A Comprehensive Monograph on Ezetimibe (DB00973)

Introduction and Drug Identification

[Ezetimibe is a landmark small-molecule therapeutic agent and the first of its kind, belonging to the novel class of selective cholesterol-absorption inhibitors.][1][ Its development and introduction into clinical practice marked a significant advancement in the management of hyperlipidemia. The drug's therapeutic action is predicated on a unique mechanism that is distinct from the widely used statin class of drugs; rather than inhibiting the endogenous synthesis of cholesterol, ezetimibe targets its absorption in the gastrointestinal tract.][3][ This novel approach provides a complementary strategy for lowering elevated levels of low-density lipoprotein cholesterol (LDL-C).]

[Approved for medical use in the United States in 2002, ezetimibe has become a cornerstone of modern lipid-lowering therapy.][3][ It is frequently prescribed as an adjunctive treatment to statins, a combination that leverages two distinct and synergistic pathways to achieve more potent LDL-C reduction than either agent can accomplish alone. It is also utilized as a monotherapy for patients who are intolerant to statins or for whom statin therapy is otherwise inappropriate.][3][ The clinical importance and widespread adoption of ezetimibe are underscored by its prescription volume; in 2022, it was the 79th most commonly prescribed medication in the United States, accounting for over 8 million prescriptions.][3][ Its role in cardiovascular risk reduction has been solidified through major clinical outcome trials, establishing it as a valuable tool in the armamentarium against atherosclerotic cardiovascular disease.]

[The chemical classification of ezetimibe as a β-lactam, specifically an azetidin-2-one derivative, is a point of significant scientific interest.][4][ While the β-lactam ring is most famously associated with antibiotics like penicillins and cephalosporins, in ezetimibe it is part of a molecular scaffold that confers no antimicrobial activity. Instead, its function is that of an antimetabolite and anticholesteremic agent.][7][ This structural distinction is not accidental but rather the result of targeted drug discovery efforts aimed at identifying a molecule that could specifically interfere with the physiological process of cholesterol absorption.][4][ The discovery of ezetimibe represents a triumph of rational drug design, where a specific biological target—the Niemann-Pick C1-Like 1 (NPC1L1) protein—was identified, and a unique chemical entity was developed to modulate its function. This approach contrasts sharply with the discovery of statins, which originated from the study of naturally occurring fungal metabolites. Ezetimibe's unique structure is therefore directly responsible for its highly specific pharmacological action, setting it apart mechanistically and chemically from all other classes of lipid-modifying drugs.]

Nomenclature and Identification

[The precise identification of ezetimibe is established through a standardized system of chemical nomenclature and unique registry numbers.]

• Systematic (IUPAC) Name:[ The formal chemical name for ezetimibe is (3R,4S)-1-(4-fluorophenyl)-3--4-(4-hydroxyphenyl)azetidin-2-one.][3][ This name precisely describes the molecule's stereochemistry and the arrangement of its functional groups.]
• Chemical Structure:[ Ezetimibe is characterized by a β-lactam core, specifically an azetidin-2-one ring. This ring is substituted at position 1 with a 4-fluorophenyl group, at position 4 with a 4-hydroxyphenyl group, and at position 3 with a 3-(4-fluorophenyl)-3-hydroxypropyl side chain. The specific stereoisomer used clinically is the (3R,3'S,4S) enantiomer, which is crucial for its biological activity.][4]
• Key Identifiers:[ A comprehensive list of identifiers is provided in Table 1, ensuring unambiguous reference across scientific databases and regulatory documents. These include its CAS (Chemical Abstracts Service) Number, DrugBank accession number, and various other database identifiers.][3]
• Synonyms and Brand Names:[ In research and development, ezetimibe was known by the code SCH 58235.][8][ Commercially, it is marketed under several brand names worldwide, most notably Zetia®, Ezetrol®, and Ezedoc®.][3]

Physicochemical Properties

[The physical and chemical properties of ezetimibe dictate its formulation, stability, and pharmacokinetic behavior.]

• Molecular Formula and Weight:[ The molecular formula of ezetimibe is C24​H21​F2​NO3​, with a corresponding molecular weight of approximately 409.43 g/mol.][4]
• Appearance:[ In its pure form, ezetimibe is a white to off-white crystalline powder.][11]
• Solubility:[ Ezetimibe exhibits poor aqueous solubility, being practically insoluble in water. It is, however, freely to very soluble in organic solvents such as ethanol, methanol, and acetone.][10][ This lipophilicity is a critical determinant of its pharmacokinetic profile. The insolubility in aqueous media prevents the development of an intravenous formulation, making it impossible to determine its absolute bioavailability directly.][13]
• Stability and Storage:[ The compound is stable at ambient temperature and has a melting point of approximately 163°C.][12][ For laboratory and shipping purposes, it is considered a non-hazardous chemical and can be shipped at ambient temperature. For long-term storage, conditions of 0 - 4°C (short term) or -20°C (long term) in a dry, dark environment are recommended.][10]

Table 1: Physicochemical and Identification Properties of Ezetimibe

Property	Value	Source(s)
Systematic (IUPAC) Name	(3R,4S)-1-(4-fluorophenyl)-3--4-(4-hydroxyphenyl)azetidin-2-one	3
CAS Number	163222-33-1	3
DrugBank ID	DB00973	3
PubChem CID	150311	3
UNII	EOR26LQQ24	3
ChEBI ID	CHEBI:49040	3
Synonyms	SCH 58235, Zetia, Ezetrol, Ezedoc	3
Molecular Formula	C24​H21​F2​NO3​	7
Molecular Weight	409.43 g/mol	4
Appearance	White to off-white crystalline powder	11
Solubility	Practically insoluble in water; freely soluble in ethanol, methanol, acetone	10
Melting Point	Approx. 163°C	12

Regulatory and Commercial Landscape

[The regulatory and commercial trajectory of ezetimibe illustrates its evolution from a novel monotherapy to a fundamental component of combination lipid-lowering strategies. This history reflects shifts in clinical understanding, the results of major outcome trials, and the complex dynamics of the pharmaceutical market, including patent lifecycles and commercial strategies.]

Initial FDA Approval and Brand Name

[Ezetimibe was first brought to the U.S. market by Merck/Schering-Plough (via its subsidiary MSP Singapore Company, LLC) under the brand name ]Zetia®[. The U.S. Food and Drug Administration (FDA) granted initial approval on October 25, 2002.][5][ The approved formulation was a 10 mg oral tablet, which has remained the standard dose for all its indications.][5]

Development of Fixed-Dose Combinations (FDCs)

[The true clinical and commercial value of ezetimibe was rapidly understood to lie in its synergy with statins. This led to the development of a series of successful fixed-dose combination (FDC) products, which simplify treatment regimens and improve patient adherence.]

• Vytorin® (ezetimibe/simvastatin):[ The first FDC, Vytorin®, was approved by the FDA on July 23, 2004.][20][ By combining ezetimibe with the widely prescribed statin simvastatin, Vytorin® established the dual-inhibition strategy as a mainstream therapeutic option. Its clinical utility was later reinforced when its label was updated in January 2012 to include positive results from the Study of Heart and Renal Protection (SHARP) in patients with chronic kidney disease.][20]
• Liptruzet® (ezetimibe/atorvastatin):[ To capitalize on the market dominance of another blockbuster statin, Merck developed Liptruzet®, which combined ezetimibe with atorvastatin. It was approved on May 3, 2013.][23][ However, the Liptruzet® brand was later discontinued in the U.S..][24][ This commercial outcome may be partly attributable to the fact that atorvastatin (Lipitor®) was already available as a generic medication at the time of Liptruzet's launch, potentially limiting the market viability of a higher-priced branded combination.]
• Roszet® (ezetimibe/rosuvastatin):[ The FDC portfolio was further expanded with the approval of Roszet® on March 23, 2021.][27][ This product pairs ezetimibe with rosuvastatin, another potent statin, offering clinicians another convenient option for aggressive LDL-C lowering.]
• Nexlizet® (ezetimibe/bempedoic acid):[ A significant strategic evolution occurred with the approval of Nexlizet® on February 26, 2020.][29][ This FDC is notable because it combines ezetimibe with a non-statin agent, bempedoic acid, which is an adenosine triphosphate-citrate lyase (ACL) inhibitor. This combination provides an oral, non-statin option for dual-pathway lipid lowering. The therapeutic role of this combination was substantially broadened in March 2024, when the FDA approved a new label for Nexlizet® for cardiovascular risk reduction in both primary and secondary prevention patients, importantly,] regardless of statin use[.][29][ This update positions Nexlizet® as a key alternative for statin-intolerant patients, elevating it beyond a simple add-on therapy.]

Emergence of Generic Formulations

[The patent exclusivity for Zetia® eventually expired, paving the way for generic competition. The first generic versions of ezetimibe 10 mg tablets were approved by the FDA around June 2017, with initial approvals granted to manufacturers such as Glenmark Pharmaceuticals, Amneal, Sandoz, and Watson Labs.][5][ Since then, numerous other companies have entered the market with generic ezetimibe.][5][ Similarly, generic versions of the ezetimibe/simvastatin FDC (Vytorin®) became available starting in 2017.][33][ The availability of low-cost generic ezetimibe has been a critical factor in its widespread adoption, cementing its role as a cost-effective, guideline-recommended second-line agent in lipid management algorithms.][34]

[The regulatory and commercial history of ezetimibe is a compelling case study in modern pharmaceutical strategy. It began as a niche monotherapy but quickly found its primary value as a synergistic partner to statins. This led to a wave of FDC development, a strategy designed to maximize clinical benefit and extend market presence. The trajectory of these FDCs has been shaped by the patent lifecycles of their statin components and the overall market landscape. Ultimately, the genericization of ezetimibe itself has democratized its use, making it an accessible and indispensable tool for achieving lipid goals in a broad patient population.]

Table 2: FDA Approval History of Ezetimibe-Containing Products in the U.S.

Brand Name	Generic Name (Components)	Company	Initial Approval Date	Key Indications / Label Updates
Zetia®	ezetimibe	Merck/Schering-Plough	Oct 25, 2002	Treatment of primary hyperlipidemia, HoFH, and sitosterolemia.5
Vytorin®	ezetimibe / simvastatin	Merck/Schering-Plough	Jul 23, 2004	Combination therapy for primary hyperlipidemia and HoFH.20 Label updated (Jan 2012) with SHARP trial data for CKD patients.22
Liptruzet®	ezetimibe / atorvastatin	Merck	May 3, 2013	Combination therapy for primary hyperlipidemia and HoFH. Brand has been discontinued in the U.S..23
Nexlizet®	ezetimibe / bempedoic acid	Esperion Therapeutics	Feb 26, 2020	Combination with a non-statin (ACL inhibitor) for primary hyperlipidemia.29 Label expanded (Mar 2024) for CV risk reduction, regardless of statin use.32
Roszet®	ezetimibe / rosuvastatin	Althera Life Sciences	Mar 23, 2021	Combination therapy for primary non-familial hyperlipidemia and HoFH.27

Comprehensive Pharmacological Profile

[The pharmacological profile of ezetimibe is defined by its unique mechanism of action, its predictable effects on plasma lipids, and a pharmacokinetic profile optimized for its site of action.]

A. Mechanism of Action

[Ezetimibe represents a distinct class of lipid-lowering agents, acting through a mechanism that is fundamentally different from statins, fibrates, and bile acid sequestrants.]

Primary Target and Selectivity

[The primary therapeutic action of ezetimibe is the potent and highly selective inhibition of cholesterol absorption from the small intestine.][3][ This effect is mediated through its specific molecular target: the]

Niemann-Pick C1-Like 1 (NPC1L1) protein[.][4][ NPC1L1 is a critical multi-transmembrane domain sterol transporter protein that is densely expressed on the apical membrane (brush border) of enterocytes in the jejunum, the primary site of cholesterol absorption.][3][ Ezetimibe also acts on NPC1L1 expressed on the canalicular membrane of hepatocytes, where it interferes with the reabsorption of cholesterol excreted in the bile, thus disrupting the enterohepatic circulation of cholesterol.][3][ The drug's action is highly selective for this pathway and does not interfere with the absorption of triglycerides, bile acids, or fat-soluble vitamins such as A, D, and E.][4]

Molecular Pathway

[Upon oral administration, ezetimibe and its pharmacologically active metabolite, ezetimibe-glucuronide, are delivered to the small intestine. There, they bind with high affinity to a specific site on the NPC1L1 protein, believed to be within one of its extracellular/transmembrane loops.][41][ This binding event is thought to induce a conformational change in the NPC1L1 protein, which disrupts its normal function. The prevailing model suggests that ezetimibe's binding prevents the NPC1L1/cholesterol complex from docking with the clathrin/AP2 (adaptor protein 2) complex.][3][ The clathrin/AP2 complex is essential for initiating the process of vesicular endocytosis, whereby the cell membrane invaginates to internalize the NPC1L1 transporter along with its bound cholesterol. By blocking this crucial internalization step, ezetimibe effectively traps dietary and biliary cholesterol within the intestinal lumen, preventing its entry into the enterocyte and promoting its subsequent excretion in the feces.][39]

Downstream Consequences

[The localized inhibition of cholesterol absorption in the gut triggers a cascade of systemic effects that culminate in the lowering of circulating LDL-C:]

1. Reduced Cholesterol Delivery to the Liver:[ By blocking intestinal absorption, ezetimibe significantly reduces the amount of cholesterol that is packaged into chylomicrons by enterocytes and delivered to the liver via the lymphatic system and bloodstream.][3]
2. Depletion of Hepatic Cholesterol Stores:[ The diminished supply of cholesterol from the intestine leads to a depletion of the intrahepatic cholesterol pool.][13]
3. Upregulation of Hepatic LDL Receptors:[ The liver senses this state of relative cholesterol deficiency. In a homeostatic response, hepatocytes activate sterol regulatory element-binding proteins (SREBPs), which in turn upregulate the transcription and expression of the gene for the LDL receptor. This results in an increased density of LDL receptors on the surface of liver cells.][34]
4. Enhanced Clearance of Circulating LDL-C:[ The increased number of active LDL receptors enhances the liver's ability to capture and clear LDL particles (and their cholesterol cargo) from the bloodstream, leading to a significant reduction in serum LDL-C concentrations.][3]

[This entire mechanism is complementary to that of statins. While statins block the ]production[ of cholesterol within the liver, ezetimibe blocks the ]supply[ of cholesterol to the liver from the gut. This dual-inhibition strategy is the foundation of its powerful synergistic effect when used in combination therapy.]

B. Pharmacodynamics

[The pharmacodynamic effects of ezetimibe are characterized by its consistent impact on the lipid profile and other related biomarkers.]

Lipid-Lowering Effects

[As a ]monotherapy[, a standard 10 mg daily dose of ezetimibe produces a reliable and clinically meaningful lipid-modifying effect. It inhibits intestinal cholesterol absorption by an average of 54%.][39][ This translates to the following approximate changes in serum lipids:]

• LDL-C:[ A reduction of 18% to 20%.][6]
• Total Cholesterol (Total-C):[ A reduction of 12% to 15%.][6]
• Apolipoprotein B (Apo B):[ A reduction of 15% to 20%.][6]
• Triglycerides (TG):[ A reduction of 7% to 9%.][6]
• High-Density Lipoprotein Cholesterol (HDL-C):[ A modest increase of approximately 3%.][40]

[When used in ]combination therapy[, the addition of ezetimibe 10 mg to ongoing statin therapy provides a substantial incremental benefit. It produces an additional LDL-C reduction of approximately 14% to 25% on top of the effect achieved by the statin alone.][34][ This powerful synergy can result in total LDL-C reductions ranging from 34% to 61%, depending on the specific statin and dose used.][37][ This effect is particularly valuable because it allows patients to reach aggressive LDL-C targets without needing to escalate to the highest, and potentially less-tolerated, doses of statins.]

[The interaction between ezetimibe and statins is more than merely additive; it can be described as a form of complementary antagonism. Statin therapy, by inhibiting hepatic cholesterol synthesis, triggers a compensatory biological response: the upregulation of intestinal cholesterol absorption, mediated by NPC1L1.][40][ This is an inherent mechanism of resistance to statin therapy. Ezetimibe directly targets and blocks this very compensatory pathway. Therefore, when used in combination, ezetimibe not only contributes its own independent LDL-lowering effect but also negates a key adaptive mechanism by which the body counteracts the statin's action. This explains the robust and consistent synergistic efficacy observed in numerous clinical trials and forms the scientific rationale for the development of ezetimibe/statin FDCs.]

Other Pharmacodynamic Effects

• Plant Sterol Reduction:[ Ezetimibe is a primary therapy for the rare genetic disorder homozygous sitosterolemia. By inhibiting NPC1L1, it effectively blocks the intestinal absorption of plant sterols (phytosterols) like sitosterol and campesterol, leading to a significant reduction in their elevated plasma levels.][3]
• Compensatory Cholesterol Synthesis:[ As a direct consequence of reduced cholesterol absorption, the body initiates a compensatory increase in endogenous cholesterol synthesis in the liver.][42][ This highlights the body's tight homeostatic control over cholesterol levels and further underscores the rationale for combining ezetimibe with a statin, which directly inhibits this compensatory synthesis pathway.]
• Pleiotropic Effects:[ Emerging research suggests that ezetimibe may possess beneficial effects beyond lipid lowering. These include potential anti-inflammatory, antioxidant, and direct anti-atherogenic properties.][7][ Furthermore, studies have shown it can improve the non-alcoholic fatty liver disease (NAFLD) activity score and, by virtue of its action on NPC1L1 (a protein hijacked by some viruses for entry), may block the entry of hepatitis B and C viruses into hepatocytes.][3]

C. Pharmacokinetics (ADME)

[The pharmacokinetic profile of ezetimibe is unique and perfectly suited to its mechanism of action, characterized by rapid metabolism to an active form and extensive enterohepatic recycling that prolongs its presence at the site of action.]

Absorption

[Following oral administration of a 10 mg dose, ezetimibe is absorbed from the small intestine. However, peak plasma concentrations (Cmax​) of the parent drug are low (3.4 to 5.5 ng/mL) and are reached relatively late, with a time to peak (Tmax​) of 4 to 12 hours.][12][ In contrast, its major active metabolite reaches much higher concentrations (]

[Cmax​ of 45 to 71 ng/mL) much more quickly (Tmax​ of 1 to 2 hours).][12][ The absolute bioavailability of ezetimibe cannot be precisely determined because the compound is virtually insoluble in aqueous media suitable for intravenous injection.][13][ The presence of food in the stomach has a minimal effect on the overall extent of absorption (AUC), although a high-fat meal can increase the]

[Cmax​ of the parent drug by 38%.][13][ This allows the drug to be taken with or without food without a significant loss of efficacy.]

Distribution

[Both ezetimibe and its active metabolite, ezetimibe-glucuronide, are highly bound to human plasma proteins, with binding exceeding 90%.][12][ This extensive protein binding limits the amount of free drug available for distribution into tissues but helps maintain a stable plasma concentration. The apparent volume of distribution is approximately 107.5 L.][13]

Metabolism

[Ezetimibe undergoes rapid and extensive metabolism, but not through the cytochrome P450 (CYP) system that is responsible for the metabolism of many other drugs, including several statins. Instead, its primary metabolic pathway is ]Phase II glucuronide conjugation[, which occurs predominantly in the wall of the small intestine and in the liver.][3][ This reaction converts ezetimibe into its sole major metabolite,]

ezetimibe-glucuronide[. This metabolite is not an inactive byproduct; it is pharmacologically active and at least as potent as the parent compound in inhibiting cholesterol absorption.][42][ Ezetimibe-glucuronide constitutes the vast majority (80% to 90%) of the total drug-related compounds circulating in the plasma.][12][ The lack of significant Phase I oxidative metabolism via CYP enzymes is a key feature that explains ezetimibe's low potential for many common drug-drug interactions.][3]

Excretion and Half-Life

[Both ezetimibe and ezetimibe-glucuronide are eliminated slowly from the plasma, with a long terminal half-life of approximately 22 hours.][3][ This long half-life, which allows for convenient once-daily dosing, is a direct result of extensive]

enterohepatic recycling[. After being formed in the liver, ezetimibe-glucuronide is excreted into the bile, which is then released into the small intestine. In the intestine, the active metabolite can once again inhibit NPC1L1 before being reabsorbed into the bloodstream, creating a continuous cycle.][13][ This recycling mechanism acts as a drug delivery system, ensuring a sustained and high concentration of the active drug at its intestinal target while keeping systemic exposure relatively low. This pharmacokinetic property can be thought of as creating a "virtual potency," where a low oral dose exerts a powerful and prolonged local effect.]

[Ultimate elimination from the body occurs primarily through the feces, which accounts for approximately 78% of an administered dose (with unchanged ezetimibe being the major component). A smaller portion, approximately 11%, is excreted in the urine (with ezetimibe-glucuronide being the major component).][12]

Table 3: Summary of Ezetimibe Pharmacokinetic Parameters

Parameter	Value for Ezetimibe (Parent Drug)	Value for Ezetimibe-Glucuronide (Active Metabolite)	Source(s)
Cmax​ (10 mg dose)	3.4–5.5 ng/mL	45–71 ng/mL	12
Tmax​ (10 mg dose)	4–12 hours	1–2 hours	12
Plasma Half-life (t1/2​)	Approx. 22 hours	Approx. 22 hours	3
Plasma Protein Binding	>99.5%	88–92%	12
Primary Metabolism	Glucuronide conjugation	N/A (is the metabolite)	3
Primary Excretion Route	Feces (~78% of total dose)	Urine (~11% of total dose)	12
Key Feature	Extensive enterohepatic recycling of both compounds	13

Clinical Efficacy and Therapeutic Use

[The clinical utility of ezetimibe is defined by its approved indications, its straightforward dosing regimen, and a robust body of evidence from pivotal clinical trials that have established its role in reducing both LDL-C and cardiovascular events.]

A. Approved Indications

[Ezetimibe is officially indicated by regulatory authorities, such as the U.S. FDA, as an adjunctive therapy to dietary modification for the management of several types of dyslipidemia.][3][ Its primary goal is to reduce elevated levels of atherogenic lipoproteins.]

• Primary Hyperlipidemia:[ Ezetimibe is used to lower elevated levels of total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). In this setting, it can be prescribed either as a monotherapy for patients who cannot tolerate statins or as a combination therapy with a statin to achieve greater LDL-C reduction.][3]
• Mixed Hyperlipidemia:[ In patients with elevations in both cholesterol and triglycerides, ezetimibe is approved for use in combination with fenofibrate to specifically target the reduction of LDL-C.][3]
• Homozygous Familial Hypercholesterolemia (HoFH):[ For patients with this severe genetic disorder, ezetimibe is used as an adjunct to statin therapy (typically atorvastatin or simvastatin). It may also be used alongside other lipid-lowering treatments, such as LDL apheresis, if available.][3]
• Homozygous Sitosterolemia (Phytosterolemia):[ Ezetimibe is specifically indicated for this rare inherited condition to reduce the markedly elevated plasma levels of plant sterols, namely sitosterol and campesterol, by blocking their intestinal absorption.][3]

B. Dosage, Administration, and Formulations

[The administration of ezetimibe is designed for simplicity and ease of use, promoting long-term adherence in patients with chronic conditions.]

• Dosage:[ The recommended and standard dose of ezetimibe is ]10 mg taken orally once a day[.][15][ This single dosage strength applies to all approved indications in both adult and pediatric populations.]
• Administration:[ Ezetimibe can be administered at any time of day, with or without food, as food does not significantly impact its overall efficacy.][19][ For optimal adherence, patients are often advised to take it at approximately the same time each day. A critical administration instruction pertains to its use with bile acid sequestrants (e.g., cholestyramine, colestipol, colesevelam). Because these agents can bind to ezetimibe in the gut and prevent its absorption, ezetimibe must be taken] at least 2 hours before or 4 hours after[ the administration of a bile acid sequestrant.][45]
• Formulations:[ Ezetimibe is available as a single-ingredient 10 mg tablet, sold under the brand name Zetia® and numerous generic labels. It is also a component of several fixed-dose combination tablets, which offer the convenience of a single pill for dual therapy. These include combinations with simvastatin (Vytorin®), atorvastatin (Liptruzet®, discontinued), rosuvastatin (Roszet®), and bempedoic acid (Nexlizet®).][3]

C. Analysis of Pivotal Clinical Trials

[The clinical evidence for ezetimibe has evolved significantly over time. While early studies focused on its lipid-lowering efficacy (a surrogate endpoint), its value was ultimately cemented by large-scale cardiovascular outcome trials (CVOTs) that demonstrated its ability to reduce hard clinical events.]

[The journey of ezetimibe's clinical validation is a narrative of scientific persistence and redemption. Initial enthusiasm based on its potent LDL-C-lowering effect was met with significant skepticism following the publication of trials like ENHANCE, which used a surrogate endpoint (carotid intima-media thickness, CIMT) and failed to show a clinical benefit despite successful lipid reduction.][40][ This led to a period of controversy where the drug's role was questioned. The turning point came with the results of large, long-term, and rigorously designed CVOTs. These trials were essential in proving that the LDL-C reduction achieved by ezetimibe translates into a tangible reduction in cardiovascular events. This progression from surrogate endpoint uncertainty to proven outcomes benefit not only validated the drug but also helped define the specific high-risk patient populations who stand to gain the most from its use.]

• IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial):[ This was the landmark trial for ezetimibe.]
• Design:[ A large-scale, double-blind, randomized trial that enrolled 18,144 patients who had recently experienced an acute coronary syndrome (ACS).][37][ Patients were randomized to receive either simvastatin 40 mg monotherapy or a combination of simvastatin 40 mg plus ezetimibe 10 mg.][3]
• Key Findings:[ Over a median follow-up of six years, the addition of ezetimibe to simvastatin led to a statistically significant reduction in the primary composite endpoint (a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization). The event rate was 32.7% in the combination group versus 34.7% in the simvastatin-alone group, representing a 2% absolute risk reduction (p=0.016).][34][ On the lipid front, the combination therapy lowered LDL-C by an additional 24% compared to simvastatin alone, achieving a median on-treatment LDL-C of 53.7 mg/dL versus 69.5 mg/dL.][34]
• Significance:[ IMPROVE-IT was the first trial to demonstrate that adding a non-statin, LDL-lowering agent (ezetimibe) to a statin could provide incremental cardiovascular benefit. It strongly supported the "lower is better" hypothesis for LDL-C and established that the clinical benefit derived from ezetimibe is directly proportional to the magnitude of LDL-C reduction it provides.][40][ This trial was instrumental in securing ezetimibe's place in guidelines for high-risk secondary prevention.]
• SHARP (Study of Heart and Renal Protection):[ This trial carved out a critical niche for ezetimibe in another high-risk population.]
• Design:[ A randomized, placebo-controlled trial involving over 9,000 patients with moderate to severe chronic kidney disease (CKD), a population with high cardiovascular risk but in whom lipid-lowering therapy was less studied.][40][ The study compared the effects of an ezetimibe 20 mg/simvastatin 10 mg combination against placebo.]
• Key Findings:[ The ezetimibe/simvastatin combination safely and significantly reduced the risk of major atherosclerotic events (defined as MI, coronary death, non-hemorrhagic stroke, or any revascularization procedure) by 17% compared to placebo.][40]
• Significance:[ SHARP provided definitive evidence for the safety and efficacy of an ezetimibe-statin combination in the CKD population. The positive results led to an update of the Vytorin® label and provided clinicians with a clear, evidence-based strategy for managing cardiovascular risk in these patients.][22]
• EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older):[ This trial addressed the important question of primary prevention in the elderly.]
• Design:[ A randomized, controlled trial conducted in a Japanese population of patients aged 75 years or older with elevated LDL-C and risk factors, but without pre-existing coronary artery disease.][51][ It compared ezetimibe 10 mg monotherapy against dietary counseling alone.]
• Key Findings:[ Ezetimibe monotherapy was found to significantly reduce the incidence of the primary composite outcome, which included sudden cardiac death, myocardial infarction, coronary revascularization, or stroke.][51]
• Significance:[ Along with subgroup analyses from IMPROVE-IT, the EWTOPIA 75 trial provided powerful evidence that ezetimibe is particularly effective and beneficial for primary prevention in elderly patients (≥75 years).][51][ This is especially important as the role and safety of high-intensity statins in this age group have been a subject of debate.]

Table 4: Overview of Pivotal Ezetimibe Clinical Outcome Trials

Trial Acronym	Patient Population	Intervention(s)	Comparator	Primary Endpoint	Key LDL-C Reduction	Key Outcome Result	Source(s)
IMPROVE-IT	18,144 patients post-Acute Coronary Syndrome (ACS)	Ezetimibe 10 mg + Simvastatin 40 mg	Simvastatin 40 mg	Composite of CV death, MI, stroke, unstable angina hospitalization, revascularization	Additional 24% reduction (53.7 vs 69.5 mg/dL)	2.0% absolute risk reduction (32.7% vs 34.7%; p=0.016)	34
SHARP	>9,000 patients with Chronic Kidney Disease (CKD)	Ezetimibe 10 mg + Simvastatin 20 mg	Placebo	Major atherosclerotic events (MI, coronary death, stroke, revascularization)	32% reduction vs placebo at mid-point	17% relative risk reduction in major atherosclerotic events	22
EWTOPIA 75	>3,700 Japanese patients ≥75 years (primary prevention)	Ezetimibe 10 mg	Dietary counseling	Composite of sudden cardiac death, MI, revascularization, stroke	Significant reduction vs control	Significant reduction in primary composite outcome	51

Safety and Tolerability Profile

[Ezetimibe is characterized by a favorable safety and tolerability profile, a feature that has contributed significantly to its widespread clinical use. The risks associated with its use are well-defined and generally manageable.]

General Tolerability

[In extensive clinical trials, ezetimibe has been shown to be generally well-tolerated. When administered as a monotherapy or in combination with HMG-CoA reductase inhibitors (statins), the overall incidence of adverse events and the rate of discontinuation due to these events were comparable to those observed with placebo.][12]

Common Adverse Reactions

[The most frequently reported adverse reactions (defined as occurring in ≥2% of patients and at a higher rate than placebo) vary slightly depending on whether ezetimibe is used alone or with a statin.]

• Monotherapy:[ In placebo-controlled trials of ezetimibe monotherapy, the most common adverse events included upper respiratory tract infection, diarrhea, arthralgia (joint pain), sinusitis, pain in an extremity, and fatigue.][3]
• Co-administered with a Statin:[ When initiated concurrently with a statin, the most common adverse reactions included nasopharyngitis, myalgia (muscle pain), upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in an extremity, and fatigue.][12]

Serious Safety Concerns and Warnings

[While generally safe, there are several serious potential adverse effects associated with ezetimibe, primarily when used in combination with other lipid-lowering agents.]

• Myopathy and Rhabdomyolysis:[ Ezetimibe carries a warning for myopathy (defined as muscle pain, tenderness, or weakness accompanied by elevated creatine kinase [CK] levels) and the more severe condition of rhabdomyolysis, which can lead to acute kidney injury.][54][ The risk of these events with ezetimibe monotherapy is very rare. However, the risk is a well-known characteristic of statin and fibrate therapies. Consequently, most post-marketing cases of rhabdomyolysis associated with ezetimibe have occurred in patients who were concurrently taking a statin.][12][ The risk for skeletal muscle toxicity is amplified by factors such as higher statin doses, advanced age (>65 years), female gender, uncontrolled hypothyroidism, and renal impairment.][55][ Patients should be counseled to promptly report any unexplained muscle symptoms. If myopathy is suspected or diagnosed, ezetimibe and any concomitant statin or fibrate should be discontinued immediately.][12]
• Liver Enzyme Abnormalities (Hepatotoxicity):[ Increases in serum transaminases (ALT and AST) have been reported.][54][ With monotherapy, the incidence of consecutive elevations (defined as ≥3 times the upper limit of normal [ULN]) is low and similar to that of placebo (0.5% vs. 0.3%).][12][ When ezetimibe is co-administered with a statin, this incidence rises to approximately 1.3% (compared to 0.4% for patients on a statin alone).][12][ These elevations are typically asymptomatic, are not associated with cholestasis (impaired bile flow), and tend to return to baseline either upon discontinuation or with continued treatment. However, rare post-marketing cases of more serious drug-induced liver injury (DILI), including hepatitis and severe hepatocellular damage, have been documented, leading some regulatory bodies like Health Canada to issue warnings.][60][ As a precaution, it is recommended that liver enzyme tests be performed at baseline and as clinically indicated thereafter. If transaminase elevations of ≥3x ULN persist, withdrawal of the medication should be considered.][19]
• Hypersensitivity Reactions:[ Rare but serious allergic reactions have been reported in post-marketing surveillance. These include anaphylaxis, angioedema (swelling of the face, lips, tongue, and throat), rash, and urticaria (hives).][3]
• Other Rare Post-Marketing Reports:[ Other infrequent but notable adverse events reported include pancreatitis, cholelithiasis (gallstones), cholecystitis (inflammation of the gallbladder), and thrombocytopenia (low platelet count).][12][ The risk of cholelithiasis is thought to be increased when ezetimibe is used in combination with fibrates, as both drug classes can increase the concentration of cholesterol in the bile.][54]

[The safety profile of ezetimibe is nuanced and largely defined by its predominant role as an add-on therapy. While its intrinsic risk profile is low and comparable to placebo in monotherapy trials, its safety evaluation in the real world is inextricably linked to that of the statins with which it is most often paired. The primary warnings for myopathy and liver enzyme elevations are amplified in the context of combination therapy. However, it is crucial to recognize that the primary driver of these risks is often the statin component, and these risks are known to be dose-dependent. A key clinical application of ezetimibe is its "statin-sparing" effect; adding ezetimibe allows clinicians to achieve aggressive LDL-C goals using lower or moderate-intensity statin doses instead of escalating to high-intensity doses.][37][ As demonstrated in trials like RACING, this strategy can lead to a net]

reduction[ in statin-related intolerance and adverse events.][65][ This makes the combination a valuable safety-enhancing strategy, particularly for fragile patient populations like the elderly.]

Contraindications

[The use of ezetimibe is contraindicated in specific situations:]

• [Patients with a known hypersensitivity to ezetimibe or any of its excipients.][3]
• [When used in combination with a statin, all contraindications pertinent to that specific statin apply to the combination therapy. The most significant of these are:]
• [Patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.][3]
• [Use during pregnancy and lactation.][55]

Black Box Warning Status

[It is important to note that ezetimibe ]does not have an FDA black box warning[ on its label.][56][ The absence of this most serious level of warning reflects the regulatory assessment that its risks, while real, are manageable and do not outweigh its established clinical benefits when used as directed.]

Table 5: Summary of Adverse Reactions Associated with Ezetimibe

Category / Body System	Adverse Reaction	Incidence in Monotherapy (vs. Placebo)	Incidence in Combination Therapy (vs. Statin alone)	Clinical Notes / Management
Common (≥2%)	Upper Respiratory Tract Infection	Common, > Placebo	Common, > Statin alone	Generally mild and self-limiting.
	Diarrhea	Common, > Placebo	Common, > Statin alone	Usually transient.
	Arthralgia (Joint Pain)	Common, > Placebo	Common, > Statin alone	Monitor symptoms.
	Myalgia (Muscle Pain)	Infrequent	Common, > Statin alone	Monitor for signs of myopathy.
	Nasopharyngitis	N/A	Common, > Statin alone	Generally mild.
Serious	Myopathy/Rhabdomyolysis	Very rare	Increased risk vs. statin alone	Risk increases with higher statin doses, age >65, renal impairment. Discontinue immediately if suspected. Counsel patients to report muscle pain/weakness.
Hepatic	Elevated Transaminases (≥3x ULN)	0.5% (vs 0.3% placebo)	1.3% (vs 0.4% statin alone)	Perform LFTs at baseline and as clinically indicated. Consider withdrawal if elevations persist.
	Drug-Induced Liver Injury (DILI)	Rare post-marketing reports	Rare post-marketing reports	Discontinue immediately if suspected.
Gastrointestinal	Pancreatitis	Rare post-marketing reports	Rare post-marketing reports	Evaluate patients with abdominal pain.
	Cholelithiasis / Cholecystitis	Rare post-marketing reports	Increased risk with fibrates	If suspected with fenofibrate, perform gallbladder studies. Avoid use with other fibrates.
Immune System	Hypersensitivity Reactions (Anaphylaxis, Angioedema)	Rare post-marketing reports	Rare post-marketing reports	Contraindicated in patients with known hypersensitivity.

Drug and Food Interactions

[Ezetimibe's interaction profile is relatively favorable compared to many other cardiovascular drugs, largely due to its minimal reliance on the cytochrome P450 (CYP) enzyme system for metabolism. However, several clinically important interactions, primarily pharmacokinetic and pharmacodynamic in nature, require careful management.]

Drug-Drug Interactions

[The most significant interactions involve drugs that interfere with ezetimibe's absorption, transport, or have overlapping toxicity profiles.]

• Cyclosporine:[ Co-administration of ezetimibe and cyclosporine (an immunosuppressant) results in a significant increase in the systemic exposure of both drugs.][15][ This interaction necessitates careful monitoring of cyclosporine concentrations to avoid toxicity, particularly in patients with severe renal impairment, who may experience even greater elevations in drug levels.][67]
• Fibrates:[ This interaction has two components.]

1. Pharmacokinetic:[ Co-administration with fibrates, such as fenofibrate and gemfibrozil, can increase the plasma concentration of total ezetimibe.][57]
2. Pharmacodynamic:[ More critically, both ezetimibe and fibrates can increase the concentration of cholesterol in gallbladder bile. This shared mechanism increases the risk of developing cholelithiasis (gallstones).][54][ For this reason, if a patient receiving ezetimibe and fenofibrate develops symptoms suggestive of gallstones (e.g., right upper quadrant pain), gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. The co-administration of ezetimibe with fibrates other than fenofibrate is generally not recommended due to a lack of adequate study data.][54]

• Bile Acid Sequestrants:[ This is a direct absorption interaction. Bile acid sequestrants, including cholestyramine, colestipol, and colesevelam, work by binding bile acids in the intestine. They can also bind to co-administered drugs, including ezetimibe, significantly decreasing its absorption and systemic exposure, thereby rendering it less effective.][42][ To manage this interaction, a specific dosing schedule must be followed:] ezetimibe should be administered at least 2 hours before or at least 4 hours after[ the bile acid sequestrant.][45]
• Warfarin:[ While not a consistent or predictable interaction, post-marketing reports have suggested that adding ezetimibe to the regimen of a patient stabilized on warfarin (a coumarin anticoagulant) may lead to elevations in the International Normalized Ratio (INR).][57][ Therefore, it is prudent to monitor the INR appropriately when initiating or adjusting ezetimibe therapy in patients taking warfarin.]
• Other Potential Interactions:[ A broader screen of potential interactions reveals that drugs affecting UDP-glucuronosyltransferase (UGT) enzymes or transporters like OATP1B1 could theoretically alter ezetimibe levels.][9][ For instance, strong inducers of these pathways, such as rifampin or apalutamide, may decrease ezetimibe exposure.][13]

[The interaction profile of ezetimibe is a key clinical advantage. Its primary reliance on Phase II glucuronidation for metabolism, rather than the more crowded Phase I CYP450 pathways, makes it a predictable and safer choice for patients on multiple medications (polypharmacy), a common scenario in the elderly and those with multiple comorbidities. The most clinically relevant interactions are not metabolic but rather involve interference with absorption (bile acid sequestrants) or overlapping pharmacodynamic risks (fibrates). The most frequently cited interaction concern in clinical practice—grapefruit juice—is a classic case of "guilt by association," as the restriction applies not to ezetimibe but to its common statin partners. This clean metabolic profile reinforces its utility as a straightforward and reliable second-line agent.]

Drug-Food Interactions

• Direct Food Interactions:[ There are ]no known clinically significant direct interactions[ between ezetimibe and any specific foods or beverages.][15][ This is why it can be taken with or without meals without compromising its efficacy.][47]
• Indirect Interaction via Statins (Grapefruit Juice):[ A critical point of clarification for patient counseling involves grapefruit and grapefruit juice. Ezetimibe itself is not metabolized by CYP3A4 and therefore does not interact with grapefruit. However, several commonly prescribed statins—including atorvastatin, simvastatin, and lovastatin—]are[ metabolized by CYP3A4. Grapefruit juice is a potent inhibitor of this enzyme, and its consumption can lead to dangerously elevated levels of these statins, increasing the risk of myopathy and rhabdomyolysis. Because ezetimibe is so frequently co-prescribed with these statins (either as separate pills or in FDCs like Vytorin®), patients are often advised to avoid grapefruit products altogether to prevent this serious interaction with the statin component of their therapy.][58]
• General Dietary Recommendations:[ It is essential to emphasize that ezetimibe therapy is not a substitute for a healthy lifestyle. It is always indicated as an ]adjunct to a heart-healthy, low-cholesterol, low-saturated-fat diet[.][3]

Table 6: Clinically Significant Drug-Drug Interactions with Ezetimibe

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Cyclosporine	Inhibition of drug transporters (e.g., OATP1B1)	Significant increase in plasma concentrations of both ezetimibe and cyclosporine	Monitor cyclosporine concentrations closely, especially in patients with severe renal impairment.	15
Fibrates (Fenofibrate, Gemfibrozil)	Pharmacodynamic: Both increase cholesterol saturation of bile. Pharmacokinetic: Fibrates increase ezetimibe exposure.	Increased risk of cholelithiasis (gallstones).	If cholelithiasis is suspected in a patient on ezetimibe and fenofibrate, perform gallbladder studies. Co-administration with fibrates other than fenofibrate is not recommended.	54
Bile Acid Sequestrants (Cholestyramine, Colesevelam, Colestipol)	Pharmacokinetic: Sequestrants bind to ezetimibe in the GI tract, preventing its absorption.	Decreased absorption and efficacy of ezetimibe.	Administer ezetimibe at least 2 hours before or 4 hours after the bile acid sequestrant.	46
Warfarin	Pharmacodynamic (mechanism unclear)	Potential for increased INR has been reported post-marketing.	Monitor INR appropriately when initiating or adjusting ezetimibe therapy in patients taking warfarin.	57

Guidance for Use in Special Populations

[The use of ezetimibe requires special consideration in certain patient populations due to differences in physiology, metabolism, and the available balance of evidence for efficacy and safety.]

A. Pediatric Patients

[The use of ezetimibe in children and adolescents is restricted to specific genetic dyslipidemias where the benefits of early lipid-lowering are considered to outweigh the risks.]

• Approved Indications and Age Limits:
• Heterozygous Familial Hypercholesterolemia (HeFH):[ Approved for use in combination with a statin in patients aged 10 years and older.][45]
• Homozygous Familial Hypercholesterolemia (HoFH):[ Approved for use in combination with a statin in patients aged 10 years and older.][46]
• Homozygous Familial Sitosterolemia:[ Approved as an adjunct to diet in patients aged 9 years and older.][45]
• Efficacy and Safety Data:[ The approval in younger populations is supported by clinical trial data. A key multicenter, randomized, placebo-controlled study (NCT00867165) evaluated ezetimibe 10 mg monotherapy in children aged 6 to 10 years with primary hypercholesterolemia (mostly HeFH).][43][ The study found that ezetimibe was well-tolerated and produced clinically relevant lipid reductions, including a significant 27% reduction in LDL-C compared to placebo, with a safety profile similar to that seen in older populations.][43][ A recent network meta-analysis of 13 trials in patients under 18 with HeFH further confirmed that ezetimibe, statins, and their combination are all effective and did not find evidence of adverse effects on maturation or safety compared to placebo in the short term.][76]
• Pharmacokinetics:[ Pharmacokinetic studies have shown no clinically significant differences in ezetimibe exposure between adolescents (ages 10-18) and adults. However, pharmacokinetic data in children younger than 10 years are not available.][12]

B. Geriatric Patients (≥65 years)

[The geriatric population represents a group for whom ezetimibe has demonstrated a particularly favorable benefit-to-risk profile.]

• Pharmacokinetics and Dosing:[ While plasma concentrations of total ezetimibe are approximately two-fold higher in elderly individuals (≥65 years) compared to their younger counterparts, no dosage adjustment is required.][14][ Clinical trials have shown that the overall safety and effectiveness are comparable between older and younger patients.][57]
• Enhanced Clinical Efficacy:[ A compelling body of evidence suggests that elderly patients, especially those aged 75 and older, derive a disproportionately large absolute benefit from ezetimibe therapy.]
• [A pivotal secondary analysis of the ]IMPROVE-IT[ trial revealed that adding ezetimibe to simvastatin in patients aged ≥75 years resulted in a striking 8.7% absolute risk reduction for the primary cardiovascular endpoint. This contrasts with a modest 0.9% absolute risk reduction in patients younger than 65. Consequently, the number needed to treat (NNT) to prevent one cardiovascular event was only 11 in the elderly group, compared to 125 in the younger cohort.][34]
• [The ]EWTOPIA 75[ trial further supported this finding, demonstrating a primary prevention benefit of ezetimibe monotherapy in a Japanese population aged ≥75 years.][51]
• Safety Considerations:[ Elderly patients are more vulnerable to statin-associated muscle symptoms. The statin-sparing effect of ezetimibe is therefore particularly valuable in this population. Combination therapy with a moderate-intensity statin and ezetimibe has been shown to achieve similar LDL-C reduction as high-intensity statin monotherapy but with a significantly lower incidence of muscle-related side effects.][64][ However, for severely frail elderly individuals, the benefit of any lipid-lowering therapy, including ezetimibe, is uncertain and may not be warranted.][77]

[The enhanced efficacy of ezetimibe in the elderly has a strong physiological basis. Cholesterol metabolism shifts with age; endogenous cholesterol synthesis tends to decline, while intestinal cholesterol absorption increases.][51][ Statins work by inhibiting synthesis, whereas ezetimibe works by inhibiting absorption. In an older individual, the primary driver of their cholesterol pool is increasingly the absorption pathway—the very pathway that ezetimibe targets. This age-related physiological shift primes the elderly for a more robust response to ezetimibe, providing a clear mechanistic explanation for the outsized clinical benefit observed in trials. This suggests a potential for a more personalized, mechanism-based approach to lipid-lowering, where age could be a key factor in prioritizing ezetimibe therapy.]

C. Patients with Renal Impairment

• Pharmacokinetics and Dosing:[ In patients with severe renal disease (e.g., creatinine clearance ≤30 mL/min/1.73 m²), the systemic exposure (AUC) to total ezetimibe is increased by approximately 1.5-fold.][14][ Despite this,] no dosage adjustment of ezetimibe is necessary[ when it is used as a monotherapy in patients with any degree of renal impairment.][56]
• Safety and Efficacy:[ The SHARP trial definitively established the cardiovascular benefit of an ezetimibe/simvastatin combination in patients with CKD.][49][ Retrospective studies have corroborated that ezetimibe is both effective and safe in this population, with some evidence suggesting it may even produce a more pronounced LDL-C reduction, possibly due to modest drug accumulation.][49][ The primary safety concern is the increased risk of statin-associated myopathy in CKD patients; therefore, when ezetimibe is combined with simvastatin, simvastatin doses exceeding 20 mg should be used with caution in patients with an eGFR <60 mL/min/1.73 m².][55]

D. Patients with Hepatic Impairment

[The use of ezetimibe in patients with liver disease is stratified by the severity of the impairment.]

• Pharmacokinetics:[ Systemic exposure to ezetimibe increases progressively with the degree of hepatic dysfunction. Compared to healthy subjects, the mean AUC for total ezetimibe is increased approximately 1.7-fold in patients with mild impairment (Child-Pugh score 5-6), 3- to 4-fold in those with moderate impairment (Child-Pugh score 7-9), and 5- to 6-fold in those with severe impairment (Child-Pugh score 10-15).][12]
• Dosing and Recommendations:
• Mild Hepatic Impairment (Child-Pugh 5-6):[ No dosage adjustment is required.][3]
• Moderate to Severe Hepatic Impairment (Child-Pugh 7-15):[ Ezetimibe is ]not recommended[ for these patients. The clinical consequences of the significantly increased drug exposure are unknown, and the potential risks are considered to outweigh the benefits.][3]

E. Pregnancy and Lactation

• Pregnancy:[ There is a lack of adequate and well-controlled studies of ezetimibe in pregnant women. Due to this lack of human safety data, ezetimibe monotherapy is generally not recommended during pregnancy (it was formerly assigned FDA Pregnancy Category C).][3][ When ezetimibe is combined with a statin, the combination is] strictly contraindicated[ in pregnancy, as statins are known to have the potential to cause fetal harm by interfering with cholesterol synthesis, which is essential for fetal development.][55]
• Lactation:[ It is not definitively known if ezetimibe is excreted into human breast milk, but animal data (presence in rat milk) suggest that it is likely.][54][ Recent, albeit limited, human data from two nursing mothers found very low levels of ezetimibe and its active metabolite in breast milk, with a predicted relative infant dose of less than 1%, suggesting that exposure to the infant would be minimal and likely acceptable.][83][ However, official guidance remains cautious, advising that ezetimibe should only be used if the potential benefit to the mother justifies the potential risk to the infant.][54][ As with pregnancy, combination therapy with a statin is] contraindicated[ during breastfeeding.][55]

Ezetimibe in the Lipid-Lowering Armamentarium: A Comparative Analysis

[Ezetimibe occupies a distinct and strategic position within the modern armamentarium of lipid-lowering therapies. Its value is best understood through a comparative analysis with the two other major classes of drugs used for intensive LDL-C reduction: statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.]

A. Comparison with Statins

[Statins are the undisputed first-line therapy for hypercholesterolemia, but ezetimibe serves as their ideal complement.]

• Mechanism of Action:[ The two classes have fundamentally different and synergistic mechanisms. Statins inhibit the enzyme HMG-CoA reductase in the liver, blocking the rate-limiting step of endogenous cholesterol ]synthesis[.][40][ Ezetimibe inhibits the NPC1L1 protein in the intestine, blocking the] absorption[ of dietary and biliary cholesterol.][37]
• Efficacy:[ As monotherapy, statins are more potent, capable of reducing LDL-C by 35% to 60%, depending on the agent and dose.][40][ Ezetimibe monotherapy provides a more modest LDL-C reduction of approximately 18%.][37][ However, the key clinical application is combination therapy, where adding ezetimibe to a statin provides an additional LDL-C reduction of about 15% to 25%.][34]
• Side Effect Profile:[ Both drug classes carry risks of myopathy and liver enzyme elevations. However, these risks are generally considered to be more pronounced and dose-dependent with statins.][55][ Ezetimibe is often better tolerated, and its addition can facilitate a "statin-sparing" approach, allowing patients to achieve LDL-C goals with lower, better-tolerated statin doses.][37]
• Cost and Administration:[ Both are available as oral, once-daily medications. With the widespread availability of generic formulations for both ezetimibe and most statins, combination therapy is generally inexpensive and accessible.][34]

B. Comparison with PCSK9 Inhibitors

[PCSK9 inhibitors represent the most potent class of LDL-C-lowering agents, and their comparison with ezetimibe highlights a trade-off between maximal efficacy and practical considerations like cost and administration.]

• Mechanism of Action:[ PCSK9 inhibitors are monoclonal antibodies (e.g., evolocumab, alirocumab) or small interfering RNA (siRNA) therapies (e.g., inclisiran) that work extracellularly. They target and inhibit PCSK9, a protein that promotes the degradation of LDL receptors in the liver. By blocking PCSK9, these drugs increase the number of LDL receptors on the surface of hepatocytes, dramatically enhancing the clearance of LDL-C from the blood.][37][ This mechanism is distinct from both statins and ezetimibe.]
• Efficacy:[ PCSK9 inhibitors are significantly more potent than ezetimibe as an add-on therapy. When added to maximally tolerated statins, they can lower LDL-C by an additional 50% to 70%.][35][ This far exceeds the ~15-25% additional reduction provided by ezetimibe. A triple-therapy regimen of a statin, ezetimibe, and a PCSK9 inhibitor can lower LDL-C by as much as 85%.][35]
• Side Effect Profile:[ PCSK9 inhibitors are generally very well-tolerated. Their most common side effect is mild-to-moderate injection-site reactions. Importantly, they do not appear to carry the same risks of myopathy or liver enzyme abnormalities associated with statins.][37]
• Cost and Administration:[ This is the most significant differentiating factor. PCSK9 inhibitors are expensive biologic drugs that require administration via subcutaneous injection every 2 to 4 weeks (for monoclonal antibodies) or twice-yearly (for inclisiran).][35][ In stark contrast, ezetimibe is an inexpensive, orally administered, once-daily tablet.]

C. Role in Clinical Practice Guidelines

[Major clinical practice guidelines from organizations like the American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) provide a clear, stepwise algorithm for lipid management that defines ezetimibe's role.]

1. First-Line Therapy:[ Maximally tolerated statin therapy remains the cornerstone and undisputed first-line treatment for cardiovascular risk reduction in patients with or at high risk for ASCVD.][87]
2. Second-Line Therapy:[ For patients who fail to achieve their LDL-C goal (e.g., <70 mg/dL for high-risk patients or <55 mg/dL for very high-risk patients) on a maximally tolerated statin dose, or for those who are statin-intolerant, ]ezetimibe is the universally recommended next agent to add[.][37][ This recommendation is based on its proven cardiovascular outcome benefit (IMPROVE-IT), favorable safety profile, oral convenience, and low cost as a generic.]
3. Third-Line Therapy:[ If LDL-C goals are still not met on a combination of a maximally tolerated statin and ezetimibe, a ]PCSK9 inhibitor is then recommended[ as the third-line agent to achieve further, more aggressive LDL-C reduction.][37]

[This tiered approach reflects a careful balancing of efficacy, safety, cost, and practicality. Ezetimibe's established position in these guidelines is not a reflection of it being the most potent agent, but rather of its optimal "value proposition." It occupies the crucial therapeutic middle ground, offering a moderate, outcome-proven efficacy boost with high safety, oral convenience, and low cost. It effectively bridges the gap between the foundational therapy (statins) and the highly potent but more burdensome and expensive therapy (PCSK9 inhibitors), making it an indispensable tool in the lipid-lowering algorithm.]

Table 7: Comparative Profile of Ezetimibe, Statins, and PCSK9 Inhibitors

Feature	Ezetimibe	Statins	PCSK9 Inhibitors
Mechanism of Action	Inhibits intestinal cholesterol absorption (NPC1L1 inhibitor)	Inhibit hepatic cholesterol synthesis (HMG-CoA reductase inhibitors)	Increase hepatic LDL receptor recycling (PCSK9 inhibition)
Typical LDL-C Reduction	~18% (monotherapy); ~15-25% (add-on to statin)	35-60% (monotherapy, dose-dependent)	~50-70% (add-on to statin)
Route of Administration	Oral	Oral	Subcutaneous Injection
Dosing Frequency	Once daily	Once daily	Every 2-4 weeks or twice-yearly
Key Side Effects	Generally well-tolerated; diarrhea, arthralgia. Rare myopathy/liver enzyme elevations.	Myopathy, rhabdomyolysis, liver enzyme elevations (dose-dependent).	Injection-site reactions. Generally well-tolerated with low systemic side effect profile.
Cost	Low (generic available)	Low (most are generic)	High
Place in Guidelines	Second-line: Add to statin if LDL-C goal not met. First-line for statin intolerance.	First-line: Cornerstone of therapy.	Third-line: Add to statin + ezetimibe if LDL-C goal still not met.

Conclusion and Future Perspectives

Summary of Ezetimibe's Profile

[Ezetimibe has firmly established itself as a vital component of modern lipid management. As the first-in-class cholesterol absorption inhibitor, its unique mechanism of action, which complements that of statins, has proven to be a cornerstone of combination therapy for hypercholesterolemia. Its profile is characterized by moderate efficacy, an excellent safety and tolerability record, a low potential for drug-drug interactions, and the convenience of a once-daily oral formulation. The widespread availability of low-cost generic versions has further solidified its position. The narrative of ezetimibe's clinical development, from early uncertainty to validation through landmark cardiovascular outcome trials like IMPROVE-IT, SHARP, and EWTOPIA 75, has unequivocally demonstrated its ability to reduce cardiovascular events. This benefit is particularly pronounced in well-defined high-risk populations, including patients with recent acute coronary syndromes, those with chronic kidney disease, and, most notably, the elderly.]

Ongoing Research and Future Directions

[The clinical story of ezetimibe is not over. Current and future research is focused not on replacing it, but on building upon its established foundation by exploring its role in novel combination therapies and its potential utility in new therapeutic paradigms.]

• Novel Fixed-Dose Combinations:[ The success of combining ezetimibe with other agents continues to drive innovation.]
• Obicetrapib:[ The phase 3 TANDEM trial (NCT06005597) has shown promising results for a fixed-dose combination of ezetimibe with obicetrapib, a novel cholesteryl ester transfer protein (CETP) inhibitor. This combination achieved a nearly 50% reduction in LDL-C compared to placebo with good tolerability, suggesting it could become a powerful new oral, non-statin option for intensive lipid lowering.][90]
• AZD0780:[ AstraZeneca is conducting a Phase 1 trial (D7960C00017) to investigate the pharmacokinetics, safety, and efficacy of a new investigational agent, AZD0780, when added to ezetimibe-based regimens (including ezetimibe alone, ezetimibe/rosuvastatin, and ezetimibe/bempedoic acid). The study is estimated to complete in August 2025 and highlights the central role of ezetimibe in next-generation combination strategies.][92]
• Exploring New Therapeutic Questions:
• Aspirin-Sparing Strategies:[ A large, long-term randomized trial, GUIDE-CAC (NCT06722521), is currently underway to compare an intensive lipid-lowering strategy using a statin-ezetimibe combination ]without[ aspirin to a standard strategy of statin monotherapy ]with[ aspirin in patients with high coronary artery calcification.][93][ With an estimated completion in 2032, this trial has the potential to reshape primary prevention guidelines by questioning the necessity of aspirin when very low LDL-C levels are achieved.]
• Impact on Gut Microbiota:[ Recognizing that ezetimibe acts within the intestine, an ongoing clinical trial (NCT06784557) is directly investigating how combination therapy with atorvastatin and ezetimibe affects the composition of the gut microbiota compared to high-intensity statin monotherapy.][94][ This research could unveil new mechanistic insights into ezetimibe's effects on cardiovascular health beyond simple cholesterol absorption.]
• Reinforcing the Foundation of Combination Use:[ The design of contemporary clinical trials reinforces ezetimibe's foundational role. For instance, a Phase 4 study (NCT06431763) comparing the potent PCSK9 inhibitor inclisiran to bempedoic acid is enrolling patients who are already on a maximally tolerated statin, with or without ezetimibe.][95][ This design treats the statin/ezetimibe combination as the standard-of-care baseline upon which newer therapies are tested.]

Final Synthesis and Concluding Remarks

[Ezetimibe's journey from a drug with a novel but unproven mechanism to a guideline-endorsed staple of cardiovascular medicine is a testament to the importance of rigorous, long-term clinical outcome research. Its future appears secure, not as a standalone agent, but as the indispensable and versatile "foundational non-statin." It has become the default, cost-effective partner for virtually any other lipid-lowering therapy, from legacy statins to emerging drug classes. The current research landscape treats ezetimibe as an integral part of the baseline therapy, seeking to determine the incremental benefit of adding new agents ]to[ it. This positioning as the universal "plus-one" in oral lipid management, driven by its complementary mechanism, high safety, and low cost, ensures its long-term relevance and value. As the field of preventive cardiology moves toward increasingly personalized and aggressive LDL-C targets, ezetimibe will remain a critical tool for achieving those goals safely and effectively in a diverse range of patients worldwide.]

Works cited

1. Ezetimibe - StatPearls - NCBI Bookshelf, accessed July 15, 2025, https://www.ncbi.nlm.nih.gov/books/NBK532879/
2. www.ncbi.nlm.nih.gov, accessed July 15, 2025, https://www.ncbi.nlm.nih.gov/books/NBK532879/#:~:text=Ezetimibe%20is%20a%20medication%20used,of%20selective%20cholesterol%2Dabsorption%20inhibitors.
3. Ezetimibe - Wikipedia, accessed July 15, 2025, https://en.wikipedia.org/wiki/Ezetimibe
4. Ezetimibe | C24H21F2NO3 | CID 150311 - PubChem, accessed July 15, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Ezetimibe
5. Generic Zetia Availability - Drugs.com, accessed July 15, 2025, https://www.drugs.com/availability/generic-zetia.html
6. Ezetimibe: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed July 15, 2025, https://www.medcentral.com/drugs/monograph/64335-302039/ezetimibe-oral
7. ezetimibe (CHEBI:49040) - EMBL-EBI, accessed July 15, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:49040
8. Ezetimibe (Ezetrol, SCH 58235, CAS Number: 163222-33-1) | Cayman Chemical, accessed July 15, 2025, https://www.caymanchem.com/product/16331/ezetimibe
9. Showing BioInteractions for Ezetimibe (DB00973) | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/drugs/DB00973/biointeractions
10. Ezetimibe | SCH-58235 | CAS#163222-33-1 - MedKoo Biosciences, accessed July 15, 2025, https://www.medkoo.com/products/7656
11. Ezetimibe | CAS 163222-33-1 | SCBT - Santa Cruz Biotechnology, accessed July 15, 2025, https://www.scbt.com/p/ezetimibe-163222-33-1
12. (EZETIMIBE) TABLETS - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021445s019lbl.pdf
13. Ezetimibe: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/drugs/DB00973
14. 21445 Zetia Clinical Pharmacology Biopharmaceutics Review Part 1 - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21445_Zetia_biopharmr_P1.pdf
15. Ezetimibe (Zetia): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD, accessed July 15, 2025, https://www.webmd.com/drugs/2/drug-64335/ezetimibe-oral/details
16. www.caymanchem.com, accessed July 15, 2025, https://www.caymanchem.com/product/16331/ezetimibe#:~:text=Ezetimibe%20is%20an%20inhibitor%20of,the%20apical%20membrane%20of%20enterocytes.&text=It%20reduces%20cholesterol%20absorption%20in,mg%2Fkg%20per%20day)..&sa=D&source=editors&ust=1752570830525875&usg=AOvVaw3Ba3mYD1SsXx_Zst04lT8N)
17. [Ezetimibe (250 mg)] - CAS [163222-33-1] - USP Store, accessed July 15, 2025, https://store.usp.org/product/1269028
18. Drug Approval Package: Zetia (ezetimibe) NDA #21445 - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21445_Zetia.cfm
19. Ezetimibe Uses, Dosage, Side Effects - Drugs.com, accessed July 15, 2025, https://www.drugs.com/ezetimibe.html
20. Vytorin (ezetimibe/simvastatin) FDA Approval History - Drugs.com, accessed July 15, 2025, https://www.drugs.com/history/vytorin.html
21. Drug Approval Package: Vytorin (Ezetimibe/Simvastatin) NDA, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-687_Vytorin.cfm
22. New FDA Approved Labeling For VYTORIN® (Ezetimibe/Simvastatin) Includes Results From the Study of Heart and Renal Protection (SHARP) in Patients With Moderate to Severe Chronic Kidney Disease, accessed July 15, 2025, https://www.merck.com/news/new-fda-approved-labeling-for-vytorin-ezetimibe-simvastatin-includes-results-from-the-study-of-heart-and-renal-protection-sharp-in-patients-with-moderate-to-severe-chronic-kidney-disease/
23. FDA Approves Merck's LIPTRUZET™ (ezetimibe and atorvastatin), a New Product That Can Help Powerfully Lower LDL Cholesterol, accessed July 15, 2025, https://www.merck.com/news/fda-approves-mercks-liptruzet-ezetimibe-and-atorvastatin-a-new-product-that-can-help-powerfully-lower-ldl-cholesterol/
24. Liptruzet (atorvastatin and ezetimibe) FDA Approval History - Drugs.com, accessed July 15, 2025, https://www.drugs.com/history/liptruzet.html
25. Drug Approval Package: Liptruzet (ezetimibe and atorvastatin) NDA #200153 - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/200153_liptruzet_toc.cfm
26. Liptruzet: Side Effects, Dosage & Uses - Drugs.com, accessed July 15, 2025, https://www.drugs.com/liptruzet.html
27. Roszet (ezetimibe and rosuvastatin) FDA Approval History - Drugs.com, accessed July 15, 2025, https://www.drugs.com/history/roszet.html
28. Roszet (rosuvastatin/ezetimibe) – New drug approval, accessed July 15, 2025, https://professionals.optumrx.com/content/dam/optum3/professional-optumrx/news/rxnews/drug-approvals/drugapproval_roszet_2021-0326.pdf
29. Nexlizet (bempedoic acid and ezetimibe) FDA Approval History - Drugs.com, accessed July 15, 2025, https://www.drugs.com/history/nexlizet.html
30. Bempedoic acid/ezetimibe - Wikipedia, accessed July 15, 2025, https://en.wikipedia.org/wiki/Bempedoic_acid/ezetimibe
31. Esperion announces FDA approval of the Nexlizet (bempedoic acid and, accessed July 15, 2025, https://esperion.gcs-web.com/node/11236/pdf
32. U.S. FDA Approves Broad New Labels for NEXLETOL® and NEXLIZET® to Prevent Heart Attacks and Cardiovascular Procedures in Both Primary and Secondary Prevention Patients, Regardless of Statin Use | Esperion Therapeutics, Inc., accessed July 15, 2025, https://www.esperion.com/news-releases/news-release-details/us-fda-approves-broad-new-labels-nexletolr-and-nexlizetr-prevent
33. Generic Vytorin Availability - Drugs.com, accessed July 15, 2025, https://www.drugs.com/availability/generic-vytorin.html
34. Ezetimibe: A Lipid-Lowering Drug for Older Patients and Older Cardiologists - HCPLive, accessed July 15, 2025, https://www.hcplive.com/view/ezetimibe-a-lipid-lowering-drug-for-older-patients-and-older-cardiologists
35. Lipid-lowering therapy. What comes after the standard treatment? (Statin/Ezetimibe/PCSK9), accessed July 15, 2025, https://www.escardio.org/Councils/Council-for-Cardiology-Practice-(CCP)/Cardiopractice/lipid-lowering-therapy-what-comes-after-the-standard-treatment-statin-ezetimi
36. www.ahajournals.org, accessed July 15, 2025, https://www.ahajournals.org/doi/10.1161/01.cir.0000072345.98581.24#:~:text=5-,What%20Is%20the%20Mechanism%20of%20Action%20of%20Ezetimibe%3F,reduction%20of%20serum%20LDL%2DC.
37. Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors - PMC, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7379114/
38. Ezetimibe therapy: mechanism of action and clinical update - PMC, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3402055/
39. Pharmacology of ezetimibe | European Heart Journal Supplements - Oxford Academic, accessed July 15, 2025, https://academic.oup.com/eurheartjsupp/article/4/suppl_J/J5/333444
40. Ezetimibe therapy: mechanism of action and clinical update - PMC, accessed July 15, 2025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402055/
41. The Mechanism of Action of Ezetimibe (Zetia) on the Inhibition of Cholesterol Absorption, accessed July 15, 2025, https://www.ebmconsult.com/articles/ezetimibe-mechanism-action-inhibit-cholesterol-absorption-intestine
42. Pharmacotherapy Update | Ezetimibe (Zetia™), accessed July 15, 2025, https://www.clevelandclinicmeded.com/medicalpubs/pharmacy/marapr2003/ezetimibe.htm
43. Efficacy and Safety of Ezetimibe Monotherapy in 6-10 Year Old Children with Heterozygous Familial or Non-familial Hypercholesterolemia | Request PDF - ResearchGate, accessed July 15, 2025, https://www.researchgate.net/publication/257734669_Efficacy_and_Safety_of_Ezetimibe_Monotherapy_in_6-10_Year_Old_Children_with_Heterozygous_Familial_or_Non-familial_Hypercholesterolemia
44. (PDF) The pharmacokinetics of ezetimibe - ResearchGate, accessed July 15, 2025, https://www.researchgate.net/publication/231586522_The_pharmacokinetics_of_ezetimibe
45. Ezetimibe: MedlinePlus Drug Information, accessed July 15, 2025, https://medlineplus.gov/druginfo/meds/a603015.html
46. Ezetimibe Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed July 15, 2025, https://www.drugs.com/dosage/ezetimibe.html
47. How and when to take ezetimibe - NHS, accessed July 15, 2025, https://www.nhs.uk/medicines/ezetimibe/how-and-when-to-take-ezetimibe/
48. Ezetimibe (oral route) - Mayo Clinic, accessed July 15, 2025, https://www.mayoclinic.org/drugs-supplements/ezetimibe-oral-route/description/drg-20067172
49. Safety and Efficacy of Ezetimibe in Patients With and Without Chronic Kidney Disease at a Pharmacist-Managed Clinic | MDedge, accessed July 15, 2025, https://www.mdedge.com/fedprac/article/272526/cardiology/safety-and-efficacy-ezetimibe-patients-and-without-chronic-kidney-disease-pharmacist-managed-clinic
50. Renal and Vascular Protective Effects of Ezetimibe in Chronic Kidney Disease - J-Stage, accessed July 15, 2025, https://www.jstage.jst.go.jp/article/internalmedicine/53/4/53_53.0649/_article
51. Ezetimibe treatment in the elderly to reduce cardiovascular event - Open Access Journals, accessed July 15, 2025, https://www.openaccessjournals.com/articles/ezetimibe-treatment-in-the-elderly-to-reduce-cardiovascular-events-14279.html
52. Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75) | Circulation - American Heart Association Journals, accessed July 15, 2025, https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.039415
53. Intensive Lipid-Lowering Slashes CVD in Elderly ACS Patients - TCTMD.com, accessed July 15, 2025, https://www.tctmd.com/news/intensive-lipid-lowering-slashes-cvd-elderly-acs-patients
54. Label: EZETIMIBE tablet - DailyMed, accessed July 15, 2025, https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5b3842f6-c80a-47b8-8a82-b69e465b05f7
55. 35223509T REV 23 Reference ID: 3076051 - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021445s033lbl.pdf
56. This label may not be the latest approved by FDA. For current ..., accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021445s042lbl.pdf
57. Drug Monograph: Ezetimibe (Zetia) - EBM Consult, accessed July 15, 2025, https://www.ebmconsult.com/articles/monograph-ezetimibe-zetia
58. Merck Receives Complete Response Letter from the U.S. FDA for ZETIA® (ezetimibe) and VYTORIN® (ezetimibe and simvastatin), accessed July 15, 2025, https://www.merck.com/news/merck-receives-complete-response-letter-from-the-u-s-fda-for-zetia-ezetimibe-and-vytorin-ezetimibe-and-simvastatin/
59. What are the considerations for prescribing Zetia (ezetimibe) in patients with abnormal liver function tests? - Dr.Oracle, accessed July 15, 2025, https://www.droracle.ai/articles/164372/zetia-and-abnormal-liver-function-test
60. Can Zetia (ezetimibe) elevate liver enzymes? - Dr.Oracle AI, accessed July 15, 2025, https://www.droracle.ai/articles/174648/can-zetia-elevate-liver-enzymes
61. Can Zetia (ezetimibe) cause liver damage? - Drugs.com, accessed July 15, 2025, https://www.drugs.com/medical-answers/zetia-ezetimibe-liver-damage-3566243/
62. Ezetrol (ezetimibe) and the Risks of Drug-Induced Liver Injury and Severe Cutaneous Adverse Reactions - Recalls and Safety Alerts, accessed July 15, 2025, https://recalls-rappels.canada.ca/en/alert-recall/ezetrol-ezetimibe-and-risks-drug-induced-liver-injury-and-severe-cutaneous-adverse
63. Ezetimibe | Davis's Drug Guide for Rehabilitation Professionals, accessed July 15, 2025, https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139011052
64. Safety and efficacy of moderate-intensity statin with ezetimibe in elderly patients with atherosclerotic cardiovascular disease - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/39709592/
65. Combination Moderate-Intensity Statin and Ezetimibe Therapy for Elderly Patients With Atherosclerosis | JACC, accessed July 15, 2025, https://www.jacc.org/doi/10.1016/j.jacc.2023.02.007
66. Taking ezetimibe with other medicines and herbal supplements - NHS, accessed July 15, 2025, https://www.nhs.uk/medicines/ezetimibe/taking-ezetimibe-with-other-medicines-and-herbal-supplements/
67. Zetia (ezetimibe) dosing, indications, interactions, adverse effects, and more, accessed July 15, 2025, https://reference.medscape.com/drug/zetia-ezetimibe-342454
68. Zetia interactions: Other medications, alcohol, and more, accessed July 15, 2025, https://www.medicalnewstoday.com/articles/drugs-zetia-interactions
69. Foods to avoid if you are taking Zetia - Optum Perks, accessed July 15, 2025, https://perks.optum.com/blog/546-2
70. Common questions about ezetimibe - NHS, accessed July 15, 2025, https://www.nhs.uk/medicines/ezetimibe/common-questions-about-ezetimibe/
71. perks.optum.com, accessed July 15, 2025, https://perks.optum.com/blog/546-2#:~:text=Zetia%20(ezetimibe)%20is%20a%20medication,avoid%20grapefruits%20or%20grapefruit%20juice.
72. Who can and cannot take ezetimibe - NHS, accessed July 15, 2025, https://www.nhs.uk/medicines/ezetimibe/who-can-and-cannot-take-ezetimibe/
73. Ezetimibe - Westside Pediatrics, accessed July 15, 2025, https://nywestsidepeds.com/child-health-library/healthwise/?DOCHWID=a603015
74. Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/25841542/
75. Pediatric Study to Evaluate the Efficacy and Safety of Ezetimibe Monotherapy in Children With Primary Hypercholesterolemia (P05522) | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT00867165
76. Efficacy and safety of statins, ezetimibe and statins-ezetimibe therapies for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review, pairwise and network meta-analyses of randomised controlled trials - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/39343641/
77. Severely frail elderly patients do not need lipid-lowering drugs, accessed July 15, 2025, https://www.ccjm.org/content/84/2/131
78. What are the considerations for using Zetia (ezetimibe) in a patient with impaired renal function (GFR 49)? - Dr.Oracle, accessed July 15, 2025, https://www.droracle.ai/articles/145604/i-would-like-to-start-zetia-for-a-pt-wtih-low-kidney-function-gfr-is-49-is-this-safe
79. Ezetimibe Disease Interactions - Drugs.com, accessed July 15, 2025, https://www.drugs.com/disease-interactions/ezetimibe.html
80. Pregnancy, breastfeeding and fertility while taking ezetimibe - NHS, accessed July 15, 2025, https://www.nhs.uk/medicines/ezetimibe/pregnancy-breastfeeding-and-fertility-while-taking-ezetimibe/
81. Ezetimibe / rosuvastatin (Roszet) Use During Pregnancy - Drugs.com, accessed July 15, 2025, https://www.drugs.com/pregnancy/ezetimibe-rosuvastatin.html
82. Is Ezetimibe safe during lactation? - Dr.Oracle AI, accessed July 15, 2025, https://www.droracle.ai/articles/2015/ezetemibe-in-lactation
83. Ezetimibe - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed July 15, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501635/
84. Is ezetimibe a statin drug? - Drugs.com, accessed July 15, 2025, https://www.drugs.com/medical-answers/ezetimibe-statin-drug-3553493/
85. ezetimibe and PCSK9 inhibition join the mainstream of lipid‑lowering therapy | Wójcik | Reviews in Health Care, accessed July 15, 2025, https://journals.seedmedicalpublishers.com/index.php/rhc/article/view/1263/1567
86. PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations - PubMed, accessed July 15, 2025, https://pubmed.ncbi.nlm.nih.gov/35508320/
87. The New 2018 Cholesterol Guidelines: Filling Gaps and Expanding Opportunities, accessed July 15, 2025, https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.118.038629
88. PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified re - The BMJ, accessed July 15, 2025, https://www.bmj.com/content/bmj/377/bmj-2021-069066.full.pdf
89. Recommendations for use of ezetimibe and/or PCSK9 inhibitors in patients with elevated LDL-C | Annals of Internal Medicine - ACP Journals, accessed July 15, 2025, https://www.acpjournals.org/doi/10.7326/J22-0060
90. Obicetrapib-Ezetimibe Combo Therapy Halves LDL Cholesterol Levels Relative to Placebo, accessed July 15, 2025, https://consultqd.clevelandclinic.org/obicetrapib-ezetimibe-combo-therapy-halves-ldl-cholesterol-levels-relative-to-placebo
91. Obicetrapib Plus Ezetimibe Reduced LDL-C in Patients With or at Risk of Atherosclerotic Cardiovascular Disease - Pharmacy Times, accessed July 15, 2025, https://www.pharmacytimes.com/view/obicetrapib-plus-ezetimibe-reduced-ldl-c-in-patients-with-or-at-risk-of-atherosclerotic-cardiovascular-disease
92. A Study to Investigate the Pharmacokinetics, Safety, Tolerability, and Efficacy of AZD0780 with Ezetimibe Combinations in Healthy Adults with Elevated LDL-C. - AstraZeneca Clinical Trials, accessed July 15, 2025, https://www.astrazenecaclinicaltrials.com/study/D7960C00017/
93. GUIDE-CAC: Statin-Ezetimibe Without Aspirin vs. Statin Monotherapy With Aspirin in High Coronary Calcification | ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT06722521
94. Study Details | Effect of Ezetimibe on Gut Microbiota - ClinicalTrials.gov, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT06784557?cond=%22Ezetimibe%22&aggFilters=status:not%20rec&rank=3
95. A Study to Investigate LDL-cholesterol Lowering With Inclisiran Compared to Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease. | Novartis, accessed July 15, 2025, https://www.novartis.com/clinicaltrials/study/nct06431763