Long-Term Safety of Dpp-4 Inhibitors: An Insight from Clinical Trials and Real-World Evidence

Md Nematullah¹, Javed Akhtar Ansari^1*, Mukhtar Ahmad², Najish Parveen¹, Syed Shadab Ahmad¹, Syed Mehdi Hasan Zaidi¹

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ABSTRACT

Type 2 diabetes mellitus (T2DM) is a major global health challenge characterized by chronic hyperglycaemia, insulin resistance, and progressive β-cell dysfunction. Effective management involves long-term glycaemic control while minimizing the adverse effects. Dipeptidyl peptidase-4 (DPP-4) inhibitors are an important class of oral antihyperglycemic agents that work through the enzymatic degradation of incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), enhancing glucose-dependent insulin secretion, suppressing glucagon release, and supporting metabolic homeostasis. The most widely used drugs, such as sitagliptin, saxagliptin, linagliptin, and alogliptin, are well-tolerated and generally considered safe, making them suitable for use in elderly patients and those with chronic kidney disease (CKD). CVOTs, including SAVOR-TIMI 53 and EXAMINE, have demonstrated overall cardiovascular safety; however, saxagliptin has been associated with an increased risk of cardiovascular complications. Renal outcomes are largely neutral, with modest reductions in albuminuria but no consistent decline in long-term estimated glomerular filtration rate (eGFR). Concerns regarding malignancy, pancreatitis, infections, and autoimmune conditions have not been established in controlled studies, underscoring the need for continued real-world safety assessment.

Keywords: Type 2 Diabetes Mellitus; DPP-4 Inhibitors; GLP-1; GIP; Real-World Evidence; Drug safety.

How to cite this article: Nematullah M, Ansari JA, Ahmad M, Parveen N, Ahmad SS, Zaidi SMH. Long-Term Safety of Dpp-4 Inhibitors: An Insight from Clinical Trials and Real-World Evidence. Int J Drug Deliv Technol. 2026;16(5s): 579-597; DOI: 10.25258/ijddt.16.5s.75

Source of support: Nil.

Conflict of interest: None