#407 ‒ Preventing cardiovascular and Alzheimer's disease: lowering LDL early, APOE4, and promising new therapies | Michael Davidson, M.D.

September 14, 2026

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5 min read

When LDL treatment starts too late

Michael Davidson’s father died of a heart attack at age 47. Davidson was 16. His brother, who avoided statins until his forties, needed bypass surgery at 44. Davidson himself took niacin in medical school and started a statin as soon as they became available. He has never had a cardiac event. That family experiment—an N of one, as he calls it—shaped his entire career and explains why he now sees LDL as something to treat the way we treat blood pressure or smoking: not based on ten-year risk, but because it is a causal driver of disease.

The eight-gram rule and why prevention must start young

Davidson’s central argument is simple and data-driven. He describes the “eight-gram rule”: eight grams of cholesterol exposure over a lifetime leads to heart disease. That can be 200 mg/dL for 40 years, or 100 mg/dL for 80 years, or 80 mg/dL for 100 years. The implication is that keeping LDL below 80 mg/dL throughout life essentially prevents atherosclerosis. This reframes prevention entirely. Instead of asking whether a 30-year-old has a high short-term risk, Davidson asks whether that person has a causal risk factor that will accumulate damage over decades.

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What you'll learn

1 (00:13) **Episode Introduction and Guest Background** - Peter Attia introduces the episode and guest Michael Davidson, a cardiologist and lipidologist.
2 (03:13) **Personal Motivation and the Case for Early Prevention** - Davidson shares his family history and argues for treating LDL early in life, like blood pressure or smoking.
3 (12:15) **Why LDL Treatment Lags Behind Hypertension and Diabetes** - The discussion explores why LDL lowering is more contentious than treating other risk factors.
4 (15:12) **Introduction to CETP Inhibition and the Story of Torcetrapib** - Davidson explains the mechanism of CETP and the dramatic failure of Pfizer's first-in-class drug.
5 (23:52) **The HDL Hypothesis and Subsequent CETP Failures** - The history of the HDL hypothesis is reviewed, followed by the neutral results from Roche's and Lilly's CETP inhibitors.
6 (32:09) **The Merck Trial (REVEAL) Saves the Class** - The large REVEAL trial with anacetrapib provided the first positive proof-of-concept for CETP inhibition.
7 (37:43) **Obicetrapib: A More Potent and Differentiated Molecule** - Davidson details the origin, potency, and unique profile of obicetrapib, the drug he is now developing.

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Guests on this episode

Peter Attia

Show Notes

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Michael Davidson is a world-renowned cardiologist, lipidologist, and the founding CEO of NewAmsterdam Pharma. He begins this episode by sharing how his family history shaped his interest in lipidology and primary prevention. He explains why prevention should focus on causal drivers of disease rather than near-term risk and examines the causal relationship between LDL and atherosclerotic cardiovascular disease. Michael then traces the complicated history of CETP inhibitors—from the original rationale that raising HDL would reduce cardiovascular risk to the failures of torcetrapib, dalcetrapib, and evacetrapib—and explains how lessons from these trials ultimately led to the development of obicetrapib. He reviews the phase 2 and phase 3 trials of obicetrapib, its effects on LDL-C, apoB, LDL particle number, and Lp(a), the ongoing cardiovascular outcomes trial, and where the drug could fit alongside statins and other lipid-lowering therapies. Peter and Michael discuss the relationship between statins and diabetes risk, then turn to the potential role of obicetrapib in Alzheimer's disease prevention, exploring the genetics of APOE4 and CETP, cholesterol metabolism within the brain, and emerging biomarker data. Finally, Peter and Michael explore the benefits of omega-3 fatty acids and the challenge of delivering DHA to the brain, as well as ongoing work on klotho in preparation for clinical trials. They discuss the potential for AI to transform clinical trials and the scientific and financial challenges of developing new therapies for cardiovascular and neurodegenerative disease.

We discuss:

Michael's path to lipidology, and his passion for primary prevention [3:30];
Reframing prevention around causal drivers rather than time horizon [9:30];
What CETP inhibition does, the evolutionary biology of CETP, the HDL-raising rationale, and Pfizer's torcetrapib failure [15:00];
Why raising HDL is thought to be beneficial, a quick review of the functions of HDL, and how this connects to torcetrapib [24:00];
The graveyard of CETP inhibitors: Roche's dalcetrapib, Lilly's evacetrapib, and Merck's REVEAL trial [27:15];
The causality of LDL in cardiovascular disease [34:30];
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