BackgroundWeight control has consistently been regarded as a significant preventive measure against diabetic nephropathy. however, the potential impact of substantial fluctuations in body fat during this process on the risk of diabetic nephropathy remains uncertain. This study aimed to investigate the association between body fat variation rate and diabetic nephropathy incident in American patients with type 2 diabetes.MethodsThe study used data from the Action to Control Cardiovascular Risk in diabetes (ACCORD) trial to calculate body fat variation rates over two years and divided participants into Low and High groups. The hazard ratio and 95% confidence interval were estimated using a Cox proportional hazards model, and confounding variables were addressed using propensity score matching.ResultsFour thousand six hundred nine participants with type 2 diabetes were studied, with 1,511 cases of diabetic nephropathy observed over 5 years. High body fat variation rate was linked to a higher risk of diabetic nephropathy compared to low body fat variation rate (HR 1.13, 95% CI 1.01–1.26). Statistically significant interaction was observed between body fat variation rate and BMI (P interaction = 0.008), and high level of body fat variation rate was only associated with increased risk of diabetic nephropathy in participants with BMI > 30 (HR 1.34 and 95% CI 1.08–1.66).ConclusionsAmong participants with Type 2 Diabetes Mellitus, body fat variation rate was associated with increased risk of diabetic nephropathy. Furthermore, the association was modified by BMI, and positive association was demonstrated in obese but not non-obese individuals. Consequently, for obese patients with diabetes, a more gradual weight loss strategy is recommended to prevent drastic fluctuations in body fat.Trial registrationClinical Trials. gov, no. NCT000000620 (Registration Date 199909).Graphical