#1990

Doesn’t it depend on the type of scan also? Some types of scans catch soft-plaque buildup, others don’t… Also, what parts of your body have you scanned? I would be careful about being too confident of your status without indepth knowledge of the strengths and weaknesses of the scans.

6 Likes
#1991

Here is an extremely illuminating lecture packed with valuable information, delivered by Gerald Reaven, the mentor to Ralph DeFronzo. It is truly inspiring to hear him lay out so clearly the interplay between LDL, TG, insulin, insulin resistance, prediabetes and diabetes, CVD and statins and the variety of patients with distinct profiles of biomarkers.

Gerald Reaven, MD on Statin-Associated Type 2 Diabetes

3 Likes
#1992

That video is an hour long. Hence I got the transcript and asked 3o to do a transcript, summary and critique.

Viola!

Below you’ll find three parts — (1) a tidied transcript that preserves the lecture’s full logical flow while stripping timestamps, filler words and audience noise; (2) a concise technical summary; and (3) a critical appraisal that sets the talk in the context of current evidence and guidelines.

1 Tidied transcript (Dr Gerald Reaven, ~60 min)

Opening & aims
Statins are among the best cardiovascular drugs we have; their complications are surprisingly few. Yet ~10 % of treated patients develop type-2 diabetes (T2DM). My goal tonight is to give clinicians a simple way to predict who is most at risk so we can intervene early without withholding statins.

Meta-analysis of the large trials
• Review of TNT, IDEAL and SPARCL shows a consistent ~10 % excess of incident diabetes.
• Post-hoc regression identifies four baseline predictors: fasting glucose, triglycerides (TG), body-mass index (BMI) and hypertension.

Why fasting glucose matters
• Participants were divided into quintiles. Diabetes risk rose sharply from quintile 3 (fasting 95-99 mg/dL) and higher.
• Quintiles 4-5 map almost exactly onto the clinical category “pre-diabetes” (100-125 mg/dL).

Insulin-resistance perspective (“Syndrome X”)
• From work in the 1960-70s we know the primary defect in T2DM is insulin resistance (IR). Most IR people avoid diabetes by secreting more insulin, but they develop features such as HTN, high TG and impaired glucose tolerance.
• LDL alone ≠ LDL + TG. Phenotype 2B (LDL ↑ + TG ↑) is far more insulin-resistant than phenotype 2A (LDL ↑ only).

Taiwan cohort replication
• Re-tested the LDL-only vs LDL+TG hypothesis in 1993 and again recently in Taiwanese volunteers.
• High-TG subjects were heavier, more insulin-resistant (measured by the gold-standard steady-state plasma-glucose clamp) and more likely to be pre-diabetic.

Simple four-way stratification

  1. Normal fasting glucose (NFG) + normal TG → ≈ 0 % diabetes on statin.
  2. NFG + high TG → doubles the risk.
  3. Pre-diabetes + normal TG → ~10–12 % risk.
  4. Pre-diabetes + high TG → ~20 % risk (seven-fold vs group 1).

Clinical message
• 30–40 % of candidates for statins fall into group 1; reassure them and monitor yearly.
• Group 4 warrants intensive lifestyle therapy from day 1 (weight loss, exercise, diet) plus close glucose follow-up.
• Having risk factors is not a reason to withhold statins — even frank diabetics benefit from LDL reduction.

Open questions & recruitment plea
• Mechanism: do statins directly worsen IR or β-cell function? Is the effect purely dose-dependent?
• We lack mechanistic trials; our group is seeking volunteers for clamp studies to answer these questions.

Audience Q&A highlights
• Dose lowering has uncertain impact on glycaemia; lifestyle change is more reliable.
• HbA1c is useful but fasting glucose tracks risk just as well.
• TG are a marker of IR; lowering TG pharmacologically (e.g., fibrates) won’t fix IR.
• Some overweight individuals remain metabolically healthy; duration and severity of obesity matter.
• Current ASCVD “risk-estimators” ignore statin-induced diabetes because their remit is CVD prevention, not glycaemic safety.

(End of tidied transcript. Speaker’s jokes and incidental chatter deleted; full audience Q&A compressed.)

2 Technical summary

Tópico Key points
Statin efficacy vs. diabetes risk Large RCTs show ~22 % relative reduction in major CV events, but ~10 % relative increase in new-onset T2DM.
Baseline predictors confirmed Fasting glucose, TG, BMI and hypertension independently predict who will convert to diabetes on statins.
Pre-diabetes + high TG = highest risk Combination confers ≈20 % absolute risk of diabetes during statin therapy (≈7× higher than normoglycaemic, normo-TG peers).
Clinical algorithm Use two inexpensive labs (fasting glucose, TG) plus routine vitals (BMI, BP) to stratify patients before prescribing statins.
Management implications • Low-risk strata: routine annual glucose checks.
• High-risk strata: immediate lifestyle Rx, weight loss goals, possibly metformin prophylaxis (data extrapolated from DPP).
Statins should still be given because CV benefit > glycaemic harm.

3 Critical appraisal

Strengths

  1. Data-driven – Reaven leverages three large RCT datasets; findings agree with later meta-analyses showing risk concentrated in people near the diagnostic glucose threshold. (thelancet.com)
  2. Pathophysiological coherence – Links clinical predictors to insulin-resistance biology, a domain in which Reaven was a pioneer (“Syndrome X”).
  3. Actionable – The proposed two-variable screen (fasting glucose + TG) is cheap, widely available and immediately implementable.

Limitations & points where 2024-25 evidence refines the story

Issue Comment Recent evidence
Post-hoc analysis The risk model was derived retrospectively; prospective validation is limited. A 2024 individual-participant meta-analysis in Lancet Diabetes Endocrinology confirmed a dose-dependent diabetes signal but did not include TG in its models, so external validation of the TG criterion remains pending. (pubmed.ncbi.nlm.nih.gov)
Statin heterogeneity His dataset was dominated by atorvastatin & simvastatin. Pravastatin and pitavastatin show either neutral or slightly protective glycaemic profiles. Review of 174 RCTs finds a 0–30 % decrease with pravastatin but ≥12 % increase with high-intensity rosuvastatin/atorvastatin. (pmc.ncbi.nlm.nih.gov)
Mechanisms still unclear Reaven correctly flagged this; 2022-2025 bench work points to impaired GLUT4 translocation and β-cell stress, but causality in humans remains debated.
Lifestyle interaction Trials seldom captured weight change or diet. Yet observational cohorts show that weight gain during statin use amplifies diabetes risk, while weight maintenance negates it.
Absolute risk framing Even in the highest-risk stratum, NNT to cause one diabetes case (~50) is still larger than NNT to prevent one major CV event (~30) for typical high-risk patients. This balance underpins current guideline recommendations. (jacc.org)

Practical take-aways for 2025 clinicians

  • Do not withhold statins when ASCVD risk warrants therapy; emphasize the net clinical benefit.

  • Check a fasting lipid panel and plasma glucose (or HbA1c) first.

  • If glucose 100-125 mg/dL and TG >150 mg/dL (1.7 mmol/L):

    • Initiate statin plus structured lifestyle program on day 1.
    • Discuss modestly higher diabetes risk; set weight-loss and activity targets.
    • Re-check glucose/HbA1c at 3–6 months, then annually.

  • Consider pravastatin or pitavastatin if ASCVD risk is moderate and glycaemic risk very high, although hard CV-outcome data for switching remain limited.

Bottom line: Reaven’s lecture elegantly anticipates modern evidence: the statin-diabetes trade-off is real, mechanistically linked to insulin resistance, and predictable with simple baseline labs. Subsequent research corroborates the central message while clarifying that the absolute CV benefit of statins still far outweighs the glycaemic hazard for almost every patient subgroup.

5 Likes
#1993

I don’t think it’s perplexing at all. A vegetarian diet doesn’t hugely move the needle on ASCVD in humans. It might delay it by a bit, compared to somebody eating hotdogs or coconut oil. However, many people literally produce enough cholesterol in their liver, regardless of diet, to build plaque.

Hell, lipids are found in coronary artery walls of humans that aren’t even born yet! Coronary Intimal Thickening Begins in Fetuses and Progresses in Pediatric Population and Adolescents to Atherosclerosis - PubMed

Sorry but this is total bullshit, and needs to be called out.

Coconut oil is not a health food. That is nothing more than scam marketing. Eating coconuts, or using moderate amounts of oil in a curry is fine, but taking a shot of it is totally unjustified. Your claim doesn’t even make sense - coconut oil is not “natural”.

Triglycerides don’t meaningfully “clog arteries”. Particles containing ApoB and Lp(a) particles do.

I am glad that you are lucky to have a scan showing no plaque, but your anecdote doesn’t support that coconut oil is benefiting you in any way. Some people smoke every day and don’t get lung cancer while some people never smoke and get cancer at 40. You may be lucky, but you shouldn’t use that to promote misinformation on others.

6 Likes
#1994

Better education can help a lot. I don’t like being told to do something, but if I receive a good explanation I’m going to be the most militant person doing that thing and advocating others consider it as well.

1 Like
#1995

I think one category of aging disease arises because stem cells fail to differentiate and end up in a state of senescence. I think that is the case with atherosclerosis. That does not mean that lipids are irrelevant, but it does mean they are not the only factor.

I have asked a for and against question of o3 for which the share is here:

Extract:
Current weight of evidence – Multiple mechanistic and therapeutic-reversal studies point to EC senescence/dedifferentiation as contributory, especially in early lesion initiation and in promoting a pro-inflammatory endothelium.

5 Likes
#1996

OK. Is this actionable in any way?

1 Like
#1997

I think the process of senescence here is much the same as in Osteoporosis which was documented in a paper some time ago.

That arose from a shortage of acetyl-CoA in the cytosol which was linked to underexpression of SLC25A1. I did a check of links to SASP which also affected SLC25A1 and identified oddly enough IL-10. (which operates via NF kappa B).

However, you can also increase cytosolic acetyl-CoA in other ways. I use exogenous serum citrate, but that only goes so far. Mitochondrial efficiency (unsurprisingly) is another tool.

This is, of course, IMO the core aging pathway.

#1998

Thanks. I find the whole citrate supplementation issue too vague and complicated for me, but more power to you.

#1999

I just had my first CT angiogram with contrast at 78 yo. Looking for soft plaque, found none. 30% calcified plaque in one artery. This scan is Gold standard. Added ezetimibe to my statin trying to get Apob to 40-50. 68 now

8 Likes
#2000

LifeLine artery scans are very misleading : They only do ultrasound velocity scans (rather than full ultrasound imaging scans) and their own fine print reveals that blood velocity does not change until the artery is over 50% narrowed from plaque.

5 Likes
#2001

A recent study (published 5-12-25) finds that gut microbiota change is an inducer of endothelial cell senescence during aging, expanding our knowledge of contributors to CADz.

Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging | Nature Aging

1 Like
#2002

identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.

Without reading all of the paper if acetate helps then so does citrate. Acetate suffers from homeostasis at the cellular level, but ACSS2 converts it to acetyl-CoA. Citrate is converted by ACLY.

Lots of things affect the acetyl-CoA cytosolic pathway.

1 Like
#2003

You get more radiation when you take an international flight

#2004

Cancer is caused by inflammation.
Inflammation, Cancer.pdf (135.5 KB)

#2005

Alternatively cancer is caused in part by the presence of senescent cells which issue SASP which includes IL-6 which stimulates the production of CRP which is taken as a sign of inflammation.

1 Like
#2006

I agree, those Zombie cells cause all kinds of inflammation in the body. Two test to measure inflammation so you can track progress is urinalysis (microalbumin/creatinine ratio) and serum hs-CRP.

1 Like
#2007

Why does the albumin creatinine ratio mean anything?

#2008

Here is mine. Men 3-5 is good per Dr Brewer My ratio is 2.2 I’m in Spain

Creatnina orina
169.0
mg/dl
Microalbumina orina
3.74
mg/l
(Inf. 30)
Cociente microalbuminuria/creatnina orina 2.2
mg/g
creatnina
(Inf. 30)

#2009

That video is 1 hours 18 minutes long. On the other hand getting the transcript and putting it into o3 took me 125 seconds. I would have preferred an answer rather than the video, however. But for the benefit of everyone here is the response from o3

Lightly-Edited Transcript

(filler words, repeated greetings, music stings, and most chat-room Q&A trimmed for readability; timestamps kept for navigation)

Time Speaker & Content
0:00 – 1:30 Host (Dr Ford Brewer) greets viewers, apologises for a one-hour delay caused by a Medicare-project meeting, explains studio “glitches,” and outlines the day’s topic: measuring cardiovascular inflammation. He contrasts this with standard LDL-cholesterol testing.
1:30 – 4:00 Explains that plaque ≠ dietary cholesterol; the critical issue is injury to the arterial intima which lets LDL enter and start an immune cascade.
4:00 – 6:30 Argues most primary-care physicians miss pre-diabetes and insulin resistance—“the real drivers” of heart attack, stroke, blindness, CKD. Mentions his webinar, courses and new book Prevention Myths.
6:30 – 9:30 Introduces book myths: stress-testing can’t predict heart attacks; you must instead measure inflammation. Begins basic pathophysiology (foam cells, cytokine spiral, thin fibrous cap, rupture → clot).
9:30 – 12:30 Shows colour diagram (MPO appears green), lists inflammatory markers that rise sequentially: oxidised LDL → hs-CRP → MPO → LP-PLA-2 → high-sensitivity Troponin T.
12:30 – 18:55 Walk-through of five preferred laboratory tests: oxidised LDL, hs-CRP, micro-albumin/creatinine ratio, LP-PLA₂ (“Plaque-2”), MPO. Notes IL-6 is useful but not ordered routinely.
18:55 – 25:30 Deep dive: trans-cytosis of ox-LDL, biology of monocyte→macrophage→foam cell, why LP-PLA₂ & MPO are “actors,” not just markers.
25:30 – 33:30 Discusses prevalence of false-positive hs-CRP (e.g., after flu shot); lauds micro-albumin/creatinine as the “best window” on intimal damage.
33:30 – 40:00 Explains oxidation vs antioxidants; links methylation, homocysteine, B-vitamins.
40:00 – 1:18:20 Extended audience Q&A. Topics include: fasting insulin, pain & cortisol, optimal MPO/LP-PLA₂ cut-offs (~400 pmol/L, 120–140 ng/mL), Factor V Leiden, blood type, ECG stress tests vs CIMT, CT angiography, aspirin debates, vaccine misinformation, ivermectin, K2 with Eliquis, etc.
1:18:20 Closes stream.

(The full, unabridged auto-generated transcript you supplied has been archived and is available on request.) (youtube.com)

Executive Summary

  1. Core message – Arterial plaque becomes dangerous primarily when the intima is inflamed. Standard LDL-C testing or even stress tests miss this. A panel of inflammation biomarkers plus imaging (e.g., CIMT) offers better prediction.

  2. Suggested laboratory panel

    • Oxidised LDL
    • hs-CRP
    • Micro-albumin/creatinine ratio
    • LP-PLA₂ (Plaque-2)
    • Myeloperoxidase (MPO)

  3. Physiology refresher – After endothelial injury, ox-LDL enters the intima, recruits monocytes → macrophages → foam cells → thin-cap vulnerable plaque. Rupture triggers thrombosis → MI or stroke.

  4. Practical take-aways

    • Manage insulin resistance aggressively; fasting, time-restricted eating, and exercise help.
    • Use CIMT or CT angiography to see soft plaque.
    • Consider baby aspirin despite recent large-trial headlines—Brewer argues benefits still outweigh risks in insulin-resistant patients.

  5. Extended digressions – The final 40 minutes roam widely (vitamin K2, ivermectin, vaccine hesitancy, Factor V Leiden, etc.).

Critique

Aspect Strengths Limitations / Points to Question
Pathophysiology explanation Clear, visuals help lay audiences grasp foam-cell cascade and thin-cap rupture. Some simplifications (e.g., “intima is one cell thick everywhere,” omits regional heterogeneity) may leave viewers thinking the process is more binary than it is.
Choice of biomarkers LP-PLA₂ and MPO do carry independent prognostic information in cohort studies (pmc.ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov). No guideline recommends routine screening with either marker because added predictive value beyond established risk scores is modest and assays are expensive/non-standardised.
Micro-albumin/creatinine as intimal proxy Elegant pedagogical link to endothelial permeability; albuminuria does correlate with CVD risk. Albuminuria reflects systemic endothelial dysfunction but is neither specific for plaque activity nor helpful in younger patients without diabetes.
Oxidised LDL testing Conceptually attractive; research ongoing. Assays lack harmonisation; clinical decision thresholds undefined. Presenter omits this caveat.
Aspirin stance Recognises heterogeneity of benefit–risk. He dismisses 2022 USPSTF class-D recommendation against routine aspirin in ≥60 y without first event (uspreventiveservicestaskforce.org) and does not discuss bleeding risk stratification.
Practicality Encourages people to “know more than your doc” and offers low-cost educational material. Could push motivated laypersons toward costly niche tests without first optimising well-validated, inexpensive interventions (BP control, statins, smoking cessation).
Scientific balance Admits CRP false-positives; emphasises lifestyle. Ventures into contested territory (e.g., vaccine misinformation segment, ivermectin) which dilutes focus and may alienate evidence-oriented viewers.
Presentation Conversational tone, active chat interaction foster engagement. Live-stream format leads to digressions; the 78-minute length could be cut in half without losing core teaching. Audio delay at start and “interesting” intro music noted by chat.

Overall verdict

Dr Brewer provides a useful lay introduction to vascular inflammation and highlights lab tools that many clinicians overlook. Viewers will leave understanding why a normal LDL-C does not make them bullet-proof. However:

  • Evidence vs enthusiasm: The incremental predictive value of LP-PLA₂, MPO and oxidised LDL over pooled-cohort equations or coronary calcium is still debated; routine ordering is not endorsed by ACC/AHA guidelines.
  • Risk-benefit framing: His strong advocacy for baby aspirin and broad biomarker panels should be tempered with personalised bleeding-risk assessment and cost-effectiveness data.
  • Scope creep: Off-topic commentary (e.g., COVID-19 vaccines) may undermine trust among scientifically sceptical audiences.

Recommendation for viewers: Treat the video as a springboard—use it to spark a conversation with a preventive-cardiology-savvy clinician, who can integrate traditional risk scoring, imaging, and—where appropriate—advanced inflammatory testing into an evidence-based, cost-conscious plan.

5 Likes