GIP/GLP-1 Dual Agonists Drug-Drug Interaction Table: Complete Prescriber Reference

Which drugs are GIP/GLP-1 dual agonists?

Tirzepatide is a dual agonist: the FDA labels for Mounjaro and Zepbound describe it as a glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist, a dual agonist rather than a pure GLP-1 agonist [1][2]. Semaglutide (Ozempic, Wegovy, Rybelsus) and orforglipron (Foundayo) activate the GLP-1 receptor; their interaction sections are not tirzepatide's interaction section [3][5].

That distinction matters here. A rule written for orforglipron's CYP3A4 interactions, for example, is not automatically a tirzepatide rule.

The interaction table

Insulin and sulfonylureas

Tirzepatide labeling warns that combining it with insulin or an insulin secretagogue raises the risk of hypoglycemia, including severe hypoglycemia, and advises considering a lower dose of the insulin or secretagogue at initiation [1]. The same hypoglycemia warning appears on the Wegovy and Foundayo labels [3][5].

How large the risk is depends on the drug and the trial. In the orforglipron label's type 2 diabetes trial, plasma glucose below 54 mg/dL was reported in 7% of patients taking a sulfonylurea versus 0.5% of those not taking one [5]. That is orforglipron, not tirzepatide.

Oral contraceptives

The tirzepatide 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 [1]. The instruction is tied to dose escalation, not just the first injection.

The class is not uniform. The orforglipron label uses 30 days after starting and after each dose increase [5]. Semaglutide labels carry no such advice, and a tablet interaction study found no clinically significant change in ethinyl estradiol or levonorgestrel exposure [3]. The 4-week rule is specific to tirzepatide.

The gastric-emptying statement

Tirzepatide delays gastric emptying and may affect absorption of oral medicines [1]. The Wegovy label advises closer clinical or laboratory monitoring for certain oral medicines [3]; that is not a tirzepatide-specific instruction. For oral drugs in general, including narrow therapeutic index drugs, the tirzepatide statement is the general warning that gastric emptying is delayed and absorption may change [1].

One example from a related product: with the oral semaglutide tablet, levothyroxine exposure rose 33% [3]. That is a semaglutide finding, not a tirzepatide one.

What else the labels warn about

The interaction table does not cover the class safety warnings that apply regardless of co-medication: acute pancreatitis, severe GI reactions (not recommended in severe gastroparesis), acute kidney injury from volume depletion, gallbladder disease, serious hypersensitivity, diabetic retinopathy complications and pulmonary aspiration during anesthesia or deep sedation, as listed on the Wegovy and Foundayo labels [3][5]. Zepbound carries a boxed warning about thyroid C-cell tumors and is contraindicated for people with a personal or family history of medullary thyroid carcinoma or MEN 2 [1].

Practical summary

• Insulin or a sulfonylurea: the label advises considering a lower dose of that drug when starting [1].
• Oral contraceptives: for tirzepatide, the label advises a non-oral method or a barrier method for 4 weeks after starting and for 4 weeks after each dose increase [1].
• Narrow therapeutic index oral drugs: tirzepatide delays gastric emptying and may affect absorption of oral medicines [1]. The Wegovy label separately advises closer monitoring for some oral medicines [3].
• A second GLP-1 receptor agonist: the Wegovy, Saxenda, Zepbound and Foundayo labels say concomitant use is not recommended [3][4][1][5].