255-Latest therapeutics in CVD, APOE’s role in Alzheimer’s disease, familial hypercholesterolemia

KEYPOINTS

• 01

  Cardiovascular disease dwarfs every other killer.

  Kastelein, a professor of genetic medicine at the University of Amsterdam who has spent decades running a large lipid clinic, frames the conversation with global numbers: atherosclerotic disease kills far more people each year than cancer (about 12–13 million), so it is 'not even close'. Early in his career he still saw fatal or severe heart attacks in FH patients aged 20–30.

• 02

  Familial hypercholesterolemia is common and starts in childhood.

  Heterozygous FH is now thought to affect about 1 in 250 people, making it the most frequent autosomal dominant disorder. More than 3,500 mutations can produce the phenotype. In children with a clinical diagnosis a mutation is found about 95% of the time (roughly 95% LDL receptor, 4.5% APOB, 0.5% PCSK9 gain-of-function), versus maybe 50–60% in adults.

• 03

  FH is a syndrome diagnosis, not a single LDL number.

  An LDL cutoff of about 190 mg/dL is common, but many people at 200 have secondary causes like high triglycerides, type 2 diabetes, untreated thyroid or kidney disease. Heterozygous and homozygous FH distributions overlap, so diagnosis needs family history, pedigrees and physical signs. Referral bias meant his early patients all had LDL over 300.

• 04

  Physical signs appear as cholesterol deposits.

  Tendon xanthomas on the backs of the hands and the Achilles, the corneal arcus and eyelid deposits (xanthelasma) are classic, though the first real symptom used to be a heart attack. A milder genetic subset exists; among about 25,000 heterozygous patients found, he has never seen that subset have heart attacks in their 20s or 30s.

• 05

  Treating early likely adds 15–20 years of life.

  Children start statins (plus ezetimibe if needed) with a modest pediatric target below 130 mg/dL. Attia pushes back that healthy kids have LDL around 20–30 and newborns roughly 10 mg/dL, a natural experiment showing low LDL is safe. Their pediatric cohort, followed for 10 years after a NEJM trial, supports early treatment.

• 06

  About 10% of heterozygous FH is 'severe' and resists triple therapy.

  Starting from 300 mg/dL, a statin's roughly 45% cut plus ezetimibe and a PCSK9 inhibitor may still leave some patients above 100–120. For homozygous FH the state of the art is high-dose statin, ezetimibe, evolocumab and evinacumab (Regeneron's ANGPTL3 antibody), with apheresis as an option.

• 07

  LDL causality is settled.

  Kastelein says he 'doesn't even listen' anymore to claims that LDL isn't causal; Mendelian randomization across many genes, not just FH, shows the same dose-response. The thrifty-gene idea: FH may have protected against infection and was less dangerous around 1860, before modern diets.

• 08

  CETP inhibitors failed for clear reasons.

  Pfizer's torcetrapib raised blood pressure in phase 2 and in the large trial 'killed more people than it saved' (2006). Others failed on HDL-focused thinking. Merck's anacetrapib REVEAL trial, done by Oxford with 30,000 patients, worked only modestly because it lowered LDL just 17% from a baseline of about 60, an absolute drop of only about 11 mg/dL.

• 09

  Obicetrapib is far more potent.

  At 1 mg in phase 1 it lowered LDL 27%; at 10 mg it inhibits CETP about 97%, cutting LDL roughly 50% on top of high-intensity statins, raising HDL about 165% and lowering Lp(a) 56% (43% at 5 mg) in the ROSE trial. Kastelein is directly involved in its development, so treat his optimism accordingly. Phase 3 includes BROADWAY (~2,400 patients, 52 weeks), BROOKLYN (~300 heterozygous FH) and PREVAIL (~9,000 with established ASCVD and baseline LDL near 100).

• 10

  APOE4 fails at moving cholesterol in the brain.

  About 65% of Alzheimer's patients carry at least one E4. Kastelein cites roughly 16-fold risk for E4/E4 and 4.5-fold for E3/E4; Attia thinks the data suggest closer to 10-fold and four-fold. Mechanistically E4 is a poor acceptor and a poor donor of cholesterol, failing both to clear excess and to supply deficient brain cells.