The association of HDL-cholesterol levels with incident major adverse cardiovascular events and mortality in 0.6 million individuals with type 2 diabetes: a population-based retrospective cohort study

Background: High levels of high-density lipoprotein cholesterol (HDL-C) are previously considered protective against cardiovascular diseases (CVD), but recent studies suggest an increased risk of adverse events at very high HDL-C levels in the general population. It remains to be elucidated such a relationship in diabetes, a condition with high cardiovascular risks. We examined the association of HDL-C levels with the risk of major adverse cardiovascular events (MACE) and mortality in type 2 diabetes.

Methods: This retrospective cohort study identified individuals with type 2 diabetes who had HDL-C records (2008-2020) from the electronic health record database of the Hong Kong Hospital Authority. They were classified into three groups based on their first-recorded HDL-C levels following diabetes diagnosis: low (≤ 40 mg/dL), medium (> 40 and ≤ 80 mg/dL) and high HDL-C (> 80 mg/dL) groups. The primary outcome was incident MACE (composite of myocardial infarction, stroke, heart failure, and cardiovascular mortality). Cox regression model and restricted cubic spline analysis were employed to assess the relationship between HDL-C and adverse outcomes.

Results: Among 596,943 individuals with type 2 diabetes included, 168,931 (28.30%), 412,863 (69.16%), and 15,149 (2.54%) were classified as low HDL-C, medium HDL-C, and high HDL-C groups, respectively. Over a median follow-up of 79.5 months, both low and high HDL-C groups had higher risk of incident MACE compared to the medium HDL-C group (HR 1.24, 95% CI 1.23-1.26, P < 0.001; HR 1.09, 95% CI 1.04-1.13, P < 0.001). The spline curves revealed a U-shaped association between HDL-C levels and incident MACE (non-linear p < 0.001). Similar U-shaped relationship was observed for all-cause and non-cardiovascular mortality.

Conclusions: Our study demonstrated a U-shaped association between HDL-C levels and incident MACEs and all-cause and non-cardiovascular mortality in individuals with type 2 diabetes, highlighting the need for mechanistic studies on the adverse outcomes seen at high HDL-C levels in type 2 diabetes.