Can Januvia (sitagliptin) and tirzepatide be given together?

Combination of Januvia (Sitagliptin) and Tirzepatide

You are correct—Januvia (sitagliptin) and tirzepatide should NOT be given together. Both are incretin-based therapies, and combining agents from the incretin classes (DPP-4 inhibitors like sitagliptin and GIP/GLP-1 receptor agonists like tirzepatide) is explicitly contraindicated by current diabetes management guidelines. 1

Why This Combination Is Inappropriate

Mechanistic Redundancy

• Sitagliptin is a DPP-4 inhibitor that works by preventing the breakdown of endogenous GLP-1 and GIP, thereby increasing their circulating levels. 2, 3
• Tirzepatide is a dual GIP/GLP-1 receptor co-agonist that directly activates both GIP and GLP-1 receptors with pharmacologic doses of exogenous agonist. 4
• When tirzepatide is already providing supraphysiologic receptor activation, preventing the breakdown of endogenous incretins with sitagliptin adds no meaningful benefit—the receptors are already maximally stimulated by the exogenous agonist. 4

Explicit Guideline Prohibition

• The 2024 DCRM guidelines explicitly state: "do not combine agents from the incretin classes (GIP/GLP-1 RAs, GLP-1 RAs, and dipeptidyl peptidase 4 [DPP4] inhibitors) with each other." 1
• This prohibition applies to all combinations within the incretin class, including DPP-4 inhibitors with any GLP-1 or dual GIP/GLP-1 receptor agonist. 1

Clinical Implications

What to Do Instead

• If a patient is on sitagliptin and you want to initiate tirzepatide, discontinue the sitagliptin first. 1
• Tirzepatide has demonstrated superior glycemic control and weight loss compared to DPP-4 inhibitors, making it the preferred agent when escalation is needed. 5, 4
• Tirzepatide monotherapy reduces HbA1c by 1.24-2.58% and body weight by 5.4-11.7 kg, with 23.0-62.4% of patients achieving HbA1c <5.7%. 4

When Combination Therapy Is Appropriate

• Combination therapy in diabetes should involve agents with complementary (not overlapping) mechanisms of action. 1
• Appropriate combinations with tirzepatide include: metformin, SGLT2 inhibitors, thiazolidinediones, or basal insulin (with dose adjustment to minimize hypoglycemia risk). 1, 5
• Avoid combining tirzepatide with sulfonylureas or glinides together, as both increase hypoglycemia risk. 1

Common Pitfall to Avoid

• Do not assume that "more incretin effect is better." Once you provide exogenous receptor agonism with tirzepatide, adding a DPP-4 inhibitor provides no additional glycemic benefit and only increases medication burden and cost without improving outcomes. 1, 4