Written by Sabina Kapkayeva Pharm.D. candidate and Regina Ginzburg, Pharm.D., CDCES, BC-ADM

Glucagon-like peptide-1 (GLP-1 agonists) and glucose-dependent insulinotropic peptides (GIP) are increasingly being used in the management of diabetes and/or for weight loss. Several GLP-1 agonist medications available today are known to have interactions with oral hormonal contraceptives, but not through the usual pharmacokinetic Cytochrome P-450 pathway.

These medications significantly impact gastric emptying and lead to altered absorption of certain medications, including oral hormonal contraceptives. A recent study evaluating delayed gastric emptying with tirzepatide (Mounjaro®) and oral contraceptives showed an approximate 20% decrease in overall exposure of oral contraceptives after a single 5 mg dose of tirzpetide.¹ As a result of this study, the manufacturer recommends using barrier contraception for 4 weeks after either the initiation or a dosage increase, or to switch to a non-oral contraception.² Of note, semaglutide (Ozempic®, Wegovy®), liraglutide (Victoza®), and dulaglutide (Trulicity®) did not seem to affect the bioavailability of oral contraceptives.^3-5

Alternatively, exenatide (Bydureon®) and lixisenatide (Adlyxin®) were found to diminish the therapeutic effect of oral contraceptives. A clinical trial evaluating the effect of exenatide on the pharmacokinetics of a combination oral contraceptive found that taking the contraceptive 30 minutes after exenatide injection resulted in reduced peak concentration (Cmax) of the estrogen and levonorgestrel component and a delay in time taken to reach peak concentration (Tmax) by 3 to 4 hours.⁶ As a result, package labeling advises patients to administer oral hormonal contraceptives at least one hour prior to exenatide and more frequent blood glucose monitoring is warranted when patients on exenatide begin hormonal contraceptive therapy, as dose adjustments to exenatide may be necessary.⁷ The prescribing information for lixisenatide discusses drug interaction studies which showed that when contraceptives were administered 1 or 4 hours after lixisenatide, their Cmax was decreased and Tmax was delayed by 1 to 3 hours. However, when taken 1 hour before or 11 hours after there was no significant effect. Therefore, to avoid potential interactions it is recommended to take oral contraceptives either at least 1 hour before or at least 11 hours after lixisenatide administration.⁸

Of note, there is evidence supporting improvement in menses irregularity and fertility in some women with polycystic ovarian syndrome (PCOS) who achieved sufficient weight loss.⁹ People classified as overweight or obese have increased insulin resistance, which can cause hyperandrogenemia, affecting follicle development. It is nevertheless important to note that weight loss is not a cure-all for PCOS; many with PCOS are classified as having a normal weight based on their BMI. As GLP-1 agonists can produce a weight loss of 5-15%, several preliminary studies evaluating the use of this class of medications have shown more frequent menses after a GLP-1 agonist was added to metformin regimen in women with PCOS. While these individuals were not on an oral contraceptive, one should be aware that pregnancy can occur regardless after starting a GLP-1 agonist.

Summary of GLP-1 agonists interactions with oral contraceptive pills (OCPs) and recommendations for patient care:

RHAP Resources:

Your Birth Control Choices Fact Sheet

Sources:

1. Skelley JW, Swearengin K, York AL, Glover LH. The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception. J Am Pharm Assoc (2003). 2024;64(1):204-211.e4. doi:10.1016/j.japh.2023.10.037

2. Mounjaro (tirzepatide) Prescribing Information. Indianapolis, IN: Lilly USA LLC; Accessed November 2024: https://pi.lilly.com/us/mounjaro-uspi.pdf?s=pi

3. Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. 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. doi:10.1002/jcph.443

4. de la Peña A, Cui X, Geiser J, Loghin C. No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide. Clin Pharmacokinet. 2017 Nov;56(11):1415-1427. doi: 10.1007/s40262-017-0531-7. PMID: 28357715.

5. Jacobsen LV, Vouis J, Hindsberger C, Zdravkovic M. Treatment with liraglutide–a once-daily GLP-1 analog–does not reduce the bioavailability of ethinyl estradiol/levonorgestrel taken as an oral combination contraceptive drug. J Clin Pharmacol. 2011 Dec;51(12):1696-703. doi: 10.1177/0091270010389471. Epub 2011 Jan 12. PMID: 21228406.

6. Kothare PA, Seger ME, Northrup J, Mace K, Mitchell MI, Linneberg H. Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label randomized, crossover trial. BMC Clin Pharmacol. 2012 Mar 19; 12:8. doi: 10.1186/1472-6904-12-8. PMID: 22429273; PMCID: PMC3378442.

7. Exenatide (Bydureon) Prescribing Information. Wilmington, DE: Astra Zeneca USA. Accessed November 2024: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022200s026lbl.pdf

8. Lixisenatide (Adlyxin) Prescribing Information. Bridgewater, NJ: Sanofi-Aventis USA. Accessed November 2024: https://products.sanofi.us/adlyxin/adlyxin.pdf

9. Papaetis GS, Kyriacou A. GLP-1 receptor agonists, polycystic ovary syndrome and reproductive dysfunction: Current research and future horizons. Adv Clin Exp Med. 2022 Nov;31(11):1265-1274. doi: 10.17219/acem/151695. PMID: 35951627.

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