Cardiovascular and Kidney Outcomes across the Glycemic Spectrum: Insights from the UK Biobank.

BACKGROUND Treatment guidelines for pre-diabetes primarily focus on glycemic control and lifestyle management. Few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population. OBJECTIVES To characterize cardiovascular and kidney outcomes across the glycemic spectrum. METHODS Among participants in the UK Biobank without prevalent type 1 diabetes, cardiovascular, or kidney disease, Cox models tested the association of glycemic exposures (type 2 diabetes [T2D], pre-diabetes, normoglycemia) with outcomes (ASCVD, chronic kidney disease [CKD], and heart failure), adjusting for demographic, lifestyle, and cardiometabolic risk factors. RESULTS Among 336,709 individuals (mean age 56.3 years, 55.4% female), 46,911 (13.9%) had pre-diabetes and 12,717 (3.8%) had T2D. Over median follow-up of 11.1 years, 6,476 (13.8%) individuals with pre-diabetes developed ≥1 incident outcome, of whom only 802 (12.4%) developed T2D prior to an incident diagnosis. Pre-diabetes and T2D were independently associated with ASCVD (pre-diabetes: aHR 1.11 [95% CI 1.08-1.15], P<0.001; T2D: aHR 1.44 [95% CI 1.37-1.51], P<0.001), CKD (pre-diabetes: aHR 1.08 [95% CI 1.02-1.14], P<0.001; T2D: aHR 1.57 [95% CI 1.46-1.69], P<0.001), and heart failure (pre-diabetes: aHR 1.07 [95% CI 1.01-1.14], P=0.03; T2D: aHR 1.25 [95% CI 1.14-1.37], P<0.001). Compared with HbA1c <5.0%, covariate-adjusted risks increased significantly for ASCVD above HbA1c 5.4%, CKD above HbA1c 6.2%, and heart failure above HbA1c 7.0%. CONCLUSIONS Pre-diabetes and T2D were associated with ASCVD, CKD, and heart failure, but a substantial gradient of risk was observed across HbA1c levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.