Pre-Pregnancy GLP-1 Therapy and Gestational Diabetes: Why Discontinuation Timing Matters

Glucagon-like peptide-1 receptor agonists and tirzepatide have changed how we manage obesity and type 2 diabetes. As a result, many women of reproductive age are now using these treatments before they conceive. This rise has led clinicians to receive more questions about the lasting metabolic effects once a pregnancy starts. A recent multinational study explores this issue by looking at the risk of gestational diabetes after these women used the medication before conception.

The study relies on a large health research network. Researchers looked at data from January 2015 to April 2025. This large-scale analysis allows for strong comparisons across different patient groups. Therefore, the results are important for preconception advice and assessing obstetric risks.

Study Design and Methodological Rigor

Investigators carried out a retrospective cohort study involving women aged 18 to 45 years. The participants had no diabetes diagnosis prior to the study. Researchers used a 1:1 ratio for propensity score matching, which considered factors such as demographics, body mass index, hemoglobin A1c, and other relevant health conditions.

The main group focused on women who stopped their medication more than 90 days before conception. This group had used the medication between 6 and 18 months before their pregnancy visit. Meanwhile, a secondary analysis looked at another group of women who filled a prescription within 90 days of conception, representing a sudden halt in treatment.

This design allows for a direct comparison between planned and unplanned stopping of the medication. Risk ratios were calculated separately for each matched group. This means the study could examine the timing of stopping as a separate factor. As a result, it can differentiate between the ongoing effects of the medication and changes driven by other metabolic factors.

Gestational Diabetes Risk After Planned Discontinuation

Among women who stopped therapy more than 90 days before conception, the rate of gestational diabetes was similar to that of non-users. Specifically, the matched group included 892 women. Gestational diabetes developed in 16.3 percent of those who had used the medication, compared to 16.8 percent of the controls. The risk ratio was 0.967, with a confidence interval from 0.719 to 1.315.

Importantly, this similar risk persisted even with a noticeable difference in weight gain during pregnancy. Women with prior treatment saw an average body mass index increase of 1.8 kg per square meter during pregnancy. In contrast, controls gained an average of 1.2 kg per square meter. Thus, treated women had an additional weight gain of 0.6 kg per square meter.

A follow-up analysis confirmed these results using a different matching strategy based on when treatment started. Treated women had a higher average body mass index of 37.0 kg per square meter, while controls had 35.0 kg per square meter. Still, the rate of gestational diabetes was similar across both groups, resulting in a risk ratio of 0.988.

Elevated Risk Following Abrupt Discontinuation

The secondary analysis yielded different results. Among 578 women who stopped therapy within 90 days of conception, the risk of gestational diabetes significantly increased. The risk ratio reached 1.536, indicating a 53 percent higher risk compared to controls. This difference was statistically significant, with a confidence interval of 1.020 to 1.955.

Researchers linked this increased risk to a greater spike in body mass index following abrupt discontinuation. Women who stopped suddenly had an extra weight gain of 1.3 kg per square meter compared to controls. This rebound was more pronounced than in the planned discontinuation group. Thus, the timing and speed of weight regain after stopping treatment seem crucial for understanding gestational metabolic outcomes.

Mechanisms Underlying Post-Discontinuation Metabolic Rebound

GLP-1 receptor agonists and dual GIP-GLP-1 agonists influence insulin secretion, stomach emptying, and appetite control. Once treatment stops, these effects fade within a certain timeframe. Appetite control tends to diminish first in many patients, often before full metabolic balance returns. This pattern can lead to a rapid increase in calorie intake before insulin sensitivity can adjust.

When treatment stops suddenly, this transition period is shorter. So, weight regain happens faster before the body can adjust to a new metabolic state. The growth of fat tissue during this narrow window may mainly affect visceral fat areas, which are closely linked to insulin resistance and gestational glucose issues.

In contrast, planned discontinuation more than 90 days before conception allows for a more gradual adjustment. The body seems to stabilize its signaling linked to incretins before the pregnancy demands begin. This stability could explain why planned discontinuation resulted in a gestational diabetes risk similar to non-users. Thus, how quickly the treatment stops influences the differing outcomes more than past treatment alone.

Clinical Implications for Preconception Counseling

These findings highlight the importance of discussing when to stop medication during preconception counseling. Clinicians treating women with obesity or type 2 diabetes should advise on tapering medication well ahead of conception attempts. Stopping suddenly, often after a positive pregnancy test, can unintentionally raise metabolic risks. Structured plans for tapering should be initiated during family planning consultations to help reduce this risk.

Additionally, monitoring weight in the period immediately after stopping therapy is essential. Rapid weight gain after discontinuing these medications may indicate increased risks during pregnancy. Early identification of significant weight changes could lead to closer monitoring of glucose levels once pregnancy is confirmed. This method aligns with existing approaches to assess gestational diabetes risk based on metabolic history.

Preconception care programs are increasingly including personalized counseling for women taking incretin-based therapies. Given the changing landscape of these medications, good communication between obstetric and endocrinology teams is beneficial. Discussing the timing of discontinuation should happen before contraception is stopped, when possible. This coordination may help maintain the metabolic advantages gained during treatment.

Limitations and Directions for Future Research

Some limitations should be considered when interpreting these results. The study’s retrospective design relies on health records that may have gaps. Additionally, it cannot fully account for unmeasured factors like diet and exercise during the period after stopping. Information on prescription fills also does not perfectly reflect actual adherence.

The authors frame their conclusions as generating hypotheses rather than providing definitive answers. Future studies should confirm the relationship between how quickly treatment is stopped and gestational diabetes risk. These studies could also clarify the best tapering methods and monitoring timelines. This research focus is highly significant for public health.

Conclusion

This multinational cohort study provides encouraging evidence regarding the planned discontinuation of therapy. Gestational diabetes risk was similar to non-users when medication stopped more than 90 days before conception. However, stopping abruptly close to conception significantly elevated the risk, likely due to rapid weight regain.

These findings shift the clinical focus from whether prior exposure poses a risk to how discontinuation should be managed. Structured, gradual tapering during family planning may help maintain metabolic benefits into early pregnancy. As incretin-based therapies become more integrated into care, the strategy for stopping will likely be a standard part of preconception counseling.

References

Banerjee, M., Dutta, S., & Dasgupta, S. (2026). Pre-pregnancy GLP-1 receptor agonist or tirzepatide use and gestational diabetes risk: Evaluating pharmacodynamic carry-over versus post-discontinuation metabolic rebound in a multinational federated cohort. Diabetes, Obesity and Metabolism. Advance online publication. https://doi.org/10.1111/dom.70853

Harper, T., Kuohung, W., Sayres, L., Willis, M. D., & Wise, L. A. (2023). Optimizing preconception care and interventions for improved population health. Fertility and Sterility, 120(3), 438-448. https://doi.org/10.1016/j.fertnstert.2022.12.014

Sweeting, A., Hannah, W., Backman, H., Wong, V. W., Ma, R. C., Immanuel, J., Kapur, A., Dias, S., Bapayeva, G., Kihara, A. B., & Hod, M. (2024). Epidemiology and management of gestational diabetes. Lancet, 404(10448), 175-192. https://doi.org/10.1016/S0140-6736(24)00825-0