Frequency of Low HDL Cholesterol and the Dose-Dependent Risk of Type 2 Diabetes: A Longitudinal Cohort Study

Although low high-density lipoprotein cholesterol (HDL-C) is an established risk factor for type 2 diabetes (T2D), most studies have relied on single-point measurements. We investigated whether persistent low HDL-C levels were associated with an increased risk of incident T2D in young adults.

We included 1,840,251 individuals from the Korean National Health Insurance Service database (2009-2012) who underwent 4 consecutive annual health examinations. Participants were categorized into 5 groups according to the frequency of low HDL-C exposure (0-4 times; <40 mg/dL in men and <50 mg/dL in women). The risk of incident T2D was assessed using multivariable Cox proportional hazards models over a mean follow-up of 6.5 years.

The risk of T2D increased significantly with increasing frequency of low HDL-C exposure (p<0.0001). The hazard ratios (95% confidence intervals [CIs]) for incident T2D were 1.472 (95% CI, 1.433-1.512), 1.786 (95% CI, 1.730-1.844), 1.990 (95% CI, 1.919-2.063), and 2.021 (95% CI, 1.941-2.105) for the groups with low HDL-C exposure 1, 2, 3, and 4 times, respectively, compared with the 0-time group (p for trend <0.0001). Subgroup analyses revealed consistent associations across all strata, with stronger associations among participants aged <30 years, women, and those with body mass index <25 kg/m².

A clear dose-response relationship was observed, indicating that cumulative exposure to low HDL-C levels was strongly associated with an increased risk of T2D. This association remained robust regardless of metabolic status, although it was more pronounced in younger adults, women, and non-obese individuals.