HDL cholesterol

Don't try to raise your HDL, and don't read a very high HDL as protection that cancels out a high LDL cholesterol or apoB. The number worth acting on is the count of plaque-building particles.

What HDL is

High-density lipoprotein (HDL) is one of the particles that carry cholesterol through the blood. It was long called "good cholesterol" because it carries cholesterol away from tissues and back to the liver. The HDL cholesterol (HDL-C) figure on a lipid panel is the mass of cholesterol inside these particles.

A very high reading is not necessarily a sign of extra-healthy particles. Very high HDL often signals dysfunctional particles that have lost their anti-inflammatory and cholesterol-offloading capacity, or it is driven by heavy alcohol intake, which carries its own mortality.

Both ends of the curve carry risk, the high end less clearly

The relationship with death from any cause is U-shaped: both low and very high HDL go with higher mortality. The high end is less clear-cut than often claimed, and all of the evidence is observational.

• Two Copenhagen cohorts of about 116,000 adults. Death from any cause was lowest at an HDL of about 1.9 mmol/L (73 mg/dL) in men and 2.4 mmol/L (93 mg/dL) in women. Compared with men at the lowest-risk level, men at 2.5–2.99 mmol/L (97–115 mg/dL) had about a third higher death rate, and men at 3.0 mmol/L (116 mg/dL) or above about twice the rate. In women a clear excess appeared only at 3.5 mmol/L (135 mg/dL) or above, at about two-thirds higher.^[1]
• Seventeen cohorts with about 19.6 million people, pooled. Extremely high HDL went with about 15% higher death from any cause, but the rise in cardiovascular death was not statistically clear, and in women neither rose.^[2]
• A Korean cohort of about 115,000 adults aged 40–69 without diabetes. Men with HDL above 2.1 mmol/L (80 mg/dL) had about 31% higher risk of dying from any cause than men at 1.0–1.6 mmol/L (40–60 mg/dL) after adjusting for the usual confounders. The result was borderline and seen only in men under 60; women showed no such rise.^[3]

Raising HDL with drugs has mostly failed

If HDL itself protected the heart, drugs that raise it should prevent events. A whole class of them, the CETP (cholesteryl ester transfer protein) inhibitors, was tested in large randomised trials, and the results falsify the idea.

• Torcetrapib raised HDL by 72% and lowered LDL by about 25%, yet in 15,067 high-risk patients already on atorvastatin it was stopped early because the risk of death rose by about 58%. It also raised blood pressure and aldosterone, an off-target effect the investigators suspected, though they could not rule out harm from the drug class itself.^[4]
• Evacetrapib more than doubled HDL and also cut LDL, yet was halted for futility with no effect on events at all.^[5]
• Anacetrapib, the one drug in the class that did modestly reduce events in a large outcome trial, cut major coronary events by about 9% (10.8% against 11.8%) over about four years in 30,449 people with atherosclerotic disease already on intensive statins. It doubled HDL but also lowered non-HDL cholesterol by 18%, and its small benefit is in line with that fall.^[6]

Genetic studies point the same way. In about 103,000 people, gene variants that mimic this drug class lowered the risk of major cardiovascular events only in proportion to how far they lowered apoB, the protein that marks each plaque-building particle.^[7]

Alcohol does not protect the heart through HDL

Alcohol raises HDL, and that was once the main argument that moderate drinking protects the heart. That idea has collapsed under genetic analysis; see Alcohol.

What to do

1. Read HDL as a marker. Low HDL is a flag for metabolic risk; very high HDL is not a bonus.
2. Don't take a very high HDL as a reason to ignore a high LDL cholesterol or apoB. Risk follows the number of plaque-building particles; see Cholesterol.
3. Don't chase HDL with drugs. Raising HDL itself has not prevented heart attacks; where a drug in this class helped, the benefit tracked its fall in non-HDL cholesterol.

Further reading

• Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J 2017.^[8]
• Zhang G, et al. Association between extremely high-density lipoprotein cholesterol and adverse cardiovascular outcomes: a systematic review and meta-analysis. Front Cardiovasc Med 2023.^[9]
• Barter PJ, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007.^[10]
• Bowman L, et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med 2017.^[11]
• Ference BA, et al. Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk. JAMA 2017.^[12]