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Title: GLP-1 Receptor Agonists: Reducing blood sugar, weight, and contraception efficacy? 

Sera Andras, PharmD, UK HealthCare PGY2 Ambulatory Care Resident 

Tirzepatide (Mounjaro), a novel GIP and GLP-1 receptor agonist has added another tool to the arsenal of medications used to treat type 2 diabetes mellitus. The drug works by increasing glucose-dependent insulin secretion, decreasing inappropriate glucagon secretion, and slowing gastric emptying.¹ Although highly effective at reducing blood glucose and weight, the drug’s mechanism may also affect the absorption of certain medications – specifically oral contraceptives. 

This potential interaction is due to tirzepatide’s delayed gastric emptying properties. This delay is largest after the first dose and diminishes over time. Oral contraceptive medications are dependent on threshold concentrations for efficacy.² Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean Cmax of ethinyl estradiol, norgestimate, and norelgestromin (the active metabolite of norgestimate) was reduced by 59%, 66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in tmax of 2.5 to 4.5 hours was observed.

Of note, the prescribing information also acknowledges that this mechanism may impact the absorption of all concomitantly administered medications, and patients on narrow therapeutic index drugs should be closely monitored. 

Does this warning apply to GLP-1 receptor agonists? 

• Dulaglutide (Trulicity): No dose adjustment is required for oral contraceptives.³

• Exenatide (Byetta & Bydureon): Administer oral contraceptive at least one hour before administration of exenatide.^4,5

• Liraglutide (Victoza): No specific recommendation for oral contraceptives stated in the package insert.⁶

• Lixisenatide (Adlyxin): Administer oral contraceptive one hour before or at least 11 hours after administration of lixisenatide.⁷

• Semaglutide (Ozempic & Rybelsus): No dose adjustment required for oral contraceptives.^8,9

How to address interaction with oral contraceptives:

• Discuss risks versus benefits of continuing a medication that may decrease the efficacy of a patient’s contraceptive method.

• Suggest using a barrier method of contraception for 4 weeks after starting tirzepatide and for 4 weeks after each dose escalation.

• Consider changing to a non-oral contraceptive method. These methods will not carry the same interaction risk as oral methods since they avoid first pass metabolism. The U.S. Medical Eligibility Criteria for Contraceptive Use may help guide treatment decisions.¹⁰ 

Beyond the potential for decreased efficacy due to delayed gastric emptying, GLP-1 receptor agonists and tirzepatide may lead to significant gastrointestinal adverse effects such as diarrhea and vomiting. If experienced for prolonged periods of time, this also has the potential to decrease oral contraceptive efficacy. In general, if a patient experiences vomiting or diarrhea for > 48 hours, back-up contraception should be used for 7 days after symptom resolution. More detailed recommendations can be seen here: CDC Selected Practice Recommendations for Contraceptive Use.¹¹ 

References:

1. MOUNJARO (tirzepatide) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2022.

2. Kapitza C, Nosek L, Jensen L, et al. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55(5) 497-504. 

3. TRULICITY (dulaglutide) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

4. BYETTA (exenatide) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2005.

5. BYDUREON (exenatide extended-release) [package insert]. Wilmington, DE: AstraZeneca; 2005.

6. VICTOZA (liraglutide) [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2010. 

7. ADLYXIN (lixisenatide) [package insert]. Bridgewater, NJ: Sanofi Company; 2016.

8. OZEMPIC (semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2017.

9. RYBELSUS (semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2017.

10. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65(No. RR-3):1-104. DOI: http://dx.doi.org/10.15585/mmwr.rr6503a1 

11. Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65(no. RR-4):1 – 66. DOI:http://dx.doi.org/10.15585/mmwr.rr6504a1