Biologics: No Free Lunch, but Instructive: Do NOT Lower LDL

OpenEvidence AI suggested I look at the CANTOS trial. A biologic was used that did NOT lower LDL but lowered CRP (inflammation). The results were superior compared to Repatha, but still riddled with problems.

FrugalDoc

7/5/202612 min read

Standard-of-care medicine has only one solution for you - a drug. After LDL-lowering, which always fails, they are targeting inflammation with their expensive monoclonal antibodies (biologics). But inflammation is ALWAYS downstream of the real cause, and that is usually an infection of some type.

Inflammation is a RESPONSE - not a treatment TARGET. Inflammation results from your immune response. The real solution and treatment target are what CAUSE the inflammation.

Sometimes lowering inflammation is essential when it is severe. Steroids are used for that purpose. However, ALL anti-inflammatories impact the immune response and, if taken continuously, make you more vulnerable to disease. These 2 studies prove that.

To be clear, even though the CANTOS study showed some benefits, overall the impact of this drug is NEGATIVE. There are far better alternative, both pharmaceutical and natural.

I will provide the conversation with AI on biologics that lower inflammation in a moment, but here I summarize the 2 trials on biologics (monoclonal antibodies) to lower inflammation.

Question: What was used in the CIRT trial, and what were the key results?

The Cardiovascular Inflammation Reduction Trial (CIRT) evaluated whether reducing systemic inflammation using low-dose methotrexate would lower the rate of recurrent cardiovascular events in patients with stable atherosclerosis. [1, 2]

What Was Used in the Trial

  • Intervention: Low-dose methotrexate (target dose of 15 to 20 mg orally per week) combined with 1 mg of daily folate to mitigate potential side effects. [1, 2]

  • Control: A matching placebo, also taken weekly. [1, 2]

  • Participants: Nearly 4,800 men and women who had suffered a previous heart attack or had severe coronary artery disease, and who also had type 2 diabetes or metabolic syndrome. All participants were kept on optimized background therapies (e.g., statins, aspirin). [1, 2]

Key Results

  • No Cardiovascular Benefit: Low-dose methotrexate did not reduce the primary composite cardiovascular endpoints (heart attacks, strokes, or cardiovascular death) compared to the placebo. [1, 2]

  • No Inflammatory Reduction: The intervention unexpectedly had no discernible effect on lowering key inflammatory biomarkers, including interleukin-1β, interleukin-6, or high-sensitivity C-reactive protein (hsCRP). [1, 2]

  • Increased Adverse Events: Patients taking methotrexate experienced a significantly higher rate of side effects, including liver-enzyme elevations, reductions in white blood cell counts, and an increased incidence of non-basal-cell skin cancers. [1]

Due to the lack of efficacy and evidence of futility, the trial was stopped early. The results of the study were published in the New England Journal of Medicine. [1, 2]

References; https://www.nejm.org/doi/full/10.1056/NEJMoa1809798 and https://www.sciencedirect.com/science/article/pii/S2452302X22003370

THE RISK - TO - BENEFIT IS NOT THERE FOR EITHER OF THESE INTERVENTIONS!

The reason I looked at these 2 studies is that OpenEvidence AI suggests I do. This is all your doctor has in his/her tool chest. They do NOT know the root cause (or don't want to treat at that level). A cured patient is a lost customer. This came about because I challenged the AI about the action of statins. Any benefit found in a small group of men with severe cardiovascular disease came about NOT by the lowering of LDL, but the PROVEN antibiotic effect of statins. If you are taking a statin, you are taking an antibiotic for life!

Question: What was used in the CANTOS trial, and what were the key results?

The CANTOS trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) was a landmark phase 3 clinical trial evaluating whether directly targeting inflammation could prevent heart attacks and strokes. [1, 2, 3]

What Was Used

  • The Drug: Canakinumab, a monoclonal antibody that specifically targets and neutralizes the inflammatory cytokine Interleukin-1β (IL-1β). [1, 2]

  • The Regimen: Participants received subcutaneous injections of canakinumab once every 3 months at one of three tested doses (50 mg, 150 mg, or 300 mg), or a placebo, in addition to standard-of-care medications (such as statins). [1, 2, 3, 4, 5]

  • The Population: The trial enrolled 10,061 patients worldwide who had a history of a previous heart attack (myocardial infarction) and persistently elevated levels of high-sensitivity C-reactive protein (hs-CRP, a primary marker for systemic inflammation). [1, 2]

Key Results

  • Lowered Cardiovascular Events: The 150-mg dose of canakinumab significantly reduced the combined primary endpoint (non-fatal heart attack, non-fatal stroke, or cardiovascular death) by 15% compared to the placebo. This effect was achieved without lowering LDL cholesterol, proving that targeting inflammation alone is a viable strategy for preventing cardiovascular events. [1, 2, 3, 4]

  • Lung Cancer Reduction: An exploratory analysis revealed unexpected, profound benefits regarding oncology. Canakinumab use resulted in a 51% reduction in overall cancer mortality and a 67% reduction specifically in fatal lung cancers, establishing a new connection between inflammation and cancer progression. [1, 2, 4]

  • Safety Concerns: Patients treated with canakinumab experienced a statistically significant increase in fatal infections (such as sepsis) compared to those on the placebo. [1, 2]

References 1 and 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC5685554/ and https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.311984

Here is the discussion and results prompted by OpenEvidence wrt the CANTOS trial - proving the LDL lowering is NOT the action that provides any benefit.

The CANTOS trial provides what is arguably the most powerful single piece of evidence supporting the argument developed in the previous conversation — that inflammation, not LDL, is the primary driver of atherosclerotic mortality, and that statins work largely through anti-inflammatory mechanisms that pure LDL-lowering agents cannot replicate.

FrugalDoc Comment: HOWEVER, THESE DATA ALSO SHOW THAT LOWERING INFLAMMATION IS NOT THE ROOT CAUSE - AND LOWERING INFLAMMATION CAUSES MORE HARM THAN GOOD - EXCEPT MAYBE IN THE SHORT TERM - BUT LONG-TERM LOWERING INFLAMMATION IS A DISASTER TO YOUR HEALTH.

CANTOS: The Definitive Proof-of-Concept

The CANTOS trial (n=10,061, median follow-up 3.7 years) tested canakinumab, a monoclonal antibody that selectively neutralizes IL-1β — a pure anti-inflammatory agent with zero effect on lipid levels. All patients had prior MI and elevated hsCRP (≥2 mg/L), and nearly all were already on statins.[1]

The results were striking: canakinumab 150 mg reduced the primary composite endpoint (nonfatal MI, nonfatal stroke, or CV death) by 15% (HR 0.85; 95% CI 0.74–0.98; p = 0.021) — a relative risk reduction virtually identical to that observed in the major PCSK9 inhibitor trials — yet achieved entirely without any change in LDL-C.[2][3] Coronary revascularization was reduced by 30% across all doses (p < 0.001), reflecting reduced plaque progression.[2]

The following table from the original NEJM publication shows the full outcomes data:

The hsCRP and IL-6 Response: "Lower Is Better" for Inflammation

A prespecified secondary analysis revealed that the benefit of canakinumab was entirely concentrated in patients who achieved on-treatment hsCRP < 2 mg/L. In this group:[4]

  • - MACE reduced by 25% (HR 0.75; 95% CI 0.66–0.85; p < 0.0001)

  • - Cardiovascular mortality reduced by 31% (HR 0.69; 95% CI 0.56–0.85; p = 0.0004)

  • - All-cause mortality reduced by 31% (HR 0.69; 95% CI 0.58–0.81; p < 0.0001)

In patients who did not achieve hsCRP < 2 mg/L, there was no significant benefit for any endpoint.[4][5]

The IL-6 analysis was even more dramatic. Patients who achieved on-treatment IL-6 below the median experienced:[6]

  • - 52% reduction in cardiovascular mortality (HR 0.48; 95% CI 0.34–0.68; p < 0.0001)

  • - 48% reduction in all-cause mortality (HR 0.52; 95% CI 0.40–0.68; p < 0.0001)

Again, those who did not achieve IL-6 reduction had no benefit.[6] This establishes that the magnitude of benefit tracks with the magnitude of inflammation reduction, not with any lipid parameter.

Table 2 Incidence Rates and Hazard Ratios for Major Clinical Outcomes and All-Cause Mortality.

The critical observation: canakinumab matched PCSK9 inhibitors on MACE reduction without touching LDL, while PCSK9 inhibitors achieved dramatic LDL reductions without reducing mortality.

This directly demonstrates that the cardiovascular event reduction attributed to LDL lowering may actually be mediated by inflammation reduction.

CIRT: The Negative Control That Proves the Pathway Matters

The CIRT trial (n=4,786) tested low-dose methotrexate — a broad-spectrum anti-inflammatory — in patients with stable atherosclerosis. Unlike CANTOS, methotrexate failed to reduce IL-1β, IL-6, or CRP and showed no cardiovascular benefit (HR 0.96; 95% CI 0.79–1.16).[7]

This comparison demonstrates that not all anti-inflammatory approaches work — specifically targeting the IL-1β → IL-6 → CRP innate immunity pathway is what matters.[8][9] This is the same pathway that statins suppress through mevalonate pathway inhibition, and that PCSK9 inhibitors do not affect.

Colchicine: Further Confirmation

Low-dose colchicine (0.5 mg/day), which inhibits the NLRP3 inflammasome (the upstream activator of IL-1β), has now been validated in two major RCTs:[3][10]

  • - COLCOT (n=4,745, post-MI): 23% reduction in composite CV endpoint (HR 0.77; p = 0.02), with a remarkable 74% reduction in stroke[10]

  • - LoDoCo2 (n=5,522, stable CAD): 31% reduction in composite CV endpoint (HR 0.69; p < 0.001)[10]

  • - Meta-analysis of all colchicine trials: 25% reduction in MI, stroke, or CV death (HR 0.75; 95% CI 0.61–0.92)[10]

Like canakinumab, colchicine achieves these benefits without any effect on lipid levels. And like PCSK9 inhibitors, all-cause mortality was neutral (HR 1.08; 95% CI 0.71–1.62).[10] The 2023 AHA/ACC Chronic Coronary Disease Guidelines now include a Class 2a recommendation for low-dose colchicine in secondary prevention.[11]

The Unexpected Cancer Signal

Perhaps the most remarkable CANTOS finding was the dose-dependent reduction in lung cancer. At the 300 mg dose:[12]

  • - Incident lung cancer reduced by 67% (HR 0.33; 95% CI 0.18–0.59; p < 0.0001)

  • - Fatal lung cancer reduced by 77% (p = 0.0002)

  • - Total cancer mortality reduced by 51% (HR 0.49; 95% CI 0.31–0.75; p = 0.0009)

This was an exploratory finding, and the subsequent CANOPY-A trial of canakinumab as adjuvant therapy in resected NSCLC did not meet its primary endpoint of disease-free survival.[13] However, a 2026 Cell study identified a 14-protein plasma signature that could identify patients most likely to benefit from IL-1β inhibition for cancer prevention, suggesting the CANTOS signal was real but requires patient selection.[14]

This cancer finding is relevant to the statin comparison because statins also reduce cancer incidence in observational studies — an effect that could be mediated through their anti-inflammatory and antimicrobial properties rather than LDL lowering. HOWEVER, some studies show that statin therapy INCREASES cancer rates. Statins JUST DON'T WORK!

References

  1. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. Ridker PM, Everett BM, Thuren T, et al. The New England Journal of Medicine. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914.

  2. Clinician's Guide to Reducing Inflammation to Reduce Atherothrombotic Risk: JACC Review Topic of the Week. Ridker PM. Journal of the American College of Cardiology. 2018;72(25):3320-3331. doi:10.1016/j.jacc.2018.06.082.

  3. Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement: A Report of the American College of Cardiology. Mensah GA, Arnold N, Prabhu SD, Ridker PM, Welty FK. Journal of the American College of Cardiology. 2025;:S0735-1097(25)07555-2. doi:10.1016/j.jacc.2025.08.047.

  4. Relationship of C-Reactive Protein Reduction to Cardiovascular Event Reduction Following Treatment With Canakinumab: A Secondary Analysis From the CANTOS Randomised Controlled Trial. Ridker PM, MacFadyen JG, Everett BM, et al. Lancet (London, England). 2018;391(10118):319-328. doi:10.1016/S0140-6736(17)32814-3.

  5. Targeting the Immune System in Atherosclerosis: JACC State-of-the-Art Review. Zhao TX, Mallat Z. Journal of the American College of Cardiology. 2019;73(13):1691-1706. doi:10.1016/j.jacc.2018.12.083.

  6. Modulation of the Interleukin-6 Signalling Pathway and Incidence Rates of Atherosclerotic Events and All-Cause Mortality: Analyses From the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Ridker PM, Libby P, MacFadyen JG, et al. European Heart Journal. 2018;39(38):3499-3507. doi:10.1093/eurheartj/ehy310.

  7. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. Ridker PM, Everett BM, Pradhan A, et al. The New England Journal of Medicine. 2019;380(8):752-762. doi:10.1056/NEJMoa1809798.

  8. Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis. Ridker PM. Circulation Research. 2019;124(3):437-450. doi:10.1161/CIRCRESAHA.118.313129.

  9. Targeting Inflammation After Acute Myocardial Infarction. Imbesi A, Greco A, Spagnolo M, et al. Journal of the American College of Cardiology. 2025;86(15):1146-1169. doi:10.1016/j.jacc.2025.07.064.

  10. Low-Dose Colchicine for Secondary Prevention of Coronary Artery Disease: JACC Review Topic of the Week. Nelson K, Fuster V, Ridker PM. Journal of the American College of Cardiology. 2023;82(7):648-660. doi:10.1016/j.jacc.2023.05.055.

  11. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Writing Committee Members, Virani SS, Newby LK, et al. Journal of the American College of Cardiology. 2023;82(9):833-955. doi:10.1016/j.jacc.2023.04.003.

  12. Effect of Interleukin-1β Inhibition With Canakinumab on Incident Lung Cancer in Patients With Atherosclerosis: Exploratory Results From a Randomised, Double-Blind, Placebo-Controlled Trial. Ridker PM, MacFadyen JG, Thuren T, et al. Lancet (London, England). 2017;390(10105):1833-1842. doi:10.1016/S0140-6736(17)32247-X.

  13. Canakinumab as Adjuvant Therapy in Patients With Completely Resected Non-Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized Clinical Trial. Garon EB, Lu S, Goto Y, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2024;42(2):180-191. doi:10.1200/JCO.23.00910.

  14. Plasma Signals of Lung Tumor Promotion for Molecular Cancer Prevention. Pandya T, Zagorulya M, Leung MM, et al. Cell. 2026;189(13):3903-3921.e26. doi:10.1016/j.cell.2026.05.005.

  15. Critical data‐based re‐evaluation of minocycline as a putative specific microglia inhibitor. Möller T, Bard F, Bhattacharya A, et al. Glia. 2016;64(10):1788-94. doi:10.1002/glia.23007.

  16. Relation Between Lipophilicity and Pharmacological Behavior of Minocycline, Doxycycline, Tetracycline, and Oxytetracycline in Dogs. Barza M, Brown RB, Shanks C, Gamble C, Weinstein L. Antimicrobial Agents and Chemotherapy. 1975;8(6):713-20. doi:10.1128/AAC.8.6.713.

  17. Minocycline: A neuroprotective agent for hypoxic‐ischemic brain injury in the neonate?. Buller KM, Carty ML, Reinebrant HE, Wixey JA. Journal of Neuroscience Research. 2009;87(3):599-608. doi:10.1002/jnr.21890.

  18. Plasma and Brain Concentrations of Doxycycline After Single and Repeated Doses in Wild-Type and APP23 Mice. Lucchetti J, Fracasso C, Balducci C, et al. The Journal of Pharmacology and Experimental Therapeutics. 2019;368(1):32-40. doi:10.1124/jpet.118.252064.

  19. Chlamydia Pneumoniae Can Infect the Central Nervous System via the Olfactory and Trigeminal Nerves and Contributes to Alzheimer's Disease Risk. Chacko A, Delbaz A, Walkden H, et al. Scientific Reports. 2022;12(1):2759. doi:10.1038/s41598-022-06749-9.

  20. Minocycline Protects Schwann Cells From Ischemia-Like Injury and Promotes Axonal Outgrowth in Bioartificial Nerve Grafts Lacking Wallerian Degeneration. Keilhoff G, Schild L, Fansa H. Experimental Neurology. 2008;212(1):189-200. doi:10.1016/j.expneurol.2008.03.028.

  21. Minocycline Promotes Remyelination in Aggregating Rat Brain Cell Cultures After Interferon-Γ Plus Lipopolysaccharide-Induced Demyelination. Defaux A, Zurich MG, Honegger P, Monnet-Tschudi F. Neuroscience. 2011;187:84-92. doi:10.1016/j.neuroscience.2011.04.053.

  22. Minocycline Up-Regulates the Expression of Brain-Derived Neurotrophic Factor and Nerve Growth Factor in Experimental Autoimmune Encephalomyelitis. Chen X, Ma L, Jiang Y, et al. European Journal of Pharmacology. 2012;686(1-3):124-9. doi:10.1016/j.ejphar.2012.04.043.

  23. Minocycline Alleviates Peripheral Nerve Adhesion by Promoting Regulatory Macrophage Polarization via the TAK1 and Its Downstream Pathway. Li Y, Zhang Z, Xu K, et al. Life Sciences. 2021;276:119422. doi:10.1016/j.lfs.2021.119422.

  24. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. Sabatine MS, Giugliano RP, Keech AC, et al. The New England Journal of Medicine. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664.

  25. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Chou R, Cantor A, Dana T, et al. JAMA. 2022;328(8):754-771. doi:10.1001/jama.2022.12138.

  26. Wouldn't it be better to treat people with an anti-inflammatory antibiotic like minocycline cited in the references above, or doxycycline, both of which have powerful anti-inflammatory effects (MMP)? Clarithromycin is also pleotropic, with both antimicrobial and anti-inflammatory properties (NFKB). Can you suggest some nutrients that would also be viable replacements for statins and do NOT have adverse effects on people over 60?

What CANTOS Conclusively Demonstrates

1. Inflammation reduction alone — without any lipid lowering — reduces cardiovascular events by the same magnitude as PCSK9 inhibitors that lower LDL by 60%. This is the single most important finding in modern cardiovascular medicine for understanding mechanism.[1][2]

2. The benefit tracks with inflammation reduction, not LDL reduction. The 31% mortality reduction in CANTOS responders (hsCRP < 2) versus zero mortality reduction with PCSK9 inhibitors (despite LDL < 30 mg/dL) makes the case unambiguously.[4][6]

3. The specific pathway matters. The IL-1β → IL-6 → CRP axis is the critical target. Methotrexate, which does not suppress this pathway, provided no benefit. Statins, which do suppress this pathway (via mevalonate/NF-κB inhibition), provide mortality benefit. PCSK9 inhibitors, which do not suppress this pathway, provide event reduction but no mortality benefit.[8][7]

4. The trade-off of immunosuppression. Both CANTOS and colchicine trials showed increased fatal infections — the same trade-off discussed in the earlier conversation about the body's inflammatory response being protective. Canakinumab's failure to reduce all-cause mortality in the overall population was likely because the reduction in cardiovascular deaths was offset by increased deaths from infection. This perfectly illustrates the dual nature of inflammation: suppressing it reduces atherosclerotic events but increases susceptibility to infection.[9]

The 2025 ACC Scientific Statement on Inflammation and Cardiovascular Disease now formally recognizes that residual inflammatory risk (elevated hsCRP on statin therapy) is important and recommends hsCRP screening in patients with secondary prevention.[3]

Would you like to explore how the infectious hypothesis of atherosclerosis — specifically, the role of C. pneumoniae in plaque inflammation — relates to the CANTOS findings, given that IL-1β is the primary cytokine produced by macrophages infected with C. pneumoniae?