407 ‒ Preventing cardiovascular and Alzheimer’s disease: lowering LDL early, APOE4, and more

KEYPOINTS

• 01

  Atherosclerosis is driven by cumulative LDL exposure—the '8 gram rule'.

  Davidson, a lipidologist whose father died of a heart attack at 47, frames risk as lifetime cholesterol burden: roughly 200 mg/dL for 40 years, 100 mg/dL for 80 years, or 80 mg/dL for 100 years all add up to the same exposure that produces heart disease. Plaque forms relatively rapidly in the 20s–40s, so that decade is when the most effective treatment matters.

• 02

  Prevention should target causal drivers, not 10-year risk scores.

  Peter credits Allan Sniderman with reframing the argument: instead of treating 5-, 10- or 15-year risk, treat the causes of disease. A 30-year-old's 10-year risk is low by any calculator, but Davidson says the goal is preventing heart disease at 80 or 90. He notes extra care around pregnancy for women.

• 03

  HDL-raising was a seductive hypothesis that failed repeatedly.

  Observational data suggested every 1% rise in HDL cut risk about 3%, so CETP inhibitors—which raise HDL 50–75%—looked like a cure. Pfizer's torcetrapib failed (~2006) with off-target harms; Roche's dalcetrapib raised HDL ~30–40% with no LDL effect and no MACE benefit; Lilly's evacetrapib was stopped for futility after about two years despite ~75% HDL increases. Niacin on top of statins (HPS2-THRIVE) also failed.

• 04

  Merck's REVEAL proved the benefit tracks LDL, not HDL.

  In about 30,000 patients, anacetrapib lowered LDL-C ~17% (~11 mg/dL absolute), and the modest event reduction matched what LDL lowering predicts: about 22% relative risk reduction per 1 mmol/L (38.7 mg/dL). Mendelian randomization similarly says HDL-C is not causal; some high-HDL genes such as SR-B1 variants raise risk.

• 05

  Obicetrapib is a far more potent, low-dose CETP inhibitor.

  Earlier CETP inhibitors were dosed at 100 mg-plus; obicetrapib at 5–10 mg lowered LDL 40–50% and raised HDL ~150% in the short TULIP study (8–12 weeks). NewAmsterdam, which raised $200 million in its Series A in early 2021, ran phase 3 and the PREVAIL outcomes trial in parallel.

• 06

  The phase 3 program shows consistent additional LDL lowering.

  ROSE and ROSE2: ~45–50% as monotherapy, ~55% with ezetimibe. BROOKLYN in familial hypercholesterolemia: about 40% further reduction, roughly 100 to 60 mg/dL at 12 months. BROADWAY in ASCVD patients on maximal statins (70% high-intensity): ~35% at 12 weeks, sustained to 52. TANDEM with ezetimibe: ~50%. PREVAIL, at 400+ sites globally, would support approval for secondary prevention.

• 07

  ApoB and LDL-P may move less than LDL-C on CETP inhibition.

  Davidson acknowledges discordance among LDL-C, LDL particle number and apoB with CETP inhibitors—relevant for clinicians tracking apoB. Obicetrapib also lowers Lp(a), similar to PCSK9 inhibitors' 15–20%, though the reason is unclear.

• 08

  APOE4 is a lipid gene, and HDL is the lipoprotein that touches the brain.

  About 20–25% of people carry one E4 and ~2–3% are homozygous, with roughly 10x Alzheimer's risk. Davidson's model: E4 impairs astrocyte cholesterol clearance; excess cholesterol leaves only as 24- or 27-hydroxycholesterol, becomes toxic and inflammatory, and amyloid and tau follow. HDL may deliver antioxidants and remove cholesterol and amyloid. He argues statins don't cause Alzheimer's.

• 09

  Biomarkers suggest an effect, especially in E4 homozygotes.

  A pilot of about 13 E4 patients with MCI showed CSF 24- and 27-hydroxycholesterol falling (not seen with statins) and stable cognition, though it was open-label and unpowered. In a prespecified BROADWAY substudy (2,500 patients), p-tau217 rose less overall; in E4/E4 participants it was over 20% better than placebo, with p-tau181, Aβ42/40, GFAP and neurofilament light all improving.

• 10

  Davidson argues high-dose statins are outdated.

  80 mg atorvastatin made sense 25 years ago when nothing else existed; now ezetimibe, PCSK9 inhibitors, bempedoic acid and others allow combinations. He calls pricing PCSK9 inhibitors at $16,000 a year a blunder that slowed adoption.

• 11

  Small companies can take risks big pharma won't.

  Davidson argues biotech's nimbleness—no corporate hierarchy, willingness to start an outcomes trial alongside phase 3—is why obicetrapib was revived after big companies abandoned the class. NewAmsterdam bet on starting PREVAIL early, and phase 3 success then let it raise the cash to finish. He also notes competitive pressure from China, where he says chemists vastly outnumber those in the U.S.