What is the clinical evidence from this study?

Study design: Cohort. Population: Hyperlipidemia (n=93948). Intervention: High visit-to-visit variability in HDL-C (highest quartile of average real variability) vs. Low visit-to-visit variability in HDL-C (lowest quartile of average real variability). Primary outcome: Incident peripheral artery disease (PAD) (aHR 1.13, 95% CI 1.004-1.27, p=0.002 for trend).

November 12, 2025Circulation Journal2 citationsOpen Access

Lipid Variability and the Risk of Incident Peripheral Artery Disease

YTYing‐Chang Tung TTTsung-Han Tsai YHYu-Jui Hsieh

Key Result

High visit-to-visit variability in high-density lipoprotein cholesterol significantly increased the risk of incident peripheral artery disease by 13% compared to low variability.

Study Design

Type

Cohort (n=93,948)

Multicenter

Yes

Structured PICO

Does high visit-to-visit variability in HDL-C increase the risk of incident peripheral artery disease in patients with hyperlipidemia?

Population

93,948 patients with hyperlipidemia in Taiwan, mean age 62.3, 51.8% male. Key inclusion: diagnosed with hyperlipidemia between 2007 and 2013, with annual lipid measurements over 4 consecutive years.

Intervention

High visit-to-visit variability in high-density lipoprotein cholesterol (HDL-C), measured as average real variability (ARV) over a 4-year period

Comparator

Lowest quartile of HDL-C variability (Q1)

Outcome

Incident lower extremity peripheral artery disease (PAD), including claudication, percutaneous or surgical revascularization, critical limb ischemia, and amputation, over a mean 5.9-year follow-uphard clinical

Visit-to-visit variability in HDL-C is independently associated with an increased risk of incident peripheral artery disease in patients with hyperlipidemia, providing incremental prognostic value beyond mean lipid levels.

Main Result

Effect estimate: aHR 1.13 (95% CI 1.004-1.27)

Absolute Event Rate: 3.4% vs 2.6%

p-value: p=0.002 for trend

Limitations

Observational design cannot establish a causal relationship between HDL-C variability and incident PAD.
Potential influence of residual or unmeasured confounders, such as lifestyle factors and medication adherence.
Ankle-brachial index and degree of peripheral artery stenosis were unstructured data and could not be extracted.
Used ARV and VIM as measures of variability rather than considering the full HDL-C trajectory over time.
Absence of lipoprotein (a) data precluded further analysis.
Event rate may have been underestimated if patients presented to non-study hospitals.

Abstract

BACKGROUND: Emerging evidence highlights the clinical significance of lipid variability in cardiovascular disease and adverse outcomes. This study investigated the relationship between lipid variability and incident peripheral artery disease (PAD) risk. METHODS AND RESULTS: We identified 93,948 patients in the Chang Gung Research Database in Taiwan who had been diagnosed with hyperlipidemia between 2007 and 2013 and had annual lipid measurements over 4 consecutive years. Lipid levels, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, as well as their visit-to-visit variability, were assessed over the 4-year period. Patients were followed until December 31, 2019 for incident PAD development. Over a mean 5.9-year follow-up, 2,735 patients (2.5%) developed PAD. Mean lipid levels were significantly associated with incident PAD. Of note, the average real variability (ARV) in HDL-C was independently associated with increased PAD risk (adjusted hazard ratio 1.13; 95% confidence interval 1.004-1.27 for highest vs. lowest quartile of HDL-C ARV; P for trend=0.002). Sensitivity analysis using variability independent of the mean as the HDL-C variability index confirmed this finding. Consistency was observed across all subgroup analyses. CONCLUSIONS: In this multi-institutional database analysis, visit-to-visit variability in HDL-C was significantly associated with the risk of incident PAD, independent of traditional risk factors for atherosclerosis, mean lipid levels, and the use of lipid-lowering therapy.

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