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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.

Key Publications

  • NEWJun Head-to-head comparative effectiveness of empagliflozin versus dapagliflozin and DPP-4 inhibitors on clinical and metabolic outcomes: a nationwide propensity-matched study. (Scientific reports, 2026, PMID 42342812): "This retrospective study compared the clinical and metabolic effectiveness of empagliflozin (EMPA) versus dapagliflozin (DAPA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) using real-world data from the Korean National Health Insurance Service (2013-2024)."
  • May Real-world evidence of urinary tract infections and genital tract infections with sodium-glucose cotransporter-2 inhibitors (SGLT2i) alone or in combination with dipeptidyl peptidase-4 inhibitors (DPP4i) in individuals with type-2 diabetes mellitus in India. (BMC endocrine disorders, 2026, PMID 42163184): "The impact of combining SGLT2i with Dipeptidyl peptidase-4 inhibitors (DPP4i) on infection risk also requires investigation in this setting."
  • May Association Between Dipeptidyl Peptidase-4 Inhibitor Use and Acute Kidney Injury in Patients With Diabetes Mellitus: A Disproportionality Analysis Based on the FAERS. (In vivo (Athens, Greece), 2026, PMID 42049410): "Although dipeptidyl peptidase-4 inhibitors (DPP4is) are widely used in the treatment of diabetes, a known risk factor for renal function decline, the potential association between DPP4i use and acute kidney injury (AKI) remains controversial."
  • Jun Association of GLP-1 Receptor Agonists With Hepatic Decompensation in the All of Us Research Program. (Diabetes, obesity & metabolism, 2026, PMID 41847743): "To evaluate the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) initiation and the risk of hepatic decompensation compared with dipeptidyl peptidase 4 inhibitors (DPP4is) in a racially and ethnically diverse cohort of adults with Type 2 diabetes."
  • Jun Association between glucagon-like peptide-1 receptor agonists and femur fracture risk in type 2 diabetes: A large-scale target trial emulation. (Bone, 2026, PMID 41819195): "...femur fracture risk associated with GLP-1 RAs versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in T2DM patients..."
  • May Sustained glucagon-like peptide-1 receptor agonist treatment improves glycemic control and reduces all-cause mortality compared to dipeptidyl peptidase-4 inhibitors: A real-world target trial emulation in type 2 diabetes. (Diabetes, obesity & metabolism, 2026, PMID 41741950): "Sustained glucagon-like peptide-1 receptor agonist treatment improves glycemic control and reduces all-cause mortality compared to dipeptidyl peptidase-4 inhibitors: A real-world target trial emulation in type 2 diabetes."
  • May Repurposing SGLT2 and DPP-4 inhibitors for mild cognitive impairment in type 2 diabetes mellitus: Insights from proteomics, target prediction and molecular docking. (British journal of pharmacology, 2026, PMID 41587770): "Accordingly, there is a growing interest in the potential neuroprotective benefits of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT2is)."
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