GLP-1 Receptor Agonists Drug-Drug Interaction Table

What the labels cover

GLP-1 receptor agonist labels cover interactions in a few defined areas: hypoglycemia when a GLP-1 drug is combined with insulin or an insulin secretagogue, possible changes in absorption of other oral medicines, and, on some products, oral contraceptives [1][2][4]. The rules are product-specific. Both the Wegovy (semaglutide) and Foundayo (orforglipron) labels say delayed gastric emptying may affect absorption of oral medicines; the Wegovy label additionally advises considering increased clinical or laboratory monitoring for medicines with a narrow therapeutic index [1][2]. Foundayo adds limits on strong CYP3A4 inhibitors and inducers and on simvastatin [2].

Insulin and insulin secretagogues

All GLP-1 drugs raise hypoglycemia risk when combined with insulin or a sulfonylurea, and the labels advise considering a lower dose of the insulin or sulfonylurea when starting [1][2]. The Wegovy label warns that the risk of hypoglycemia, including severe hypoglycemia, is increased when semaglutide is used with insulin or an insulin secretagogue, and notes that the addition of Wegovy in patients treated with insulin has not been evaluated [1]. The Foundayo label gives the same instruction to consider reducing the insulin or secretagogue dose [2].

Foundayo's label reports what that risk looked like in its type 2 diabetes trial: glucose below 54 mg/dL occurred in 7% of patients taking orforglipron with a sulfonylurea versus 0.5% of those not taking one [2].

Oral medicines and gastric emptying

The Wegovy and Foundayo labels both state that the drug delays gastric emptying and has the potential to affect absorption of concomitantly administered oral medicines [1][2]. The Wegovy label advises considering increased clinical or laboratory monitoring for oral medicines that have a narrow therapeutic index or that require clinical monitoring [1].

The Wegovy interaction section also reports a measured change: in a drug interaction study with the semaglutide tablet, levothyroxine exposure increased 33% (90% CI 1.25 to 1.42) [1].

The Wegovy label adds that in clinical pharmacology trials with semaglutide 1 mg once weekly by injection, semaglutide did not affect the absorption of orally administered medicines [1].

Oral contraceptives: not a class rule

The labels split by product. For tirzepatide, the label advises switching to a non-oral contraceptive method or adding a barrier method for 4 weeks after starting and for 4 weeks after each dose increase [4]. For Foundayo, the same advice applies for 30 days after starting and 30 days after each dose escalation, and hormonal contraceptives that are not taken orally should not be affected [2].

The semaglutide labels carry no such advice, and a semaglutide tablet interaction study found no clinically significant change in ethinyl estradiol or levonorgestrel [1].

Orforglipron: CYP3A4 and simvastatin rules

Foundayo has specific dose limits and avoidance advice for medicines that strongly inhibit or induce CYP3A4 [2]. With a strong CYP3A4 inhibitor, the maximum Foundayo dose is 9 mg once daily, and strong inhibitors that also inhibit OATP1B, such as ritonavir, are to be avoided because they are expected to significantly increase orforglipron concentrations [2]. Strong CYP3A4 inducers are to be avoided because induction of CYP3A4 decreases orforglipron exposure and may reduce effectiveness; with moderate inducers, the label says to monitor effectiveness and escalate the orforglipron dose as needed [2].

Foundayo's label says simvastatin acid exposure doubled when the two drugs were used together, and advises a simvastatin limit of 20 mg once daily [2].

Tablets: how they are taken

The Wegovy tablet label instructs patients to take the tablet on an empty stomach in the morning with up to 4 ounces of water, and to wait at least 30 minutes before eating food, drinking beverages or taking other oral medicines [1]. The levothyroxine finding above came from a separate interaction study with the semaglutide tablet [1].

Foundayo may be taken with or without food [2].

Summary table