Can a patient take Januvia (Sitagliptin) and Mounjaro (Tirzepatide) together?

Combining Januvia and Mounjaro: Not Recommended

You should not combine Januvia (sitagliptin) and Mounjaro (tirzepatide) because they have overlapping mechanisms of action, and adding a DPP-4 inhibitor like sitagliptin to a GLP-1 receptor agonist provides minimal additional glycemic benefit while increasing costs and potential side effects. 1

Why This Combination Doesn't Make Sense

Overlapping Mechanisms

• Januvia (sitagliptin) is a DPP-4 inhibitor that works by increasing insulin secretion and reducing glucagon secretion in a glucose-dependent manner, with a mechanism of action that overlaps with Mounjaro (tirzepatide) 1
• Tirzepatide is a dual GIP and GLP-1 receptor agonist that already stimulates insulin secretion when hyperglycemia is present and inhibits glucagon secretion 2, 3
• The American Diabetes Association recommends selecting the most effective single agent rather than combining medications with overlapping mechanisms 1

Efficacy Hierarchy

• Tirzepatide has significantly higher glucose-lowering efficacy than DPP-4 inhibitors, reducing HbA1c by 2.01-2.30 percentage points compared to sitagliptin's 0.4-0.9% reduction 4, 5
• The American Heart Association recommends considering medication efficacy hierarchy, with tirzepatide having higher glucose-lowering efficacy than DPP-4 inhibitors 1
• In head-to-head trials, tirzepatide demonstrated superior glycemic control and greater weight loss compared to GLP-1 receptor agonists, making it far more potent than DPP-4 inhibitors 4

What to Do Instead

If Currently on Both Medications

• The American College of Physicians recommends assessing current glycemic control and maintaining the more effective agent (typically tirzepatide) if A1C is at target with current therapy 1
• Discontinue the sitagliptin and continue tirzepatide alone, as the tirzepatide provides superior efficacy 1

If Additional Glycemic Control Is Needed

• Consider optimizing the dose of tirzepatide before adding other agents (doses available: 5 mg, 10 mg, and 15 mg weekly) 1, 4
• Alternative approaches for additional glycemic control include adding metformin, SGLT2 inhibitors, or basal insulin, which have complementary mechanisms of action 1
• Metformin primarily targets fasting glucose by reducing hepatic glucose production and improves insulin sensitivity without increasing hypoglycemia risk 5
• SGLT2 inhibitors work through renal glucosuria and provide cardiovascular and renal benefits independent of glucose-lowering effects 6

Safety Considerations

Gastrointestinal Side Effects

• The American Diabetes Association recommends evaluating the risk of gastrointestinal side effects when combining DPP-4 inhibitors and GLP-1 receptor agonists 1
• Tirzepatide alone causes nausea (17-22%), diarrhea (13-16%), and vomiting (6-10%) 4
• Adding sitagliptin would not reduce these side effects and provides no meaningful benefit 1

Hypoglycemia Risk

• Tirzepatide has minimal hypoglycemia risk when used without sulfonylureas or insulin (0.2-1.7% incidence) 4
• DPP-4 inhibitors have minimal risk of hypoglycemia when used as monotherapy, but the combination offers no advantage 5

Special Population Considerations

Patients with Obesity

• For patients with obesity, tirzepatide alone provides significant weight loss benefits (5.5-11.2 kg greater than comparators), making additional DPP-4 inhibitor therapy counterproductive 1, 4

Patients with Cardiovascular Disease

• For patients with cardiovascular disease, the American College of Cardiology recommends using tirzepatide or GLP-1 receptor agonists over DPP-4 inhibitors 1
• Sitagliptin showed cardiovascular safety but no cardiovascular benefit in the TECOS trial 7, 8

Patients with Renal Impairment

• If renal function is a concern and dose adjustments are needed, this still does not justify combining both medications 7
• Tirzepatide can be used across all levels of renal function, though cardiovascular outcomes data are still pending 9

Common Pitfall to Avoid

Do not continue both medications simply because the patient was previously on sitagliptin before starting tirzepatide. The superior efficacy of tirzepatide makes the DPP-4 inhibitor redundant and wasteful 1, 4.