No Lower Limit? Strikingly Low LDL-C Levels Boost Cardiovascular Protection With No Added Safety Risk

#1

The long-standing debate over just how low we can safely push low-density lipoprotein cholesterol (LDL-C) has a definitive new answer. Long-term data from the open-label extension of the landmark FOURIER trial (FOURIER-OLE) confirms that pushing LDL-C down to ultra-low levels—even below 20 mg/dL—continues to slash cardiovascular risk with absolutely no signs of long-term safety penalties.

While the connection between high LDL-C and atherosclerotic cardiovascular disease (ASCVD) is a cornerstone of modern cardiology, doctors have long wondered about the floor. Is there a point of diminishing returns for efficacy, or worse, a threshold where extreme cholesterol depletion harms neurological function, cellular integrity, or hormone synthesis?

The newly released long-term data puts those concerns to rest.

The Study Protocol

To map the long-term efficacy and safety of extreme LDL-C lowering, researchers tracked patients transitioning from the original FOURIER trial—a randomized, placebo-controlled study of the PCSK9 inhibitor evolocumab—into the FOURIER-OLE open-label extension.

  • The Cohort: 6,635 patients with stable ASCVD transitioned into the extension phase, all receiving open-label evolocumab regardless of their original treatment assignment.
  • The Timeline: Patients were followed for an additional median of 5 years, with some followed up to a maximum of 8.6 years when combining the parent and extension trials.
  • The Metrics: Achieved LDL-C levels were calculated using an average of the first two measurements during the extension phase. Patients were stratified into five distinct cholesterol tiers to look for trends.

The Findings: The Lower, The Better

The results demonstrated a highly consistent, monotonic relationship: lower achieved LDL-C directly correlated with a lower risk of major cardiac events. Crucially, this benefit did not plateau, persisting all the way down to the lowest measured tier of under 20 mg/dL (<0.5 mmol/L).

Achieved LDL-C Tier (mg/dL) Patient Count (N=6,559) Percentage of Cohort
< 20 1,604 24%
20 to < 40 2,627 40%
40 to < 55 1,031 16%
55 to < 70 486 7%
≥ 70 811 12%

Even after rigorous multivariable modeling to adjust for baseline health factors, the trend remained highly statistically significant (p < 0.0001). Patients in the ultra-low tiers experienced significantly fewer events making up the primary efficacy endpoint (a composite of cardiovascular death, myocardial infarction, stroke, unstable angina hospitalizations, or coronary revascularization).

Reassuring News on Long-Term Safety

For longevity and preventative medicine enthusiasts, the most critical takeaway from this analysis is the safety profile. Concerns have historically circulated around whether ultra-low cholesterol might provoke cognitive decline, accelerate cataract formation, or disrupt blood vessels enough to cause brain bleeds.

The long-term data from FOURIER-OLE showed no statistically significant associations between lower achieved LDL-C levels and an increased risk of any monitored safety issue. Specifically, pushing LDL-C below 20 mg/dL did not increase rates of:

  • Neurocognitive or muscle-related adverse events
  • New-onset diabetes
  • Hemorrhagic stroke
  • Cataract-related adverse events
  • New or recurrent cancers
  • Serious adverse events or non-cardiovascular death

Longevity Implications

For years, the cardiovascular medicine community has operated under the mantra “lower is better.” These extension data lengthen that timeline to “lower is better, for longer.”

By proving that maintaining physiological LDL-C levels akin to those of a newborn baby (<20 mg/dL) for up to 8.6 years is both safe and highly protective against heart attacks and strokes, the study provides strong justification for aggressive, early, and sustained lipid-lowering therapies in high-risk patients. When it comes to preventing the world’s number one killer, pushing cholesterol to the absolute floor appears to be a winning strategy. @adssx @CronosTempi @desertshores
Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE

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#2

I noticed that @desertshores seemed concerned about the risks of ultra-low LDL-C, so I wanted to share this paper. Hopefully, it puts your mind at ease a little.

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#3

Thanks, I’ll add my bempedoic acid back to my stack. That will put my LDL back to ~34 mg/dl. The weight of the evidence is that lower is better. But then again there are always the outliers who don’t agree. I will ignore them and keep my cholesterol levels as low as I can.

In another area, evidence suggests that metformin is the first-line drug for glucose control. Strangely enough, after taking metformin for decades, I became intolerant to metformin. I get diarrhea when I take metformin. So now I’m on imeglimin and Jardiance and sitagliptin.

Metformin is more effective than the three together. They keep HEMOGLOBIN A1c in a good range, 5.4%, compared to metformin, 5.2%. But they don’t keep my fasting glucose as low as metformin did. I would recommend metformin to control glucose levels if you can tolerate it. IMO metformin is better than any other med for glucose control. Of course, if your natural glucose levels are okay and you want to lower them a little bit, then Jardiance is the best bet.

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#4

Right. However, there are other considerations and concerns. I think low/ultralow LDL levels have been acknowledged as CV protective, and we see it confirmed repeatedly. The worry is about how we get there. Because for example high dose niacin will drop the LDL number, but not offer CV protection, unlike statins. Meanwhile some worry that while statins offer cardiovascular protection all right, they might not offer much in ACM, which is ultimately the bigger prize - as studies show, worries about statins and dementia, cancer etc. are largly unwarranted, for many there are still questions about muscoskeletal impact. I personally don’t worry about statins (I’m on pitavastatin 4mg/day), but others still have questions. There are still questions about PCSK9i and a dementia signal (MR study). There are questions about effectiveness of ezetimibe in event prevention. And so on. In other words the fight to establish “lower is better” has largely been settled and the battle has moved on to the agents themselves. FWIW, I’m on pita, BA and EZ, but taking my time with PCSK9i and waiting on more agents to come to market including against Lp(a).

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#5

Here’s one that you only need one dose:

You try it. I’m not gonna try it.

I. Executive Summary

This peer review and clinical analysis evaluates the therapeutic efficacy, biological framework, and safety parameters of VERVE-102 as presented in the Phase 1b Heart-2 clinical trial data. The core thesis posits that a single-dose in vivogenomic base-editing intervention targeting hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) can successfully mimic naturally occurring cardioprotective loss-of-function mutations. This shifts the clinical management paradigm of atherosclerotic cardiovascular disease (ASCVD) from chronic, compliance-dependent therapeutic adherence to a permanent, single-course resolution.

Epidemiological and multi-territorial imaging data—most notably demonstrated by the prospective Progression of Early Subclinical Atherosclerosis (PESA) cohort study—confirm a linear, non-threshold association between cumulative low-density lipoprotein cholesterol (LDL-C) particle burden and subclinical vascular atheroma progression. Furthermore, large-scale Mendelian randomization trials have validated that lifelong genetic deficiencies in functional PCSK9 provide proportional protection against lifetime cardiovascular mortality without major systemic adverse effects. VERVE-102 operationalizes these findings by delivering an adenine base editor (ABE) encapsulated in an N-acetylgalactosamine (GalNAc)-conjugated lipid nanoparticle (LNP), ensuring highly specific parenchymal hepatic uptake via asialoglycoprotein receptors. Mechanistically, the editor alters a single target base pair to permanently turn off the hepatic PCSK9 gene, halting the degradation of hepatic low-density lipoprotein receptors (LDLR) and establishing a sustained clearance pathway for circulating atherogenic particles.

Interim clinical data from 35 adult participants with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD) demonstrate significant biomarker modulation. At the maximum evaluated dose of 1.0 mg/kg, VERVE-102 induced an 88% mean reduction in circulating PCSK9 protein and a corresponding 62% mean reduction in serum LDL-C, with therapeutic durability tracking up to 18 months post-infusion. However, serious translational gaps and clinical headwinds persist. Unlike traditional small molecule or monoclonal antibody interventions, genomic base editing introduces an irreversible somatic alteration with latent risks of off-target genotoxicity. Although the updated GalNAc-LNP configuration successfully mitigated the acute thrombocytopenia and severe transaminitis that halted its predecessor molecule (VERVE-101), approximately 75% of subjects in the Heart-2 trial still reported mild-to-moderate adverse events, including transient transaminase spikes and low-grade infusion-related reactions. Because this remains an open-label, single-ascending-dose Phase 1b study lacking a concurrent placebo control arm, long-term safety registries extending to 15 years and robust Phase 3 trials evaluating hard clinical endpoints (major adverse cardiovascular events, or MACE) are mandatory prior to broad clinical translation.

II. Insight Bullets

  1. Atherosclerotic cardiovascular disease (ASCVD) remains the leading global driver of mortality, demanding highly potent lipid-lowering strategies.
  2. Apolipoprotein B (ApoB)-containing lipoproteins, specifically low-density lipoprotein particles, are established as directly causal agents in arterial atherogenesis.
  3. Pathological overabundance of circulating low-density lipoprotein cholesterol (LDL-C) promotes particle retention within the subendothelial intimal space of arteries.
  4. Entrapped intimal lipoproteins undergo oxidative and enzymatic modifications, triggering local endothelial activation and leukocyte recruitment.
  5. Persistent endothelial inflammatory signaling cascades accelerate the structural progression of subclinical vascular plaques.
  6. Advanced atheromatous lesions featuring soft, lipid-rich necrotic cores possess high susceptibility to mechanical fibrous cap rupture.
  7. Acute plaque rupture exposes highly thrombogenic core material to the bloodstream, precipitating luminal thrombosis and subsequent myocardial or cerebral infarction.
  8. Standard clinical therapeutics have historically relied on daily, lifelong oral administration of small-molecule HMG-CoA reductase inhibitors (statins).
  9. Monoclonal antibodies and small interfering RNAs (siRNAs) targeting circulating PCSK9 represent highly effective but costly secondary maintenance options.
  10. Deep, sustained reductions in circulating LDL-C can arrest lesion development, stabilize vulnerable fibrous caps, or prompt modest plaque regression.
  11. The prospective Progression of Early Subclinical Atherosclerosis (PESA) study utilized non-invasive multi-territory imaging in over 4,000 asymptomatic individuals.
  12. Data from the PESA trial confirm that subclinical atheromas develop silently decades prior to symptom manifestation or abnormal functional stress testing.
  13. The PESA cohort demonstrated a continuous, linear relationship between LDL-C exposure and multi-vascular plaque burden, with no safe lower threshold.
  14. Mendelian randomization studies circumvent the confounding variables of traditional clinical trials by evaluating inherited genetic variations.
  15. Human cohorts possessing lifelong loss-of-function variations in the PCSK9 gene manifest profoundly suppressed lifetime incidence of ASCVD.
  16. Conventional oral and injectable lipid-lowering drugs require perfect lifelong adherence, which is rarely achieved in real-world clinical practice.
  17. VERVE-102 introduces a therapeutic paradigm shift by utilizing in vivo somatic genomic editing to permanently modify hepatic lipid metabolic pathways.
  18. The platform employs CRISPR-Cas9-derived base editing technology to execute highly precise single-nucleotide conversions without double-stranded DNA breaks.
  19. VERVE-102’s molecular architecture uses an adenine base editor (ABE) to introduce a precise transition mutation within the hepatic PCSK9 locus.
  20. Permanent genomic inactivation of hepatic PCSK9 blocks the synthesis and secretion of the functional extracellular proprotein convertase.
  21. Circulating PCSK9 normally binds directly to the extracellular domain of hepatic low-density lipoprotein receptors (LDLR), targeting them for lysosomal degradation.
  22. Genetic silencing of PCSK9 preserves cellular LDLR survival, increasing steady-state surface receptor density on sinusoidal hepatocyte membranes.
  23. Elevated cell-surface LDLR expression drives accelerated, receptor-mediated endocytosis and lysosomal clearance of circulating atherogenic LDL particles.
  24. Phase 1b (Heart-2) clinical trial data show a dose-dependent reduction in circulating PCSK9 protein, reaching 88% at the 1.0 mg/kg dose tier.
  25. Intravenous administration of the 1.0 mg/kg therapeutic dose resulted in a mean 62% reduction in circulating serum LDL-C levels.
  26. Absolute reductions in serum LDL-C achieved in the highest dose tier reached a mean decrease of approximately 78 mg/dL.
  27. The biomarker modulation induced by a single therapeutic dose of VERVE-102 demonstrated stable durability for up to 18 months of clinical follow-up.
  28. Oral small molecules and injectable monoclonal antibodies feature immediate reversibility upon treatment cessation, returning lipid profiles to baseline.
  29. Somatic base editing via VERVE-102 creates an irreversible genomic modification, providing no endogenous or exogenous pharmacological “off-switch.”
  30. The absolute therapeutic potency of in vivo base editing relies entirely on achieving high target-tissue transduction efficiency throughout liver parenchyma.
  31. Maximizing LDL-C suppression necessitates the permanent modification of a substantial proportion of the functional host hepatocyte pool.
  32. The long-term safety profile of permanent somatic gene disruption remains unknown due to brief clinical tracking windows.
  33. The initial iteration of this technology (VERVE-101) was permanently paused in April 2024 following treatment-related severe transaminitis and thrombocytopenia.
  34. VERVE-101’s acute toxicities were attributed to off-target immune activation and cellular damage driven by its specific lipid nanoparticle (LNP) formulation.
  35. The optimized VERVE-102 construct incorporates an upgraded LNP delivery vehicle chemically conjugated with N-acetylgalactosamine (GalNAc) residues.
  36. GalNAc targeting leverages hepatocyte-specific asialoglycoprotein receptors to enhance liver avidity while minimizing systemic extrahepatic exposure.
  37. Interim Phase 1b safety analysis reveals that approximately 75% of clinical study participants experience some form of adverse event.
  38. The vast majority of reported adverse events are non-serious, consisting of transient fatigue, mild pyrexia, and localized infusion reactions.
  39. Self-limiting, transient elevations in alanine aminotransferase (ALT) indicate acute metabolic and structural stress within hepatocytes post-LNP uptake.
  40. The unblinded, open-label design of the Phase 1b trial lacks a simultaneous placebo control arm, hindering definitive differentiation of real versus perceived adverse events.
  41. Broad clinical deployment of VERVE-102 requires extensive prospective registries up to 15 years to monitor for delayed off-target genotoxicity or oncogenesis.
  42. Complete eradication of ischemic cardiac events cannot be accomplished by lipid reduction alone, as non-atherosclerotic vascular pathologies persist.

III. Adversarial Claims & Evidence Table

Claim from Video Speaker’s Evidence Scientific Reality (Current Data) Evidence Grade Verdict
High levels of cholesterol-containing lipoproteins are directly causal factors in atherogenesis and ASCVD. Decades of general consensus and discovery within the cardiology field. Confirmed by massive meta-analyses and global consensus statements establishing ApoB particles as inherently atherogenic. Ference et al., 2017 Level A Strong Support
The PESA study (mislabeled as “Pisa” in video) demonstrates a linear relationship between LDL-C and plaque burden in healthy adults. Mentions an imaging study tracking blood vessel plaques across several years in over 4,000 individuals. Prospective cohort data of 4,184 asymptomatic adults proved 63% had subclinical plaques, with a direct linear relationship to LDL-C even at “normal” ranges. Fernández-Friera et al., 2015 Level C Strong Support
Mendelian randomization trials show individuals with lifetime loss-of-function mutations in PCSK9 have drastically reduced cardiovascular risk. Brief description of genetic cohorts split by mutations that drop cholesterol for their entire life course. Large-scale genetic analyses show that naturally occurring PCSK9 loss-of-function variants (e.g., R46L) reduce LDL-C exposure and CHD risk across a lifetime. Ference et al., 2016 Level C Strong Support
A single 1.0 mg/kg dose of VERVE-102 leads to a durable 60% reduction in circulating LDL-C. Topline data points retrieved directly from the newly released Verve-102 clinical trial results. Phase 1b Heart-2 trial data for 35 participants demonstrated an 88% mean PCSK9 reduction and a 62% mean LDL-C reduction at 1.0 mg/kg, durable up to 18 months. Patel et al., 2026 Level B Plausible (Biomarker efficacy verified; final long-term cohort replication ongoing)
VERVE-102 utilizes CRISPR-Cas9 base editing technology to replace one nucleotide in the PCSK9 gene sequence. Mechanistic description of molecular gene alteration within liver cells. Verified. VERVE-102 utilizes an adenine base editor mRNA and guide RNA to execute an A•T to G•C transition, introducing a premature stop codon without double-stranded DNA breaks. Lilly/Verve Clinical Registry, 2026 Level B Strong Support
Predecessor off-target liver toxicities have been successfully addressed and resolved in the newer VERVE-102 version. Mentions historic liver side effects and asserts they have been mitigated by design updates. True for interim timelines. VERVE-101 was halted due to transaminitis/thrombocytopenia; VERVE-102 incorporates GalNAc-LNPs which show zero treatment-related SAEs or dose-limiting toxicities in early data. TCTMD Heart-2 Report, 2025 Level B Plausible (Early safety enhanced, but long-term registry tracking is required)
Over 70% of clinical trial participants experienced adverse events during the study. Direct citation of Phase 1 clinical trial safety readouts. Topline analysis confirms ~75% of participants experienced an adverse event, with 31% experiencing a treatment-related adverse event, primarily mild infusion reactions and fatigue. Patel et al., 2026 Level B Strong Support

IV. Actionable Protocol (Prioritized)

High Confidence Tier (Backed by Level A/B Evidence)

  • First-Line HMG-CoA Reductase Inhibition: Implement maximally tolerated high-intensity statin therapy (e.g., Atorvastatin 40–80 mg or Rosuvastatin 20–40 mg daily) as the primary therapeutic baseline to achieve aggressive competitive inhibition of cholesterol biosynthesis, backed by extensive multi-decade Level A meta-analyses.
  • Secondary Oral Monotherapy Conjugation: Add Ezetimibe (10 mg daily) to block Niemann-Pick C1-Like 1 (NPC1L1)-mediated intestinal cholesterol absorption if statin monotherapy fails to lower LDL-C or ApoB levels below risk-stratified targets.
  • Reversible Recombinant Biologic Deployment: For high-risk individuals with heterozygous familial hypercholesterolemia (HeFH) or established ASCVD exhibiting inadequate response to oral regimens, administer injectable monoclonal antibodies targeting extracellular PCSK9 (e.g., Evolocumab 140 mg every 2 weeks) or small interfering RNA molecules (e.g., Inclisiran 284 mg every 6 months), validated by multi-center Level B randomized controlled trials (such as the FOURIER and ODYSSEY trials).

Experimental Tier (Backed by Level C/D Evidence with High Safety Margins)

  • Multi-Territorial Non-Invasive Vascular Screening: Deploy direct phenotype screening using carotid and femoral artery 2D/3D duplex ultrasound alongside non-contrast computed tomography (CT) for Coronary Artery Calcium (CAC) scoring in asymptomatic individuals aged 40–54. This approach moves past statistical risk calculators to identify subclinical, silent plaque development early, as supported by observational cohort data from the PESA Study.

Red Flag Zone (Claims Lacking Safety Data / “Safety Data Absent”)

  • Avoidance of Commercial or Premature Somatic Gene Editing: Absolute contraindication for the use of in vivobase-editing therapeutics (such as VERVE-102) outside regulated clinical research environments (NCT06164730). While biomarker performance is highly potent, long-term safety data are absent. Somatic genome editing represents a permanent modification with irreversible physiological changes. Until long-term registries (up to 15 years) rule out delayed transaminitis, off-target insertional mutagenesis, or oncogenesis, this intervention must be avoided by low-risk individuals or those whose conditions can be managed with traditional, reversible pharmacology.

1. LNP Bio-distribution and GalNAc Substrate Targeting

The predecessor molecule, VERVE-101, utilized a non-targeted lipid nanoparticle (LNP) formulation that caused significant off-target cellular uptake, triggering acute transaminitis and thrombocytopenia. To resolve this, VERVE-102 incorporates an upgraded LNP delivery platform conjugated with N-acetylgalactosamine (GalNAc) carbohydrate clusters. GalNAc functions as a highly specific, high-affinity ligand for the asialoglycoprotein receptor (ASGPR), an endocytic transmembrane protein highly expressed on the sinusoidal surface of parenchymal hepatocytes. Upon binding, the LNP undergoes rapid receptor-mediated endocytosis, confining the therapeutic payload to the liver tissue and preventing systemic extrahepatic toxicity.

#6

The evidence clearly leans toward benefits or at least no harms from ultra-low circulating LDL-C. The brain has its own mechanism for regulating cholesterol and the evidence I have seen suggests that levels too low or too high can be a serious problem. How the LDL-C fraction (or more determinatively Apo(b)) break out is more complicated.

All of this said, even if I were young enough to benefit from the practical elimination of circulating LDC-C, I would not do so. It is an extreme measure on multiple fronts and history has shown is that what was certainly true as a medical fact turned out to be certainly false as a medical fact. These 180’s can take decades of course, and we humans cannot always afford to wait them out.

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#7

What matters most is plaque buildup prevention and the thresholds at which plaque starts forming are between 50mg/dL and 80mg/dL depending on how many risk factors you have. Most people can achieve said levels with a statin and maybe ezetimibe or bempedoic acid.

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#8

Well, there is other factors to consider IMO and while as low as possible (i.e. 20’s) may be a good idea for people in high-risk category, I myself have zero interest in being lower than 40’s. I take a bit of a practical approach to this and many other medical interventions. i.e. not every human dies/will die of heart disease regardless of their LDL levels, and not every human that has normal or a bit high LDL numbers will develop a heart/plaque problem. I knew and have also heard cases of people with LDL in high 90’s and low 100’s that are perfectly healthy and either lived to 100 or are approaching 100 without ever taking any statins. So, the madness that we have to eradicate LDL by trying every lowering drug out there may be a bit of an overkill. I would love to see mine in the 45-60 range (not there yet, at 72) and I wouldn’t even care to lower it further if I ever saw it at 55 as an example.

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#9

Yes. And we are not merely considering outliers. Roughly 75% of individuals hospitalized for an acute coronary event have LDL-C (low-density lipoprotein cholesterol) levels that fall within standard “normal” or acceptable ranges, and nearly 50% have levels traditionally classified as “optimal” (<100 mg/dL).Roughly 18% of people hospitalized for an acute event have LDL-C less than 70 mg/dL. Apo(b) discordance explains some of this and inflammation even more in my judgment but I think the consensus of the experts is that there are factors we do not yet fully understand. Still, unless one knows otherwise with some certainty, bet on the main effects.

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#10

Which inflammatory markers do you consider critical? Personally, I doubt hs-CRP is a good choice. What are your thoughts?

#11

For ASCVD, I think CRP is a good metric. There might be better metrics but we have such a large baseline on it and its inverse association with ASCVD that it is perhaps the most useful. Other metrics that look at oxidized LDL embed an inflammatory component contingently but the data are more sparse. Depending on where you set the marker, only 10% of the ASCVD statistics are associated with a CRP of 0.5 and under. This is partially an extrapolation because we only have robust metrics on under 1.0 where (as I recall) less than 23% have a CRP of 1.0 or lower.

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#12

I think for inflammation it is a great choice. I have an immune disorder (yet to be named) and have plenty of inflammation, and I can literally predict (if it will higher or lower than my previous test) my hs-CRP by the way I feel about inflammation. As an example, on my last test, I knew my hs-CRP would be higher than on my prior test (obviously I wouldn’t know the number by how much) and lo and behold it was 1.8 as opposed to 1.3 five months earlier. So, by that measure alone I know hs-CRP is a good indicator of inflammation. If I were to take a test today, I know for sure I’m lower, most likely close to 1.

#13

I’d look at IL-6, though you have to hunt around to find reasonably priced tests.

#14

Agreed on Il-6 which is why I always mention a baseline CRP (not a single measure) because you approximate comparability in a test that most insurances will pay for.

I’m migrating toward ClycA but even there, Il-6 retains merit.

While IL-6 remains the premier single-cytokine indicator of upstream causal vascular risk, GlycA outperforms CRP by serving as a stable, integrated metric of chronic coronary inflammation that avoids the confounding acute-phase spikes characteristic of native C-reactive protein and to some extent Il-6. Even then, I think GlycA may be too sensitive to minor but persistent localized inflammation such as might be seen in minor dental issues.

#15

The study summary doesn’t mention the results in regard to overall mortality (which makes me suspicious). There have been many studies showing statins modestly improve cardiovascular outcomes but have no (or negative) effect on overall mortality.

#16

Most studies on statins show either no effect or a lower all-cause mortality.

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#17

UK Biobank - 9% atorvastatin.

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#18

Here is the annualized all-cause mortality breakdown based on the actual LDL-C levels they achieved:

  • < 20 mg/dL: 2.65%
  • 20 to < 40 mg/dL: 2.87%
  • 40 to < 55 mg/dL: 3.72%
  • 55 to < 70 mg/dL: 4.30%
  • ≥ 70 mg/dL: 3.93%
#19

Interesting to me that you use “normal” LDL and until recent “optimum” when all my labs have used 100 for years as the normal range when reporting (many don’t have words like normal or optimal but use reference).

As you know, normal is just 95% middle most of the time. So by that standard, you would expect somewhere around 95% of patients with anything to be in the normal range which makes 75% perfectly reasonable.

But who has been using the normal range for LDL as the reference range recently?

100 is the right cutoff for a long time now. The question really is should it be 70? Guidelines say you need a risk factor but AI tells me that 90% of US adults have a risk factor and the AHA say 48% have heart disease. Sounds like 70 is the more relevant number with 55 being optimum.

If the labs flag it, people will be more inclined to treat it. Which is the right answer.

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#20

I put ‘normal’ in quotations.

The point I have made in a few posts is that LDL-C is not an atherogenic particle. That “honor” belongs to Apo(b) and even more so --at least on a per particle basis – to Lp(a). The reason we see these reasonably high but by no means perfect correlations between LDL-C levels and certain forms of ASCVD is that LDL-C accounts for 75.6% of the variability in Apo(b) levels, with a correlation coefficient of r = .96 (P < .001) in some general population studies. Discordance can be high in the unexplained variance, including according to some genetic profiles and some racial differences. Some Asians, for example, can have LDL-C levels in the middle of what is generally considered a healthy range, even below that, yet have destructively high levels of Apo(b). Anyone concerned with managing that facet of ASCVD would be well advised (i.e., better aligned with science) to manage to Apo(b) and ignore LDL-C.

Separately, lab value labels are typically more sophisticated than representing simple anchors to distributions statistics. Some metrics, Lp(a) for example, are heavily skewed (right tail in this case) and the normative labels account for that in clinical anchors.