What are the contraindications for Glucagon-like peptide-1 (GLP-1) and Dipeptidyl peptidase-4 (DPP-4) therapy, according to the American Diabetes Association (ADA) guidelines?

From the Guidelines

GLP-1 receptor agonists and DPP-4 inhibitors are not recommended in patients with a history of medullary thyroid carcinoma, Multiple Endocrine Neoplasia syndrome type 2, pancreatitis, or severe gastrointestinal disease, including gastroparesis, as well as those with severe renal impairment, according to the most recent American Diabetes Association (ADA) guidelines 1. When considering the use of GLP-1 receptor agonists, such as semaglutide, dulaglutide, and liraglutide, it is essential to weigh the potential benefits against the risks, particularly in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2, as these medications have been associated with thyroid C-cell tumors in animal studies 1. Additionally, GLP-1 receptor agonists are contraindicated in patients with a history of pancreatitis or severe gastrointestinal disease, including gastroparesis, and require caution in patients with severe renal impairment, with dose adjustments often necessary 1. DPP-4 inhibitors, such as sitagliptin, saxagliptin, and linagliptin, are not recommended as first-line therapy due to their modest efficacy compared to other options and require dose adjustments in patients with severe renal impairment 1. The decision to use these medications should be individualized based on patient characteristics, comorbidities, and preferences, with careful consideration of potential risks and benefits, prioritizing morbidity, mortality, and quality of life as the primary outcomes 1. Key considerations include:

• Contraindications: history of medullary thyroid carcinoma, Multiple Endocrine Neoplasia syndrome type 2, pancreatitis, or severe gastrointestinal disease, including gastroparesis
• Cautions: severe renal impairment, dose adjustments necessary
• Potential risks: thyroid C-cell tumors, pancreatitis, gastrointestinal disease, hypoglycemia
• Benefits: improved glycemic control, weight loss, cardiovascular risk reduction It is crucial to carefully evaluate the potential benefits and risks of GLP-1 receptor agonists and DPP-4 inhibitors in each patient, considering their individual characteristics, comorbidities, and preferences, to ensure optimal management of type 2 diabetes and minimize adverse outcomes 1.

From the FDA Drug Label

The American Diabetes Association (ADA) recommends that GLP-1 receptor agonists and DPP-4 inhibitors not be used in patients with a history of pancreatitis or thyroid cancer. The FDA drug label does not answer the question about GLP-1 and DPP4 therapy not recommended, citing ADA guidelines most recent.

From the Research

GLP-1 and DPP-4 Therapy Not Recommended

• The American Diabetes Association (ADA) guidelines do not explicitly state when GLP-1 and DPP-4 therapy is not recommended, but studies suggest that these therapies may not be suitable for certain patients.
• According to a study published in 2022 2, GLP-1 agonists and DPP-4 inhibitors are safe with respect to the risk of pancreatitis and pancreatic cancer compared to placebo.
• However, another study published in 2024 3 found that while DPP-4 inhibitors are not associated with an increased risk of pancreatitis or pancreatic cancer, subgroup analyses showed that sitagliptin was associated with a significant reduction in pancreatitis risk compared to the control group.
• A review of the literature published in 2024 4 found mixed data regarding the relationship between GLP-1 RA and DPP-4 inhibitors and pancreatic cancer, with some trials suggesting that they might increase the risk.
• A study published in 2011 5 found that GLP-1 receptor agonists and DPP-4 inhibitors have a positive effect on body weight, blood pressure, diabetic dyslipidemia, hepatic steatosis markers, and myocardial function, which could reduce the burden of cardiovascular disease in patients with diabetes.
• A systematic review and meta-analysis published in 2025 6 found that long-acting GLP-1RA reduce the incidence of major adverse cardiovascular events, hospitalization for heart failure, and kidney events, and all-cause mortality in type 2 diabetes, with no significant heterogeneity by GLP-1RA administration route (subcutaneous vs. oral).

Specific Patient Populations

• Patients with a history of pancreatitis or pancreatic cancer may need to be cautious when using GLP-1 and DPP-4 therapy, as the evidence is mixed regarding the risk of these conditions 3, 4.
• Patients with cardiovascular disease may benefit from GLP-1 and DPP-4 therapy, as these agents have been shown to reduce the risk of major adverse cardiovascular events and hospitalization for heart failure 6.
• Patients with kidney disease may also benefit from GLP-1 and DPP-4 therapy, as these agents have been shown to reduce the risk of kidney events and slow the progression of kidney disease 6.