| Summary: | Abstract Background Omarigliptin is a potent, selective, oral dipeptidyl peptidase 4 (DPP4) inhibitor with a half-life that allows weekly dosing. Inflammation or insulin resistance might be pathological mediators of cardiovascular events in patients with type 2 diabetes. Methods Whether omarigliptin has anti-inflammatory effects that result in decreased levels of high-sensitivity C-reactive protein (hsCRP) and anti-insulin resistance effects that decrease levels of homeostatic model assessment of insulin resistance (HOMA-IR) were investigated. Patients were allocated to continue with daily DPP4 inhibitors (control, n = 28) or to switch from daily DPP4 inhibitors to weekly omarigliptin (omarigliptin, n = 56). Fasting blood and urine samples were collected before, and every 3 months after intervention for 1 year. Results Omarigliptin tended to elicit reductions in fasting blood glucose (FBG), LDL-cholesterol, triglyceride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), the urinary albumin-to-creatinine ratio (ACR) with logarithmic transformation (log ACR), and systolic and diastolic blood pressure, but the differences did not reach statistical significance compared with control. Values for HDL-cholesterol tended to increase, but also did not reach statistical significance compared with control. Omarigliptin significantly decreased HOMA-IR, remnant-like particle cholesterol (RLP-C), and hsCRP with logarithmic transformation (log hsCRP) compared with control. However, omarigliptin did not affect hemoglobin A1c (HbA1c), body mass index (BMI), and estimated glomerular filtration rates (eGFR). Conclusion Omarigliptin decreased inflammation and insulin resistance without affecting HbA1c or BMI. Although how DPP4 inhibitors affect cardiovascular (CV) outcomes remains uncertain, omarigliptin might confer CV benefits at least in part, via pleiotropic anti-inflammatory or anti-insulin resistance effects. Trial registration UMIN Clinical Registry (UMIN000029288). Registered 22 September, 2017, https://upload.umin.ac.jp/UMIN000029288
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