Low Cholesterol Won’t Save You. Measure This Instead.
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37% of people with very low LDL bad cholesterol still have atherosclerosis, plaque in their arteries, despite optimal cholesterol. Despite decades of medical innovation focused on lowering LDL like turning a pig into irony bacon, cardiovascular disease remains a world-leading killer. If you can get heart disease with pristine optimal LDL, and lowering LDL further hasn't erased the cardiovascular disease epidemic, why are we still doubling down? Why insist on making one number the whole story? Why miss the cardiovascular forest for a stupid little cholesterol shrub? Playing devil's advocate, maybe we just haven't gotten LDL low enough. These questions will be tackled, plus what to measure instead.
Very low LDL cholesterol levels did not prevent atherosclerosis: 12% relative difference, not nothing, but pitiful payoff. Long list of risk factors carry far greater consequence than LDL alone. This is a clear systemic problem. Why this is personal: loved one of a friend suffered a heart attack. LDL doesn't belong in the center of the room; it deserves far less attention.
Newsletter at staycuriousmetabolism.com for details, references, early access to data digests. Community is top three overall bestseller in science globally. Offers master class on cholesterol-lowering drugs and guide to why this is divisive. About information, not prescriptions.
Roadmap
Chapter 1: What happens when LDL cholesterol is optimal. Chapter 2: What critics say. Chapter 3: What I'm saying and not saying. Chapter 4: Why this is personal. Chapter 5: The not low enough trap. Chapter 6: Biomarkers you should track.
Review of paper in journal Atherosclerosis: prevalence of atherosclerosis in adults with optimal LDL cholesterol <70 mg/dL (group mean 57, super low). Some question if atherosclerosis can develop at all with LDL <70 mg/dL. Punchline: 37% of individuals with LDL <70 (mean 57) still had evidence of atherosclerosis. Specifically, 30% had positive coronary artery calcium score; 18% in highest quartile for carotid intima-media thickness (thickness of carotid arteries to brain), some overlap. Not even coronary CT angiography for soft plaque; 37% probably underestimates actual plaque burden.
To be fair, 37% is modestly lower than overall population prevalence of 49% (12% relative difference). But pitiful payoff for driving LDL to very low levels. Landscape changing: new drugs lowering LDL, total cholesterol, ApoB lower while risk factors like insulin resistance, obesity, diabetes persist.
Concrete comparison: Lipoprotein Insulin Resistance score (LPIR) shows much stronger association with cardiovascular disease. In 28,000-individual study in JAMA Cardiology, adjusted hazards ratio for LPIR was 6.4 vs. 1.38 for LDL cholesterol (540% increased risk vs. 38%; LPIR 14-fold more powerful predictor of new coronary heart disease than LDL). Not proportional medicine; distorted, not serving patients.
Criticisms: Only small fraction (3%) of cohort had LDL <70 (mean 57). But 3% is 263 individuals; >1 in 3 with very low LDL having atherosclerosis is a signal worth taking seriously.
Second criticism: single time point lipid measurement may not capture lifetime LDL exposure. But individuals were untreated (exclusion criteria), a key strength. Studies naturally low LDL (not medicated) to differentiate from pleiotropic benefits of medications often misattributed to LDL/ ApoB lowering. Avoids mistaking medication effects like reducing inflammation in metabolically unwell people for LDL lowering alone.
Punchline: In two diverse cohorts of untreated patients with optimal very low LDL (presumably lifelong), atherosclerosis still showed up.
Look at larger puzzle: risk factors like obesity, type 2 diabetes, insulin resistance (LPIR vs. LDL data), elevated blood pressure, chronic inflammation, smoking history carry far greater consequence than LDL alone. When LDL monopolizes spotlight, framing is incomplete and harmful: pulls attention/resources from factors that matter more toward what's easiest to monetize/medicalize (LDL, smashable with drugs).
Not arguing bad intentions; clear systemic problem perpetuating metabolic health epidemic including cardiovascular disease. Spotlight driven by incentive structures/business models, not best for patients. LDL-lowering therapies: $10B+ annualized industry; statins alone $20B/year, uptrending. Dictates teaching, research funding, guidelines. Not incompatible with lipid drugs being useful in right patients, but naive to ignore pharma influence. Cardiovascular disease still leading cause of morbidity/mortality: unacceptable. Widen the lens.
Spent countless hours in doctor's offices chastised for untreated lipid levels; arteries remain perfectly clean. More troubling: friends/family/loved ones not doing well despite optimal LDL on multi-drug management. Example: loved one of friend had heart attack with LDL 51 (below study average). They lived but were stunned/confused, believing low LDL meant safe zone/protection. Had greater risks: obesity, pre-diabetes, smoking history (no longer smoker). Those never took center stage; focus remained LDL. Impression: low enough LDL = get out of jail free card. Not rare; huge problem.
Steelmanning conventional argument: if mean LDL 57 doesn't make atherosclerosis orphan disease, solution is 40/30/20/10 or zero. Reveals keyhole thinking in siloed cardiology: success defined by single biomarker/organ vs. whole person health.
Possible in theory that driving LDL/ ApoB to zero prevents events, but dodges: what tradeoffs? LDL therapies not benign. Statins increase diabetes risk, suppress GLP-1 levels, worsen insulin resistance, impair mitochondrial function, contribute to muscle loss. Patients face tradeoffs; maybe justified in poor metabolic health/multiple risks. But LDL not carrying bulk of risk. Need wider view.
LDL doesn't belong in center of room; deserves far less attention. Shift spotlight to broader metabolic health driving true risk for proportional/rational/patient-centered medicine.
Not cutoffs from on high; based on physiology/judgment. Starter list of six:
- hsCRP: <1 mg/L. Marker of systemic inflammation; <1 associated with lower CV risk, better endothelial function, reduced inflammatory burden.
- HbA1c: <5.5%. Reflects ~3-month average glucose; <5.5% lower risk microvascular/macrovascular complications. Even 5.6% can conceal variability/hyperinsulinemia.
- Fasting insulin: <7 μU/mL. Proxy for insulin sensitivity; elevated precedes abnormal glucose, reflects metabolic strain.
- Triglycerides: <80 mg/dL (better than general <150). Marker metabolic health/liver insulin resistance; low reflects efficient fat burning/VLDL turnover. Linked to CV risk > LDL. Noisy; fast 12-16 hours water-only.
- HDL cholesterol: >50 mg/dL (female), >40 mg/dL (male). Correlates with reverse cholesterol transport, insulin sensitivity, metabolic health (litmus test, not causal). Complex; consider subfractionation with caution.
- Waist-hip ratio: <0.85 (female), <0.9 (male). Reflects visceral adiposity; linked to insulin resistance, inflammation, CV risk, Alzheimer's. Lower = healthier distribution; reduces high Lp(a) risk.
Not anti-lipid management; pro-bigger picture/informed decisions. Some paint as villain despite nuance/resources like master class on cholesterol drugs pros/cons. Takeaway: not that LDL/ ApoB don't matter; meaning misallocated. Mistaken prominence for importance, familiarity for truth. LDL crowds out richer understanding of CV risk. System optimizes for easy-to-track/target drugs vs. what keeps people healthy. Let me know if reasonable. Stay curious.
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