What is the relationship between circulating cholesterol levels and atherosclerotic cardiovascular disease (ASCVD) and mortality?

The Relationship Between Circulating Cholesterol Levels and ASCVD and Mortality

Both LDL cholesterol and triglyceride-rich lipoproteins have strong causal relationships with atherosclerotic cardiovascular disease (ASCVD) and mortality, with evidence showing that lower levels of these lipids are associated with reduced risk of cardiovascular events and all-cause mortality. 1, 2

LDL Cholesterol and ASCVD Risk

Epidemiological Evidence

• Population studies consistently demonstrate a continuous relationship between elevated LDL cholesterol (LDL-C) and increased ASCVD risk 1
• Cross-country comparisons show that populations with higher LDL-C levels have higher rates of ASCVD than those with lower concentrations 1
• Within populations, individuals with higher cholesterol levels have greater ASCVD rates, even after adjusting for other risk factors 1

Causal Relationship

• The most dramatic evidence of LDL-C's atherogenicity comes from familial hypercholesterolemia (FH), where elevated LDL-C results from hepatic LDL receptor deficiency 1
• In heterozygous FH, LDL-C is elevated about 2-fold; in homozygous FH, LDL-C is at least 4 times increased 1
• FH patients commonly develop premature ASCVD, even without other risk factors, demonstrating LDL-C's causal role 1

Treatment Benefits

• Numerous randomized controlled trials (RCTs) have documented ASCVD risk reduction from cholesterol-lowering therapies 1
• The relationship follows "the lower, the better" principle - the more LDL-C is lowered, the greater the risk reduction 1
• Meta-analyses of statin trials show that risk reduction extends into very low LDL-C ranges, with no apparent lower threshold below which benefits cease 1
• Genetic epidemiology shows that persons with lifelong low cholesterol levels have particularly low ASCVD prevalence, supporting "the longer, the better" principle 1

Triglyceride-Rich Lipoproteins and ASCVD Risk

Epidemiological Evidence

• Elevated triglycerides and remnant cholesterol are strongly associated with increased risk of ASCVD and all-cause mortality 1, 2
• In the Copenhagen City Heart Study and Copenhagen General Population Study, increasing triglycerides were associated with increasing all-cause mortality, whereas this relationship was not observed for total cholesterol 1
• For individuals with nonfasting triglycerides >5 mmol/L (440 mg/dL) versus <1 mmol/L (88 mg/dL), the risk was increased:
  • 17-fold and 5-fold for myocardial infarction in women and men, respectively
  • 6-fold and 3-fold for ischemic heart disease in women and men
  • 5-fold and 3-fold for ischemic stroke in women and men
  • 4-fold and 2-fold for all-cause mortality in women and men 1

Genetic Evidence for Causality

• Mendelian randomization studies provide strong evidence for a causal relationship between triglyceride-rich lipoproteins and ASCVD 1
• Loss-of-function mutations in APOC3 resulted in:
  • 44% reduction in nonfasting triglycerides
  • 41% reduced risk of ASCVD 1
• For all-cause mortality, a genetically derived 1-mmol/L (89 mg/dL) lower concentration in nonfasting triglycerides due to LPL genetic variation reduced the risk by 50% 1

Relationship Between Different Cholesterol Fractions and Outcomes

LDL-C vs. Remnant Cholesterol

• Both LDL-C and remnant cholesterol show strong associations with myocardial infarction risk 1
• Elevated total cholesterol was associated with increased death from cardiovascular disease, but not with increased death from cancer or other causes 1
• In contrast, elevated triglycerides were associated with increased mortality from cardiovascular disease, cancer, and other causes 1

Non-HDL Cholesterol

• Non-HDL cholesterol (total cholesterol minus HDL cholesterol) represents both LDL and remnant cholesterol combined 1
• Recent meta-analyses of statin trials found that non-HDL-C correlates more closely with ASCVD risk than LDL-C alone 1

Clinical Implications

Risk Stratification

• The American College of Cardiology/American Heart Association guidelines emphasize that ASCVD risk factors measured in young and middle-aged adults are associated with short-term (≤10 years), long-term (≥15 years), and lifetime risk for ASCVD 1
• Measuring and updating ASCVD risk factors every 4-6 years improves both short- and long-term risk prediction 1

Treatment Targets

• For patients with established ASCVD, those with LDL-C ≥100 mg/dL have significantly higher rates of subsequent cardiovascular events compared to those with LDL-C <70 mg/dL (hazard ratio 1.31) 3
• The American Heart Association categorizes triglyceride levels as:
  • Normal (<150 mg/dL)
  • Borderline high (150-199 mg/dL)
  • High (200-499 mg/dL)
  • Very high (≥500 mg/dL) 2

Special Considerations

Gender Differences

• Women may have greater cardiovascular risk from elevated triglycerides than men 2
• In observational studies, the risk increase associated with elevated triglycerides was consistently higher in women than in men 1

Residual Risk

• Despite aggressive LDL-C reduction, ASCVD events can still recur, suggesting that other lipid fractions like triglyceride-rich lipoproteins contribute to residual risk 4, 5
• Approximately 21% of adults have elevated remnant cholesterol >1 mmol/L (39 mg/dL), which is largely caused by overweight-obesity and diabetes mellitus 1

Clinical Management Implications

• Aggressive lipid management should target both LDL-C and triglyceride-rich lipoproteins to comprehensively reduce ASCVD risk 2, 4
• Treatment with high-intensity statins significantly reduces both LDL-C and triglycerides, leading to reduced cardiovascular events 6
• In the TNT study, atorvastatin 80 mg/day reduced LDL-C to 73 mg/dL and triglycerides to 128 mg/dL, resulting in a 22% relative risk reduction in major cardiovascular events compared to atorvastatin 10 mg/day 6
• For patients with high cholesterol absorption (approximately one-third of the population), statin monotherapy may not be sufficient, and combination therapy with cholesterol absorption inhibitors may be needed 7

The evidence clearly demonstrates that both LDL cholesterol and triglyceride-rich lipoproteins have strong, independent relationships with ASCVD and mortality risk, supporting comprehensive lipid management strategies targeting multiple lipid fractions for optimal cardiovascular risk reduction.