Why can't DPP-4 (Dipeptidyl Peptidase-4) inhibitors and GLP-1 (Glucagon-Like Peptide-1) receptor agonists be taken together?

DPP-4 Inhibitors and GLP-1 Receptor Agonists Should Not Be Used Together

Concurrent use of dipeptidyl peptidase-4 (DPP-4) inhibitors with GLP-1 receptor agonists (GLP-1 RAs) or dual GIP/GLP-1 RAs is not recommended due to lack of additional glucose lowering beyond that of a GLP-1 RA alone. 1

Mechanism of Action and Redundancy

• Both medication classes work through the same incretin pathway, making their combination pharmacologically redundant 2
• DPP-4 inhibitors work by blocking the enzyme that breaks down endogenous GLP-1, thereby increasing natural GLP-1 levels 2
• GLP-1 RAs directly activate GLP-1 receptors with synthetic analogues, bypassing the need for DPP-4 inhibition 2
• Using both medications simultaneously provides no synergistic effect as they target the same pathway 2

Evidence Against Combination Therapy

• The American Diabetes Association's 2025 Standards of Care explicitly states that concurrent use of DPP-4 inhibitors with GLP-1 RAs is not recommended 1
• The KDIGO 2022 clinical practice guideline for diabetes management in CKD also explicitly recommends against using GLP-1 RAs in combination with DPP-4 inhibitors 2
• Clinical data shows that combining once-weekly GLP-1 RAs with DPP-4 inhibitors provides only modest improvement in glycemic control with minimal weight loss benefits, similar to monotherapy with either agent alone 3
• The combination is not cost-effective and unlikely to provide synergistic effects 3

Comparative Efficacy

• GLP-1 RAs provide greater HbA1c reduction (0.5-1.5%) and significant weight loss benefits 2, 4
• DPP-4 inhibitors offer only moderate glucose-lowering efficacy (0.4-0.9%), are weight neutral, and are administered orally 2, 5
• Head-to-head clinical trials have consistently demonstrated that GLP-1 RAs provide superior glycemic control and weight loss compared to DPP-4 inhibitors 4

Recommended Treatment Approach

• When intensifying therapy, guidelines recommend starting with metformin, then adding SGLT2 inhibitors (especially in patients with CKD), and then adding GLP-1 RAs if glycemic targets are not met 2
• For patients with type 2 diabetes and CKD who have not achieved glycemic targets with metformin and SGLT2i, guidelines specifically recommend a long-acting GLP-1 receptor agonist rather than a DPP-4 inhibitor 2
• In adults with type 2 diabetes and no evidence of insulin deficiency, a GLP-1 RA is preferred to insulin 1
• If insulin is used, combination therapy with a GLP-1 RA is recommended for greater glycemic effectiveness and beneficial effects on weight and hypoglycemia risk 1

Safety Considerations

• Both medication classes have distinct side effect profiles 2
• DPP-4 inhibitors have potential concerns regarding pancreatitis, and some agents (saxagliptin and alogliptin) have associations with increased risk of heart failure hospitalization 2, 1
• GLP-1 RAs are associated with gastrointestinal adverse events, particularly nausea, vomiting, and diarrhea 4
• When switching from a DPP-4 inhibitor to a GLP-1 RA, improved glycemic control and weight loss are typically observed 4

Clinical Decision Making

• When a patient is already on a GLP-1 RA, adding a DPP-4 inhibitor provides no additional benefit and should be avoided 1, 2
• When a patient is on a DPP-4 inhibitor but requires additional glycemic control, consider switching to a GLP-1 RA rather than adding it on top of the DPP-4 inhibitor 2, 4
• For patients who cannot tolerate GLP-1 RAs due to gastrointestinal side effects, a DPP-4 inhibitor may be an alternative option, but they should not be used together 2, 6