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Cited by 200Pregnancy and Medication ImpactGestational Diabetes Research and ManagementPharmacological Effects and Toxicity Studies

Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy

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Cesta, Carolyn E., Rotem, Ran, Bateman, Brian T., Chodick, Gabriel, Cohen, Jacqueline M., Furu, Kari, Gissler, Mika, Huybrechts, Krista F. +7 more·2024·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2023.6663PMC PMC10714281
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Abstract

Importance: Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown. Objective: To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant. Design, Setting, and Participants: This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth. Exposure: Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester. Main Outcomes and Measures: Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed. Results: Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively. Conclusions and Relevance: Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.

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Research works printed but not linked: 2

  1. [23]Kitzmiller JL, Ferrara A, Peng T, Cissell MA, Kim C. Preexisting Diabetes and Pregnancy. In: Cowie CC, Casagrande SS, Menke A,, eds. Diabetes in America. Bethesda (MD) no conflicts of interest. National Institute of Diabetes and Digestive and Kidney Diseases; 2018. 33651557
  2. [24]National Institute for Health and Care Excellence. Guidelines In: Diabetes in pregnancy: management from preconception to the postnatal period. London: National Institute for Health and Care Excellence (NICE) Copyright NICE 2020. 2020. 32212588

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Authors
Cesta, C. E., Rotem, R., Bateman, B. T., Chodick, G., Cohen, J. M., Furu, K., Gissler, M., Huybrechts, K. F., Kjerpeseth, L. J., Leinonen, M. K., Pazzagli, L., Zoega, H., Seely, E. W., Patorno, E., & Hernández-Díaz, S.
Affiliations
  • Karolinska Institutet (SE)
  • Harvard University (US)
  • Stanford Medicine (US)
  • Maccabi Healthcare Services (IL)
  • Norwegian Institute of Public Health (NO)
  • University of Turku (FI)
  • Brigham and Women's Hospital (US)
  • Finnish Institute for Health and Welfare (FI)
  • School of Population Health, Faculty of Medicine & Health, UNSW Sydney, Sydney, New South Wales, Australia
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
Corresponding author
Cesta, Carolyn E.
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2024-02-01
Volume
184
Issue
2
Pages
144
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2023.6663
PMC
PMC10714281
OpenAlex
W4389553854
Cited by
200
References
35
Citations by year
2026: 90 · 2025: 79 · 2024: 31
FWCI
51.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Internal Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Opin vísindi (Opin vísindi) (submittedVersion, cc-by-nc-sa)
  • Opin vísindi (Opin vísindi) (submittedVersion, other-oa)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • European Commission (844728)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD097778)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Keywords
GLP-1 receptor agonists, type 2 diabetes in pregnancy, major congenital malformations, teratogenicity, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, insulin, prenatal exposure, pregnancy safety, liveborn infants, first trimester
MeSH terms
Glucagon-Like Peptide-1 Receptor, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Insulin, Pregnancy, Sulfonylurea Compounds, Cohort Studies, Dipeptidyl-Peptidase IV Inhibitors

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