#129 - Tom Dayspring, M.D.: The latest insights into cardiovascular disease and lipidology

KEYPOINTS

• 01

  ApoB-carrying particles are the core driver of atherosclerosis.

  Dayspring, a lipidologist who practiced internal medicine in New Jersey for 37 years, describes a growing consensus. Attia lays out the model: smoking and high blood pressure injure the artery lining, and apoB particles act as the 'Trojan horse' that carries cholesterol into the artery wall. There it is retained and oxidized, setting off an inflammatory repair response that builds plaque. Each atherogenic particle carries exactly one apoB molecule: apoB-100 for liver-made particles, and the shorter apoB-48 for chylomicrons from the gut.

• 02

  ApoB is the preferred metric, and cost is no longer an excuse.

  Because of their long half-life, 90–95% of apoB particles are LDLs, so apoB works essentially as a particle count that also captures VLDL remnants, IDL and Lp(a). Attia's practice switched from LDL-P after going through three particle-count technologies in eight years. Dayspring cites Allan Sniderman's work showing that even non-HDL cholesterol leaves roughly 20–30% of people misclassified compared with apoB.

• 03

  Lower is better, and physiological apoB is probably under 50 mg/dL.

  Dayspring notes newborns have apoB under 50 mg/dL, and trials show the greatest risk reduction when it is pushed that low. Guidelines suggest at least a 50% reduction in higher-risk people. PCSK9 inhibitors now routinely bring apoB to 20–40 mg/dL. He stresses that halving plasma cholesterol (say 200 to 100 mg/dL) barely changes total-body cholesterol, because most cholesterol sits in cell membranes and tissues, not in circulating lipoproteins.

• 04

  HDL cholesterol is a poor target.

  HDL cholesterol was adopted from 40- to 50-year-old epidemiology. Decades of trials that raised it have been neutral at best and harmful at worst, and Mendelian randomization studies of HDL genes are neutral too. Dayspring calls HDLs 'fire engines' of many types: an average particle carries about 45 cholesterol molecules and can carry some 150 different proteins. HDL function matters, but there is no good clinical test for it yet.

• 05

  Lp(a) is 'the most dangerous particle you've never heard of.'

  Lp(a) is an LDL-like particle with apo(a) attached. Its level is genetic, so a single test is enough: if it isn't high at 18, it won't be at 68. For heart attacks before 60 in the family, Attia's rule is 'Lp(a) until proven otherwise.' Yet some people with high Lp(a) reach 80 with little plaque, which suggests risk depends on more than concentration. A recent study found Lp(a) particles carrying apoC3, a 'double whammy' that makes them harder to clear.

• 06

  Lp(a)-specific drugs are still in trials, and Lp(a) isn't yet a treatment target.

  Second-generation antisense drugs that work in the liver are in development, and Novartis has acquired one that has entered phase 3. Dayspring explains why the first trial enrolls only people with very high Lp(a): Mendelian data suggest the drop has to be large to help, and a failed first trial would kill the drug. For now the target is apoB. Statins may nudge Lp(a) up slightly, but they lower other LDLs so much that net risk falls.

• 07

  Statin strategy: there's residual risk, and the dose debate is real.

  Statins reduce events but leave plenty of residual risk. Trials suggest that if you decide to use one, you should pick the most potent (atorvastatin or rosuvastatin) at maximum dose. Dayspring personally prefers to start lower, depending on risk, rather than use the 'gorilla dose' on day one. Before starting, he urges a CAC scan, an Lp(a) test, family history and blood pressure.

• 08

  Ezetimibe and bempedoic acid add non-statin ways to lower apoB.

  Mendelian randomization predicted that blocking gut absorption of cholesterol would cut events before ezetimibe's outcome trial confirmed it. On its own, ezetimibe lowers LDL-C about 10–18% and apoB a bit less. Bempedoic acid blocks ATP citrate lyase upstream of HMG-CoA reductase. It is a prodrug activated only in the liver and isn't taken up by muscle, so it should avoid the muscle aches that limit statins, which Dayspring thinks are more common than trials show.

• 09

  Omega-3s only lower triglycerides at serious doses: about 4 g/day.

  Dayspring says 1–2 g won't do much for triglyceride-rich lipoproteins. With Bill Harris he questions whether EPA alone is uniquely beneficial or whether 4 g of combined EPA plus DHA would work too. It is also unclear whether people with triglycerides below 150 and residual apoB risk would benefit.

• 10

  Fibrates are underappreciated in the right patient.

  Earlier fibrate trials were badly designed and often didn't target people with high triglycerides. A selective PPAR-alpha modulator is in big outcome trials. Niacin is 'a dead drug' that appears in no guideline, though a few Lp(a) specialists still use it selectively.