Liu 2006: Non-HDL-C in Metabolic Syndrome Patients

Background

The Women's Health Study (WHS) provided a unique opportunity to examine lipid predictors in a large cohort of initially healthy women. Dr. Liu and colleagues analyzed whether non-HDL cholesterol offered advantages over LDL cholesterol for cardiovascular risk prediction in this population.

Study Design

Population: 27,673 apparently healthy American women enrolled in the WHS Age: 45 years and older at baseline Follow-up: 10 years of prospective observation Endpoints: Total cardiovascular events (fatal and non-fatal MI, stroke, revascularization)

Methodological strengths:

• •Large sample size with adequate power for subgroup analyses
• •Healthy cohort (primary prevention population)
• •Standardized lipid measurements
• •Rigorous endpoint adjudication
• •Long-term follow-up

Principal Findings

Overall Predictive Performance: Non-HDL-C demonstrated stronger association with CVD events than LDL-C across the full triglyceride spectrum. The hazard ratio per standard deviation increase was higher for non-HDL-C compared to LDL-C.

Triglyceride Subgroup Analysis: The superiority of non-HDL-C was most pronounced in women with elevated triglycerides:

TG Level	Non-HDL-C Performance
<150 mg/dL	Comparable to LDL-C
150-199 mg/dL	Moderately superior
≥200 mg/dL	Substantially superior

Risk Reclassification: Using non-HDL-C instead of LDL-C correctly reclassified a significant proportion of women, particularly those with:

• •Elevated triglycerides
• •Metabolic syndrome features
• •Discordant LDL-C/non-HDL-C values

Clinical Implications for Women

This study had specific relevance for women's cardiovascular health:

1. •Hormonal considerations: Women often have higher HDL-C and different TG metabolism
2. •Metabolic syndrome: Post-menopausal women frequently develop atherogenic dyslipidemia
3. •Risk underestimation: LDL-C may underestimate risk in women with elevated TG
4. •Screening implications: Non-HDL-C provides more complete risk picture

Mechanistic Insights

The study reinforced understanding of why non-HDL-C outperforms LDL-C:

Triglyceride-Rich Lipoproteins (TRL):

• •VLDL and remnant particles are atherogenic
• •TRL contribution increases with metabolic dysfunction
• •LDL-C calculation becomes unreliable as TG rises

Small Dense LDL:

• •Common in insulin resistance states
• •Same LDL-C, more LDL particles
• •Non-HDL-C better reflects particle burden

Guideline Impact

This study contributed to:

• •ATP III update recommendations (2004)
• •Growing consensus for non-HDL-C targets
• •Recognition of sex-specific lipid patterns
• •ACC/AHA guideline discussions on risk assessment

Metabolic Health Perspective

For women undergoing metabolic changes (perimenopause, menopause, weight gain, or developing insulin resistance), this study emphasizes that:

1. •Standard LDL-C may be falsely reassuring when metabolic health declines
2. •Non-HDL-C captures the shift toward atherogenic dyslipidemia
3. •Lifestyle intervention targeting insulin sensitivity improves both TG and non-HDL-C
4. •Comprehensive assessment requires looking beyond LDL-C alone

The WHS data strongly supports using non-HDL-C as a primary lipid target, especially in women with any features of metabolic syndrome.