy failed to achieve the American Diabetes Association hemoglobin A1c goal of less than 7%. However, 73% of the patients treated with insulin also failed to achieve this threshold.18 The conclusion: Glyburide can be as effective as insulin.
Because diminished insulin secretion and sensitivity characterize both gestational and type 2 diabetes, oral hypoglycemic agents that address one or both of these abnormalities would seem to have the greatest potential efficacy. Therapy can consist of a single drug or a combination of oral hypoglycemic and antihyperglycemic agents acting on different abnormalities. Oral administration of these agents offers greater patient acceptance and compliance.
Sulfonylureas. First-generation sulfonylurea drugs, which included tolbutamide and chlorpropamide, were replaced by second-generation agents such as glyburide and glipizide.
Meglitinides. Oral insulin secretagogues were approved for clinical use in the late 1990s. Among this group, repaglinide has gained acceptance as a fast-acting, premeal therapy to limit postprandial hyperglycemia.1
Biguanides. Phenformin was withdrawn from the American market in 1977 because of the side effect of lactic acidosis. In 1995, metformin was approved for use in the United States.1
Thiazolidinediones. Troglitazone, the first agent in this group, was reported to have a high rate of hepatic toxicity and was withdrawn from the market in 2000. Newer agents in this class such as rosiglitazone and pioglitazone are widely used in clinical practice, without reported hepatic toxicity.1
Alpha-glucosidase inhibitors. Acarbose reduces intestinal absorption of starch and glucose. It has excellent potential for use in pregnancy without risk of adverse fetal exposure.1
REFERENCE
1. Hardmons JG, Limbird LE, eds. Goodman and Gilman’s “The Pharmacologic Basis of Therapeutics.” 9th ed. New York: McGraw-Hill; 1996;1712-1792.
