Can patients be on both Glucagon-like peptide-1 receptor agonist (GLP1RA) and Dipeptidyl peptidase-4 inhibitor (DPP4i) simultaneously?

Patients Should Not Be on Both GLP-1RA and DPP-4i Simultaneously

Patients should not be on both GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) simultaneously as these medications work through the same pathway and their combination is specifically contraindicated in clinical guidelines. 1

Mechanism of Action and Rationale

Both medication classes work through the incretin pathway but in different ways:

• DPP-4 inhibitors: Block the enzyme that breaks down endogenous GLP-1
• GLP-1 receptor agonists: Directly activate GLP-1 receptors with synthetic analogs

Using both simultaneously is:

1. Pharmacologically redundant
2. Not associated with additional glycemic benefit
3. Potentially increases risk of adverse effects
4. Explicitly contraindicated in guidelines

Evidence from Guidelines

The 2024 DCRM guidelines clearly state: "Do not combine incretin classes (GLP-1 RA, GIP/GLP-1 RA, DPP4i)" 1. This recommendation appears in the section on hypoglycemia and heart failure risk, indicating safety concerns with combining these medication classes.

The 2018 ACC Expert Consensus Decision Pathway similarly states: "GLP-1RA should not be coadministered with DPP4 inhibitors given that they both work through GLP-1 signaling and have not been approved for use together" 1.

Appropriate Medication Selection Algorithm

For patients with type 2 diabetes requiring therapy beyond metformin:

1. First-line combination: Metformin + SGLT2i for most patients with eGFR ≥30 ml/min/1.73m² 1

2. When additional therapy is needed:

   • Preferred option: Add GLP-1RA (especially with established cardiovascular disease, obesity, or need for greater A1C reduction) 1
   • Alternative option: Add DPP-4i (especially when weight neutrality, lower cost, or oral administration is preferred) 1

3. When switching between incretin therapies:

   • When switching from DPP-4i to GLP-1RA: Discontinue the DPP-4i when initiating GLP-1RA 2
   • When switching from GLP-1RA to DPP-4i: Discontinue GLP-1RA when initiating DPP-4i

Clinical Considerations

• Efficacy comparison: GLP-1RAs provide superior glycemic control and weight loss compared to DPP-4i 3, 4
• Cardiovascular benefits: Several GLP-1RAs have demonstrated cardiovascular benefit, while DPP-4i are generally neutral 3, 4
• Safety concerns: Combining GLP-1RA with DPP-4i may potentially increase risk of certain adverse events, including some tumor-related adverse effects 5

Common Pitfalls to Avoid

1. Redundant prescribing: Some clinicians may mistakenly believe that combining these agents provides additive benefit due to their different mechanisms, but this is not supported by evidence

2. Failure to discontinue: When transitioning from DPP-4i to GLP-1RA, the DPP-4i should be discontinued rather than continued alongside the new medication 2

3. Cost implications: Using both medications simultaneously increases treatment cost without providing additional clinical benefit

Conclusion

The evidence clearly indicates that GLP-1RA and DPP-4i should not be used simultaneously. When intensifying therapy, clinicians should choose one incretin-based therapy based on patient characteristics, comorbidities, and preferences, but should not combine them.