The Frontier

Davidson advocates for primordial cardiovascular prevention, proposing the "8-gram rule" where 8 grams of lifetime LDL exposure triggers heart disease. Keeping lifetime LDL below 80 mg/dL can successfully prevent atherosclerosis before plaque starts to form.

Attia compares managing high LDL to smoking cessation, arguing that doctors should treat causal risk factors regardless of a young patient's low 10-year risk score. Waiting to treat a causal driver of disease defies basic preventative medicine logic.

Pfizer's early CETP inhibitor torcetrapib failed due to an off-target molecule design that stimulated aldosterone secretion in the adrenal glands. This toxic effect raised blood pressure and increased mortality, leading to the trial's termination in 2006.

Davidson notes that Roche's dalcetrapib raised HDL without changing LDL or clinical outcomes. Lilly's evacetrapib lowered LDL but was stopped for futility after only two years, which Davidson argues was too brief to show a clinical benefit.

The REVEAL trial proved that CETP inhibition lowers cardiovascular events by tracking 30,000 patients over four years. Anacetrapib lowered LDL by 17% and reduced major events by 9%, but Merck abandoned it because the lipophilic drug accumulated persistently in fat.

Obicetrapib is a highly potent CETP inhibitor that lowers LDL by up to 45% as a monotherapy. The ongoing global Prevail trial will assess cardiovascular outcomes in 9,500 patients on maximum-tolerated statins over a minimum follow-up of 2.5 years.

Obicetrapib reduces small LDL particles by 90% and lowers Lp(a) by approximately 50%. Davidson emphasizes that unlike statins, which can slightly increase diabetes risk, CETP inhibitors systematically lower the risk of developing diabetes.

The brain contains 25% of the body's cholesterol, utilizing isolated metabolism where ApoB is entirely absent. Genomic studies like the Bronx Aging Study show that CETP loss-of-function mutations eliminate the elevated Alzheimer's risk typically observed in APOE4 carriers.

In the Broadway trial, homozygous APOE4 carriers treated with obicetrapib saw over 20% reduction in the Alzheimer's biomarker p-tau 217 compared to placebo. The drug also improved other key neurodegenerative markers, including NfL and GFAP.

Davidson recounts developing Epinova, an omega-3 formulation containing EPA and DHA, which failed to show cardiovascular efficacy in the Strength Trial when tested at a 4-gram daily dose.