GLP-1RA & DPP-4 inhibitors: a non-recommended combination in diabetes
Insights from the Clinical Department: Dr. Shiri Guy-Alfandary, Pharm D.
Alert Category: Duplicate therapy module
Case Description: Common alerts for prescribing two medications belonging to the incretin family.
Clinical Rationale:
In recent years, new diabetes medications have been introduced that mimic the physiological mechanism of glucose regulation in response to rising blood sugar levels—known as incretins.
Incretins, such as GLP-1 (Glucagon-Like Peptide 1), are secreted by endocrine cells in the gastrointestinal tract after a meal and help lower glucose levels. They enhance glucose-dependent insulin secretion from the pancreas, reduce glucagon levels in response to elevated glucose, slow gastric emptying, and contribute to increased satiety.
Endogenous GLP-1 has a very short half-life of approximately 1-2 minutes and is rapidly inactivated by the enzyme DPP-4 (Dipeptidyl Peptidase 4). These insights led to the development of two pharmacological classes aimed at increasing GLP-1 levels and its effects:
DPP-4 inhibitors – Prolong the half-life of endogenous GLP-1.
GLP-1 receptor agonists (GLP-1 RAs) – Resistant to degradation by DPP-4.
GLP-1 RAs are more effective in reducing glucose levels compared to DPP-4 inhibitors. Additionally, they offer significant clinical benefits, including reduced cardiovascular morbidity and mortality, decreased progression of nephropathy, and weight loss (whereas DPP-4 inhibitors are weight-neutral).
While combining different drug classes is common in diabetes treatment to achieve target outcomes, the combination of these two classes—which share an overlapping mechanism of action—is not recommended. This combination adds to the patient's medication burden and unnecessary costs (DPP-4 inhibitors are not included in the national drug formulary) without providing meaningful additional efficacy. Moreover, it may increase the risk of side effects.
The latest guidelines from the American Diabetes Association (ADA), the American Association of Clinical Endocrinology (AACE), and the U.S. Food and Drug Administration (FDA) do not support the combined use of GLP-1 RAs (including dual GIP/GLP-1 RAs) with DPP-4 inhibitors due to the lack of additional clinical benefit.
Recommendation
Recommend considering discontinuation of DPP-4 inhibitors and continuing with GLP-1 agonists.
References:
Lajthia E, Bucheit JD, Nadpara PA, et al. Combination therapy with once-weekly glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a case series. Pharm Pract (Granada). 2019 Oct-Dec;17(4):1588. Available at: https://doi.org/10.18549/PharmPract.2019.4.1588
Samson SL, Vellanki P, Blonde L, et al. American Association of Clinical Endocrinology Consensus Statement: Comprehensive Type 2 Diabetes Management Algorithm – 2023 Update. Endocr Pract. 2023;29(5):305-340. Available at: https://doi.org/10.1016/j.eprac.2023.02.001.
Gallwitz, Baptist. (2019). Clinical Use of DPP-4 Inhibitors. Frontiers in Endocrinology. 10.3389/fendo.2019.00389, 10.
Nauck, Michael A. Addition of dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes. Diabetes Obesity and Metabolism. (2):200-207. dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.12802.
American Diabetes Association. (2019). Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes −2019. Diabetes Care. 42 (Suppl 1).
Davies, M.J., D'Alessio, D.A., Fradkin, J., Kernan, WN., Mathieu, C., Mingrone, G., et al. (2018). Management of hyperglycemia in type 2 diabetes, 2018, a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 41:2669–701.
Scheen, André J. (2017). Pharmacotherapy of ‘treatment resistant’ type 2 diabetes. Expert Opinion on Pharmacotherapy. 10.1080/14656566.2017.1297424, 18, 5, (503-515). tandfonline.com/doi/full/10.1080/14656566.2017.1297424