From the Guidelines
DPP4 inhibitors should not be taken with GLP1 agonists due to the lack of additional glucose-lowering benefits beyond that of a GLP1 agonist alone. This recommendation is based on the most recent and highest quality study, which suggests that concurrent use of DPP4 inhibitors with a GLP1 receptor agonist (RA) or a dual GIP and GLP1 RA is not recommended 1. The study, published in 2025 in the journal Diabetes Care, highlights the lack of additional glucose-lowering effects when combining these two medication classes.
When considering the use of DPP4 inhibitors and GLP1 agonists together, it is essential to weigh the potential benefits against the potential risks and costs. While both medication classes work on the incretin system to improve blood glucose control, their mechanisms of action are different. DPP4 inhibitors prevent the breakdown of naturally occurring GLP1, whereas GLP1 agonists directly stimulate GLP1 receptors at much higher levels than the body naturally produces. However, the combination of these medications may not provide significant additional benefits, and the cost-effectiveness of this combination is a concern.
It is also important to consider the potential side effects of combining DPP4 inhibitors and GLP1 agonists. GLP1 agonists are commonly associated with nausea, vomiting, and diarrhea, while DPP4 inhibitors are generally well-tolerated. Patients should maintain regular blood glucose monitoring when using this combination and report any unusual side effects to their healthcare provider. Another study published in 2022 in the journal Gastroenterology also advises caution when using GLP1 RAs in combination with other medications, including insulin or insulin secretagogues, due to the potential risk of hypoglycemia 1.
In terms of specific medications, examples of DPP4 inhibitors include sitagliptin, saxagliptin, linagliptin, and alogliptin, while examples of GLP1 agonists include semaglutide, liraglutide, dulaglutide, and exenatide. However, the most recent and highest quality study suggests that the combination of these medications is not recommended, regardless of the specific medications used 1.
Key points to consider when evaluating the use of DPP4 inhibitors and GLP1 agonists together include:
- Lack of additional glucose-lowering benefits beyond that of a GLP1 agonist alone
- Potential risks and costs associated with combining these medications
- Different mechanisms of action for DPP4 inhibitors and GLP1 agonists
- Potential side effects, including nausea, vomiting, and diarrhea associated with GLP1 agonists
- Importance of regular blood glucose monitoring and reporting unusual side effects to healthcare providers.
From the Research
Combination Therapy of DPP4 Inhibitors and GLP1 Agonists
- The use of DPP4 inhibitors and GLP1 agonists in combination is a topic of interest in the treatment of type 2 diabetes, as both classes of drugs have shown benefits in improving glycemic control and reducing the risk of hypoglycemia 2, 3.
- Studies have investigated the efficacy and safety of combining DPP4 inhibitors with GLP1 agonists, with some trials suggesting that this combination may be effective in reducing HbA1c levels and promoting weight loss 3, 4.
- However, other studies have raised questions about the benefits of combining these two classes of drugs, citing potential limitations in terms of efficacy and safety 5.
Efficacy and Safety of Combination Therapy
- A systematic review of randomized controlled trials found that the combination of DPP4 inhibitors and GLP1 analogues with insulin resulted in significant reductions in HbA1c levels, with minimal effects on weight and hypoglycemia rates 3.
- Another study found that the addition of a DPP4 inhibitor to ongoing therapy with a GLP1 receptor agonist resulted in increased intact GLP1 and GIP concentrations, but had marginal, non-significant effects on glycemic control 5.
- The safety profile of combination therapy with DPP4 inhibitors and GLP1 agonists appears to be favorable, with minimal reports of adverse events or hypoglycemia 2, 4.
Clinical Implications
- The decision to use DPP4 inhibitors and GLP1 agonists in combination should be individualized, taking into account the patient's clinical characteristics, medical history, and response to therapy 4, 5.
- Further studies are needed to fully elucidate the benefits and risks of combination therapy with DPP4 inhibitors and GLP1 agonists, including long-term trials and head-to-head comparisons with other treatment regimens 3, 6.