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REVIEW ARTICLE

Colchicine Plus Rosuvastatin/Ezetimibe for Residual Cardiovascular Risk:

Mechanistic Rationale, Safety Concerns and Research Priorities

Teimuraz Sogulasvhili1,ID, Natia Gamkrelidze1,ID, Natalia Pavliashvili1,ID, Lado Kvatchadze1,2,ID, Maia Katsadze1,ID

Received: 19 Jun 2026; Accepted: 20 Jul 2026; Available online: 24 Jul 2026
References
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ABSTRACT

Atherosclerosis, a major global health challenge, is driven by both abnormal lipid metabolism and systemic inflammation. Although combination hypolipidemic therapy, such as HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors and cholesterol-absorption inhibitors, has proven effective in lowering cholesterol levels, a significant residual cardiovascular risk, driven by systemic inflammation, persists. Colchicine, a time-tested anti-inflammatory drug that modulates the NOD-like receptor protein 3 (NLRP3) inflammasome pathway, has recently been approved and supported by major guidelines for secondary cardiovascular prevention. However, there is currently a lack of direct scientific evidence regarding the co-administration of colchicine with potent dual lipid-lowering therapy (rosuvastatin/ezetimibe). This narrative review outlines the mechanistic rationale for this triple-combination approach. Current evidence supports both intensive LDL-C (low-density lipoprotein cholesterol) lowering and inflammation-targeted therapy as important strategies in ASCVD (atherosclerotic cardiovascular disease) prevention; however, direct clinical evidence for colchicine combined with rosuvastatin/ezetimibe remains insufficient. Future trials should evaluate whether this combination improves lipid and inflammatory biomarkers, plaque-stability markers, and cardiovascular outcomes, while carefully monitoring for muscle toxicity and the risk of drug-drug interactions.

Keywords. Atherosclerosis; Colchicine; Ezetimibe; Inflammation; Rosuvastatin.


DOI: 10.52340/GBMN.2026.01.01.180
INTRODUCTION

Atherosclerosis is fundamentally a dual-pathology disease driven by both mechanical lipid deposition and chronic vascular inflammation. 1-3 While standard-of-care intensive hypolipidemic therapy - such as the fixed-dose combination of rosuvastatin and ezetimibe - effectively lowers low-density lipoprotein cholesterol (LDL-C) and reduces overall cardiovascular risk, it does not eliminate it. 4,5

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A significant residual inflammatory risk often persists despite optimal lipid control, serving as a strong, independent predictor for recurrent adverse cardiovascular events. 6 To address this, colchicine has emerged as a highly cost-effective, targeted anti-inflammatory strategy for secondary cardiovascular prevention due to its ability to modulate the NLRP3 inflammasome. 7 However, a critical evidence gap remains regarding the co-administration of colchicine with the potent rosuvastatin/ezetimibe combination - a strategy that conceptually targets both primary mechanisms of atherosclerosis simultaneously.

 

Clarifying residual risks

Despite intensive standard-of-care hypolipidemic therapy, a significant proportion of patients with atherosclerotic cardiovascular disease (ASCVD) continue to experience recurrent events. To properly evaluate advanced therapeutic strategies, it is necessary to deconstruct this ongoing vulnerability into distinct clinical domains:

  • Residual lipid risk: Persistent ASCVD risk due to LDL-C, non-HDL-C, ApoB (Apolipoprotein B), Lp(a) (Lipoprotein(a)), triglyceride-rich remnants, or oxidized LDL despite therapy (Indicators: LDL-C, ApoB, non-HDL-C, Lp(a), TG(Triglycerides), oxLDL).

  • Residual inflammatory risk: Persistent ASCVD risk associated with vascular inflammation despite adequate lipid lowering (Indicators: hs-CRP (high-sensitivity C-reactive protein), IL-6 (Interleukin-6), IL-1β (Interleukin-1 beta) pathway activation).

  • Residual thrombotic risk: Persistent risk related to platelet activation, coagulation, NETosis, and endothelial dysfunction (Indicators: D-dimer, platelet activity, NET markers).

  • Residual metabolic risk: Risk driven by diabetes, obesity, insulin resistance, fatty liver, and metabolic syndrome (Indicators: HbA1c, insulin resistance, waist circumference).

 

Within this framework, the pharmacological agents discussed in this review operate across complementary axes. Colchicine primarily addresses residual inflammatory risk, whereas the rosuvastatin/ezetimibe regimen primarily targets LDL-C/ApoB-related lipid risk. Therefore, the proposed combination strategy is mechanistically strongest for a patient phenotype characterized by both inadequately controlled lipid risk and chronically elevated inflammatory markers.

 

Literature search strategy

To identify relevant literature regarding the dual targeting of lipid metabolism and vascular inflammation in atherosclerosis, a structured literature search was conducted. The search strategy was designed to capture foundational mechanistic studies, pivotal clinical trials, and recent pharmacovigilance data. The review was conducted as a narrative mechanistic review.

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The primary databases queried were PubMed and Google Scholar. The search, restricted to literature published between 2009 and 2026, used the following keywords and phrases: colchicine, rosuvastatin, ezetimibe, atherosclerosis, residual risk, MACE (Major Adverse Cardiovascular Events), colchicine cardiology, and colchicine statins side effects.

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To ensure the relevance and quality of the synthesized evidence, strict inclusion and exclusion criteria were applied, and the gathered literature was prioritized according to a predefined evidence hierarchy (TAB.1).

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TABLE 1. Literature search and selection strategy

Literature search and selection strategy

Abbreviations: ASCVD, Atherosclerotic Cardiovascular Disease; RCT, Randomized Controlled Trials.

REVIEW

Lipid-driven mechanisms of atherosclerosis

Atherosclerosis is a multifactorial disease characterized by interrelated processes that lead to extensive damage to the vascular system. The etiology of atherosclerosis is attributed to classical risk factors such as hypercholesterolemia (elevated LDL-C), hypertension, diabetes mellitus, smoking, and a sedentary lifestyle, as well as genetic factors.8 The pathogenesis of atherosclerosis is attributed to a dual mechanism: the mechanical deposition of lipids and cholesterol (LDL-C) in the arterial wall and the associated chronic inflammation of the arteries (vascular inflammation). As noted, inflammation contributes substantially to residual cardiovascular risk, particularly among patients with elevated hs-CRP despite LDL-C lowering. The small size of LDL-C enables it to penetrate the endothelium.

 

Inflammatory mechanisms of atherosclerosis

The chronic inflammatory response within the arterial wall is not an isolated process; it is actively driven and amplified by several systemic comorbidities and lifestyle behaviors.

 

Important exacerbating factors

Hypertension

High blood pressure is believed to contribute to endothelial dysfunction, arterial calcification, and disruption of established atherosclerotic plaques in regions of turbulent flow, such as arterial bifurcations. 9

 

Hyperglycemia/Diabetes

The proposed mechanism for diabetes is the formation of 'metabolic memory' due to the accumulation of difficult-to-metabolize Advanced Glycosylation End Products (AGEs). Hyperglycemia is believed to contribute to oxidative stress and excessive free radical formation, ultimately resulting in endovasculitis. 10

 

Smoking

Nicotine is believed to cause damage to the vascular intima and induce inflammatory damage and pyroptosis (inflammatory cell death). 11

 

Evidence for intensive LDL-C lowering

Traditional strategies for managing lipids mostly involved adjusting cholesterol levels using statins. These drugs work by inhibiting the activity of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme that functions in the liver to reduce the rate of cholesterol synthesis. Statins provide several other benefits besides reducing lipids: they reduce oxidative stress and inflammation in blood vessels, and stabilize arterial plaque.

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Pharmacological mechanisms and efficacy

Statins inhibit the activity of the HMG-CoA reductase enzyme, thereby limiting cholesterol synthesis in liver cells. When liver cells synthesize cholesterol at a slower rate, they compensate by increasing the number of LDL-C receptors on the cell membrane. This increases LDL-C clearance from the bloodstream, thereby lowering LDL-C levels with statin therapy. In contrast to statins, ezetimibe has a different mechanism of action: it reduces cholesterol absorption in the intestine. Fixed-dose combination therapy with a potent statin and ezetimibe has proved to exert more pronounced effects than simply increasing the dose of a statin to twice the original dose. 5,6

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Despite their efficacy, statins have clearly documented dose-dependent side effects. These can range from potential liver toxicity, increases in ALT/AST, and myopathy to, in rare cases, rhabdomyolysis and increased values in creatine kinase (CK). Of note, even more latent is the risk of new-onset diabetes with rosuvastatin, 12,13 as demonstrated in the JUPITER TRIAL (2008), reminding us to consider the full metabolic picture in drug efficacy. 14 Most importantly, though ongoing statins reduce cardiovascular risk, this risk never completely disappears in the face of ongoing inflammation. This indicates room to tackle this ongoing risk by therapeutic means. Emerging anti-inflammatory therapy: since inflammation is considered a core driver of atherosclerosis, targeting it is high-impact and high-priority. Cholesterol crystal formation in atherosclerotic plaques may result in both mechanical damage and immune activation, thereby triggering the expression of various inflammatory cytokines, like IL-1β. 15

 

Evidence for inflammation-targeted therapy

The necessity of precision in anti-inflammatory targets was definitively established by contrasting the CANTOS 16 and CIRT 17 trials. The CANTOS trial, utilizing the targeted IL-1β inhibitor canakinumab, successfully reduced recurrent cardiovascular events in patients with prior myocardial infarction and elevated CRP (C-reactive protein). Its primary significance lies not in establishing canakinumab as a routine clinical tool - given its associated infection risks and high costs - but in biologically validating the inflammatory hypothesis of atherothrombosis independent of lipid lowering. 18

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Conversely, the CIRT trial investigated low-dose methotrexate, a broad anti-inflammatory agent. Methotrexate failed to reduce the incidence of cardiovascular events, notably because it did not lower IL-1β, IL-6, or CRP levels. This stark contrast demonstrates that broad suppression of inflammation is insufficient to reduce cardiovascular risk; therapeutic success requires specific modulation of the IL-1β/IL-6/CRP pathway. 19

 

Endothelin-1 (ET-1)

ET-1 is a potent vasoconstrictor and inflammatory mediator, directly related to endothelial dysfunction. Rosuvastatin improves endothelial function by reducing preproendothelin-1 mRNA levels and enhancing nitric oxide availability. Colchicine also plays an additive role by inhibiting tubulin-mediated transport of E-selectin to the endothelium. This, in turn, reduces leukocyte adhesion and, ultimately, their activation, leading to ET-1 release. 20

 

Colchicine: mechanism and clinical trials

However, colchicine has good scientific evidence for cardiovascular risk reduction, which is also approved by various other authorities such as the FDA. 21

 

NLRP3 pathway dampening

Colchicine attenuates NLRP3 inflammasome activation in the innate immune system. This reduces the secretion of major inflammatory mediators, particularly IL-1β and IL-18 (Interleukin-18). 7

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Inhibition of microtubule polymerization and leukocyte trafficking

Inhibition of tubulin polymerization disrupts the cellular cytoskeleton and impairs leukocyte trafficking. That disruption reduces the adhesion and movement of monocytes and neutrophils toward inflamed blood vessels, mainly by downregulating E-selectin expression. 22 It also decreases the production of superoxide by neutrophils, helping to regulate TNF-α production from liver macrophages.

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To appropriately contextualize these therapeutic targets, it is necessary to stratify the supporting mechanisms by their current level of evidentiary backing:

  • Strong clinical evidence: LDL-C reduction by rosuvastatin/ezetimibe.

  • Strong/moderate clinical evidence: Colchicine reduction of clinical events in chronic CAD.

  • Moderate biomarker evidence: CRP/IL-6 reduction.

  • Mechanistic/limited clinical evidence: MMP modulation.

  • Mechanistic evidence: ET-1 modulation.

  • Emerging mechanistic evidence: NETosis suppression.

  • Hypothesis only: Triple-combination superiority.

 

Why combine colchicine with rosuvastatin plus ezetimibe?

Dual-pathway

Modulation of plaque stability indicators: MMPs and endothelin

In addition to lowering CRP and LDL-C levels, combining rosuvastatin with colchicine may also improve the stability of atherosclerotic lesions by modulating the activity of two major pathogenetic circles: Matrix Metalloproteinases (MMPs) and Endothelin-1. 23

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Matrix Metalloproteinases (MMPs): MMP-2 and MMP-9 are zinc-dependent metalloproteinases that degrade the extracellular matrix of fibrous caps, rendering plaques vulnerable to rupture. Rosuvastatin has been shown to inhibit serum MMP-9 levels and increase tissue inhibitors of Metalloproteinases (TIMPs), such as TIMP-1, thereby favoring plaque stability. 22 Concurrently, colchicine inhibits MMP-9 secretion in plaques via suppression of microtubule polymerization and NLRP3 inflammasome pathways in macrophages. This suggests a complementary dual-pathway strategy: targeting MMP inhibition via two distinct cellular mechanisms offers a compelling hypothesis-generating rationale for achieving more robust stabilization of vulnerable plaques than single-agent interventions. 24

 

Suppression of NETosis

Emerging evidence suggests that colchicine inhibits the formation of Neutrophil Extracellular Traps (NETs) within the plaque - NETs are fibrous networks that promote thrombosis and plaque rupture; their suppression represents a distinct pathway of plaque stabilization beyond the NLRP3 inflammasome. 25

 

Clinical efficacy and mixed findings

Research on the benefit of colchicine in atherosclerotic cardiovascular disease (ASCVD) has yielded mixed results; thus, interpreting the current literature requires a careful and balanced approach. To better contextualize these mixed findings, TABLE 2 summarizes the landmark clinical trials, highlighting how differences in target population, intervention timing, and specific pathways affect cardiovascular outcomes.

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TABLE 2. Summary of landmark trials evaluating anti-inflammatory therapies in ASCVD

Summary of landmark trials evaluating anti-inflammatory therapies in ASCVD

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CAT, coronary artery disease; CV, cardiovascular; hs-CRP, high-sensitivity C-reactive protein; IL-1β, interleukin 1β; IL-6, interleukin 6; MACE, major cardiovascular events; MI, myocardial infarction.

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Some of the initial, small randomized, placebo-controlled trials failed to demonstrate a clear improvement in laboratory markers. For instance, Raju and colleagues, in a study evaluating 1 mg of colchicine in patients with acute coronary syndrome (ACS) and stroke, observed no statistically significant differences in outcomes such as CRP levels; meanwhile, diarrhea was frequently noted as an adverse effect. 26 Additionally, Kajikawa and his team reported reduced CRP levels but found no significant changes in hemodynamic measures among ACS patients. 27

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However, the complexity of the landscape is driven not just by inconsistent lab results, but by the timing of therapy. The recently presented CLEAR SYNERGY (OASIS 9) 28 trial (2024) - a large-scale study - demonstrated that routine post-myocardial infarction (acute phase) colchicine administration did not significantly reduce the risk of major cardiovascular events. These findings stand in contrast to the LoDoCo229 and COLCOT30 trials, which proved that colchicine significantly reduces the risk of major adverse cardiovascular events in patients with chronic cardiological conditions. While it is plausible that the initial acute-phase surge of cytokines may overwhelm colchicine's anti-inflammatory effects, this difference in clinical efficacy between acute and chronic settings is likely multifactorial. Other potential explanations for the neutral findings in CLEAR SYNERGY/OASIS-9 include variations in drug initiation timing, differences in event phenotypes, and the competing benefits of contemporary PCI combined with intensive secondary background therapies. Furthermore, discrepancies in follow-up duration, drug adherence, and, crucially, the lack of baseline hs-CRP selection to identify patients with truly elevated residual inflammatory risk must be considered when interpreting these acute-phase results.

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Other larger studies have indicated clinically important benefits, particularly in chronic settings. Nidorf and colleagues provided robust data showing that colchicine significantly reduced the risk of ACS, nonhospital cardiac arrest, and ischemic stroke over three years among patients with coronary artery disease (CAD). Their findings suggest that combining statins with colchicine could be a highly effective approach for secondary prevention. 31

 

Inflammation, plaques, and beyond

Despite mixed clinical outcomes, several recent studies consistently confirm that colchicine effectively reduces inflammatory biomarker levels. Martínez and colleagues reported a significant reduction in pro-inflammatory cytokines - including IL-1β, IL-18, and IL-6 - in CAD patients receiving active colchicine treatment. 32 Other randomized trials have corroborated these findings, demonstrating a marked decrease in systemic inflammatory markers, notably IL-6. 33,34

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Regarding its structural effects on the vasculature, Vaidya and colleagues demonstrated that colchicine therapy lowered plaque instability markers and CRP levels. Interestingly, it did not alter atheroma volume or LDL levels. This critical finding strongly suggests colchicine possesses an anti-inflammatory property that operates entirely independent of changes in the lipid profile. 35

 

Safety and pharmacovigilance

Recent animal work demonstrates that small doses of colchicine are effective at combating atherosclerosis by stabilizing plaques through restriction of foam cell formation and inflammation induced by cholesterol crystals, all without clear signs of microtubule depolymerization. 36,37

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A primary clinical concern is the safety of co-administering colchicine with statin therapy. Conventionally, hydrophilic statins were considered the safer partner with colchicine than lipophilic ones because they would not compete for CYP3A4. 38 However, new pharmacovigilance data challenge this view. A 2024 review of adverse event reports identified a statistically meaningful signal for rhabdomyolysis when the drugs are used together, even for the rosuvastatin pairing. 39

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While there are case reports detailing myotoxicity induced by the co-administration of rosuvastatin and colchicine, the exact mechanism remains to be fully elucidated. Because colchicine does not interact with the OATP1B1 transporter - a primary mechanism for statin hepatic uptake - the observed toxicity is unlikely to result from direct competition at this site. Instead, risk may be driven by broader P-glycoprotein (P-gp) interference, renal impairment, or compounding pharmacodynamic insults to the myocyte cytoskeleton. Therefore, while rosuvastatin may be a pharmacologically preferable statin partner compared with strongly CYP3A4-dependent statins, it is not risk-free, and myotoxicity remains a clinically relevant possibility (TAB.3). 38

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TABLE 3. Clinical safety and pharmacological risk domains for colchicine and statin therapy

Clinical safety and pharmacological risk domains for colchicine and statin therapy

Abbreviations: CK, creatine kinase; CYP3A4, cytochrome P450 3A4; P-gp, P-glycoprotein.

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Compounding cytoskeletal destabilization

Colchicine weakens the cytoskeleton, whereas statins can make membranes more fragile; the combined administration thus lowers the threshold for muscle cell death. 38,39

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The rationale for combining rosuvastatin and colchicine is logically consistent: it targets lipid accumulation and inflammation-mediated plaque destabilization through multiple mechanisms involving MMPs and Endothelin-1. Implementing this concept in practice requires careful consideration of pharmacovigilance levels to ensure safety.

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However, more recent pharmacovigilance data challenge the textbook assumption regarding the combination's safety profile. According to a 2024 report analyzing data from the FDA Adverse Event Reporting System (FAERS), a statistically significant drug-drug interaction has also been proposed for the combination of colchicine and rosuvastatin, associated with a rare side effect such as rhabdomyolysis: drug interaction risk (Ω025) 1.05. 39

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Future pharmacovigilance studies should not only consider dosing levels to achieve effective administration and reduce MMPs and ET-1; they should also ensure proper monitoring of muscle enzymes to confirm the safety of this drug combination.

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Beyond a potential additive benefit, recent evidence suggests a complex lipid-inflammatory trade-off, further supporting evaluation of this triple combination. A pivotal study by Demidowich et al. (2019) demonstrated that, while colchicine significantly reduces systemic inflammation, it may paradoxically increase the concentration of oxidized LDL (oxLDL) and small, dense LDL particles. This 'lipid paradox' implies that anti-inflammatory therapy alone might inadvertently worsen the qualitative lipid profile. Therefore, co-administration of a potent statin like rosuvastatin and a cholesterol absorption inhibitor like ezetimibe is conceptually indicated to counteract these potential pro-atherogenic changes, ensuring that both the quantity and quality of lipid particles are managed alongside the suppression of the NLRP3 inflammasome. 40

 

Proposed future research model

To definitively address the evidence gap regarding the co-administration of colchicine and rosuvastatin/ezetimibe, a carefully designed, randomized, double-blind, placebo-controlled trial is required. TAB.4 outlines a proposed clinical trial framework targeting patients with residual inflammatory risk.

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TABLE 4. Proposed clinical trial design for triple-combination therapy

Proposed clinical trial design for triple-combination therapy

Abbreviations: ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CCTA, coronary computed tomography angiography; CYP3A4, cytochrome P450 3A4; HDL-c, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; MRI, magnetic resonance imaging; OCT, optical coherence tomography; P-gp, P-glycoprotein.

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To translate these concepts into a clinical framework, the following step-wise decision algorithm is proposed for managing patients with high residual risk:

  • Optimize lifestyle and standard secondary prevention.

  • Initiate high-intensity statin therapy.

  • Add ezetimibe if LDL-C/ApoB remains above therapeutic goal.

  • Assess residual inflammatory risk utilizing hs-CRP.

  • Consider low-dose colchicine only if inflammatory risk persists, and there are no contraindications.

  • Routinely monitor CK, renal function, liver enzymes, symptoms, and potential drug interactions.

CONCLUSIONS

​Both lipid accumulation and vascular inflammation drive atherosclerosis. Intensive lipid-lowering therapy with rosuvastatin/ezetimibe addresses LDL-C-mediated risk. At the same time, low-dose colchicine may reduce residual inflammatory risk through microtubule-dependent effects on inflammasome activation, leukocyte trafficking, and plaque inflammation. However, direct evidence for the clinical superiority and safety of the colchicine– rosuvastatin/ezetimibe combination is currently insufficient. Future randomized studies should enroll patients with established ASCVD and persistent inflammatory risk despite optimized lipid lowering, assess LDL-C, ApoB, hs-CRP, IL-6, plaque-stability markers, and MACE, and incorporate careful monitoring for CK elevation, myopathy, renal dysfunction, hepatic dysfunction, and interacting medications.

AUTHOR AFFILIATION

1 Department of Pathophysiology, Tbilisi State Medical University, Tbilisi, Georgia

2 Department of Internal Diseases #3, Tbilisi State Medical University, Tbilisi, Georgia

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