Is there any evidence with glipizide vs glyburide for gestational diabetes treatment?

Comment by InpharmD Researcher

Clinical practice guidelines from the American College of Obstetrics and Gynecology (ACOG) and the American Diabetes Association (ADA) recommend insulin as the preferred treatment for gestational diabetes because it does not cross the placenta; however, second-generation sulfonylureas may also be used. Among the sulfonylureas, both glyburide and glipizide can cross the placenta at low rates, but glipizide is considered to cross at a more clinically significant rate, and thus glyburide is generally preferred when sulfonylurea use is indicated. However, major clinical practice guidelines do not directly reference glipizide in their recommendations regarding sulfonylurea use.

gestational diabetes glipizide glyburide

Background

The 2024 American Diabetes Association (ADA) Standards of Care in Diabetes guidelines recommend insulin as the preferred treatment for hyperglycemia in gestational diabetes. Neither metformin nor glyburide, as monotherapy or in combination, are recommended as first-line treatment since both agents can cross the placenta and reach the fetus. Other oral and non-insulin injectable antihyperglycemic agents lack long-term safety data in this population. Systematic reviews have associated glyburide use in pregnancy with higher rates of neonatal hypoglycemia and increased rates of macrosomia and neonatal abdominal circumference further complicating its use in gestational diabetes. Glipizide specifically is not mentioned in these guidelines, but it carries the same risks of sulfonylurea use in pregnancy. [1]

The 2018 American College of Obstetrics and Gynecology (ACOG) practice guidelines recommend insulin as first-line glycemic management in gestational diabetes when dietary changes fail. Unlike the 2024 ADA guidelines, ACOG does not recommend sulfonylureas, including glyburide, as alternative or second-line treatments to insulin in gestational diabetes due to evidence of adverse neonatal outcomes including macrosomia, increased neonatal intensive care unit admissions, and hypoglycemia. There is no direct glyburide vs glipizide comparison provided in the ACOG recommendations, and while it is acknowledged that glyburide has been studied more in pregnancy than glipizide, ACOG discourages its use overall in gestational diabetes regardless. [2]

References: [1] American Diabetes Association Professional Practice Committee; 15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1): S282–S294. https://doi.org/10.2337/dc24-S015
[2] ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstetrics & Gynecology 131(2):p e49-e64, February 2018. | DOI: 10.1097/AOG.0000000000002501
Relevant Prescribing Information

Glyburide [1]

Teratogenic Effects: Pregnancy Category C
-Glyburide has been shown to affect the maturation of the long bones (humerus and femur) in rat pups when given in doses 6250 times the maximum recommended human dose. These effects, which were seen during the period of lactation and not during organogenesis, are a shortening of the bones with effects to various structures of the long bones, especially in humerus and femur.
-There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, glyburide should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nonteratogenic Effects
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glyburide tablets are used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Glipizide [2]

Pregnancy
-Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits, no teratogenic effects were found. There are no adequate and well controlled studies in pregnant women. Glipizide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
-Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nonteratogenic Effects
-Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date.

References: [1] Diabeta (glyburide). Package Insert. Amneal Pharmaceuticals; December 2019.
[2] Glucotrol (glipizide). Package Insert. Graviti Pharmaceuticals Private Limited; March 2026.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any evidence with glipizide vs glyburide for gestational diabetes treatment?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

Transfer of Glyburide and Glipizide Into Breast Milk
Design

Two independent studies: Single-dose study and Daily-dose study

N= 13 (8 in single-dose study, 5 in daily-dose study)
Objective

To determine if glyburide and glipizide are excreted into breast milk and if breast-feeding from women taking these drugs causes infant hypoglycemia
Study Groups

Single-dose glyburide (n= 8)

Daily-dose glyburide or glipizide (n= 5)
Inclusion Criteria

Women with type 2 diabetes who had recently delivered and were breastfeeding

Toronto: women used insulin during pregnancy
Long Beach: women had cesarean sections, type 2 diabetes not controlled by diet alone, and a pediatrician assigned to their newborn
Exclusion Criteria

Toronto: Known type 1 or gestational diabetes, severe hepatic or renal dysfunction, adrenal or pituitary insufficiency, history of drug/alcohol abuse, using steroids, thiazides, antibiotics, or β-blockers, or any condition affecting lactation
Long Beach: Gestational age <37 weeks, infant with intrauterine growth retardation, infant hypoglycemia within 24h of birth, major birth defect, or no pediatrician assigned
Methods

This study was conducted in two parts: a single-dose study in Toronto and a daily dose study in Long Beach.

For the single-dose study, glyburide 5 or 10 mg was given. Maternal blood and milk samples were collected for 8 hours

The daily-dose study in Long Beach discharged women who underwent Cesarean section either nonmicronized glyburide 5 mg or immediate-release glipizide 5 mg. Maternal blood and milk samples, and infant blood glucose measured 5-16 days postpartum.
Duration

Single-dose study: 8 hours post-dose

Daily-dose study: 5-16 days postpartum
Outcome Measures

Primary: Detection of glyburide and glipizide in breast milk

Secondary: Infant blood glucose levels
Baseline Characteristics  

Single-dose glyburide (n= 8)

 Daily-dose glyburide or glipizide (n= 5)
Mean age, years

36

 Not specified
Mean maternal weight, kg

90.8

 Not specified
Results  

Single-dose glyburide

 Daily-dose glyburide or glipizide
Detection in breast milk

Not detected

 Not detected
Infant blood glucose

Normal (3 infants)

 Normal (3 infants)
Maximum theoretical infant
dose as % weight-adjusted maternal dose

1.5% (5 mg), 0.7% (10 mg)

 28% (glyburide), 27% (glipizide)
Adverse Events

No hypoglycemia observed in nursing infants
Study Author Conclusions

Neither glyburide nor glipizide were detected in breast milk, and hypoglycemia was not observed in nursing infants. Both agents appear to be compatible with breastfeeding at the doses tested.
Critique

The study is limited by small sample sizes and the insensitivity of the assay in the daily-dose study. This study did not randomize or provide a reason for drug selection in the Long Beach cohort.

 

References:
[1] [1] Feig DS, Briggs GG, Kraemer JM, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care. 2005;28(8):1851-1855. doi:10.2337/diacare.28.8.1851

A Comparison of Glyburide and Insulin in Women with Gestational Diabetes Mellitus
Design

Randomized controlled trial

N= 404
Objective

To compare the efficacy and safety of glyburide versus insulin in achieving glycemic control in women with gestational diabetes mellitus
Study Groups

Glyburide (n= 201)

Insulin (n= 203)
Inclusion Criteria

Women with singleton pregnancies and gestational diabetes, fasting plasma glucose concentrations of at least 95 mg/dL and less than 140 mg/dL, between 11 and 33 weeks of gestation
Exclusion Criteria

Not explicitly stated, but implied exclusion of women with fasting plasma glucose concentrations less than 95 mg/dL initially treated with diet
Methods

Women were randomly assigned to receive glyburide or insulin. Glyburide was started at 2.5 mg orally in the morning, increased weekly up to 20 mg if needed. Insulin was started at 0.7 units/kg subcutaneously three times daily, adjusted weekly. Blood glucose was monitored seven times daily. 
Duration

Treatment and follow-up occurred from 11 to 33 weeks of gestation until delivery
Outcome Measures

Primary: Achievement of desired glycemic control

Secondary: Maternal and neonatal complications, including rates of macrosomia, hypoglycemia, and admission to neonatal intensive care unit
Baseline Characteristics   Glyburide (n= 201) Insulin (n= 203)
Age, years 29±7 30±6
BMI ≥27.3 before pregnancy, % 70 65
Nulliparity, % 28 29
Family history of diabetes, % 43 45
Previous gestational diabetes, % 12 11
Previous delivery of infant with macrosomia, % 18 22
Screening plasma glucose, mg/dl 169±28 169±31
Week of gestation 24±7 25±7
Week of gestation at delivery 38.7±1.6 38.5±2.1
Results   Glyburide (n= 201) Insulin (n= 203) p-value
Blood glucose concentrations during treatment, mg/dL 105 ± 16  105 ± 18 0.99
Large size for gestational age, % 12 13 0.76
Macrosomia, % 7 4 0.26
Hypoglycemia, % 9 6 0.25
Admission to neonatal intensive care unit, % 6 7 0.68
Adverse Events No significant differences in maternal or neonatal complications between the glyburide and insulin groups. Glyburide was not detected in the cord serum of any infant.
Study Author Conclusions Glyburide is a clinically effective alternative to insulin therapy in women with gestational diabetes, achieving similar glycemic control and perinatal outcomes.
Critique The study provides strong evidence for the use of glyburide as an alternative to insulin in gestational diabetes, with a robust randomized controlled design. However, the study is limited by its focus on a specific population (predominantly Hispanic, Medicaid recipients), which may affect the generalizability of the findings to other populations.
References:
[1] [1] Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343(16):1134-1138. doi:10.1056/NEJM200010193431601