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Raising HDL didn't cut heart disease
HDL and health
High HDL does mark good metabolic health: people with it rarely also have high CRP, an inflammatory marker, or dysregulated blood glucose. That association made the ratio of LDL to HDL look like the thing that matters, which was the prevailing view when Layne Norton started graduate school around 2005.
Natural randomization
Mendelian randomization uses natural randomization: some people secrete more or less HDL because of their genes. Heart disease is a lifetime exposure problem that typically doesn't appear until the 50s, 60s, and 70s, so two-year or five-year trials can't pick up differences, but these natural experiments can. Comparing low and high HDL secretors with other key variables such as LDL held consistent shows no effect on heart disease.
LDL and apoB
LDL looks different under the same lens. Lifetime exposure produces a linear, dose-dependent effect on heart disease, and the particle that matters most is apolipoprotein B, which tracks LDL. LDL can also penetrate the endothelium, so a mechanism exists. In Framingham data, people with high HDL and low LDL had lower risk than people with high HDL and high LDL, and the same pattern held among people with low inflammation.
Why did HDL-raising drugs fail?
Pfizer's trial of torcetrapib, called ILLUMINATE, was stopped in 2006 after more deaths occurred in the treatment group. The drug raised HDL by about 70 percent but also raised blood pressure. Later CETP inhibitors such as dalcetrapib and evacetrapib also raised HDL without a clear cardiovascular benefit. The results helped move attention from HDL levels to LDL and apoB.
Why does apolipoprotein B track risk so well?
Every LDL, VLDL, and lipoprotein(a) particle carries exactly one molecule of apoB. Counting apoB therefore counts the number of particles that can enter the artery wall. Two people with the same LDL cholesterol can have different particle counts, because particles vary in how much cholesterol they carry. Studies like the INTERHEART trial found apoB to apoA-I ratios strongly predicted heart attack.
What did the big HDL genetics study find?
In 2012 in The Lancet, Benjamin Voight and colleagues studied a gene variant that raises HDL cholesterol. People who carried it had higher HDL for life but showed no lower risk of heart attack. By contrast, genetic variants that raise LDL showed an increase in risk in proportion to the LDL level. The study included about 170,000 people.
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