Interleukin-1 and the CANTOS Trial: Anti-inflammatory Therapy for Cardiovascular Disease
Canakinumab, an interleukin-1β inhibitor, demonstrated significant reduction in cardiovascular events in patients with previous myocardial infarction and elevated inflammatory markers, but is not currently recommended for routine cardiovascular risk reduction due to increased infection risk, high cost, and availability of more effective alternatives.
Role of Interleukin-1 in Cardiovascular Disease
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a crucial role in the atherothrombotic process:
- Acts as an upstream modulator of interleukin-6 and C-reactive protein (CRP)
- Undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 (NLRP3) inflammasome
- This activation process is promoted by cholesterol crystals in atherosclerotic plaques
- Contributes to all phases of atherosclerosis development
The CANTOS Trial: Key Findings
The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) was a landmark trial that tested the inflammatory hypothesis of atherothrombosis 1:
- Enrolled 10,061 patients with previous myocardial infarction and high-sensitivity CRP ≥2 mg/L
- Randomized to placebo or canakinumab (50 mg, 150 mg, or 300 mg subcutaneously every 3 months)
- Primary endpoint: nonfatal MI, nonfatal stroke, or cardiovascular death
- Median follow-up: 3.7 years
Results:
- The 150 mg dose reduced the primary endpoint by 15% (HR 0.85; 95% CI, 0.74-0.98; p=0.021) 1
- Significant reduction in CRP levels without affecting lipid levels
- Total cardiovascular events were reduced with all doses of canakinumab (rate ratios vs. placebo: 0.80 for 50 mg, 0.79 for 150 mg, and 0.78 for 300 mg) 2
- Patients who achieved hsCRP <2 mg/L had a 25% reduction in major adverse cardiovascular events 3
Safety concerns:
- Increased risk of fatal infections compared to placebo
- No significant difference in all-cause mortality
Subgroup Analyses and Special Populations
- Patients with chronic kidney disease (CKD) showed cardiovascular benefits (HR: 0.82; 95% CI: 0.68 to 1.00; p = 0.05) 4
- Greatest benefit in those who achieved on-treatment hsCRP levels below 2 mg/L (HR: 0.68; 95% CI: 0.53 to 0.86; p = 0.0015) 4
- Similar benefits observed in patients with baseline albuminuria or diabetes 4
Current Guideline Recommendations
Despite the positive findings in CANTOS, current guidelines do not recommend canakinumab for routine cardiovascular risk reduction:
- The 2024 ESC guidelines for chronic coronary syndromes note that despite efficacy, canakinumab was not developed further for cardiovascular indications due to risk of fatal infections and high costs 5
- Other anti-inflammatory approaches are being studied, including colchicine, which has shown promising results in the COLCOT and LODOCO2 trials 5
- Current guidelines prioritize SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular risk reduction in patients with diabetes and cardiovascular disease 5, 6
Clinical Implications and Practical Considerations
Strengths of the CANTOS approach:
- Provided proof-of-concept for the inflammatory hypothesis of atherosclerosis
- Demonstrated cardiovascular benefits independent of lipid-lowering effects
- Identified inflammation as a viable therapeutic target
Limitations and challenges:
- Increased risk of serious infections
- High cost of therapy
- Modest absolute risk reduction (ARR of 0.55% at 48 months, NNT of 182) 5
- Not developed further for cardiovascular indications
Alternative Anti-inflammatory Approaches
Other anti-inflammatory agents being studied for cardiovascular risk reduction include:
- Low-dose colchicine: Showed benefit in COLCOT and LODOCO2 trials with better safety profile 5
- Low-dose methotrexate: Did not reduce cardiovascular events in the CIRT trial 5
Conclusion
The CANTOS trial provided important proof for the inflammatory hypothesis of atherosclerosis by demonstrating that IL-1β inhibition with canakinumab reduced cardiovascular events independent of lipid-lowering effects. However, due to increased infection risk, high cost, and modest absolute benefit, canakinumab is not currently recommended for routine cardiovascular risk reduction. Current guidelines favor other approaches, particularly SGLT2 inhibitors and GLP-1 receptor agonists, for cardiovascular risk reduction in high-risk patients.