Critical Review of Sitagliptin Efficacy as Anticancer Agent: Hope or Hype?
Keywords:
Cancer, Dipeptidyl peptidase-4 inhibitor , DPP-4 , Drug repurposing , SitagliptinAbstract
Sitagliptin, a widely prescribed DPP-4 inhibitor for type 2 diabetes, has been implicated in both protective and harmful cancer associations, yet the totality of evidence remains unresolved. This narrative review synthesized evidence from 35 original articles (2010-2026) across in silico, in vitro, in vivo, and clinical investigations. In silico docking predicts high-affinity binding to DPP4, CTNNB1, MET, CD24, and SOX4. In vitro studies demonstrate antiproliferative, pro-apoptotic, and anti-migratory effects across multiple cancer cell lines; however, most used suprapharmacological concentrations (25-100 times therapeutic levels) raise clinical relevance concerns. In vivo studies show tumor suppression in hepatocellular carcinoma, prolonged survival in ovarian cancer, and protective effects in colon cancer models, though one study reported promotion of breast cancer metastasis. Clinical evidence is contradictory: meta-analyses show no overall increased cancer risk (OR 0.91-0.93), while Taiwanese cohort studies report protective effects for breast (HR 0.718), prostate (HR 0.613), and oral cancers (HR 0.345), but increased risks for pancreatic (HR 1.40-1.50) and thyroid (HR 1.52) cancers. Large Japanese and TECOS trials found no increased risk. Proposed mechanisms include immune modulation via CXCL10/CXCR3-mediated CD8+ T-cell trafficking, AMPK activation, HIF-1α suppression, NF-κB inhibition, epigenetic modulation, and apoptosis induction. Despite promising preclinical evidence, concentration disconnect and inconsistent clinical outcomes preclude clinical recommendation of sitagliptin as an anticancer agent. Metformin remains preferred in cancer patients; however, no strong evidence supports discontinuing sitagliptin, except possibly in those with a pancreatic cancer history. Prospective biomarker-driven trials are urgently needed.
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