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Inflammation, Colchicine, and CVD Risk

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Inflammation, Colchicine, and CVD Risk Everything Old is New Again: Inflammation, Colchicine, and CVD Risk Samia Mora, MD, MHS Director, Center for Lipid Metabolomics Divisions of Cardiovascular Medicine and Preventive Medicine Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School @SamiaMoraMD [email protected] Disclosure: Dr. Mora has served as a consultant to Pfizer and Quest Diagnostics Topics to be Discussed 1. The early history of inflammation 2. Distinction between “residual cholesterol risk” and “residual inflammatory risk” as these patient groups have different reasons for recurrent events. 3. Anti-inflammatory therapies for CVD prevention: The central role of the IL-1β to IL-6 pathway of innate immunity. - CANTOS, CIRT trials - LoDoCo, COLCOT, LoDoCo2 trials 4. Lifestyle therapy to lower inflammation and cardiovascular risk. The Early History of Inflammation (Onion crushed with honey and taken with a beer) Jack DB Lancet 1997;350: 437-39 The Early History of Inflammation •Assyrians (Sumerian tablets): Anti-inflammatory effects of the willow tree leaves •Egyptians (Ebers papyrus): (Onion crushed with honey and taken with a beer) Jack DB Lancet 1997;350: 437-39 Jonathan Shaw, Harvard Magazine; 2019;46-52 Jonathan Shaw, Harvard Magazine; 2019;46-52 Cardiovascular Disease Is An Inflammatory Disease JUPITER Ridker PM et al NEJM 2008;359:2195-2207 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 Placebo 251 / 8901 P < 0.00001 0.08 0.06 - 44 % 0.04 Cumulative Incidence Cumulative Rosuvastatin 20 mg po qd 0.02 142 / 8901 0.00 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 2018/2019 ACC/AHA Risk Enhancing Factors eGFR 15-59 Ethnicity premature ASCVD CKD Family (men <55 y, women <65 y) History LDL-C ≥ 160 mg/dL Non-HDL-C ≥ 190 mg/dL Risk TGs ≥ 175 mg/dL ApoB ≥ 130 mg/dL Enhancers preeclampsia Pregnancy/ premature menopause Lp(a) ≥ 50 mg/dL or Menopause ≥ 125 nmol/L Biomarkers ABI <0.9 hs-CRP ≥ 2 mg/L Chronic Metabolic Inflammation Syndrome RA, lupus, psoriasis, HIV Grundy et al JACC 2019;73: e285 How Common is Residual Inflammatory Risk? As Common as Residual Cholesterol Risk Ridker JACC 2018;72:3320-3331 Resolution of Inflammation is an Active Process Back M et al Nat Rev Cardiol 2019;16: 389-406 From CRP to IL-6 to IL-1 Moving Upstream to Identify Novel Targets for Atheroprotection NLRP3 Inflammasome Caspase-1 Microtubule Polymerization Pro-IL-18 Pro-IL-1β Inhibitors Colchicine NLRP3 Inhibitors Activated IL-18 Activated IL-1β Interleukin-1 Inhibitors Canakinumab (Il-1b mAB) Interleukin-18 Inhibitors IL-18 IL-1β Gevokizumab (IL-1b mAB) Rilonacept (IL-1 TRAP) Anakinra (IL-1Ra) Interleukin-6 Inhibitors Tocilizumab Sarilumab Sirukimab IL-6 Olokizumab Ziltikevimab hsCRP > 3 mg/L High Vascular Risk <1 mg/L C-reactive Protein Low Vascular Risk Ridker PM. Circulation 2020;141:787-789 Interleukin-1β Inhibition Canakinumab 150 mg SQ/3 mo IL-1β IL-6 hsCRP 15-17% reduction in MACE and MACE+ 50-70% reduction in Lung Cancer Low-Dose Methotrexate 15-20 mg po / wk IL-1β IL-6 hsCRP No reduction in MACE and MACE+ No reduction in Lung Cancer Non-basal cell Ridker et al, N Engl J Med. 2017;377:1119-31 Ridker et al, N Engl J Med. 2019; 380:752-762 Skin Cancer LoDoCo Trial N = 532 Colchicine 0.5 mg po qd Open label HR 0.33 (95% CI 0.18 – 0.59) No Placebo P<0.001 Single Center 55 total events 15 colchicine, 40 control All Cause Mortality 4 colchicine, 10 control Nidorf, SM, et al; JACC 2013; 61:404-10. HR 0.77 (95% CI 0.61 – 0.96) P=0.02 Tardif JC., et al; N Engl J Med. 2019;381:2497-2505 Study design Post-myocardial infarction ≤30 days (n=4745 patients) On statin, anti-platelet agents, ±RAASi, ±BB Treated according to national guidelines PCI completed if applicable Colchicine 0.5 mg Placebo daily * daily * Primary composite endpoint: Time to first of CV death, cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization Secondary endpoints: Components of primary; composite of CV death, cardiac arrest, MI or stroke; total mortality *provided by Pharmascience (Montreal) Secondary Endpoints Endpoint Colchicine Placebo HR 95 % CI P (N = 2366) (N = 2379) Primary Composite 131 170 0.77 0.61-0.96 0.02 MI, CVA, CV arrest, urgent revascularization, CVD Secondary Composite 111 130 0.85 0.66-1.10 MI, CVA, CV arrest, CVD MI 89 98 0.91 0.68-1.21 CV Death 20 24 0.84 0.46-1.52 Resuscitated Cardiac 5 6 0.83 0.25-2.73 Arrest All Cause Mortality 43 44 0.98 0.64-1.49 Urgent Revascularization 25 50 0.50 0.31-0.81 Stroke 5 19 0.26 0.10-0.70 Pneumonia 21 9 0.03 ESC Colchicine II : LoDoCo-2 (Chronic CAD, N = 5522) 264 placebo vs 187 colchicine HR 0.69 (95% CI 0.57 – 0.83) P<0.001 Nidorf, SM, et al; NEJM2020;383:1838-47. ESC Colchicine II : LoDoCo-2 (Chronic CAD, N = 5522) 264 placebo vs 187 colchicine HR 0.69 (95% CI 0.57 – 0.83) P<0.001 Nidorf, SM, et al; NEJM2020;383:1838-47. LoDoCo2 Protocol Patients aged 35 – 82 years with proven coronary disease Clinically stable >6 months No advanced renal disease, heart failure or severe valvular heart disease 30-day open label run-in of colchicine 0.5mg daily 15.4% drop-out Tolerant, clinically stable and willing Pre-randomization Colchicine Placebo Planned to begin close-out 12 months after the last participant had been randomized* * If 331 primary events had accrued – sufficient to detect a 30% effect of therapy with 90% power Nidorf, SM, et al; NEJM2020;383:1838-47. Baseline characteristics Colchicine Placebo N=2762 N=2760 Age, years 65.8 +8.4 65.9 +8.7 Male 2305 (83.5) 2352 (85.9) Risk Factors and History Current Smoker 318 (11.5) 330 (12.0) Hypertension 1421 (51.4) 1387 (50.3) Diabetes 492 (17.8) 515 (18.7) Prior Revascularization 2419 (83.4) 2468 (84.0) Prior ACS 2323 (84.1) 2335 (84.6) - Last ACS >24m 1570 (67.6) 1609 (68.9) Nidorf, SM, et al; NEJM2020;383:1838-47. LoDoCo-2 Secondary Endpoints Colchicine Placebo Hazard Ratio P Value (N = 2762) (N = 2760) (95% CI) 1. Cardiovascular death, Myocardial infarction, 115(4.2) 157(5.7) 0.72(0.57-0.92) 0.007 or Ischemic stroke 2. Myocardial infarction or Ischemia-driven 155(5.6) 224(8.1) 0.67 (0.55-0.83) <0.001 coronary revascularization 3. Cardiovascular death or Myocardial 100(3.6) 138(5.0) 0.71(0.55-0.92) 0.010 infarction 4. Ischemia-driven coronary revascularization 135(4.9) 177(6.4) 0.75(0.60-0.94) 0.012 5. Myocardial infarction 83(3.0) 116(4.2) 0.70 (0.53-0.93) 0.014 6. Ischemic stroke 16(0.6) 24(0.9) 0.66(0.35-1.25) 7. Cardiovascular death 20(0.7) 25(0.9) 0.80(0.44-1.44) Nidorf, SM, et al; NEJM2020;383:1838-47. Residual Inflammatory or Cholesterol Risk ? Residual Cholesterol Risk Residual Inflammatory Risk LDL 110 mg/dL LDL 70 mg/dL hsCRP 1.8 mg/L hsCRP 3.8 mg/L Additional Additional LDL Reduction Inflammation Reduction IMPROVE-IT : Ezetimibe 6% RRR LoDoCo Colchicine 0.5 mg po qd 67% RRR FOURIER/SPIRE/ODYSSEY: CANTOS Canakinumab 150mg SC q 3 mo 15-20%RRR PCSK9 Inhibition q2 weeks 15-20% RRR COLCOT Colchicine 0.5mg po qd 24%RRR LoDoCo2 Colchicine 0.5 mg po qd 30% RRR Modified from Ridker PM, Eur Heart J 2016;37:1720-22 Non-Pharmacologic Approaches to Inflammation Resolution Mediterranean Diet Mediterranean Diet Inflammation Diabetes Metabolism and Insulin Resistance Age Hypertension HDL measures VLDL measures Obesity Branched chain amino acids Genetics CVD Smoking Ahmad S et al. JAMA Net Open 2019 Mediterranean Diet Lowers Chronic Inflammation % of CVD Benefit Explained by Various Risk Factors Inflammation 29% Insulin Resistance/ 28% Glucose Metabolism Body Mass Index 27 % Blood Pressure / Hypertension 26.6% Traditional Lipids 26% HDL Measures VLDL Measures Branched Chain Amino Acids LDL Measures Apolipoproteins Small Molecule Metabolites Ahmad S et al. JAMA Net Open 2018; 1:e185708 % Risk Reduction Physical Activity Lowers Chronic Inflammation % of CVD Benefit Explained by Various Risk Factors AllAll RiskRisk Factors 59% InflammatoryInflammation Markers 32.6% BloodBlood Pressure/Pressure / HypertensionHypertension 27.1% TraditionalTraditional LipidsLipids 19.1% NovelNovel LipidsLipids 15.5% BodyBody Mass Mass IndexIndex 10.1% HemoglobinHemoglobin A1c/A1c / DiabetesDiabetes 8.9% HomocysteineHomocysteine 0.7% 00 50 100100 % Risk Reduction Mora et al, Circulation 2007;116: 2110-8 Inflammation and Cardiovascular Disease 2021 Summary (1) 1. Atherosclerosis is a lipid-driven inflammatory disease. 2. In primary prevention, the JUPITER trial proved that adults with chronic inflammation benefit from statin therapy even if LDL cholesterol levels are low. 3. In secondary prevention, the CANTOS trial provided proof-of-principle that inflammation inhibition, in the absence of lipid lowering, can improve atherothrombotic outcomes. The positive CANTOS data and the neutral CIRT data for methotrexate define the central IL-1β to IL-6 pathway of innate immunity as crucial for CVD protection. Inflammation and Cardiovascular Disease 2021 Summary (2) 4.
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