Comprehensive risk factor control and its biomarker‐mediated association with diabetic microvascular complications

Abstract Aims Type 2 diabetes (T2D) confers a high risk of diabetic microvascular complications (DMCs). While multifactorial risk factor control is recommended, its associations with DMC risk, DMC‐free survival, and mediating biomarkers remain unclear. We investigated these associations in an early‐stage T2D subgroup with preserved kidney function and no prior cardiovascular or microvascular disease. Materials and methods This prospective cohort study utilized data from the UK Biobank. Control of seven modifiable factors (blood pressure, adiposity, lipid profile, HbA 1c , smoking, diet, physical activity) was assessed. DMCs were ascertained from hospital inpatient and death records, capturing severe or clinically overt events. Cox proportional hazard and flexible parametric survival models were used to estimate DMC risk and the DMC‐free survival, respectively. Mediation analysis quantified the contribution of biomarkers related to inflammation, metabolism, and organ function. Results Among 11 083 participants with T2D (mean age: 59.26 years; 61.08% men), 1716 (15.48%) developed DMCs over a median follow‐up of 11.26 years. Optimal control (≥6 factors) was associated with a hazard ratio of 0.55 (95% confidence interval 0.41–0.76) for DMCs and an additional 5.51 years (95% confidence interval 3.10–7.91) of DMC‐free survival from age 45. Biomarkers of inflammation (e.g., leukocytes, monocyte counts, neutrophil counts, C‐reactive protein), liver function (gamma‐glutamyltransferase), and energy metabolism (glycoprotein acetyls) significantly mediated these associations, explaining 1.79%–30.31% of the observed associations. Conclusions In this apparently healthy T2D population, comprehensive risk factor control is associated with a substantially lower incidence of DMCs and longer DMC‐free survival, effects partly mediated through improvements in inflammatory, metabolic, and hepatic biomarkers.