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Global Translational Medicine Anti-inflammatory therapy in CVD

1. Introduction: Managing inflammation 3. Beyond statins for LDL reduction
as a key factor in atherosclerotic While statins remain the primary therapy for dyslipidemia,
cardiovascular disease (ASCVD) gene therapy offers emerging alternatives. Approaches
ASCVD is a leading global cause of mortality, responsible include gene addition, inactivation, and editing of target
for over 17 million deaths annually. Traditional risk hepatocytes to restore cholesterol metabolism. In pre-
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factors, such as hyperlipidemia, hypertension, diabetes, clinical studies, adeno-associated virus-mediated gene
and obesity, are well established, but increasing evidence therapy has demonstrated a 98% reduction in cholesterol
highlights the pivotal role of systemic inflammation in levels, showing promise for the treatment of familial
disease progression and plaque instability. hypercholesterolemia (Figure 1). 4
The references cited in this review were identified Beyond statins, novel agents, such as ezetimibe,
through a structured literature search of PubMed and proprotein convertase subtilisin/kexin type 9 (PCSK9)
ClinicalTrials.gov from January 2000 to March 2025 inhibitors, and bempedoic acid, have emerged to effectively
using keywords such as “inflammation,” “atherosclerosis,” treat dyslipidemia (Figure 2). Ezetimibe inhibits Niemann–
“cardiovascular disease,” “interleukin,” “ApoC-III,” and Pick C1-like protein 1, a transporter of food cholesterol
“anti-inflammatory therapy.” Additional studies were from the intestinal lumen into enterocytes, reducing
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identified by manually reviewing the reference lists of LDL levels by 15 – 20%. In the Improved Reduction of
relevant articles. Only peer-reviewed studies published in Outcomes: Vytorin Efficacy International Trial, adding
English were included, with priority given to randomized ezetimibe to simvastatin resulted in a 24% reduction in
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clinical trials, large cohort studies, and landmark LDL levels and a 2% decrease in cardiovascular events.
translational investigations. PCSK9 inhibitors (e.g., alirocumab and evolocumab)
enhance LDL receptor recycling by preventing LDL
2. Evidence with statin therapy, low- receptor degradation and have resulted in >60% reduction
density lipoprotein (LDL) reduction, and in LDL levels in the Long-term Safety and Tolerability of
cardiovascular disease (CVD) prevention Alirocumab in High Cardiovascular Risk Patients with
Hypercholesterolemia Not Adequately Controlled with
Pravastatin has been studied extensively in the West of Their Lipid Modifying Therapy (ODYSSEY) and the
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Scotland Coronary Prevention Study (WOSCOPS) and Further Cardiovascular Outcomes Research with PCSK9
the Prospective Study of Pravastatin in the Elderly at Risk Inhibition in Subjects with Elevated Risk (FOURIER)
(PROSPER) trials. WOSCOPS showed a 26% reduction in trials. Bempedoic acid, an ATP citrate lyase inhibitor,
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LDL levels and a 28% reduction in cardiac mortality with showed a 21% reduction in LDL levels in the Cholesterol
pravastatin. The PROSPER trial showed a 34% reduction Lowering through Bempedoic Acid (ECT1002), an ACL-
in LDL levels and a 24% reduction in cardiac outcomes Inhibiting Regimen (CLEAR) Outcomes trial, particularly
in elderly patients. The Heart Protection Study evaluated benefiting statin-intolerant patients. A subgroup analysis
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the benefits of simvastatin in 20,000 patients with no prior of patients with baseline hs-CRP levels >2 mg/L in the
coronary events and found an 18% reduction in cardiac bempedoic acid group showed a median decrease of
mortality and a 26% reduction in coronary events in the 1.66 mg/L in hs-CRP levels at the 12-week follow-up. 10
simvastatin 40 mg daily group compared to the placebo
group. 2 4. Reduction of triglycerides and its impact
Building upon prior evidence, the Justification for on CVD
the Use of Statins in Prevention: an Intervention Trial Genetic and pharmacological approaches targeting
Evaluating Rosuvastatin trial further evaluated statins apolipoprotein C-III (ApoC-III), angiopoietin-like protein
in primary prevention, specifically in individuals with 3 (ANGPTL3), ANGPTL4, and related pathways show
LDL levels <130 mg/dL but elevated high-sensitivity promise for reducing triglycerides. ApoC-III inhibition,
C-reactive protein levels (hs-CRP; ≥2.0 mg/L). The initially observed in Amish populations with loss-of-
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trial enrolled 17,802 participants, who were randomized function mutations, correlates with a 39% reduction in
to receive either rosuvastatin 20 mg daily or placebo. triglyceride levels and a 40% decrease in ASCVD risk.
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Rosuvastatin therapy resulted in a 50% reduction in ApoC-III also upregulates inflammatory cytokines (e.g.,
LDL levels, a 37% reduction in hs-CRP levels, and a 44% interleukin-6 [IL-6] and tumor necrosis factor-alpha
reduction in major cardiovascular events. The trial was [TNF-α]), contributing to endothelial dysfunction;
terminated early due to significant cardiovascular risk therefore, inhibiting ApoC-III also reduces systemic
reduction. inflammation, potentially preventing CVD progression. 12

Volume 4 Issue 3 (2025) 13 doi: 10.36922/GTM025100024