dipeptidyl peptidase-4 inhibitors
dipeptidyl peptidase-4 inhibitors
Overview
Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, also termed DPP-4is or gliptins) are a class of oral antihyperglycemic agents widely used in the management of type 2 diabetes mellitus (T2DM). They act by blocking the enzyme dipeptidyl peptidase-4, which is responsible for the rapid degradation of incretin hormones, most notably glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, these drugs prolong the activity of endogenous incretins, thereby enhancing glucose-dependent insulin secretion, suppressing glucagon release, and improving overall glycemic control with a relatively low risk of hypoglycemia. Commonly used agents in this class include sitagliptin, saxagliptin, alogliptin, linagliptin, and vildagliptin. DPP-4 inhibitors are generally well tolerated, weight-neutral, and suitable for use across a broad range of patients, including older adults and those with renal impairment at adjusted doses.
Beyond their primary glucose-lowering role, DPP-4 inhibitors have attracted significant scientific interest for their potential pleiotropic effects on hepatic, renal, cardiovascular, and neurological systems. As the therapeutic landscape for type 2 diabetes has expanded—with newer agents such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium glucose cotransporter-2 (SGLT2) inhibitors (SGLT2 inhibitors) demonstrating cardiometabolic and organ-protective benefits—DPP-4 inhibitors have increasingly been used as active comparators in head-to-head clinical and real-world studies. This positioning reflects their established safety profile and widespread clinical use, making them a natural reference class for evaluating the incremental benefits of emerging diabetes therapies.
Focus of Latest Publications
Recent publications have continued to evaluate dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) largely in comparative effectiveness and safety studies in type 2 diabetes. In a nationwide Korean propensity-matched cohort study, empagliflozin was compared with dapagliflozin and with DPP-4 inhibitors in adults who initiated therapy and maintained treatment for more than 365 days. Relative to DPP-4 inhibitors, empagliflozin was associated with lower risks of all-cause hospitalization and kidney events, while the authors concluded that empagliflozin and dapagliflozin showed broadly similar outcomes consistent with a class effect. The study also noted that acute safety outcomes such as hypoglycemia and diabetic ketoacidosis were assessed exploratorily because the sustained-exposure design may underrepresent early events.
Other recent work has focused on adverse-event surveillance and combination therapy. A disproportionality analysis using the FAERS database examined whether DPP-4 inhibitor use was associated with acute kidney injury in patients with diabetes mellitus, reflecting ongoing concern about renal safety. In India, real-world evidence was sought on urinary tract and genital tract infections with sodium-glucose cotransporter-2 inhibitors alone or in combination with DPP-4 inhibitors in individuals with type 2 diabetes mellitus, indicating interest in infection risk when these therapies are used together.
DPP-4 inhibitors have also served as comparators in studies of glucagon-like peptide-1 receptor agonists. One real-world target trial emulation evaluated hepatic decompensation risk with GLP-1 receptor agonist initiation versus DPP-4 inhibitors in a racially and ethnically diverse cohort of adults with type 2 diabetes. Another large-scale target trial emulation compared GLP-1 receptor agonists with DPP-4 inhibitors for femur fracture risk in type 2 diabetes, and a separate real-world target trial emulation assessed sustained GLP-1 receptor agonist treatment versus DPP-4 inhibitors for glycemic control and all-cause mortality.
Beyond cardiometabolic outcomes, DPP-4 inhibitors have been explored for potential neuroprotective applications. A proteomics, target prediction, and molecular docking study investigated repurposing SGLT2 and DPP-4 inhibitors for mild cognitive impairment in type 2 diabetes mellitus, specifically examining how these agents, in combination with metformin, might confer neuroprotection.