From the Guidelines
Combining GLP-1 receptor agonists with DPP-4 inhibitors is not recommended in diabetes management due to the lack of additional glucose-lowering benefits beyond that of a GLP-1 RA alone. This recommendation is based on the most recent and highest quality study, which states that concurrent use of DPP-4 inhibitors with a GLP-1 RA or a dual GIP and GLP-1 RA is not recommended due to lack of additional glucose lowering beyond that of a GLP-1 RA alone 1. The reasoning behind this is that both medication classes work through the same incretin pathway, and when a GLP-1 receptor agonist is already providing substantial receptor stimulation, adding a DPP-4 inhibitor offers little additional effect.
Some key points to consider when managing diabetes include:
- GLP-1 receptor agonists directly activate GLP-1 receptors, while DPP-4 inhibitors work by preventing the breakdown of endogenous GLP-1
- Studies have shown only marginal improvements in HbA1c (typically less than 0.3%) when combining these medications, which doesn't justify the additional cost, pill burden, and potential for adverse effects 1
- Instead, patients requiring therapy beyond a GLP-1 agonist should consider adding medications with complementary mechanisms of action, such as SGLT-2 inhibitors, insulin, or other classes that target different pathways in glucose regulation
- This approach provides better glycemic control through synergistic effects rather than redundant mechanisms, and is supported by guidelines that recommend against combining incretin classes (GLP-1 RA, GIP/GLP-1 RA, DPP4i) 1.
Overall, the focus should be on optimizing glycemic control while minimizing potential harms and costs, and the combination of GLP-1 and DPP-4 inhibitors does not align with this goal.
From the Research
Reasons for Not Recommending GLP-1 and DPP4 Combination Therapy
- The combination of GLP-1 receptor agonists and DPP-4 inhibitors is not recommended due to a lack of evidence showing synergistic effects 2.
- Studies have shown that concomitant use of once-weekly GLP-1 RAs and DPP-4 inhibitors provides only modest improvement in glycemic control with minimal weight loss benefits, similar to monotherapy with either agent 2.
- The combination is unlikely to be cost-effective, supporting current recommendations against the use of combined incretin therapy 2.
- Clinical guidelines indicate that GLP-1 RAs and DPP-4 inhibitors are both effective for glycemic management in patients with type 2 diabetes, but GLP-1 RAs may be preferred due to greater reductions in hemoglobin A1c and weight loss observed in clinical trials 3.
- The use of DPP-4 inhibitors and GLP-1 analogues in combination with other therapies, such as metformin or insulin, has been explored, but the evidence for combination therapy with GLP-1 and DPP4 is limited 4, 5.
Efficacy and Safety of GLP-1 and DPP4 Inhibitors
- GLP-1 receptor agonists have demonstrated superior efficacy to DPP-4 inhibitors in terms of glycemic control and weight loss, but are associated with a higher incidence of gastrointestinal adverse events 3.
- DPP-4 inhibitors have a modest impact on glycemic control, are generally well-tolerated, and do not increase the risk of hypoglycemia 3.
- Both GLP-1 RAs and DPP-4 inhibitors have demonstrated safety in robust cardiovascular outcome trials, with some GLP-1 RAs showing a significant reduction in the risk of major adverse cardiovascular events in patients with pre-existing cardiovascular disease 3, 6.
Future Directions
- Further studies are needed to determine the long-term effects of GLP-1 based agents on glycemic control and their potential impact on beta-cell function in humans 4.
- The use of GLP-1 analogues and DPP-4 inhibitors in combination with other therapies, such as insulin, requires further investigation to fully understand their efficacy and safety 5.