What do low‑density lipoprotein (LDL) cholesterol and high‑density lipoprotein (HDL) cholesterol mean, including their roles, normal ranges, and implications for cardiovascular risk?

LDL and HDL Cholesterol: Meaning and Clinical Significance

LDL cholesterol ("bad cholesterol") is the primary causal driver of atherosclerotic cardiovascular disease (ASCVD), while HDL cholesterol ("good cholesterol") helps remove cholesterol from arteries and is inversely associated with cardiovascular risk.

What These Lipoproteins Mean

Low-Density Lipoprotein (LDL) Cholesterol:

• LDL is the main carrier of cholesterol in the bloodstream 1
• Elevated LDL-C directly causes atherosclerotic plaque formation in arteries
• LDL-C is almost exclusively associated with ASCVD events in individuals who already have coronary atherosclerosis 2
• In people without existing coronary atherosclerosis (coronary artery calcium score = 0), LDL-C shows minimal association with near-term cardiovascular events 2

High-Density Lipoprotein (HDL) Cholesterol:

• HDL mediates reverse cholesterol transport, removing cholesterol from peripheral tissues back to the liver 3
• HDL inhibits LDL oxidation, prevents monocyte adhesion to vessel walls, and has anti-inflammatory properties 3
• Low HDL-C (<40 mg/dL in men, <50 mg/dL in women) is an independent risk factor for coronary heart disease 3

Normal Ranges and Treatment Targets

Physiologically Optimal LDL-C Levels:

• Native hunter-gatherers, healthy newborns, and wild primates maintain LDL-C of 50-70 mg/dL without developing atherosclerosis 4
• Current evidence suggests atherosclerosis progression is minimized when LDL-C is lowered to <70 mg/dL 4

Clinical Treatment Thresholds (per ACC/AHA Guidelines):

The 2013 ACC/AHA guidelines 5 identify four groups who benefit from statin therapy:

1. Individuals with clinical ASCVD (secondary prevention)
2. LDL-C ≥190 mg/dL (primary severe hypercholesterolemia)
3. Diabetes patients age 40-75 with LDL-C 70-189 mg/dL
4. Age 40-75 with LDL-C 70-189 mg/dL and ≥7.5% 10-year ASCVD risk

Important Caveat: The 2022 ACC Expert Consensus 6 recommends targeting LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) in patients with clinical ASCVD, particularly when baseline LDL-C is ≥190 mg/dL.

Cardiovascular Risk Implications

The LDL-C/HDL-C Ratio:

• This ratio reflects lipid metabolism homeostasis 7
• Higher LDL-C/HDL-C ratios significantly increase the risk of myocardial infarction versus stable angina in coronary heart disease patients 7
• For each unit increase in LDL-C/HDL-C ratio, MI risk increases by 99% compared to angina patients 7

Critical Clinical Pitfalls:

• Very low LDL-C (<70 mg/dL) in untreated populations may paradoxically associate with increased all-cause and stroke mortality 8, though this likely reflects reverse causation (illness causing low cholesterol rather than low cholesterol causing illness)
• In contrast, therapeutically lowered LDL-C to <70 mg/dL with statins shows no major safety concerns and reduces cardiovascular events 4
• Very high LDL-C (≥190 mg/dL) increases CVD and coronary heart disease mortality risk by 49-63% 8

Treatment Approach

For patients with established ASCVD or high risk:

• High-intensity statins remain first-line therapy 5
• If LDL-C remains ≥70 mg/dL despite maximally tolerated statin therapy, add ezetimibe 6
• If still not at goal, consider PCSK9 inhibitors 6
• The goal is ≥50% LDL-C reduction AND absolute LDL-C <70 mg/dL 6

Key Point: The evidence does not support treating to specific LDL-C goals in primary prevention without considering overall ASCVD risk 5. Treatment decisions should be based on absolute risk assessment using tools like the Pooled Cohort Equations, not LDL-C levels alone.