A nationwide cohort study published in Diabetologia reports that first-trimester exposure to second-line glucose-lowering drugs, including GLP-1 receptor agonists, was not associated with an increased risk of major congenital malformations compared with insulin alone.

The drugs in question include GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors and sulfonylureas: the medications that sit behind insulin and metformin in type 2 diabetes treatment, and that are increasingly prescribed to women of reproductive age. Until now, the authors write, safety data on their use in pregnancy has been limited, which is a polite way of saying the field has been guessing.

How the study was built

Researchers used the French National Health Data System to identify singleton births after pregnancies lasting more than 22 weeks, in women aged 18 to 50 with pregestational, pharmacologically treated type 2 diabetes, from January 2011 through August 2024. First-trimester exposure was defined as at least one prescription filled from 30 days before conception through 91 days after.

Major congenital malformations were identified during the delivery stay and up to one year after birth, using ICD-10 codes following EUROCAT guidelines. Adjusted risk ratios came from Poisson regression with generalized estimating equations.

Key results

Among 19,092 eligible pregnancies, 17.5% were exposed to insulin alone in the first trimester, 34.7% to at least one second-line agent, and 10.4% to no glucose-lowering drug at all. Against the insulin-only reference group, second-line exposure was not associated with an increased risk of overall or organ-specific major malformations.

The caveat is in the sensitivity analyses. Using stricter exposure definitions, the authors report a possible small increased risk of cardiac malformations after first-trimester exposure to GLP-1 receptor agonists and sulfonylureas.

Limitations

This is claims-database work, not a trial. BMI and HbA1c values were unavailable, so the authors substituted proxies of diabetes severity for confounding adjustment, and a prescription filled is not proof a drug was taken.

The cardiac finding appeared only in sensitivity analyses, which is a weaker signal than a primary result, and the authors treat it as such.

Bottom line

The headline result is reassuring and the authors call this the largest study to date on glucose-lowering agents in pregnancy. Their own conclusion is that teratogenicity cannot be excluded, and the cardiac question is the one worth watching.