CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 22, 2024
Expiration: July 21, 2025
STEP Trials: Semaglutide for Systemic Inflammation in People With Overweight/Obesity
GLP-1 RAs have been shown to inhibit systemic inflammatory pathways.33 GLP-1 RAs also promote weight loss, which in and of itself is associated with a reduction in inflammatory markers.34 The Semaglutide Treatment Effect in People with Obesity (STEP) trials 1, 2, and 3 were placebo-controlled trials in adults ≥18 years of age for the management of weight in people with or without T2D. Concentrations of hsCRP and clinical characteristic subgroups were compared from each trial to investigate treatment effect. The green line shown represents relative change in hsCRP with semaglutide 2.4 mg and the black lines reflect change in body weight with the same dose. In each trial, hsCRP reductions reached levels >50% but weight reduction was <10%, suggesting that inflammation is not entirely driven by weight and that there may be additional anti-inflammatory properties of GLP-1 RAs.35
Cardiovascular and Kidney Benefits of Semaglutide in SELECT Trial: Patients With Overweight/Obesity and CVD
To determine if GLP-1RAs may protect against CVD risk, the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) enrolled patients older than age 45 with a CVD history, overweight or obesity with a BMI above 27 kg/m2, but without diabetes. Participants were randomized to semaglutide titrated to 2.4 mg per week or placebo with the event-driven endpoint being time to composite CVD events. For patients receiving semaglutide, there was a reduction in major CVD events by 20% (HR: 0.80; 95% CI: 0.72-0.90; P <.001]. Of interest, note that the curves begin separating early following treatment initiation, which is intriguing when you consider that it took 104 weeks for 77% of the patients to titrate to the target dose of 2.4 mg.
Additional endpoints from this evaluation included mean change in hsCRP levels from baseline. Those receiving semaglutide had a reduction of nearly 38% (mean difference -37.82 [95% CI: -39.7 to -35.9]).36 Further studies will need to determine how this hsCRP mediation relates to CVD outcomes.
Cardiovascular and Kidney Benefits of Semaglutide in SELECT Trial: Patients with Overweight/Obesity and CVD
A further analysis stemming from the SELECT study examined prespecified composite kidney endpoints as follows: time to either death from CKD, renal replacement therapy (transplant or dialysis), onset of eGFR <15 mL/min/1.73m2, persistent reduction in eGFR by ≥50% of baseline, or onset of macroalbuminuria. As a reminder, the study population did not have diabetes but did have a confirmed history of CVD. Patients receiving semaglutide saw a 22% risk reduction in the 5-point composite kidney endpoint (HR: 0.78; 95% CI: 0.63-0.96; P = 0.002). These were the first available data to suggest the benefit of GLP-1 RAs on kidney function.37
FLOW Trial: Cardiovascular and Kidney Benefits of Semaglutide for Patients with Diabetic CKD
Listen to this audio clip to hear faculty review the FLOW trial.
The Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial was a dedicated study of semaglutide in patients with T2D and CKD defined by strict eGFR and albuminuria criteria. The trial was a randomized, placebo-controlled design and patients randomized to semaglutide escalated the dose over 8 weeks to 1 mg per week. The primary endpoint was time to composite major kidney disease events including death from CKD or CVD. Key hierarchical secondary endpoints included rate of change in eGFR slope, MACE, and all-cause mortality. For the primary endpoint of major kidney disease events, there was a 24% (HR: 0.76; 95% CI: 0.66-0.88); P = .0003) reduction in the combined kidney and CV death primary endpoint. But most impressive was that significance was met for all hierarchical endpoints with significant reductions noted in the graphs you see here. Thus, semaglutide is now shown to reduce CVD death, MACE, kidney-specific component events, and also slowed the decline in eGFR slope in patients with T2D and CKD.38
Anti-Inflammatory Effects of Colchicine
Listen to this audio clip to hear faculty discuss the role of colchicine in reducing inflammation.
Colchicine has been available for many years for the treatment of gout and familial Mediterranean fever.39 But recent interest in its anti-inflammatory activity has burgeoned following evidence showing patients taking 0.5 mg daily within 30 days of an MI and those with chronic coronary disease to be at a reduced risk of acute CVD events.40 Colchicine impairs microtubular growth, preventing neutrophil activation, degranulation, and migration, in turn interfering with the neutrophil platelet interaction. The NLRP3 inflammasome described earlier is thereby disrupted, preventing the activation of IL-1β and IL-18 cytokines.40,41 There is some caution with the use of colchicine; it is contraindicated in patients with preexisting kidney failure. If you have a patient with impaired kidney function, the clearance of colchicine is reduced, and close monitoring is required for adverse drug events. Colchicine can cause GI side effects and tolerance may be an issue for some patients.41
LoDoCo2 Trial: Colchicine in Stable CAD
The first trial to test colchicine was a randomized placebo-controlled trial, Low-Dose Colchicine (LoDoCo), that included only a small number of adults with stable CVD. The significant reduction in acute CVD events (HR: 0.33; 95% CI: 0.18-0.59; P <.001) raised questions about the plausibility to warrant a second, larger study.42,43 LoDoCo2, an investigator-driven trial, randomized over 5000 adults with confirmed CVD to either placebo or colchicine 0.5 mg daily. The primary endpoint, a composite of CVD death and major CVD events only occurred in 6.8% of the colchicine group vs 9.6% of those given placebo, a 31% reduction (HR: 0.69; 95% CI: 0.57-0.83; P <.001]. Colchicine did not lower the risk of non-CV death as shown by the incidence rates (HR: 1.21; 95% CI: 0.86-1.71) compared with placebo.
Effects of Low-Dose Colchicine on MI, Stroke, and CV Death
A meta-analysis published in 2023 evaluated the addition of colchicine to target residual risk in those with established or at high risk for ASCVD.44 The study included the initial LoDoCo trial from 2013 and LoDoCo2, as well as the Colchicine Cardiovascular Outcomes Trial (COLCOT) and the Colchicine in Patients with Acute Coronary Syndromes (COPS) trials.45,46 COLCOT evaluated the use of colchicine as adjunct therapy to reduce CV events in patients who had a recent MI (within 30 days), and COPS assessed the addition of colchicine to the standard of care for patients who had evidence of coronary artery disease on coronary angiography. The results of the meta-analysis demonstrate colchicine confers a 25% reduction of 3-point MACE (MI, stroke, and CV death) when the trials are polled together.
Relative Risk Reduction With Colchicine Is Greater Than With Ezetimibe and PCSK9 Inhibition
Although there have not been head-to-head comparisons between colchicine and nonstatin lipid-lowering therapies, this slide shows a side-by-side comparison of the magnitude of benefit demonstrated in key clinical trials to provide a hypothesis generating consideration. This graph highlights the relative risk reduction of MACE from several trials, including the 31% reduction demonstrated in LoDoCo2, which is a larger reduction than that seen with some of the lipid-lowering therapies such as ezetimibe in IMPROVE-IT or the PCSK9 inhibitors in FOURIER and ODYSSEY, suggesting that the magnitude of benefit in targeting inflammation is as large or potentially larger than aiming to further target lipid lowering.29,44
Targeted Anti-inflammatory Therapy Demonstrates Substantial CV Risk Reduction Without Change in LDL-C
In this graph, we can appreciate the linear association with LDL reduction and CV risk reduction in several landmark lipid trials as that reduction in risk is proportional to the degree of LDL lowering. However, in the colchicine trials you have a very similar, if not greater relative risk reduction with no reduction in LDL.44
Pharmacokinetics of 0.5 mg vs 0.6 mg Daily Colchicine Based on Renal Function
Given the potential risks associated with using colchicine in patients with impaired renal function, it is important to evaluate its pharmacokinetics in this population. The standard dose used to treat gout is 0.6 mg.39 When using this dose in a patient with normal renal function, generally the concentration of colchicine will remain in a safe range. However, in those with renal impairment, use of colchicine at 0.6 mg risks increasing above the safe upper limit. Alternately, using the 0.5 mg dose as studied in trials targeting CV risk reduction, the concentration remains in the therapeutic range considered safe in most patients with normal and impaired renal function.44
Colchicine: The Frist FDA-Approved Drug Tackling the Residual Inflammatory Risk in CVD
Listen to this audio clip about the FDA approval of colchicine.
As a result of these studies, the FDA approved a 0.5 mg dose of colchicine for the reduction of CVD risks in adults with multiple risk factors in June of 2023.41
The 2021 European Society of Cardiology now lists colchicine as potential therapy in secondary CVD prevention when optimized therapy does not bring risk factors under control.12
Colchicine Is Now Incorporated in Society Guidelines
International guidelines have recently added colchicine as an option to consider for secondary prevention of CV events. The 2023 US guidelines formulated by the AHA, American College of Cardiology (ACC), National Lipid Association (NLA), and American Society of Preventive Cardiology (ASPC) gave colchicine a class IIb indication, for secondary CVD prevention.47 In addition, the 2021 European Society of Cardiology now lists colchicine as potential therapy in secondary CVD prevention when optimized therapy does not bring risk factors under control.12 In both guidelines, a IIb classification indicates that the recommendation is based on less established evidence or expert opinion that the benefit greatly outweighs risks to fully endorse it, preferring instead to use the term “may consider”.12,47 An example of when to consider using colchicine is in a patient whose hsCRP remains elevated despite meeting LDL target and is maximized on the standard of care therapies.
Amplification Loops in Cytokine Signaling: Rationale for IL-1β Inhibition
To revisit the NLRP3 inflammasome, its primary function is to activate the conversion of pro–IL-1β and its cousin pro–IL-18 to the biologically active IL-1β and IL-18, which then promote downstream production of the cytokines TNFα and IL-6. IL-6 induces hepatic production of acute phase reactants that augment fibrinogen production. Two such reactants are CRP and serum amyloid A (SAA), which can be used as biomarkers reflecting the activity of the cytokine cascade. Of note, the experimental monoclonal antibody targeting IL-1β (canakinumab) was shown to reduce IL-6 but not IL-18, indicating its highly selective blockade within the inflammasome.48
CANTOS: Canakinumab Anti-inflammatory Thrombosis Outcome Study
The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) explored the efficacy of IL-1β inhibition in the secondary prevention of CVD events. CANTOS enrolled patients following an MI and who also had residual inflammatory risk defined by an hsCRP ≥2 mg/L. Three canakinumab doses, 50 mg, 150 mg or 300 mg (begun with a loading dose) were administered subcutaneously every 3 months until the primary efficacy endpoint of time to first CVD event. Though the key analyses were pairwise comparisons between groups, additional modeling compared incident rates of aggregate canakinumab data vs placebo.49 Of note, patients were excluded if their eGFR was <30 mL/min/1.73m2 at their first visit or if they had a kidney transplant.49
CANTOS: Primary Cardiovascular Endpoints
CANTOS was the first phase III trial with data confirming the hypothesis that directly targeting inflammation resulted in a reduction in CVD events. Canakinumab produced dose-dependent reductions in the inflammatory biomarkers IL-6 and hsCRP, but little or no change was observed in LDL-C for any dose. For those receiving either the 150- or 300-mg dose there was a 15% reduction in MACE (nonfatal MI, nonfatal stroke, or CV death) and a 17% reduction in MACE+ (MACE along with unstable angina requiring revascularization). These reflect significant CVD benefits.50
CANTOS Responders Analysis: Greater Reduction in MACE With Greater hsCRP Reduction
Of interest, a subsequent publication evaluated patients in the CANTOS trial who received canakinumab and achieved an hsCRP level <2 mg/dL from the baseline level of ≥2 mg/L. This cohort experienced a 25% reduction in MACE (HR: 0.75; 95% CI: 0.66-0.85; P = .0001), a striking contrast to the 15% reduction noted above.50,51 For those whose hsCRP remained ≥2 mg/L, only a minor and insignificant reduction in MACE occurred (HR: 0.95; 95% CI: 0.84-1.09; P = .48].51
CANTOS Responders Analysis: Greater Reduction in MACE With Greater IL-6 Reduction
Investigators also explored whether IL-6 reductions corresponded to a reduction in event rates. More than 4800 patients from CANTOS had available IL-6 data at baseline 3 months post randomization. The median IL-6 level in this group was 1.65 ng/L at 3 months, so this was used as the cut-point for comparison. Patients on canakinumab with IL-6 levels <1.65 ng/L had a 36% reduction in MACE compared to placebo (HR: 0.67; 95% CI: 0.57-0.80; P <.0001), while those with ≥1.65 ng/L IL-6 levels saw no relative change in MACE (HR: 1.00; 95% CI: 0.85-1.17; P = .97). Together, these data support the role of the IL-6 inflammatory pathway in CVD.52
CANTOS: Rate Difference in First and Subsequent CV Events
Pulling together the inflammasome hypotheses, researchers extrapolated the rate difference between first and subsequent CVD events across a population of 1000 persons over 3.7 years (the median study observation time) and plotted overall effect compared to those achieving target hsCRP and IL-6 levels. For the overall population receiving canakinumab, 77 serious CVD events were avoided (95% CI: -102 to -12; left-most dark blue bar). In comparison those achieving an hsCRP <2 mg/L were projected to avoid 105 events (95% CI: -127 to -72; left-most orange bar) and those with IL-6 levels of <1.65 ng/L avoided 141 events (95% CI: -175 to -92; left-most green bar). These data demonstrate the overall benefit of addressing the IL-1β inflammation chain.53
Inflammation Drives Residual Risk in CKD: A CANTOS Sub-Study
Though CANTOS excluded patients with a baseline eGFR <30 mL/min/1.73m2, 1092 participants did have CKD that could be stratified to a 30-60 mL/min/1.73m2 subgroup for consequent analyses.49,54 Participants without CKD had a corresponding increased risk of CVD events as plasma hsCRP, IL-6, LDL-C, and non–HDL-C quartiles increased (HRs: 1.45; 2.48; 1.64; and 1.68, respectively; all P <.0001). However, for those within the defined CKD eGFR range, only increasing quartiles of hsCRP and IL-6 were significantly associated with CVD events (HR: 1.50; P = .021 and HR: 1.84; P = .048, respectively). LDL-C and non–HDL-C could not be significantly linked (HR: 1.04; P = .80 and HR: 0.98; P = .88, respectively). For patients at known CVD risk with CKD, it appears residual inflammation plays a major predictive role in future CVD events.54
Listen to this audio clip about patients with CKD in the CANTOS trial.
Beyond Cholesterol: Can Targeted Anticytokine Therapy Reduce CVD Event Rates and Prolong Life?
We know that autoimmune and inflammatory diseases like rheumatoid arthritis confer a higher risk of developing CVD. Biologic therapies are a cornerstone of therapy for many of those conditions, with several agents available targeting various aspects of the inflammatory process (eg, IL-1, IL-6, TNFα). So, with growing evidence of the involvement of systemic inflammation in the pathophysiology of CV and CKD, can we use these same biologics agents to reduce the risk of those conditions?
CANTOS demonstrated it is possible to reduce CV events via IL-1 inhibition. Unfortunately, due to a concern about a small increased risk of fatal infections, canakinumab did not receive an FDA indication for the purposes of CVD treatment, however it is still used for treatment of certain inflammatory and autoimmune conditions.
When considering other viable targets in the inflammatory pathway, we note that IL-1 is upstream in the pathway. What if we got more targeted in the pathway and focused on inhibiting IL-6, which is a downstream marker?53
NLRP3 Inflammasome Pathway
Recalling previous graphics showing the NLRP3 inflammasome pathway, IL-6 is a cytokine released from a variety of cells once activated by IL-1 stimulation.55 Downstream, IL-6 binds to its target receptor (IL-6R) to trigger and amplify further inflammatory processes.48,56 A genetic variant of the IL-6R has been implicated in various autoimmune diseases and in asthma, but has been less well characterized in atherosclerotic disease.56 However, existing therapies used in rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis are known to intervene in the IL-6 trajectory by various mechanisms leading to further investigation into the CVD effects of IL-6 blockade.55
IL-6 and Chronic Stable Atherothrombosis: Human Translational Findings
Information thus far has painted a picture of IL-6 as a proatherogenic cytokine that connects the dots between high hsCRP and residual risk in CVD and CKD. Key concepts developed over the years are the foundation for pursuit of IL-6 research, including:
RESCUE: Antibody-Mediated IL-6 Inhibition to Reduce Inflammation
The Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (RESCUE) was a multicenter, randomized, double-blind, placebo controlled phase IIb trial that enrolled adults with CKD (eGFR >10 and <60 mL/min/1.73 m2) and documented inflammation (hsCRP ≥2 mg/L). Participants were randomized to receive placebo or 3 different doses of ziltivekimab, a new human monoclonal antibody that binds the IL-6 ligand. As a dose-finding study, patients received 7.5 mg, 15 mg, or 30 mg subcutaneously every month for 6 months.57
RESCUE Trial: IL-6 Inhibition in CKD –Change in hsCRP at 12 Wk
Listen to this audio clip to hear a faculty overview of the RESCUE trial.
The results of the RESCUE trial reflected the hypothesized effects of ziltivekimab in patients with CKD, achieving significant reductions in hsCRP levels. A dose response was noted, with ziltivekimab 15 mg and 30 mg reducing hsCRP levels by 88% and 92%, respectively. In addition, more than 90% of patients on the 30 mg dose achieved a reduction in hsCRP levels greater than 50% and an on-treatment level of <2 mg/L.57
RESCUE: Secondary Biomarker Results
However, it is expected that an IL-6 inhibitor would reduce hsCRP. This study also analyzed the impact of this agent on other biomarkers associated with atherothrombosis. In these graphs, we can see that ziltivekimab decreased fibrinogen, haptoglobin, SAA, secretory of phospholipase A2, and even lipoprotein(a), which is genetically determined.57
RESCUE Trial Summary
From the RESCUE trial, we can glean that the novel IL-6 inhibitor, ziltivekimab, reduced several markers of systemic inflammation and thrombosis that are known to promote the atherothrombotic process. Of importance, these findings were demonstrated in the critical population of patients with CKD who are at high CV risk. This population has a unique unmet therapeutic need as colchicine use is not recommended in those with significant renal impairment.
In addition, the magnitude of hsCRP lowering with ziltivekimab was nearly twice as large in the RESCUE trial compared with the that seen in the CANTOS trial with canakinumab.57 As CANTOS was a phase III trial that demonstrated a 15% to 20% reduction in CV events, we can hypothesize that further hsCRP reduction may confer greater CV event reduction.
In addition to these promising results about ziltivekimab efficacy, there were no concerning safety signals detected in this phase II trial, including a lack of bone marrow suppression, serious infection risk, hepatic toxicity, or worsening lipid levels. This suggests some promise for the future of ziltivekimab and supports its use in future outcome trials which are in progress and will be discussed over the next few slides.
ZEUS: Ziltivekimab in Patients With ASCVD/CKD and Systemic Inflammation
Listen to this audio clip to hear a faculty overview of the ZEUS trial.
The Ziltivekimab Cardiovascular Outcomes Study (ZEUS) is evaluating ziltivekimab in patients who have both ASCVD and CKD. Eligible patients must have a uACR >200 mg/g with an eGFR ≥60 mL/min/1.73 m2 or an eGFR 15 to <60 mL/min/1.73 m2. In addition, patients must have an hsCRP ≥2 mg/L for eligibility. Patients are being randomized to receive ziltivekimab 15 mg subcutaneously monthly or placebo.
This trial is event-driven, so it will end when enough events have accrued, and has a primary composite outcome of three-point MACE (CV death, nonfatal MI, or nonfatal stroke).
There are many interesting secondary endpoints being evaluated, including heart failure and individual kidney events. This trial will hopefully garner important information for patients with CKD who remain at very high risk, as we know that LDL may be a less relevant target for improving outcomes compared with targeting systemic inflammation.
ARTEMIS: Ziltivekimab Cardiovascular Outcomes Trial for Acute Myocardial Infarction
Another ongoing trial is ARTEMIS, which is investigating ziltivekimab in patients with acute MI. Patients eligible to participate include those who were admitted to the hospital for acute MI and have some risk factors including either CKD or diabetes. Of interest, hsCRP is not an eligibility requirement, however, investigators are assessing whether modification of the immune system in the acute phase of acute coronary syndrome can reduce events, as we know these individuals are at a very high risk for a subsequent event in the short term following an MI. As with ZEUS, ARTEMIS is an event-driven trial with a primary composite outcome over 3-point MACE.
HERMES: Ziltivekimab for Heart Failure
Finally, HERMES is a phase III trial evaluating ziltivekimab in patients with heart failure with preserved ejection fraction (HFpEF) and systemic inflammation. There are a lot of data about the role of inflammation in the pathophysiology of heart failure, so data from HERMES will also fill an important gap. Many patients with HFpEF have concomitant adiposity and obesity, which is also associated with increased inflammatory markers.
HERMES is aiming to enroll approximately 5600 participants who have heart failure with either mildly reduced or preserved ejection fraction above 40%. Patients will also require an hsCRP level ≥2 mg/L. The primary outcome is a composite heart failure endpoint including CV death, heart failure hospitalization, or urgent heart failure visit.
We are eagerly awaiting the results of these key phase III clinical trials and we hope they will be informative. However, in the meantime, what can we offer to patients today based on the evidence we have?
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