Back Back
Residual Inflammatory Risk in ASCVD and CKD
An Expert Cardiologist’s Insights on Addressing Residual Inflammatory Risk in Patients With ASCVD and CKD

Released: September 04, 2024

Expiration: September 03, 2025

Erin Michos
Erin Michos, MD, MHS, FACC, FAHA, FASE, FASPC
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Established therapies that offer cardiovascular and kidney protection include ACE inhibitors, ARBs, SGLT-2 inhibitors, finerenone, and semaglutide, as well as statin therapy for primary and secondary cardiovascular prevention.
  • Several agents are being investigated for their potential to target residual inflammatory risk in patients with ASCVD and/or CKD including colchicine, canakinumab, and ziltivekimab; these advances are much needed to fill the gaps for patients who remain at risk for negative outcomes despite being maximized on standard-of-care regimens.

Cardiovascular (CV) disease remains the leading cause of death in the United States and worldwide, but not enough attention has been put on chronic kidney disease (CKD). CKD is a risk-enhancing condition for CV disease. Most diabetes-associated CV risk occurs among individuals with CKD. Therapies that protect both the heart and the kidneys are important because patients with CKD are more likely to die from CV causes than progression to end-stage kidney disease.

Current Management Strategies and Treatment Gaps
Fortunately, we have made substantial progress in therapies that are both CV and kidney protective. Our foundational therapies include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, with supporting data from RENAAL and IDNT. The 3 landmark trials that studied the impact of SGLT-2 inhibitors on cohorts of patients with CKD are CREDENCE, DAPA-CKD, and EMPA CKD. These trials showed that SGLT-2 inhibitors substantially reduce the risk of adverse kidney and CV outcomes, including in patients with CKD but without diabetes. In addition, we also have data from the FIDELITY trial which shows the nonsteroidal MRA finerenone having both kidney and CV protection. More recently, the FLOW trial demonstrated that in patients with diabetic CKD and albuminuria, the GLP-1 receptor agonist semaglutide also substantially improved kidney and CV outcomes.

Those agents have become foundational therapy for organ protection, as well as the background of standard of care, which include lifestyle, smoking cession, glycemic control, blood pressure control, lipid management, weight maintenance, healthy diet, and regular physical activity. Now, we know that patients with CKD are at an increased CV risk. Statins are still recommended as first-line therapy for both primary and secondary prevention to reduce CV risk. 

When it comes to the outcomes with statins in this population, we have robust data showing that events are lower in statin-treated individuals compared with those receiving placebo. However, there are still events occurring despite maximized statin therapy in some patients. The events not prevented with statin therapy are referred to as residual risk, which is likely not only because of residual lipid factors. There are data indicating if we can get low-density lipoprotein cholesterol (LDL-C) even lower and address lipoprotein(a) or triglyceride-rich lipoproteins, that may further reduce risk. But there is also residual risk unrelated to lipids because of suboptimal control of blood pressure, diabetes, and smoking, resulting in residual risk related to systemic inflammation.

New Therapeutic Approaches: Targeting Residual Inflammatory Risk
Recently, investigators have explored outcomes associated with targeting residual inflammation in patients with atherosclerotic cardiovascular disease (ASCVD) and CKD. Colchicine is an anti-inflammatory agent that has been used to treat gout and familial Mediterranean fever for a long time. It has multiple anti-inflammatory mechanisms, including impairing microtubular growth, inhibiting neutrophil function, interfering with the neutrophil platelet interplay, and interfering with the NLRP3 inflammasome. These effects have translated to a reduction in CV events in clinical trials like LoDoCo, LoDoCo 2, and COLCOT. As a result, in June 2023, the FDA approved low-dose colchicine 0.5 mg/day for the purpose of reducing CV events among adults who have or are at high risk for ASCVD. Thereafter, colchicine has been adopted into professional society guidelines including the 2023 Chronic Coronary Disease Guidelines by the American Heart Association, American College of Cardiology, National Lipid Association, American Society of Preventive Cardiology, and 2021 European Society of Cardiology Prevention Guidelines. However, colchicine is contraindicated in severe CKD and should be used with caution in patients with mild to moderate CKD, thereby leaving an unmet need to address inflammatory residual risk in patients with CKD.

In addition to colchicine, there are other promising therapeutic strategies for targeting residual systemic inflammation. The NLRP3 inflammasome activates the conversion of pro-interleukin (IL)-1β to the biologically active IL-1β. IL-1β then also promotes the downstream production of the cytokines tumor necrosis factor-α and IL-6. Now, IL-6 induces hepatic production of acute phase reactants such as C-reactive protein (CRP). Although CRP is likely not directly causal in the atherosclerotic process, it is a good surrogate marker because it is stable in the blood, easy to measure, and a good integrator of the whole inflammatory cascade. With this information in mind, canakinumab, a human monoclonal antibody targeting IL-1β, was investigated as an option to reduce residual inflammatory risk in those with a prior myocardial infarction and a CRP level >2 mg/L in the CANTOS trial. The CANTOS trial was a landmark trial because it was the first trial to confirm the inflammatory hypothesis that in the setting of no change in lipids or LDL-C, with canakinumab therapy, there was a 15% reduction in major adverse CV events. Unfortunately, there was a very small increased risk of fatal infections seen in the CANTOS trial. Subsequently, canakinumab did not receive FDA approval for the purposes of CV disease treatment, but it is still used for the treatment of certain inflammatory and autoimmune conditions.

Treatment Strategies on the Horizon
Ziltivekimab is a monoclonal antibody that inhibits IL-6. Downstream from IL-1 in the inflammation pathway, IL-6 is a proinflammatory cytokine that contributes to systemic inflammation via the NLRP3 inflammasome pathway. IL-6 directly stimulates the hepatic production of CRP, the major biomarker of inflammatory risk. High IL-6 concentrations are associated with endothelial dysfunction, atherogenesis, acute plaque rupture, and increased risk of myocardial infarction and coronary disease. The clinical impact of ziltivekimab therapy was evaluated in the phase II RESCUE trial, which demonstrated that it substantially reduced CRP levels. In addition, investigators noted that other biomarkers of atherosclerosis, such as fibrinogen, haptoglobin, serum amyloid A, and even lipoprotein(a), were also reduced, which are encouraging signs of its potential for CV disease risk reduction. The ZEUS trial is an ongoing phase III trial evaluating ziltivekimab in patients with ASCVD and CKD vs placebo. We look forward to the results of this pivotal trial, and we hope it will provide the much-needed information about addressing systemic residual inflammatory risk in this patient population. We have a lot to look forward to with the future use of ziltivekimab since it is also being evaluated in patients with acute myocardial infarction in the ARTEMIS trial and in patients with heart failure with preserved ejection fraction in the HERMES trial.

Your Thoughts? 
How do you address residual risk in your patients with ASCVD and CKD? Get involved in the discussion by answering the poll and posting a comment below. 

Continue

Poll

1.

What strategies do you use to reduce residual risk in patients with ASCVD and CKD who are on maximized lipid-lowering therapy? (Select all that apply)

Submit