https://x.com/nicknorwitz/status/1907775095998681241
#LDL
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https://www.jacc.org/doi/10.1016/j.jacadv.2025.101686
Plaque Begets Plaque, ApoB Does Not: Longitudinal Data From the KETO-CTA Trial
Methods
One hundred individuals exhibiting KD-induced LDL-C ≥190 mg/dL, high-density lipoprotein cholesterol ≥60 mg/dL, and triglycerides ≤80 mg/dL were followed for 1 year using coronary artery calcium and coronary computed tomography angiography. Plaque progression predictors were assessed with linear regression and Bayes factors. Diet adherence and baseline cardiovascular disease risk sensitivity analyses were performed.
Results
High apolipoprotein B (ApoB) (median 178 mg/dL, Q1-Q3: 149-214 mg/dL) and LDL-C (median 237 mg/dL, Q1-Q3: 202-308 mg/dL) with low total plaque score (TPS) (median 0, Q1-Q3: 0-2.25) were observed at baseline. Neither change in ApoB (median 3 mg/dL, Q1-Q3: −17 to 35), baseline ApoB, nor total LDL-C exposure (median 1,302 days, Q1-Q3: 984-1,754 days) were associated with the change in noncalcified plaque volume (NCPV) or TPS. Bayesian inference calculations were between 6 and 10 times more supportive of the null hypothesis (no association between ApoB and plaque progression) than of the alternative hypothesis. All baseline plaque metrics (coronary artery calcium, NCPV, total plaque score, and percent atheroma volume) were strongly associated with the change in NCPV.
Conclusions
In lean metabolically healthy people on KD, neither total exposure nor changes in baseline levels of ApoB and LDL-C were associated with changes in plaque. Conversely, baseline plaque was associated with plaque progression, supporting the notion that, in this population, plaque begets plaque but ApoB does not. (Diet-induced Elevations in LDL-C and Progression of Atherosclerosis [Keto-CTA]; NCT05733325)
Characteristics of the sample population are as follows:
The inclusion criteria were
• Being on a KD for ≥24 months
• LDL-C ≤160 mg/dL from the last lipid panel drawn prior to adopting a KD
• LDL-C ≥190 mg/dL on the most recent laboratory on a KD
• An increase of ≥50% in LDL-C after adopting a KD
• HDL-C ≥60 mg/dL
• Triglycerides ≤80 mg/dL
• Glycated hemoglobin <6.0%
• Fasting glucose <110 mg/dL
• High-sensitivity C-reactive protein <2 mg/L
Exclusion criteria were
• Elevated blood pressure (systolic >130 mm Hg, diastolic >80 mm Hg)
• Type 2 diabetes or any lifetime use of antidiabetic medication
• Untreated hypothyroidism (thyroid stimulating hormone >10 mIU/mL)
• Renal insufficiency (calculated creatinine clearance of <50 mL/min with the MDRD [Modification of Diet in Renal Disease Study] equation)
• Liver enzymes >2 times the upper limit of normal at screening visit or total bilirubin >1.5
• Use of medications that elevate LDL-C (anabolic steroids, isotretinoin, immunosuppressant, amiodarone, thiazide diuretics, glucocorticoids, or thiazolidinediones)
• Use of lipid-lowering supplements or medications (statins, red yeast rice, garlic, ezetimibe, berberine, PCSK9 inhibitors)
• Genetically defined familial hypercholesterolemia
This study is being discussed there: Cardiovascular Health - #1751 by adssx
Tl;dr: misleading title, people in the study had the fastest plaque progression ever seen in a cohort.
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Is Targeting LDL-C Levels Below 70 mg/dL Beneficial for Cardiovascular and Overall Health? A Critical Examination of the Evidence
Folkert H van Bruggen et al. J Clin Med. 2025.
Abstract
Over the past two decades, cardiovascular disease (CVD) prevention guidelines have progressively lowered LDL-C targets to <70 mg/dL for high-risk individuals based on the assumption of a linear relationship between LDL-C levels and CVD risk. However, the available evidence challenges this premise. Multiple studies demonstrate a weak or inconsistent association between LDL-C levels and atherosclerosis progression at the individual patient-level. Systematic reviews supporting the linearity assumption have notable limitations, including extrapolation beyond observed LDL-C ranges and potential ecological fallacy, as meta-regression analyses rely on study-level data, while patient-level data within the same trials often show no association between LDL-C reduction and CVD outcomes. Moreover, randomized controlled trials explicitly designed to assess LDL-C targets have yielded inconclusive and biased results. LDL-C itself is a heterogeneous marker, with particle size and composition influencing its atherogenicity. The cardiovascular benefits of lipid-lowering therapies may arise in part from pleiotropic effects unrelated to LDL-C lowering. Additionally, several studies indicate that higher LDL-C levels are paradoxically associated with longevity in elderly populations that is equal to or even greater than that of the general population. Collectively, this body of evidence raises questions about the validity of current LDL-C targets < 70 mg/dL in high-risk patients. [PMID: 40429563]
From the full text:
- Lifelong elevated LDL-C may result in long CVD-free lives: Elderly individuals with high LDL-C, including those with familial hypercholesterolemia (FH), often enjoy longer, CVD-free lives, likely due to enhanced immune function and resistance to severe infections, while younger FH individuals’ CVD risk is linked to thrombosis rather than elevated LDL-C.
- Studies have also shown that low LDL-C levels are associated with an increased risk of infections, sepsis, and mortality.
- Lipid-lowering therapy benefits stem from reduction in non-LDL-C factors: The pleiotropic effects of lipid-lowering therapies, including the anti-inflammatory and antithrombotic actions of statins… contribute to cardiovascular risk reduction independently of LDL-C.
- Lack of linear association between LDL-C and risk of CVD: Minimal to no correlation has been observed between LDL-C levels and plaque progression or CAC scores at the individual patient level.
- Observational cohort studies reported a U-shaped association between LDL-C- or total cholesterol levels and the risk of all-cause mortality, with the lowest mortality risk observed at LDL-C levels ranging between 100 and 189 mg/dL.
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Thank you.
A short read. It may look long if you view the scroll bar. But if you scroll down, most of it is comprised (60%) of citations.
A recent meta-analysis of 31,245 patients across three statin trials demonstrated distinct associations between inflammatory risk and residual cholesterol risk with cardiovascular outcomes among statin users. Higher baseline hsCRP levels were significantly associated with increased incidence of MACE. Notably, the relationship between LDL-C levels and MACE was neutral across LDL quartiles (LDL-C range < 56 to >102 mg/dL) [38].
In addition, statins reduce C-reactive protein (CRP) and hs-CRP levels in patients with CVD, independent of LDL-C levels [84]. Therefore, lower post-treatment CRP levels are associated with reduced CVD event risk, regardless of achieved LDL-C levels in primary and secondary prevention [85,86].
Statins also exhibit antithrombotic effects, directly and indirectly influencing coagulation and platelet aggregation [87]. In a secondary endpoint analysis of the JUPITER trial that compared rosuvastatin 20 mg daily versus placebo, rosuvastatin reduced the risk of venous thromboembolism (VTE). Importantly, the reduction in VTE risk was independent of the baseline LDL-C level [88]. Similar to previous trials comparing anticoagulant and antiplatelet drug combinations, rosuvastatin’s antithrombotic properties may explain its observed reduction in CVD risk [89,90].
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So one author is from the “Department of Psychology”? Psychology of cholesterol?
I was just looking at platelets in Lp(a) (I have very high levels), so I rounded up a bunch of papers on statins and platelets in the cardiovascular health thread.