44 WOMEN'S HEALTH SEPTEMBER 1, 2010 • FAMILY PRACTICE NEWS DRUGS, PREGNANCY, AND LACTATION Use of Antidiabetic Agents During Pregnancy

n a previous column, I looked at the abinese), tolazamide (Tolinase), and tolbu- thetic analogue of human amylin given was discovered. No developmental toxi- ways uncontrolled hyperglycemia tamide (Orinase). They can cause marked by subcutaneous injection, but the ani- city was observed in the newborns. Iduring pregnancy causes significant and persistent neonatal hypoglycemia if mal data suggest moderate risk (struc- Pioglitazone (Actos) and rosiglitazone toxicity for the mother, embryo, fetus, taken close to birth. To prevent this toxi- tural anomalies in rats). The drug— (Avandia), thiazolidinediones used as ad- newborn, and adolescent (“Toxicity of city, therapy should be changed to insulin which slows the rate of gastric emptying, juncts to diet and exercise, lower insulin Diabetes in Pregnancy,” December in the third trimester or, at least, several prevents a postprandial rise in plasma resistance but do not promote insulin re- 2009, p. 52). days before birth. glucagon, and promotes satiety—is best lease. Animal reproduction data suggest This column examines the The second-generation sul- avoided in pregnancy. risk, but the human experience is too use of antidiabetic agents, fonylureas glipizide (Glu- Saxagliptin (Onglyza) and sitagliptin limited to assess the risk, so they should other than insulin, that are cotrol), glimepiride (Amaryl), (Januvia), inhibitors of the enzyme be avoided in pregnancy. used for non–insulin-depen- and glyburide (DiaBeta, Gly- dipeptidyl peptidase–4, are indicated as In summary, only metformin and gly- dent diabetes during preg- nase, and Micronase) are pre- monotherapy or in combination with buride have sufficient human pregnancy nancy and lactation. With in- scribed much more frequent- metformin or a thiazolidinedione to experience for them to be classified as sulin excluded, there are eight ly than the first-generation control hyperglycemia in type 2 dia- low risk in pregnancy. Although many of classes of antidiabetic agents, agents because they do not betes. Saxagliptin has no reported hu- the remaining agents will probably even- two of which are given by cause animal developmental man pregnancy experience, but tually be shown to be low risk, they are subcutaneous injections. toxicity, and can be consid- sitagliptin has limited data from the best avoided until such data are available. Although insulin therapy BY GERALD G. ered low risk. Although struc- manufacturer’s registry. No congenital In a nursing infant, hypoglycemia is a BRIGGS, remains the standard, other B.PHARM., FCCP tural anomalies have been re- anomalies attributable to sitagliptin (ei- potential complication with insulin sec- agents are sometimes used ported with these agents, the ther alone or combined with met- retagogues such as the first-generation for people with type 2 and cause appears to be hyper- formin) have been observed. Neverthe- sulfonylureas and the meglitinides. Al- gestational diabetes because of their ease glycemia rather than the drugs. less, these agents probably will not though the second-generation sulfonyl- of administration and relatively simple The two alpha-glucosidase inhibitors provide the tight glucose control need- ureas also are insulin secretagogues and dosing. However, finding the proper acarbose (Precose) and miglitol (Glyset) ed in pregnancy and are best avoided. are excreted in milk, studies have shown dose to adequately control maternal glu- delay the digestion of carbohydrates Two glucagonlike peptide–1 receptor that they do not cause infant hypo- cose levels throughout a 24-hour period within the gastrointestinal tract, thereby agonists, exenatide (Byetta) and liraglu- glycemia or other toxicities. The same is can be challenging. There are situations reducing the rise in blood glucose fol- tide (Victoza), are peptides given as sub- true for metformin. Miglitol is excreted where combining insulin with another lowing meals. In people with type 2 dia- cutaneous injections. They are indicated into milk, but based on one case, the antidiabetic agent gives the best results. betes who are not pregnant, the drugs as adjunctive therapy in type 2 diabetics amounts were clinically insignificant. Type 2 and gestational diabetes are may be used alone but are more com- who have not obtained adequate control None of the remaining agents have hu- characterized by high insulin resistance monly used in combination with a sec- with diet, exercise, and oral agents. Nei- man data during lactation but are prob- with calorie-to-insulin ratios ranging from ond-generation sulfonylurea. Animal ther drug has reported human pregnan- ably compatible with nursing. However, 5:1 to 15:1. So, a patient with a ratio of 5:1 data suggest a low risk for acarbose, but cy experience, but the animal data sug- both of the thiazolidinediones are weak consuming 2,000 kcal/day would require animal toxicity (reduced fetal weights gest an associated risk. Insulin, not these bases and will accumulate in milk, re- a daily insulin dosage of about 400 U. In and an increase in nonviable fetuses) has agents, should be added if improved glu- sulting in milk concentrations exceeding our clinic, if a patient requires 300 U/day been observed with miglitol. Less than cose control is needed. those in the mother’s plasma. ■ or more, we add metformin 500 mg twice 2% of acarbose is absorbed, but higher Similar to the sulfonylureas, the megli- daily to reduce the insulin dosage by 60%, amounts of its metabolites are measured tinides nateglinide (Starlix) and repaglin- MR. BRIGGS is a pharmacist clinical or about 180 U/day. Metformin appears in the maternal circulation. Miglitol is ide (Prandin) are oral insulin secreta- specialist in perinatal support services at to be compatible with pregnancy and readily absorbed into the systemic cir- gogues that are used either alone or with the Memorial Care Center for Women at breastfeeding, but should not be used culation, but it is not metabolized. The metformin for type 2 diabetes. The very Miller Children’s Hospital, Long Beach, alone because it will not provide ade- human pregnancy data for these agents limited human pregnancy data consist of Calif. He also is coeditor of “Diseases, quate glucose control. are very limited. cases exposed before and during early Complications, and Drug Therapy in The first-generation sulfonylureas cur- There is no human pregnancy experi- gestation. In all cases, therapy was Obstetrics.” He said he had no disclosures rently available are chlorpropamide (Di- ence with pramlintide (Symlin), a syn- changed to insulin when the pregnancy related to the topic of this column. Women With Higher BMI at Lower Risk for Glaucoma

BY JEFFREY S. EISENBERG The researchers identified 980 cases of POAG Major Finding: Higher BMI is not associated with a during follow-up. Overall, they found no associ- FROM OPHTHALMOLOGY higher risk of POAG, and in women, it was associated ations between cumulatively averaged BMI and igher body mass index is not associated with a with a 6% risk reduction in normal-tension glaucoma. either POAG subtype, and no association be- higher risk of primary open-angle glaucoma, and Data Source: Prospective cohort study of 78,777 tween height and the risk for POAG. In women, H VITALS in women, it may be associated with a reduced inci- women in the Nurses Health Study and 41,352 men however, they found that every unit increase in dence of normal-tension glaucoma, a study has shown. in the Health Professionals Follow-Up Study, from BMI was associated with a 6% reduction in the which 980 cases of POAG were identified. Even so, clinicians and patients must be cautious risk for normal-tension glaucoma. about these findings until further research substantiates Disclosures: The investigators reported no conflicts of “Although the inverse association between them and clarifies the related biologic mechanisms, cau- interest. The study was funded by grants from the Na- weight residuals and normal-tension POAG tional Institutes of Health. tioned lead researcher Dr. Louis R. Pasquale of the de- among women may be the result of chance, it is partment of ophthalmology, Harvard Medical School, reasonable to entertain [biologic] mechanisms and the Massachusetts Eye and Ear Infirmary, both in Participants in both studies completed questionnaires that may support such an association,” the researchers Boston, and his colleagues. with information about anthropometric measures, po- reported. “Perhaps some measure linked to adiposity The findings are based on data from a prospective co- tential confounders, and ophthalmic status. Also, re- or lean mass that is under sex hormonal influences may hort study of 78,777 women in the Nurses Health Study searchers evaluated medical records, including visual protect against the development of POAG. It is possi- and 41,352 men in the Health Professionals Follow-Up field data, from participants who self-reported glaucoma. ble that higher circulating estrogen levels in post- Study. Researchers followed participants in the NHS For statistical analysis, they divided the incident cas- menopausal women with higher BMI bind to estrogen from 1980 through 2004 and participants in the HPFS es by person-years accrued for each category of an- receptors expressed on retinal ganglion cells to medi- from 1986 through 2004 (Ophthalmology 2010 thropometric measure, controlled for known risk fac- ate neuroprotection.” [doi:10.1016/j.ophtha.2009.12.017]). tors for POAG, and determined the relationship By determining how anthropometric measures in- Eligible patients were aged 40 years and older, did not between anthropometric measures and POAG sub- fluence a patient’s risk of developing POAG, the re- have primary open-angle glaucoma (POAG) at baseline, type, namely high tension (more than 21 mm Hg) and searchers wrote, they may one day unlock important and underwent eye examinations during follow-up. low tension (21 mm Hg or less). clues regarding disease pathogenesis. ■