Study Shows a U-Shaped Association Between HDL-C, Major Adverse Cardiovascular Events

A study showed a U-shaped association between high levels of high-density lipoprotein cholesterol (HDL-C) levels and incident adverse cardiovascular events, as well as between all-cause and non-cardiovascular mortality, in individuals with type 2 diabetes.1

Research has previously suggested that high levels of HDL-C are protective against cardiovascular diseases, finding that each unit increase in HDL-C was linked to a decreased CVD risk by 2 – 3%.2 However, newer studies have indicated that individuals with very high HDL-C levels have an increased risk of adverse events. For instance, clinical trials with niacin and cholesteryl ester transfer protein inhibitors increased HDL-C levels but did not reduce the cardiovascular risk.3,4

Investigators wanted to see if the relationship between HDL-C levels and the risk of major adverse cardiovascular events and mortality was present in individuals with type 2 diabetes. The primary outcome was incident major adverse cardiovascular events, and investigators examined for myocardial infarction, stroke, heart failure, and cardiovascular mortality.

“Our results suggested the need to review the role of HDL-C in the cardiovascular risk prediction in type 2 diabetes,” wrote investigators, led by David Tak Wai Lui and Lanlan Li, both from the department of medicine at the University of Hong Kong in China. “High HDL-C did not protect one from [major adverse cardiovascular events] and was even associated with worse cardiovascular outcomes.”

The retrospective cohort study included 596,943 participants with type 2 diabetes who had HDL-C records (2008 – 2020) from the electronic health record database of the Hong Kong Hospital Authority. Participants were classified based on their first-recorded HDL-C levels following diabetes diagnosis: low (≤ 40 mg/dL) (n = 168,931; 28.30%), medium (> 40 and ≤ 80 mg/dL) (n = 412,863; 69.16%), and high HDL-C (> 80 mg/dL) (n = 15,149; 2.54%).

Investigators conducted a Cox regression model analysis stratified by sex, statin use, use of anti-diabetic medications, eGFR and HbA1c levels, and obesity. During the median follow-up period of 79.5 months, or about 6 and a half years, participants with low and high-density lipoprotein cholesterol levels had a greater risk of incident major adverse cardiovascular events (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.23 – 1.26; P < .001) compared with participants who had medium density lipoprotein cholesterol levels (HR, 1.09; 95% CI, 1.04 – 1.13; P < .001).

“It is also interesting to note that the excess risk of [major adverse cardiovascular events] associated with high HDL-C levels was less than that associated with low HDL-C levels,” investigators wrote.

The restricted cubic spline analysis revealed a U-shaped association between HDL-C levels and incident major adverse cardiovascular events (non-linear P < .001). Investigators also observed a similar U-shaped relationship between all-cause and non-cardiovascular mortality.

The U-shape relationship was mostly consistent across subgroups, except the association did not reach statistical significance in the younger age group. The team also observed males had more exaggerated U-shaped relationships than females.

Investigators pointed out several limitations, including not having data on lifestyle factors and including a population of predominately Chinese and individuals with type 2 diabetes. They also did not have a control group of individuals without diabetes.

“In conclusion, our study demonstrated a U-shaped association between HDL-C levels and incident [major adverse cardiovascular events] in a broad spectrum of individuals with type 2 diabetes,” investigators wrote. “The results highlight the need to attend to the cardiovascular risk profile of individuals with type 2 diabetes who have high HDL-C levels, and for mechanistic studies for the increased cardiovascular risks observed at high HDL-C levels in type 2 diabetes.”

References

1. Lui DTW, Li L, Liu X, Xiong X, Tang EHM, Lee CH, Woo YC, Lang BHH, Wong CKH, Tan KCB. 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. BMC Med. 2024 Dec 18;22(1):586. doi: 10.1186/s12916-024-03810-4. PMID: 39696353; PMCID: PMC11657474.
2. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993–2000.
3. Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.
4. Tall AR, Rader DJ. Trials and Tribulations of CETP Inhibitors. Circ Res. 2018;122(1):106–12.