In this episode, Dr. Paul Ridker, a pioneer in the field of cardiovascular inflammation, joins the CardioNerds (Dr. Gurleen Kaur, Dr. Richard Ferraro, and Dr. Nidhi Patel) to discuss the evolving landscape of inflammation as a key factor in cardiovascular risk reduction. The discussion dives into the importance of biomarkers like high-sensitivity C-reactive protein (hs-CRP) in guiding treatment strategies, the insights gleaned from landmark trials like the JUPITER and CANTOS studies, and the future of targeted anti-inflammatory therapies in cardiology.

Show notes were drafted by Dr. Nidhi Patel. Audio editing by CardioNerds academy intern, Grace Qiu. 

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

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Pearls – Targeting Inflammation for Cardiovascular Risk

1. “If you don’t measure it, you can’t treat it”: Incorporate hs-CRP into routine practice for patients at risk of cardiovascular events, as it provides crucial information for risk stratification and management.
2. Recognize the dual benefits of statins in lowering both LDL and inflammation, particularly in patients with elevated hs-CRP.
3. Encourage patients to adopt heart-healthy habits, as lifestyle changes remain foundational in reducing both cholesterol and inflammatory risk.
4. Reminder that most autoimmune or inflammatory diseases, from psoriasis to Addison’s disease to lupus to scleroderma to inflammatory bowel disease, have been shown to have elevated cardiovascular risk
5. Ongoing randomized trials including ZEUS, HERMES, and ARTEMIS will inform whether novel targeting of IL-6 can safely lower cardiovascular event rates or slow renal progression

Show notes – Targeting Inflammation for Cardiovascular Risk

Why is it important to measure both LDL and hs-CRP, and what factors increase hs-CRP?

• Inflammation and hyperlipidemia are synergistic in promoting atherosclerosis. They interact to exacerbate plaque formation and instability, increasing the risk of cardiovascular events.
• Just like we measure blood pressure and LDL to know what to treat, we should measure hs-CRP to guide targeted therapy.
• Clinical Example: in Ms. Flame’s case, despite achieving target LDL levels with statins, her elevated hs-CRP indicates ongoing inflammation and residual cardiovascular risk that should be assessed.
• Residual inflammatory risk should be assessed in both primary and secondary prevention.
• Increased BMI¹, smoking², a sedentary lifestyle³, and genetics⁴ (such as a higher risk of metabolic disease in South Asians) all raise hs-CRP levels.
• SGLTi⁵ and GLP-1 agonists⁶ have also been shown to decrease hs-CRP levels.

What data do we have to support measuring hs-CRP? 

• Women’s Health Study⁷: an early study showing that hs-CRP predicted risk at least as well as LDL cholesterol and that models incorporating hs-CRP in addition to lipids were significantly better at predicting risk than models based on lipids alone.
• JUPITER Trial⁸ (Primary Prevention): Among patients with normal LDL but elevated hs-CRP there was a 44% reduction in major cardiovascular events (>50% in MI and stroke) and a 20% reduction in all-cause mortality in patients treated with statins. These results led to changes in guidelines in recognizing the need to measure and treat inflammation.
• CANTOS Trial⁹ (Secondary Prevention): Randomized >10K patients with previous MI and hs-CRP ≥ 2mg/L and found that canakinumab reduced hs-CRP level from baseline in a dose-dependent manner, without reduction in the LDL, ApoB, TG, or blood pressure.

What are the guidelines and supportive data on using Colchicine? 

• Colchicine 0.5 mg is the first FDA-approved anti-inflammatory therapy indicated for reducing cardiovascular events among adults who have established ASCVD or are at risk of developing it.
• The use of Colchicine is supported by the LoDoCo, LoDoCo-2, and COLCOT trials, which showed a ~25-30% risk reduction in cardiovascular risk. In comparison, studies using ezetimibe¹⁰ have shown a 6-7% relative risk reduction and PCSK9 inhibitors¹¹ ~15% risk reduction for LDL reduction.
  • LoDoCo¹²– in those with stable CAD, patients who received colchicine in addition to standard of care had a significantly lower composite rate of ACS compared to those who only received standard of care at a median follow-up of 3 years.
  • LoDoCo-2¹³– randomized control, multicentric trial in patients with stable CAD showing group randomized to colchicine + standard of compare had reduced MACE compared to those with placebo + standard of care at a median follow-up of 2.8 years.
  • COLCOT¹⁴– Addition of colchicine within 30 days of ACS resulted in a reduction of the primary composite outcome of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina

What are examples of ongoing trials that will shape the future of our anti-inflammatory toolbox?

• ZEUS Trial¹⁵– ongoing trial that randomizes patients with ASCVD, hs-CRP ≥ 2 and CKD (eGFR between 15-60 OR EGFR ≥ 60 and urinary albumin-to-creatinine ratio ≥200) to Ziltivekimab or placebo, and assesses time to first occurrence of MACE.
• Hermes HFpEF¹⁶– ongoing trial that randomizes patients with HFpEF and HFmrEF to Ziltivekimab or placebo, and assesses time to first occurrence of cardiovascular death, heart failure hospitalization, or urgent heart failure visit
• Artemis Acute Ischemia¹⁷– ongoing trial that randomizes patients hospitalized with MI to Ziltivekimab or placebo, and assess time to MACE.
• Clazakizumab in patients receiving maintenance dialysis¹⁸– this study randomized adults with known cardiovascular disease and/or DM2 receiving dialysis with hs-CRP ≥ 2 to receive Clazakizumab or placebo. The primary endpoint is a reduction in hs-CRP over 12 weeks.

References – Targeting Inflammation for Cardiovascular Risk

1. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-Reactive Protein Levels in Overweight and Obese Adults. JAMA. 1999;282:2131-2135. doi: 10.1001/jama.282.22.2131
2. Tonstad S, Cowan JL. C-reactive protein as a predictor of disease in smokers and former smokers: a review. Int J Clin Pract. 2009;63:1634-1641. doi: 10.1111/j.1742-1241.2009.02179.x
3. Esteghamati A, Morteza A, Khalilzadeh O, Anvari M, Noshad S, Zandieh A, Nakhjavani M. Physical inactivity is correlated with levels of quantitative C-reactive protein in serum, independent of obesity: results of the national surveillance of risk factors of non-communicable diseases in Iran. J Health Popul Nutr. 2012;30:66-72. doi: 10.3329/jhpn.v30i1.11278
4. Anand SS, Razak F, Yi Q, Davis B, Jacobs R, Vuksan V, Lonn E, Teo K, McQueen M, Yusuf S. C-reactive protein as a screening test for cardiovascular risk in a multiethnic population. Arterioscler Thromb Vasc Biol. 2004;24:1509-1515. doi: 10.1161/01.ATV.0000135845.95890.4e
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6. Mazidi M, Karimi E, Rezaie P, Ferns GA. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. J Diabetes Complications. 2017;31:1237-1242. doi: 10.1016/j.jdiacomp.2016.05.022
7. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843. doi: 10.1056/nejm200003233421202
8. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. doi: 10.1056/NEJMoa0807646
9. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017;377:1119-1131. doi: 10.1056/NEJMoa1707914
10. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. New England Journal of Medicine. 2015;372:2387-2397. doi: 10.1056/NEJMoa1410489
11. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine. 2017;376:1713-1722. doi: 10.1056/NEJMoa1615664
12. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404-410. doi: 10.1016/j.jacc.2012.10.027
13. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383:1838-1847. doi: 10.1056/NEJMoa2021372
14. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381:2497-2505. doi: 10.1056/NEJMoa1912388
15. ZEUS – Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Participants With Established Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease and Systemic Inflammation. In; 2021.
16. Effects of Ziltivekimab Versus Placebo on Morbidity and Mortality in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation. In; 2022.
17. ARTEMIS – Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Patients With Acute Myocardial Infarction. In: Duke Clinical Research I, ed.; 2023.
18. Chertow GM, Chang AM, Felker GM, Heise M, Velkoska E, Fellström B, Charytan DM, Clementi R, Gibson CM, Goodman SG, et al. IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. Nature Medicine. 2024. doi: 10.1038/s41591-024-03043-1