The initial result for Obicetrapib at the 1 yr mark in one study was 0.79 (0.54-1.15) for 4 point MACE. It’s likely going to reduce MACE significantly, even though apoB was reduced 13.8% but non-HDL-c at -23.0% and Lp(a) -33.5%.
Re: Jason Fung’s diatribe: at the very end he did mention that rheumatoid arthritis is correlated with heart disease and the underlying mechanism seems to be: inflammation.
Also, one of the things he did not talk about at all is: genetics.
As a person with scary genetics (risk of 1.9 times for cardiovascular disease) I would like to understand what, exactly is the underlying mechanism. What is the exact cause-effect link between bad alleles on the “heart attack gene” and getting the disease? Does this genetic makeup influence inflammation?
Two years ago my LDL was right where Jason Fung calls the sweet spot for longest mortality. I discovered I had high Lp(a) of 40 and in a panic went on Repatha which lowered LDL to about 45 and Lp(a) to 27. Trigs are low and HDL is high. Fung would probably tell me jettison the cholesterol meds.
But what to do about the persistent inflammation (running about 2.0 +/-)?
Are you in your 40’s? Odds are very high that you have atherosclerotic plaque, even if you CAC and CTA scans show zero - it’s about location… not the heart or near the heart. If you are in your 60’s odds are over 90% that you have peripheral plaque, because that’s where it shows up first before hitting your heart arteries to be seen on a CAC or CTA. Bottom line: heart disease starts long before it affects the actual heart or its arteries.
Prevalence of Silent Atherosclerosis across Adult Life
“Atherosclerosis may begin in early adulthood and remain clinically silent for decades before cardiovascular disease manifests. Although silent atherosclerosis is associated with cardiovascular events and death independent of traditional cardiovascular disease risk factors, its age- and sex-specific prevalence, vascular territory distribution, and plaque volume across adult life remain incompletely defined.”
“This study of silent atherosclerosis showed that the disease was detectable in early adulthood, with age- and sex-associated increases in prevalence across arterial territories and marked increases in plaque volume.”
Dr. Carvalho does a nice breakdown of this study:
New Study Changes Understanding of How Heart Disease Starts (via Nutrition Made Simple!)
Atherosclerotic cardiovascular disease (ASCVD) remains the leading global cause of mortality, predominantly presenting without warning as sudden cardiac death or acute myocardial infarction. The paradigm of cardiovascular risk prevention has historically relied on late-stage symptom emergence, indirect risk calculators (e.g., Framingham, ASCVD Pooled Cohort Equations), and localized coronary screening such as Coronary Artery Calcium (CAC) scoring. However, the international cross-sectional REACT study (Bundgaard et al., 2026), published in The New England Journal of Medicine, evaluated 16,808 asymptomatic individuals aged 18 to 70 via comprehensive multi-territory imaging (coronary CT angiography [CCTA] alongside three-dimensional ultrasound of bilateral carotid and femoral arteries). The trial demonstrated that 57.1% of asymptomatic adults harbor subclinical atherosclerotic plaques.
Crucially, the study established that atherogenesis initiates preferentially in peripheral vascular beds decades before manifesting in the coronary tree. In cohorts aged 18–39, detectable plaque resided almost exclusively in the femoral and carotid arteries, leaving the coronary arteries structurally clear on coronary CTA. In adults aged 18–29, 5% to 10% exhibited peripheral plaque with negligible coronary involvement. Only after the fourth decade in males and the fifth decade in females did coronary plaque become prevalent, by which time peripheral plaque was already widespread. Over 80% of individuals with coronary atherosclerosis demonstrated concurrent plaque in carotid or femoral arteries.
These findings expose a fundamental translational gap: relying on CAC scoring or isolated coronary imaging generates a false sense of security in young adults, as CAC reflects advanced micro-calcification rather than soft lipid-rich atheromas, and early lesions bypass the coronary bed entirely. Screening peripheral arteries via non-invasive, radiation-free vascular ultrasound represents a more sensitive, biologically upstream diagnostic strategy. While home assessments like the Ankle-Brachial Index (ABI) offer crude identification of advanced macro-vascular obstruction, they are incapable of detecting early, non-obstructive mural plaques. Definitive intervention requires moving beyond late-stage luminal obstruction toward early systemic atherogenic risk reduction.
Insight Bullets
Epidemiologic Plaque Burden: Subclinical atherosclerotic plaque is present in 57.1% of asymptomatic individuals across the adult lifespan without previous cardiovascular diagnoses (Bundgaard et al., 2026).
Study Scope and Methodology: The findings derive from Phase 1 of the REACT study, analyzing 16,808 asymptomatic adults aged 18 to 70 across Denmark and Spain utilizing CCTA and multi-territory ultrasound.
Early-Onset Pathobiology: Detectable arterial plaque initiates in young adulthood, appearing in 5% to 10% (approximately 1 in 13) of asymptomatic individuals aged 18 to 29.
Universal Late-Stage Prevalence: By age 60 to 70, subclinical atherosclerotic lesions become the absolute statistical norm, affecting over 90% of the population.
Territorial Dissociation: Early-stage atherosclerosis manifests predominantly in peripheral vascular beds (carotid and femoral arteries) rather than the coronary vasculature.
Coronary Sparing in Youth: In individuals in their 20s and 30s with detectable plaque, lesions are localized almost entirely to the femoral or carotid territories, with coronary arteries remaining angiographically clear.
Decadal Latency: Atherosclerosis progresses silently for several decades in peripheral arteries before accumulating to detectable levels within the coronary arteries.
Multi-Vascular Extension: In adults aged 60 to 70, extensive multi-bed atherosclerosis is present in 56.3% of men and 30.7% of women across all three measured vascular beds.
Sexual Dimorphism in Onset: Men demonstrate detectable plaque accumulation approximately 5 to 10 years earlier than women.
Premenopausal Female Protection: Women maintain predominantly peripheral, low-burden plaque through their 30s and 40s, experiencing an acceleration in vascular accumulation between ages 40 and 60 corresponding to menopausal transition.
Failure of Symptom-Driven Medicine: Historical reliance on anginal symptoms fails as a preventative strategy, as luminal stenosis represents an end-stage manifestation of multi-decade disease.
Inadequacy of CAC in Young Adults: A Coronary Artery Calcium (CAC) score of zero does not rule out soft, non-calcified, rupture-prone plaque or active peripheral atherogenesis.
Myocardial Infarction at Zero CAC: Clinical events regularly occur in patients with a CAC of zero due to non-calcified plaque rupture and acute thrombosis (Mortensen et al., 2020).
CCTA Diagnostic Utility: Coronary Computed Tomography Angiography (CCTA) accurately identifies non-calcified mural plaque and luminal stenosis, but remains cost-prohibitive, exposes patients to ionizing radiation, and misses peripheral-only disease.
Peripheral Ultrasound as a Gateway: Carotid and femoral 3D ultrasound represents a low-cost, zero-radiation modality capable of identifying systemic atherosclerotic disease years prior to coronary manifestation.
Shared Vascular Biology: Atherosclerosis is a systemic pathology of the intimal layer driven by circulating apolipoprotein B particles and systemic endothelial injury, not an isolated cardiac event.
Femoral Artery Yield: Incorporating femoral artery ultrasound screening captures a substantial portion of subclinical disease that carotid imaging alone overlooks.
Carotid Intima-Media Thickness (CIMT): CIMT provides surrogate geometric metrics of arterial wall thickening, but direct plaque identification provides superior prognostic predictive value.
Home Screening Mechanics (ABI): The Ankle-Brachial Index (ABI) calculates the ratio of the highest ankle systolic pressure to the highest brachial systolic pressure.
Normal ABI Parameters: An ABI value between 1.0 and 1.4 confirms normal arterial perfusion without hemodynamically significant stenosis in the lower extremities.
Borderline Perfusion Metrics: An ABI of 0.91 to 0.99 represents borderline arterial insufficiency and early hemodynamic impairment (Aboyans et al., 2012).
Diagnostic Threshold for PAD: An ABI of 0.90 or less defines peripheral arterial disease (PAD) with high specificity for advanced flow-limiting stenoses.
Vessel Incompressibility Artifacts: An ABI greater than 1.4 indicates medial arterial calcification (Mönckeberg sclerosis) and non-compressible vessels, frequent in diabetes mellitus and end-stage renal disease.
Sensitivity Limitations of ABI: ABI relies strictly on pressure drop across a stenosis; it is completely blind to early, non-obstructive mural plaques.
Clinical Actionability Paradigm: Shifting from passive statistical risk modeling to direct image-verified biological detection allows early targeted initiation of lipid-lowering and endothelial stabilization protocols.
Actionable Protocol (Prioritized)
1. High-Confidence Tier (Level A/B Evidence)
Aggressive Lifetime ApoB / LDL-C Suppression:
Evidence Level: Level A (Ference et al., 2017). Mendelian randomization and prospective RCT meta-analyses demonstrate that the causal effect of ApoB-containing lipoproteins on atherosclerosis is determined by both absolute circulating concentration and cumulative exposure time (Area Under the Curve).
Action: Measure Apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C). In individuals with confirmed subclinical plaque, maintain clinical lipid targets (ApoB < 60 mg/dL or LDL-C < 70 mg/dL; < 55 mg/dL if multi-vessel plaque is confirmed) utilizing HMG-CoA reductase inhibitors (statins), ezetimibe, or PCSK9 inhibitors.
Strict Blood Pressure Optimization:
Evidence Level: Level A (SPRINT Research Group, 2015). Mechanical shear stress accelerates endothelial injury, monocyte adhesion, and subendothelial retention of atherogenic particles.
Action: Maintain resting blood pressure < 120/80 mmHg via sodium modulation, aerobic vascular conditioning, and first-line antihypertensive pharmacotherapy (ACEi/ARB, CCB) when lifestyle modifications fail.
Targeted CCTA / Vascular Imaging for Intermediate-Risk Reclassification:
Evidence Level: Level B (SCOT-HEART Investigators, 2018). Utilizing anatomical imaging to guide primary prevention halts disease progression and reduces non-fatal myocardial infarction rates through targeted therapy intensification.
2. Experimental Tier (Level C/D Evidence — High Safety Margin)
Dual-Territory (Carotid + Femoral) Vascular Ultrasound in Young Adults:
Evidence Level: Level C (Supported by the REACT study observational data; prospective RCTs on whether screening alters MACE outcomes remain underway).
Action: In asymptomatic patients aged 20–49 with a family history of premature ASCVD or marginal lipid/metabolic abnormalities, obtain high-resolution bilateral carotid and femoral B-mode/3D ultrasound. The detection of focal intimal plaque (> 1.2 mm thickness or protrusion > 50% into lumen) confirms active systemic atherogenesis and warrants proactive pharmacologic and lifestyle escalation.
At-Home Oscillometric ABI Screening:
Evidence Level: Level D (Extrapolated from clinical Doppler protocols; automated oscillometric cuffs introduce measurement variance compared to Doppler probes).
Action: Utilize a validated automated upper-arm blood pressure cuff in a supine position. Obtain bilateral brachial and ankle systolic pressures; divide the higher ankle systolic reading by the higher arm systolic reading per limb.
Interpretation: Values 1.00–1.40 indicate no gross hemodynamically significant occlusion. Use strictly as a low-cost screening tool for gross flow obstruction, not as an exclusion metric for early subclinical plaque.
3. Red Flag Zone (Debunked or Lacking Safety Data)
False Reassurance from CAC = 0 (“The Zero-Calcium Fallacy”):
Status: Debunked. A CAC score of zero reflects the absence of macroscopic vascular calcification, which is an end-stage response to chronic plaque inflammation. Relying on a zero score in patients under 50 years old frequently misses lipid-rich, non-calcified plaques vulnerable to erosion and rupture.
Assuming Normal ABI Rules Out Atherosclerotic Disease:
Status: Lacking Diagnostic Sensitivity. ABI drops only when an atherosclerotic lesion causes ≥ 50% luminal stenosis, creating a measurable hemodynamic pressure differential. Interpreting a normal ABI (1.0–1.4) as arterial health creates a lethal diagnostic blind spot for subclinical plaque.
Delaying Intervention for Symptom Emergence:
Status: Debunked. Angina, claudication, or transient ischemic attacks represent late structural failure. Cardiovascular intervention must be initiated based on subclinical structural pathology and cumulative atherogenic exposure, not clinical symptom manifestation.
Sorry I got busy today and missed this. My LDL bounces around between 130 and 160 normally, depending on how long it’s been since Rapa and probably other things I don’t understand. On Leqvio it went to 129. It was expected to be halved, so maybe to 75. It failed miserably. I’ve got 6 more months of it so maybe it will start to work, but so far no.
Do you have homozygous familial hypercholesterolemia, specifically a null/null LDL receptor variant? Because if not, you must have received a defective product.
For lipids it is triglycerides, total cholesterol, HDL-C, LDL-C, and non-HDL-C. When they used to measure my CRP it was always low, but I developed plaque regardless.
No pretty sure I don’t have anything crazy genetically. Grandparents made it to the 90’s, parents only high 70’s but mom had type 1 insulin dependent diabetes for 50 years. I think the drug just doesn’t work. Somebody else here, maybe 2 people have posted that they tried it and it didn’t work at all for them either. Remember the waterfall plots, people are all different.
In a patient without familial hypercholesterolemia, an apparent lack of LDL-C lowering on inclisiran is far more likely explained by administration/adherence, measurement, or a competing secondary cause of hyperlipidemia than by true pharmacologic nonresponse — genuine biological nonresponse does occur but is rare and remains mechanistically unexplained. [1-2] Across phase 3 and monotherapy trials, nearly all participants respond robustly with ~50% LDL-C reduction, and true nonresponders are the exception. [2-4] The main considerations to work through:
Most likely explanations
Missed, delayed, or incomplete dosing schedule. Inclisiran requires a specific regimen — 284 mg at baseline, again at 3 months, then every 6 months — and full effect depends on completing the loading doses. A patient checked after only the first injection, or one who missed the 3-month or subsequent dose, may show an attenuated or “absent” effect. The drug has a plasma half-life of only ~48 hours but a durable hepatic effect, so effect depends entirely on correct dosing intervals rather than any detectable drug level. [5-6]
Administration error. Because inclisiran is given by a healthcare professional subcutaneously, an improperly administered or incomplete injection can blunt the response.
LDL-C measurement timing and variability. Effect should be assessed after the regimen is established; guidelines advise measuring LDL-C ~4–6 weeks after initiation/intensification, and there is substantial inter-individual and biologic variability in measured LDL-C. Comparing a non-standardized or mistimed level to baseline can create the false impression of nonresponse. [7]
Concomitant therapy context. Response is greater with background statin therapy, since statins upregulate both LDLR and PCSK9, amplifying the benefit of PCSK9 knockdown. A patient not on (or nonadherent to) a statin may show a smaller absolute reduction than expected. Notably, adding inclisiran on top of a PCSK9 monoclonal antibody yields no additional lowering (target already saturated) — so a patient recently on a PCSK9 mAb may appear to have “no effect.” [1][6]
Secondary causes of hypercholesterolemia masking the effect. Untreated hypothyroidism, nephrotic syndrome, cholestatic liver disease, or lipid-raising medications can keep LDL-C elevated despite genuine drug activity — the net LDL-C looks unchanged because an offsetting secondary driver is present. These should be screened for whenever the response is unexpectedly poor.
High lipoprotein(a). Standard LDL-C assays include the cholesterol carried by Lp(a). In a patient with very high Lp(a), a large fraction of “LDL-C” is Lp(a)-cholesterol, which is reduced only modestly (~20%) by inclisiran, so measured LDL-C may fall less than anticipated. Real-world data, however, did not find a significant association between Lp(a) level and the degree of LDL-C reduction, so this is a partial rather than complete explanation. [1][3]
True pharmacologic nonresponse
A small number of genuine nonresponders have been observed in ORION-3, ORION-8, and the VICTORION-Mono monotherapy trial, even without statin confounding. The reasons remain unclear, and genetic factors (e.g., undiagnosed LDLR/PCSK9 variants) have been proposed but not established. This is a diagnosis of exclusion after the above are ruled out. [1-2]
Inclisiran/Leqvio was less effective than ezetimibe for me. I was one of the first people to receive it in Canada and according to my cardiologist, non responders are so common now, that Leqvio is rarely prescribed in Canada anymore.
That is really interesting, but if that’s the case then I wonder why this isn’t in the medical news? I suppose it could be some new phenomenon that for some reason didn’t show up in the studies and the news just hasn’t gotten out yet. Time will tell! In the mean time, better to stick with Repatha or Praluent.
This might be the wrong thread, but I thought this was an interesting meta-analysis that shows statins seems to moderately reduce dementia (overall HR 0.86) . The most interesting and exciting feature I thought was that there seemed to be a time dependency associated with the reduced dementia risk, with exposure for more than 3 years giving a hazard ratio of 0.37.
Now that I’ve been on high dose atorvastatin and low dose aspirin for 4 years, I’ll ask my doctor to include CRP on my next blood panel. I’m curious if it is lower after these drug interventions. My Hba1c is 5.3.
