How safe are GLP-1R agonists in early pregnancy?

A new study published in JAMA Internal Medicine examines the safety of glucagon-like peptide 1 (GLP-1) receptor agonists, along with other second-line medications used in managing diabetes in early pregnancy.

Study: Safety of GLP-1 receptor agonists and other second-line antidiabetics in early pregnancy. Image Credit: Reshetnikov_art / Shutterstock.com

Diabetes management during pregnancy

The increased incidence of type 2 diabetes mellitus (T2DM) and increasing maternal age worldwide have led to higher use of insulin, as well as second-line anti-diabetic medications (ADM) during pregnancy. This is inevitably associated with potential fetal exposure to these drugs; however, the risk of congenital anomalies following such exposure is not known.

While metformin is often prescribed to non-pregnant people with T2DM, other drugs or insulin may be added or substituted for metformin if adequate blood sugar control is not achieved. Over the past ten years, the use of second-line ADMs has increased significantly.

Nevertheless, insulin remains the ideal treatment for patients who are pregnant or are planning to become pregnant, mainly because of the lack of evidence for the safety of other ADMs during this period. Despite this, both deliberate and inadvertent use of these drugs is increasing, which has led to fetal exposure to these drugs in early pregnancy.

What did the study show?

The current study included multiple nationalities in a population-based cohort of over 500,000 pregnant women with T2D residing in the United States, Israel, and four Nordic countries. All databases comprised pregnant women with T2DM and their infants, which, if liveborn, were followed up until the end of the first year.

Almost 30% of the study cohort used ADMs periconceptionally. The second-line ADMs included GLP1-R agonists, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sodium-glucose cotransporter 2 (SGLT2) inhibitors. All ADMs were compared for use from within 90 days preconceptionally to the end of the first trimester of pregnancy.

About 50% of patients on ADMs used metformin only, with over 33% using insulin. About 9% and 6% were on sulfonylureas and GLP-1R agonists, respectively, while less than 5% were on DPP-4 and SGLT2 inhibitors, respectively.

The rate of use of various drugs differed between countries, from 32 for every 100,000 pregnancies in the Nordic countries to almost 300 for every 100,000 pregnancies in the U.S. There was a steady rise in the use of these drugs in these countries, especially GLP-1R agonists in the U.S., in the periconceptional period; however, sulfonylureas continued to be used at low levels in the Nordic countries.

Pregnant women on insulin or SGLT2 inhibitors were more likely to experience diabetic complications. SGLT2 inhibitor users had the highest rates of hypertension and cardiovascular disease, whereas women prescribed GLP-1R agonists were more likely to be obese or suffer from polycystic ovarian syndrome (PCOS).

Both DPP-4 and SGLT2 inhibitors were used by women with higher periconceptional glycated hemoglobin (HbA1C) levels. The use of second-line ADMs was commonly accompanied by insulin or metformin in 80-90% of cases.

Despite the use of these drugs, there was no increased incidence of congenital malformations in this cohort as compared to those on insulin.

Major congenital anomalies were reported in about 4% of infants overall and 5% among infants born to mothers diagnosed with T2DM. These genetic abnormalities were identified in about 10% of infants following sulfonylurea exposure, 8% with GLP1R agonists, 7% with SGLT2 inhibitors, and 6% with DPP-4 inhibitors compared to about 8% with insulin. Thus, there was no significant association between the use of these medications and major malformations.

What are the implications?

Pregnancy with T2DM is a high-risk condition for major congenital anomalies, among other adverse outcomes, thus emphasizing the need for glycemic control during this period. Insulin has been the recommended ADM during pregnancy, as it does not cross the placenta and is, therefore, unlikely to cause malformations. However, metformin is also commonly used to treat women with PCOS with infertility or T2DM in pregnancy.

In the current study, pregnant women with T2DM had higher rates of liveborn babies with major anomalies as compared to the general population. Although these findings offer reassurance regarding the safety of these drugs, further validation is essential.

One limitation of the current study is that only women with a live birth were included. Furthermore, the small number of exposures to second-line ADMs in this large cohort led to wide confidence limits of most estimates.

Continuing and constant surveillance of pregnant women prescribed these drugs is essential to understand any potential risks associated with their use.