Historical view
Decades of epidemiology showed inverse relationship between HDL-C and cardiovascular events. Higher HDL = lower events. This led to the "good cholesterol" framing and intensive interest in raising HDL therapeutically.
Why HDL-raising drugs failed
CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) raised HDL-C 30-100% in trials but failed to reduce cardiovascular events. Some even increased mortality. Niacin raised HDL but didn't reduce events when added to statins. These trial failures revealed that HDL biology is more complex than originally thought.
HDL function vs level
What HDL actually does that protects vessels:
- Cholesterol efflux, accepts cholesterol from cells, delivers to liver for clearance (reverse cholesterol transport)
- Antioxidant function, protects LDL from oxidation
- Anti-inflammatory effects
- Endothelial support
The capacity to perform these functions varies independent of HDL-C level. Two people with the same HDL-C can have very different HDL function.
The U-shaped curve
Recent epidemiology suggests very high HDL (above 80-100 mg/dL) may be associated with elevated mortality in some cohorts, a U-shaped curve. The mechanism is unclear but may involve:
- Genetic mutations causing high HDL with dysfunctional particles
- Impaired HDL particle metabolism
- Other associated factors
Low HDL still matters
Very low HDL (below 40 mg/dL in men, 50 mg/dL in women) does indicate elevated cardiovascular risk:
- Often associated with metabolic syndrome
- Reflects compromised reverse cholesterol transport
- Marker of broader metabolic dysfunction
Raising low HDL through lifestyle interventions (exercise, weight loss, smoking cessation) is appropriate. Pharmacologically raising HDL has not been shown to reduce events.
What to do
- Don't focus on HDL-C as a primary target
- Focus on ApoB (atherogenic particles) for cardiovascular risk
- If HDL is low, address underlying drivers (insulin resistance, smoking, sedentary)
- Don't aggressively pursue very high HDL
- Triglyceride/HDL ratio is more useful than HDL alone
The clinical pearl: The "raise HDL" era is over. Focus on ApoB and triglyceride/HDL ratio for cardiovascular risk assessment. Address low HDL as a marker of metabolic dysfunction, not a number to target directly.
Bottom line
HDL function matters more than level. Pharmacologically raising HDL doesn't reduce events. Very high HDL may not be protective. Low HDL signals broader metabolic issues worth addressing. Modern cardiovascular risk assessment focuses on ApoB and metabolic markers, not HDL alone.