Cardiorespiratory Fitness and Risk of Microvascular Complications in Patients with Type 2 Diabetes Mellitus

Background: To investigate the association between cardiorespiratory fitness (CRF) and the risk of incident microvascular complications in patients with type 2 diabetes mellitus (T2DM), and to assess the effect of genetic risk and potential mediation by circulating biomarkers. Methods: This prospective analysis included 3,102 adults with T2DM from the UK Biobank. CRF was estimated as maximal oxygen uptake using a submaximal cycle test and categorized as low, moderate, or high. Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident diabetic nephropathy, retinopathy, and neuropathy. Interactions with a polygenic risk score and mediating roles of biomarkers were evaluated. Results: Over a median 12.47-year follow-up, 331 nephropathy, 268 retinopathy, and 88 neuropathy cases were recorded. Compared to low CRF, moderate and high CRF were associated with 22% (HR, 0.78; 95% confidence interval [CI], 0.61 to 0.99) and 45% (HR, 0.55; 95% CI, 0.36 to 0.85) lower risks of nephropathy, respectively. Each 1-metabolic equivalent of task increment in CRF was linked to 11% lower nephropathy risk. No significant associations were found for retinopathy or neuropathy. Genetic predisposition did not modify the association between CRF and diabetic nephropathy. Triglycerides and white blood cell count accounted for 7.46% and 12.88% of the association, respectively. Conclusion: Higher CRF is independently associated with lower risk of diabetic nephropathy in T2DM, and genetic risk does not alter this relationship. The association was partially mediated by triglycerides and white blood cell count. Assessing CRF may improve risk stratification and prevention of diabetic kidney disease.