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Background  Although many clinical parameters have been identified as predictors for cardiovascular disease (CVD) development in the general population, the accurate predictor for CVD in patients with obesity is still unknown.    Objective  The study aimed to explore an additional risk factor and predictor for CVD in patients with overweight/obesity considering the interaction of obesity‐related pathophysiology.    Methods  The Japan Obesity and Metabolic Syndrome study, a multicenter prospective study, enrolled 787 outpatients, of which 318 eligible patients were analyzed. Patients with fasting plasma glucose (FPG) levels ≥6.11 and < 6.11 mmol/L were considered to have high FPG (HFPG) and normal FPG (NFPG), respectively. Thirty‐six patients who developed CVD during the 5 years follow‐up were assigned to the CVD group.    Results  Cox's proportional hazards model revealed no significant association between CVD and cystatin C‐based estimated glomerular filtration rate (eGFRcys) or creatinine‐based eGFR (eGFRcr) in the NFPG group. In the HFPG group, lower eGFRcys, but not eGFRcr, was significantly associated with CVD development. A generalized linear mixed model demonstrated greater reduction in eGFRcys levels over time with HFPG than with NFPG. Although the CVD group showed gradual reduction in eGFRcys levels, the non‐CVD group—matched using propensity scores—did not show a decline in eGFRcys levels.    Conclusions  Lower eGFRcys levels may be more accurate than eGFRcr in predicting CVD development in patients with overweight/obesity and hyperglycemia. Furthermore, eGFRcys reduction over time is associated with CVD development.    Clinical Trial Registry Number  UMIN559

Cystatin C‐based eGFR predicts cardiovascular disease in patients with overweight/obesity and hyperglycemia