Associations Between Frailty and the Increased Risk of Adverse Outcomes Among 38,950 UK Biobank Participants With Prediabetes: Prospective Cohort Study

**Background:** Prediabetes affects over 500 million adults worldwide and increases the risk of diabetes and its complications. Frailty, a state of decreased physiological reserve, is more common in individuals with prediabetes than in those with normal glucose metabolism. However, it was unclear whether frailty could identify middle-aged adults with prediabetes at highest risk for adverse outcomes beyond diabetes progression. This study aimed to systematically evaluate associations between frailty and multiple adverse outcomes in a large prospective cohort.

**Methods:** The study included 38,950 participants aged 40-64 years with prediabetes (HbA1c 5.7%-6.4%) from the UK Biobank, recruited between 2006-2010. Frailty was assessed using the frailty phenotype (FP) based on five criteria: unintentional weight loss, exhaustion, weakness (handgrip strength), slow gait speed, and low physical activity. Participants were categorized as nonfrail (FP=0), prefrail (1≤FP≤2), or frail (FP≥3). Outcomes included incident type 2 diabetes mellitus (T2DM), diabetes-related microvascular disease, cardiovascular disease (CVD), chronic kidney disease (CKD), eye disease (cataract/glaucoma), dementia, depression, and all-cause mortality, ascertained through linked hospital records and death registries over a median follow-up of 12 years. Cox proportional hazards models were adjusted for age, sex, ethnicity, education, occupation, Townsend deprivation index, alcohol, smoking, diet, BMI, and family history.

**Key Results:** At baseline, 49.1% (19,122/38,950) were prefrail and 5.9% (2,289/38,950) were frail. Frail participants had significantly higher risks for all outcomes in fully adjusted models. Compared with nonfrail participants, frail participants had hazard ratios (HR) of 1.73 (95% CI 1.55-1.92) for T2DM, 1.89 (95% CI 1.64-2.18) for microvascular disease, 1.66 (95% CI 1.44-1.91) for CVD, 1.76 (95% CI 1.45-2.13) for CKD, 1.31 (95% CI 1.14-1.51) for eye disease, 2.03 (95% CI 1.33-3.09) for dementia, 3.01 (95% CI 2.47-3.67) for depression, and 1.81 (95% CI 1.51-2.16) for all-cause mortality. Prefrail participants also showed elevated risks, though of smaller magnitude. Each 1-point increase in FP score was associated with a 10% to 42% increase in risk across outcomes. Sensitivity analyses excluding early follow-up, poor self-rated health, or using multiple imputation confirmed robustness.

**Clinical Implications:** This study demonstrates that frailty is a strong, independent predictor of a wide range of adverse outcomes in middle-aged adults with prediabetes, including not only diabetes progression but also microvascular and macrovascular complications, eye disease, dementia, depression, and mortality. The prevalence of frailty in this prediabetic population (5.9%) was nearly double that reported in the general UK Biobank population (3.3%), suggesting accelerated aging. Incorporating frailty assessment into routine primary care for middle-aged adults with prediabetes could help identify high-risk individuals who may benefit from targeted interventions such as strength training and nutritional support. The findings support a shift from a one-size-fits-all approach to a more personalized risk stratification strategy in prediabetes management.