Antidiabetic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The animal reproduction data suggest low risk, but the very limited human pregnancy experience prevents a complete assessment of the embryo–fetal risk. No congenital anomalies attributable to sitagliptin (either alone or combined with metformin) have been reported.
Although the use of sitagliptin may help decrease the incidence of fetal and newborn morbidity and mortality in developing countries where the proper use of insulin is problematic, insulin still is the treatment of choice for this disease during pregnancy. Moreover, insulin does not cross the placenta and, this eliminates the additional concern that the drug therapy itself is adversely affecting the fetus. Carefully prescribed insulin therapy will provide better control of the mother’s blood glucose, thereby preventing the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as might occur in diabetes mellitus, are associated with a number of maternal and fetal adverse effects, including fetal structural anomalies if the hyperglycemia occurs early in gestation. To prevent this toxicity, the American College of Obstetricians and Gynecologists recommends that insulin be used for types 1 and 2 diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (1,2). If a woman becomes pregnant while taking sitagliptin, changing the therapy to insulin should be considered.
The manufacturer maintains a pregnancy registry for women exposed to sitagliptin. Healthcare professionals are encouraged to report pregnancy exposures to the registry by calling the toll-free number 800-986-8999.
FETAL RISK SUMMARY
Sitagliptin is an orally active inhibitor of the dipeptidyl peptidase-4 (DPP4) enzyme. It is in the same antidiabetic subclass as linagliptin and saxagliptin. Sitagliptin is indicated as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. It also is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a thiazolidinedione when the single agent alone, with diet and exercise, does not provide adequate glycemic control. In studies in healthy and diabetic subjects, sitagliptin did not lower blood glucose or cause hypoglycemia. Sitagliptin is partially metabolized with about 79% excreted in the urine as unchanged drug. The elimination half-life after a single dose was 12.4 hours. Plasma protein binding is low (38%) (3).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats and rabbits, doses given during organogenesis that resulted in exposures about ≤30 and ≤20 times, respectively, the human exposure at the maximum recommended dose of 100 mg/day based on AUC (MRHD) were not teratogenic. At about 100 times the MRHD, an increased incidence of rib malformations was observed in offspring. A dose given to rats from gestation day 6 through lactation day 21 that resulted in exposures about 100 times the MRHD caused decreased body weight in offspring. No functional or behavioral toxicity was observed in the offspring (3).
Two-year carcinogenicity studies were conducted in male and female rats. An increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females was observed at an exposure about 60 times the MRHD. Liver tumors were not observed at about 20 times the MRHD. A similar study, performed in male and female mice with doses ≤70 times the MRHD, found no increase in the incidence of tumors in any organ. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in multiple assays. No impairment of fertility or fetal harm was observed in rats and rabbits given doses resulting in exposures that were about ≤12 times the MRHD (3).
Sitagliptin crosses the rat and rabbit placentas (3). Although it has not been studied, the drug probably crosses the human placenta. The molecular weight (about 505 for the phosphate salt), low metabolism and plasma protein binding, and prolonged elimination half-life suggest that the drug will cross to the embryo–fetus. However, the low lipid solubility might limit the exposure.
The Merck Pregnancy Registry for Januvia (sitagliptin) and Janumet (sitagliptin/metformin) covered the period August 4, 2006 through August 3, 2009 (4). During clinical trials, eight women were exposed to sitagliptin or sitagliptin/metformin during the 1st trimester. The outcomes of these pregnancies were five healthy liveborn infants, two spontaneous abortions (SABs), and one fetal death (at 34 weeks’ in a mother who took sitagliptin and metformin separately for the first 5 weeks of pregnancy). The outcomes of 16 prospectively enrolled pregnancies (exposures in the Registry are combined and do not distinguish between the two drugs) were nine live births (one set of twins), one SAB, five lost to follow-up, and two pregnancies pending. There were no congenital anomalies reported. There were six retrospectively enrolled pregnancies: two live births, three SABs, and one elective abortion at 19 weeks for encephalocele and intrauterine growth restriction (exposed to sitagliptin/metformin for 7 weeks during 1st trimester). In an internationally reported case, a woman took sitagliptin, insulin, metformin, and rosiglitazone for about 5 weeks in the 1st trimester. She gave birth at 33 weeks to a male infant with dysplastic left kidney, a missing kidney, severe hypospadias, a missing right testicle, and a poorly descended left testicle. The anomalies were consistent with diabetic embryopathy. A right inguinal hernia also was noted (4).
BREASTFEEDING SUMMARY
No reports describing the use of sitagliptin during human lactation have been located. The molecular weight (about 505 for the phosphate salt), low metabolism (about 21%) and plasma protein binding (about 38%), and prolonged elimination half-life (12.4 hours) suggest that the drug will be excreted into breast milk. The low lipid solubility might limit the exposure. The effect of this exposure on a nursing infant is unknown. Sitagliptin overdose (six times the maximum recommended human dose for 10 days) in healthy adults caused no dose-related adverse reactions (3). Thus, hypoglycemia in a nursing infant appears to be unlikely but should be monitored. The most common (≥5%) adverse reaction in adults receiving monotherapy was nasopharyngitis (3).
References
1.American College of Obstetricians and Gynecologists. Pregestational diabetes mellitus. ACOG Practice Bulletin. No. 60. March 2005. Obstet Gynecol 2005;105:675–85.
2.American College of Obstetricians and Gynecologists. Gestational diabetes. ACOG Practice Bulletin. No. 30. September 2001. Obstet Gynecol 2001;98:525–38.
3.Product information. Januvia. Merck, 2007.
4.Third Annual Report on exposure during pregnancy from the Merck Pregnancy Registry for Januvia (sitagliptin phosphate) and Janumet (sitagliptin phosphate/metformin hydrochloride) August 4, 2006 through August 3, 2009.