Effect of Hyperfiltration on the Kidneys and the Triglyceride (TG)-to-HDL Cholesterol (HDL-C) Ratio in Nondiabetic Individuals

Background: The rise of the cardio-renal-metabolic syndrome concept and broader use of SGLT2 inhibitors in non-diabetics mark a shift toward earlier intervention in kidney care. We conducted a study to assess whether glomerular hyperfiltration (GHF) or hyperinsulinemia, estimated by the TG/HDL-C ratio (TGR), more strongly predicts renal function decline in this population. Methods: This single-center observational study included individuals aged ≥18 years who underwent annual health checkups with serum creatinine measurements from 2012 to 2024. Participants were stratified by age and sex; strata with ≥200 subjects were included. GHF was defined as estimated glomerular filtration rate (eGFR) above the 95th percentile within each stratum; controls were those with eGFR >60 mL/min/1.73 m2 excluding GHF. The index date was the first checkup with GHF or the initial checkup during the study for controls. Hyperinsulinemia was estimated using TGR (cut-off: 2.1), and subjects were stratified into high and low TGR groups. Exclusion criteria were age <18, missing TG/HDL-C values, or HbA1c ≥6.5%. The primary outcome was time to a 30% eGFR decline, analyzed by Kaplan-Meier curves and Cox proportional hazards models. Results: A total of 5,654 individuals (mean age 48.7 years; 48.8% male; mean eGFR 79.0) were analyzed. GHF was observed in 611 subjects (mean eGFR 102.3), and 1,615 were categorized as high TGR. During follow-up, 183 participants (3.2%) experienced ≥30% eGFR decline. Kaplan-Meier analysis, adjusted for age and sex, showed significantly higher risk in the GHF group vs controls (log-rank p<0.001), while no significant difference was observed between high and low TGR groups (p=0.7). Cox regression showed a markedly elevated risk with GHF, while high TGR alone showed no significant association (Figure). Conclusion: GHF significantly increased renal risk regardless of TGR, while elevated TGR alone was not associated with additional risk. These findings suggest hyperfiltration is a dominant factor in renal decline among non-diabetic individuals, whereas surrogate hyperinsulinemia markers contribute little.