DPP-4 Inhibitors Should NOT Be Combined with GLP-1/GIP Receptor Agonists
Concurrent use of DPP-4 inhibitors with a GLP-1 receptor agonist or a dual GIP and GLP-1 receptor agonist is not recommended due to lack of additional glucose lowering beyond that of a GLP-1 receptor agonist alone. 1
Why This Combination Doesn't Work
The mechanism of action explains why combining these agents provides no benefit:
DPP-4 inhibitors work by preventing the breakdown of endogenous GLP-1, increasing its circulating levels by blocking the enzyme (DPP-4) that degrades it 2, 3
GLP-1 receptor agonists are exogenous GLP-1 analogs that directly activate GLP-1 receptors at pharmacologic doses, providing much more potent GLP-1 activity than what DPP-4 inhibitors can achieve through preserving endogenous GLP-1 2, 4
When you're already flooding the system with exogenous GLP-1 (or GLP-1/GIP) through receptor agonists, preserving a small amount of additional endogenous GLP-1 by blocking DPP-4 adds nothing meaningful 1
The Evidence Against Combination
The 2025 American Diabetes Association Standards of Care explicitly state this as a formal recommendation:
GLP-1 receptor agonists provide superior HbA1c reduction (0.5-1.5%) compared to DPP-4 inhibitors (0.4-0.9%) 2
The 2018 ADA/EASD consensus specifically warns against prescribing GLP-1 receptor agonists and DPP-4 inhibitors in combination 1
This prohibition extends to dual GIP and GLP-1 receptor agonists (like tirzepatide), as they work through the same GLP-1 receptor pathway 1
What You Should Do Instead
If a patient is on a DPP-4 inhibitor and needs intensification:
Switch from the DPP-4 inhibitor to a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist rather than adding them together 1
GLP-1 receptor agonists (including dual GIP/GLP-1 agonists) are preferred over DPP-4 inhibitors when injectable therapy is acceptable, given their superior efficacy for glucose lowering, weight reduction, and cardiovascular benefits 1
If combining with insulin, use the GLP-1/GIP receptor agonist with insulin rather than DPP-4 inhibitor with insulin, as this provides greater glycemic effectiveness and beneficial effects on weight and hypoglycemia risk 1
Common Pitfall to Avoid
Do not assume that because both drugs work on the incretin system they will have additive effects - the GLP-1 receptor agonist completely overshadows any benefit from DPP-4 inhibition, making the combination wasteful and exposing patients to unnecessary medication costs and potential side effects from the DPP-4 inhibitor 1