Drug Alert – Concurrent Use of GLP-1 and DPP-4

We are committed to helping our members with diabetes. Managing this disease is complex. You can assist in simplifying medication regimens by reviewing and eliminating medicines with no added clinical benefit.

The American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) recommend glucagon-like peptide 1 receptor agonists (GLP-1) as an add-on therapy to oral agents and in combination with insulin for the treatment of diabetes.* Current guidelines by the ADA and AACE, as well as the Food & Drug Administration (FDA), do NOT support combination therapy of GLP-1 and dipeptidyl peptidase 4 inhibitors (DPP-4) due to lack of added clinical benefit.

*All GLP-1 agonists (except Wegovy and Saxenda) are indicated ONLY for type 2 diabetes.

What To Do If Your Patient Is Concurrently on a DPP-4 and GLP-1 Agent

Consider stopping DPP-4 inhibitors and continuing GLP-1 agonists whenever possible.** See the tables below for applicable medications.

Advantages to utilizing GLP-1 agonists:

• Results in more potent HbA1c reduction.
• Associated with weight loss (DPP-4 inhibitors are weight-neutral).
• Showed renal and cardiovascular benefits (REWIND and LEADER trials), making them superior to DPP-4 inhibitors for the treatment of type 2 diabetes.

**Individual patient and clinical presentation factors should be taken into consideration.

Why the Combination Is Not Recommended

From a patient perspective:

• Increased pill burden, which may lead to decreased adherence.
• Increased cost (high copays, higher likelihood of reaching coverage gap sooner for Medicare members).
• Possible increased risk of side effects (gastrointestinal disturbances, pancreatitis, etc.).

From a clinical perspective:

• The mechanism of action by which GLP-1 and DPP-4 medications control blood glucose is by targeting the body’s incretin system. GLP-1 agonists act as “incretin mimetics” and DPP-4 inhibitors prevent the breakdown of endogenous incretin.
• It is common to think that using these medications together would result in improved diabetic control. However, this is not the case. Unlike endogenous incretin, GLP-1 is not broken down by the DPP-4 enzyme. Therefore, using these medications at the same time yields no additional benefit.

The following tables show the medications that contain GLP-1 agonists and DPP-4 inhibitors as standalone medicines and combination with other drugs.

References:

• 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.
• Lajthia, E., Bucheit, J.D., Nadpara, P.A., Dixon, D.L., Caldas, L.M., Murchie, M., Sisson, E.M. (2019 Dec. 12 [cited 2023 May 17]). Combination therapy with once-weekly glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a case series. Pharmacy Practice (Granada). 17(4):1588. pharmacypractice.org/index.php/pp/article/view/1588.