“In general, lower LDL is better, especially for people at increased risk for a heart attack or stroke,” says cardiologist Pamela B. Morris from the Medical University of South Carolina.
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Jacob Goldstein interviews Nir Barzilai on “What’s your Problem”:
Somewhat entertaining, I’m spending a lot of time in the truck and Jacob is really good at his job, so fun to listen to. Not an amazing interview but he brought up CTEP inhibitors and I didn’t realize they were such a longevity med. So obicetrapib may be the one to use soon. It will be called ubeslo used alone. Is there a way to cheat and get it here in the states?
CETPi might be bad for female lifespan.
The CETP locus showed a G×E-specific signal for the percentage of triglycerides in LDLs (LDL_TG_pct; P G×E = 1.8 × 10−12, P marginal = 0.98). Given the role of CETP in exchanging triglycerides from LDLs and other lipoproteins with cholesteryl esters from HDL, LDL_TG_pct might represent a key metabolic process for this protein. Notably, effect directions differed by sex (Fig. 5b and Supplementary Table 31), and LDL_TG_pct predicted all-cause and coronary artery disease mortality in both sexes (hazard ratio per unit of s.d. in UKB1: 1.23 (95% confidence interval, 1.21–1.25) and 1.25 (1.18–1.32), respectively; Fig. 5c and Supplementary Table 32). As the known causal variant (rs1801706) showed increasing effects on CETP expression46,47, these results suggested that CETP inhibition might decrease LDL_TG_pct in men but increase it in women, potentially leading to an increased female mortality risk.
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Molecular mechanism leading to human coronary atherosclerosis assessed by proteomic analysis and RNA sequences
https://academic.oup.com/eurheartj/article/47/28/3840/8676655
Pop-sci article:
New research explores the earliest stages of coronary plaque inflammation
Compound produced after eating pomegranates targets stiff-heart failure pathway, early tests suggest
Scientists at King’s College London have discovered that urolithin A—a natural compound produced in the body after consuming foods like pomegranates, walnuts and some berries—improves the heart’s ability to relax, reduces scarring and prevents harmful enlargement of the heart. The study will be published in Science Advances.
The finding could give hope to nearly half a million people in the UK who have a type of heart failure in which the heart retains its ability to pump blood but becomes stiff and less able to relax between beats, making it harder to fill with blood. This is known as heart failure with preserved ejection fraction and accounts for around half of all heart failure cases. The condition can lead to breathlessness, fatigue, reduced ability to exercise and an overall poor quality of life.
Despite its growing prevalence, effective treatments remain relatively limited. The condition is hard to treat because it is driven by many different factors—including aging, high blood pressure and diabetes. As the heart can still pump normally but becomes stiff and does not fill properly, heart failure treatments are less effective. Instead, clinicians focus on managing the underlying conditions and advise lifestyle modifications, such as weight loss and controlling blood sugar.
https://medicalxpress.com/news/2026-08-compound-pomegranates-stiff-heart-failure.html
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Video AI Summary
Overview
The video critically examines the recently released keto CTA preprint featured in the Cholesterol Code documentary, which studies plaque progression over one year in lean mass hyper responders (LMHR) following a ketogenic diet. Despite being promoted as scientifically robust, the preprint has six major statistical and methodological flaws undermining its primary conclusions that neither LDL-C exposure nor ApoB predict plaque progression. The study remains unpeer-reviewed, and its claims, especially the statistical foundations, are thoroughly questioned.
Key Issues Identified in the Study
Problem # Description Impact 1 Misdefinition of LDL-C Exposure: The study defines LDL-C exposure incorrectly as baseline LDL-C plus change during follow-up, which mathematically simplifies to follow-up LDL-C only, not true cumulative exposure (area under the curve over time). This creates a misleading interpretation of LDL-C’s role, undermining the study’s main exposure measure. 2 Improper Use of IQR in Charts: Instead of showing the standard interquartile range (25th to 75th percentile), the study plots median ± half the IQR, an unconventional, non-standard, and custom-calculated metric that artificially minimizes variability and skews the interpretation of plaque progression distributions. Distorts visualization, suggesting less variability than actually present; raises doubts about data transparency and reproducibility. 3 Failure to Report ApoB Model Results: ApoB is a central biomarker claimed to have no association with plaque progression, yet the paper omits any numerical results (coefficients, confidence intervals, model outputs) for the ApoB analyses. Important findings are insufficiently documented, preventing independent scrutiny and undermining credibility. 4 Faulty Equivalence Testing (TOST) Application: The study applies identical equivalence bounds (-0.05 to 0.05) across regression slopes that have different units and clinical meanings, violating the fundamental principles of equivalence testing. Additionally, ambiguous reporting of confidence intervals and possible use of an incorrect alpha level (80% vs. 90% CI) further confuse interpretation. Results claiming “no association” are based on statistically invalid procedures, rendering such null claims unjustified. 5 Misuse of Post Hoc Power Calculations: To justify nonsignificant findings, the authors conduct a post hoc power calculation — a method strongly discouraged in statistics — which does not confirm the absence of an effect and relies on presumptive assumptions without transparently assessing variant effect sizes. This erroneously reassures readers and misleads interpretation regarding statistical power and sample size adequacy. 6 Oversimplified, Unadjusted Regression Models: The analyses are based on crude, univariable linear regressions without controlling for basic confounders like age or sex, in an observational study with selection bias, small sample size, and a restricted LDL-C range. Coupled with noisy plaque measurements, this weakens any true association signals. The study’s design and modeling approach predispose it to false negatives and fragile conclusions rather than robust null findings. Additional Noteworthy Observations
- The study includes at least one coronary revascularization event during follow-up, but provides no clear statistical handling or impact assessment of this on plaque measures (00:05:22).
- Sample size inconsistencies are noted (n = 100, 99, 95 in different places) without adequate explanation of exclusions or their reasons (00:06:17).
- The dataset shows some cases of plaque regression over only one year, but the clinical relevance and long-term trajectory remain uncertain (00:00:59).
- Discrepancies in reporting plaque progression percentages between this and a previous retracted study (HeartFlow rapid progressors 0% vs 29%) suggest recurring data or analysis issues (14:55).
Conclusions and Implications
The presenter asserts that this keto CTA preprint fails to meet basic statistical standards and cannot legitimately support the conclusion that LDL-C exposure or ApoB levels do not predict plaque progression in LMHR individuals on keto. The study’s scientific foundation is described as “fatally flawed” and actively misleading, with the claims being based on statistically indefensible analyses and reporting. Given the study’s foundational importance to the Cholesterol Code documentary’s assertions, these flaws raise serious doubts about the documentary’s scientific rigor and credibility.
Summary Table of Critical Flaws and Consequences
Flaw Category Description Consequence Exposure Variable Definition LDL-C exposure misdefined as follow-up LDL-C, not cumulative Invalidates key predictor variable Data Representation Non-standard IQR reporting disguises true plaque progression spread Misleads on variability and distribution shape Reporting Transparency Omits ApoB model results entirely Hinders independent assessment of key claims Equivalence Testing Inappropriate, identical equivalence bounds applied; incorrect CIs Falsely supports null effect inference Statistical Power Analysis Post hoc power used instead of prospective planning Misrepresents study power and effect detectability Model Specification Crude unadjusted regressions in biased cohort Prone to confounding and false negative results The critique emphasizes that neither the statistical analyses nor study design are robust enough to safely dismiss LDL-C or ApoB as predictors of plaque progression, and cautions against basing clinical or medical decisions on these findings. It calls for better-designed and thoroughly validated studies with transparent, standard, and proper statistical approaches.
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Anti-inflammatory agents in atherosclerosis—and a need for reform: Extraordinary claims require extraordinary evidence
https://onlinelibrary.wiley.com/doi/10.1111/joim.70128
Kevin Jon Williams, a lipid metabolism researcher at Temple University, has published a Perspective in the Journal of Internal Medicine arguing that the entire enterprise of treating atherosclerosis by suppressing inflammation has failed, and that the field is refusing to admit it. He catalogues at least 57 human clinical trials of anti-inflammatory agents in atherosclerotic arterial disease spanning more than 35 years. Not one has produced a regulatory approval for a cardiovascular indication except colchicine, and colchicine’s own evidence base has been deteriorating in real time: the first three major randomized trials were positive, the three most recent were null, and the largest and longest of them all, CLEAR SYNERGY, found nothing. Meanwhile a wave of roughly 14 meta-analyses published in 2025 and 2026 has attempted to rescue the signal from that conflicting pile of trials, and those meta-analyses do not agree with one another. Williams argues this pattern is textbook regression to the truth, and calls for three reforms: neutral trial names, informed consent that discloses the field’s track record of failure, and an honest reconsideration by funders and researchers of whether inflammation is a therapeutic target in this disease at all.
For 168 years, since pathologists first saw immune cells inside human arterial plaque, medicine has harbored a seductive idea: if inflammation is in the plaque, suppressing inflammation should prevent heart attacks. It is one of the most heavily funded hypotheses in cardiovascular biology. It has also, on the evidence assembled here, failed.
Williams lays out the ledger. At least 57 human trials of anti-inflammatory agents in patients with atherosclerosis. Canakinumab, an antibody against interleukin-1 beta, was the flagship: its CANTOS trial produced a benefit only at the middle of three doses, with no dose-response relationship, plus fatal infections and sepsis. Regulators in both the United States and Europe rejected or received withdrawn applications. Methotrexate’s CIRT trial was flatly null. Darapladib, varespladib, losmapimod, succinobucol, inclacumab, salsalate, vitamin D, allopurinol: negative, or worse. Varespladib produced more heart attacks. Salsalate produced more atrial arrhythmias.
That left colchicine, a gout drug in use since antiquity and the only anti-inflammatory medication ever approved for atherosclerotic arterial disease in any jurisdiction. Two trials, COLCOT in 2019 and LoDoCo2 in 2020, won it that approval from American regulators in 2023. Then the picture inverted. In 2024, CONVINCE and CHANCE-3 failed in stroke patients. CLEAR SYNERGY, the largest colchicine trial ever run, followed 7,062 heart attack patients for three years and found no benefit on its primary outcome or any component of it, despite confirming that colchicine did lower C-reactive protein. In 2025, COCOMO-ACS found no effect on plaque structure. Co-STAR was stopped early for an excess of strokes in the colchicine arm.
The deeper point Williams makes is about what counts as evidence. When the drugs went early-positive and late-negative, the field responded not with retreat but with a dozen-plus meta-analyses reaching mutually incompatible conclusions, and with public statements from trial leaders that the new null data had “absolutely not changed my practice.” He contrasts this with the LDL-lowering drugs, where statins, ezetimibe, PCSK9 inhibitors and bempedoic acid all deliver benefit in strict proportion to how much apolipoprotein-B-containing lipoprotein they remove, across dozens of concordant trials. That is what a real signal looks like. Inflammation inhibition has never produced one. Williams’s proposed remedy is uncomfortable but simple: give trials scrupulously neutral names rather than acronyms like ARISE and STABILITY that advertise a result before it exists, tell volunteers the truth about the track record before they enroll, and give underperforming Big Ideas an explicit shelf life after which funders apply extra scrutiny. Clinical trials are stopped for futility. Perhaps whole fields should be too.
Actionable Insights
The take-home is a downgrade, not an upgrade. If you have been considering colchicine as an anti-inflammatory longevity or cardioprotective add-on, the evidence has moved against you over the last two years, and this paper explains why.
Look at the size of the wins that did exist. In COLCOT, 7.1 percent of placebo patients had a major cardiac event over roughly two years versus 5.5 percent on colchicine, a 1.6 percentage point difference, meaning about 63 people must take the drug for two years for one to avoid an event. LoDoCo2 was better: 9.6 versus 6.8 percent, about 36 treated per event avoided. Both are modest. Then the biggest trial, CLEAR SYNERGY, found 9.3 versus 9.1 percent over three years, essentially zero, while diarrhea rose from 6.6 to 10.2 percent, meaning roughly 1 in 28 treated people got diarrhea they would not otherwise have had. LoDoCo2 also showed non-cardiovascular death at 1.9 versus 1.3 percent, unexplained.
Translated to a standardized effect size, colchicine’s best result is about d = 0.20 and its pooled result across six trials about d = 0.12 to 0.17. That is a small effect, far below what statins deliver against LDL.
The durable message: the payoff in atherosclerosis has come from lowering apolipoprotein-B-containing lipoproteins early and hard, not from suppressing immune activity late.
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How nicotine attacks the blood vessels: Mapping the biological hierarchy of cardiovascular harm
https://medicalxpress.com/news/2026-08-nicotine-blood-vessels-biological-hierarchy.html
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Yes, it seems anti-inflammatories make no difference to MACE. Colchicine is looking quite weak - if someone is taking it for CVD, the question arises whether the weak at best effectiveness is worth any potential side effects, especially if it’s taken preventatively.
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