DPP-4 Inhibitors and GLP-1 Receptor Agonists Should NOT Be Used Together
Concurrent use of DPP-4 inhibitors with a GLP-1 receptor agonist is not recommended due to lack of additional glucose lowering beyond that of a GLP-1 RA alone. 1
Mechanism Explaining Why Combination is Ineffective
Both drug classes work through the incretin pathway, but in fundamentally overlapping ways that make combination therapy redundant:
- DPP-4 inhibitors work by preventing the breakdown of endogenous GLP-1, increasing its levels by approximately 2-3 fold through enzyme inhibition 2, 3
- GLP-1 receptor agonists directly activate the same GLP-1 receptors with pharmacologic doses that far exceed what DPP-4 inhibition can achieve 4
- When a GLP-1 receptor agonist is already saturating the GLP-1 receptors, preventing breakdown of endogenous GLP-1 adds no meaningful benefit 1
Clear Guideline Recommendation
The 2025 American Diabetes Association Standards of Care explicitly states that treatment with DPP-4 inhibitors should be stopped when GLP-1 receptor agonists are used 3. This recommendation is based on the understanding that:
- No additional HbA1c reduction occurs when combining these agents 1
- The combination increases medication burden and cost without clinical benefit 1
- GLP-1 receptor agonists are more potent, reducing HbA1c by 0.8-1.7% compared to DPP-4 inhibitors' 0.5-1.1% reduction 5
What to Do Instead
When escalating therapy beyond a DPP-4 inhibitor:
- Discontinue the DPP-4 inhibitor before starting a GLP-1 receptor agonist 3
- If already on a GLP-1 receptor agonist and considering additional therapy, choose from non-incretin options such as SGLT-2 inhibitors, insulin, or metformin 1
- The combination of GLP-1 receptor agonists with SGLT-2 inhibitors has demonstrated HbA1c-lowering and weight-reduction efficacy, though cardiorenal endpoint data for this specific combination are still pending 1
Common Pitfall to Avoid
Do not assume that because both drugs work on the incretin system through different mechanisms (one preventing breakdown, one directly stimulating), they would be synergistic. The clinical reality is that GLP-1 receptor agonists provide supraphysiologic receptor activation that makes endogenous GLP-1 preservation irrelevant 1, 3.