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Observational Study
. 2024 Feb 1;184(2):144-152.
doi: 10.1001/jamainternmed.2023.6663.

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

Carolyn E Cesta  1 , Ran Rotem  2   3 , Brian T Bateman  4 , Gabriel Chodick  3 , Jacqueline M Cohen  5   6 , Kari Furu  5   6 , Mika Gissler  7   8   9   10 , Krista F Huybrechts  11 , Lars J Kjerpeseth  5 , Maarit K Leinonen  7 , Laura Pazzagli  12 , Helga Zoega  13   14 , Ellen W Seely  15 , Elisabetta Patorno  11 , Sonia Hernández-Díaz  2
Affiliations
Observational Study

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

Carolyn E Cesta et al. JAMA Intern Med. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cesta reported grants from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 844728 during the conduct of the study; and participation in research projects funded by pharmaceutical companies, all regulator-mandated phase 4 studies, with all funds paid to KI (no personal fees) and no relation to work reported in this article. Dr Bateman reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Cohen reported grants from The Research Council of Norway project #301977 and grants from ADHD Research Network, Oslo University Hospital project #51379 outside the submitted work. Dr Furu reported working on a post-authorisation safety study (PASS required by EMA) of an antidiabetic drug with funding to NIPH from Novo Nordisk (no personal fees) during the conduct of the study. Dr Huybrechts reported grants from NICHD R01 HD097778 during the conduct of the study; grants to institution from Takeda and UCB as an investigator on unrelated work outside the submitted work. Dr Kjerpeseth reported grants from the Research Council of Norway (project no. 273366 with PI Dr Kari Furu, paid to the institution to fund expenses for the InPreSS project, including salary) during the conduct of the study. Dr Leinonen reported grants from Innovative Medicines Initiative Building an ecosystem for better monitoring and communicating the safety of medicines’ use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimized evidence generation, IMI ConcePTION, grant agreement number 821520 outside the submitted work. Dr Pazzagli reported a grant from FORTE Swedish Research Council for Health, Working Life and Welfare (project No. 2021-01080). Dr Patorno reported grants from the National Institute of Child Health and Development (NICHD) R01 HD097778 during the conduct of the study; grants from Boehringer Ingelheim to the Brigham and Women’s Hospital, grants from Patient Centered Outcomes Research Institute DB-2020C2-20326, and grants from Food and Drug Administration 5U01FD007213 outside the submitted work. Dr Hernández-Díaz reported grants from Takeda to her institution, personal fees from Johnson & Johnson for methods consulting, personal fees from Moderna for methods consulting, and personal fees from UCB for methods consulting outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prevalence of Periconceptional Second-Line Noninsulin Antidiabetic Medication Exposure Over Time in the Nordics, US, and Israel
The denominator contains all live-born infants per year per database. Nordic results are based on pooled data from national health registers in Finland, Iceland, Norway, and Sweden. US results based on data from the MarketScan database. Israel results based on data from Maccabi Health Service database. DPP-4 indicates dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2.
Figure 2.
Figure 2.. Prevalence of Any and Cardiac Major Congenital Malformations in Infants With Exposure to Maternal Periconception Type 2 Diabetes and Antidiabetic Medication Use
The corresponding number of exposed, number of cases, prevalence, and 95% CIs combined and for each study cohort are reported in eTable 7 in Supplement 1. ADM indicates antidiabetic medication; DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2.
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