Rosuvastatin Calcium/ Ezetimibe

Registered South African indications:

• Primary hypercholesterolaemia
  - As adjunctive therapy to diet, when response to diet and exercise is inadequate, for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C), in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia
• Homozygous familial hypercholesterolaemia (HoFH)
  - As adjunctive therapy to diet for the reduction of elevated total-C and LDL-C levels in patients with HoFH
• Prevention of cardiovascular events
  - To reduce the increased risk of atherosclerotic cardiovascular disease based on the presence of cardiovascular disease markers such as an elevated high sensitivity C-reactive protein level, age, hypertension, low HDL-C, smoking or family history of premature coronary heart disease
  - To reduce the risk of non-fatal stroke, non-fatal myocardial infarction and the need for arterial revascularisation in patients who are adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate products

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Rosuvastatin calcium/ ezetimibe can be taken as substitution therapy in adult patients adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate medicines

Registered South African contraindications

• Hypersensitivity to rosuvastatin, ezetimibe, or any excipients
• Pregnancy
• Lactation
• Women of childbearing potential, unless they are taking adequate contraceptive precautions
• Children, as safety and efficacy have not been demonstrated
• Moderate to severe hepatic impairment (Child Pugh score 7 or more)
• Active liver disease, including unexplained persistent elevations in serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN)
• Patients with severe renal impairment (CrCl<30ml/min)
• Patients receiving concomitant ciclosporin
• Patients with myopathy secondary to other lipid-lowering medicines
• Combination with fenofibrate in patients with gall bladder disease
• Patients taking fusidic acid

South African recommendations

Renal impairment

• Pharmacokinetic evaluation in patients with varying degrees of renal impairment determined that mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin, as in rosuvastatin/ezetimibe
• However, patients with severe impairment (CrCl<30ml/min) had a 3-fold increase in plasma concentration compared to healthy volunteers

Hepatic impairment

• Due to unknown effects of the increased exposure of ezetimibe, as in rosuvastatin/ezetimibe, in patients with moderate to severe hepatic insufficiency, rosuvastatin/ezetimibe is not recommended in these patients
• In a study in patients with varying degrees of hepatic impairment, there was no evidence of increased exposure to rosuvastatin, as in rosuvastatin/ezetimibe, other than in the 2 patients with the most severe liver disease (Child-Pugh scores of 8 and 9)
• In these patients, systemic exposure was increased by at least 2-fold compared with patients with lower Child-Pugh scores

Elderly

• No dosage adjustment is required for elderly patients
• Because there is no specific data in the elderly with this combination and advanced age (≥65 years) is a predisposing factor for myopathy, rosuvastatin/ezetimibe should be prescribed with caution in the elderly

Liver enzymes

• Liver function tests should be performed before initiating treatment and periodically thereafter
• Patients who develop increased transaminase levels should be monitored until the abnormalities resolve
• If an increase in ALT or AST of >3 times ULN persists, reducing the dose or withdrawing rosuvastatin/ezetimibe is recommended
• Consecutive transaminase elevations (≥3 times ULN) have been observed in controlled co-administration trials with ezetimibe and a statin, as contained in rosuvastatin/ezetimibe
• Rosuvastatin/ezetimibe should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease

Skeletal muscle effects

Rosuvastatin

• Cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin, as in rosuvastatin/ezetimibe, and with other medicines in this class
• Uncomplicated myalgia has been reported in rosuvastatin-treated patients
• In clinical trials, the incidence of myopathy and rhabdomyolysis increased at doses above the recommended range (5mg to 40mg)
• Factors that may predispose patients to myopathy include advanced age (≥65 years), hypothyroidism, and renal insufficiency
• Rosuvastatin/ezetimibe should be prescribed with caution in patients with predisposing factors for myopathy
• Patients should be advised to report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever
• Rosuvastatin/ezetimibe therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected
• The risk of myopathy may be increased with concurrent administration of other lipid-lowering therapies, ciclosporin, or HIV/HCV antiviral medicines
• Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors co-administered with colchicine; caution is advised
• Combination therapy with rosuvastatin/ezetimibe and gemfibrozil should generally be avoided
• The combination of rosuvastatin/ezetimibe and other fibrates (except fenofibrate) is not recommended
• Rosuvastatin/ezetimibe therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, or uncontrolled
  seizures)
• Immune-mediated necrotising myopathy has been reported during or after treatment with statins, including rosuvastatin
• Treatment with immunosuppressive medicines may be required for immune-mediated necrotising myopathy
• Fusidic acid must not be co-administered with statins; this combination has been associated with reports of rhabdomyolysis, including fatalities
• In patients where the use of systemic fusidic acid is considered essential, rosuvastatin/ ezetimibe treatment should be discontinued throughout the duration of fusidic acid therapy. Rosuvastatin/ezetimibe therapy may be reintroduced seven days after the last dose of fusidic acid
• Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA reductase inhibitors co-administered with daptomycin
• Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin. Consideration should be given to suspending rosuvastatin/ ezetimibe temporarily in patients taking daptomycin

Ezetimibe

• In clinical trials, the incidence of CPK greater than 10 times ULN was 0.2% for ezetimibe vs. 0.1% for placebo, and 0.1% for ezetimibe co-administered with a statin vs. 0.4% for statins alone
• Cases of myopathy and rhabdomyolysis have been reported in post-marketing experience with ezetimibe
• All patients starting therapy with rosuvastatin/ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness
• Rosuvastatin/ezetimibe should be immediately discontinued if myopathy is diagnosed or suspected
• The presence of muscle symptoms and a CPK level greater than 10 times the ULN indicates myopathy

Endocrine effects

• Increases in HbA1c and fasting serum glucose levels have been reported with rosuvastatin, as in rosuvastatin/ezetimibe
• Clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve
• Caution should be exercised if rosuvastatin/ezetimibe is administered concomitantly with medicines that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine

Prevention of cardiovascular events

• The long-term safety and efficacy of rosuvastatin treatment, as in rosuvastatin/ezetimibe, in patients commencing treatment with LDL-C <3.4 mmol/L who have been assessed to be at risk of cardiovascular events have not been established
• There is uncertainty associated with the safety of long-term intensive reduction of LDL-C to very low levels. The risk-benefit balance for longer-term use of rosuvastatin in this population has therefore not been established
• Clinically significant benefit in using rosuvastatin, as in rosuvastatin/ezetimibe, in patients without clinically evident cardiovascular disease and who are assessed as having a low risk of cardiovascular events (men >50 and women >60 years of age with hsCRP >2mg/L, but no other cardiovascular disease risk factor), has not been established

Diabetes mellitus

• Increases in HbA1c and serum glucose levels have been observed in patients treated with rosuvastatin
• An increased frequency of diabetes mellitus has been reported with rosuvastatin, as in rosuvastatin/ezetimibe, in patients with risk factors for diabetes mellitus

Interstitial lung disease

• Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy
• Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever)
• If it is suspected a patient has developed interstitial lung disease, rosuvastatin/ezetimibe should be discontinued

Parasomnias

• Statins, as in rosuvastatin/ezetimibe, may cause various parasomnias, including abnormal dreaming, nightmares (paroniria), and sleepwalking (somnambulism)
• The Centre for Adverse Reactions Monitoring (CARM) received over 70 reports of various parasomnias over a period of five years, with the most frequently reported terms being abnormal dreams, paroniria, and sleep disorder
• Commonly reported medicines include statins, varenicline, and montelukast

Race

Rosuvastatin

• A large pharmacokinetic study conducted in the US demonstrated an approximate 2-fold elevation in median exposure in Asian patients (having either Filipino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian origin) compared with a caucasian control group
• This increase should be considered when making rosuvastatin/ ezetimibe dosing decisions for Asian patients

Age and gender

• There was no clinically relevant effect of age or gender on the pharmacokinetics of rosuvastatin, as in rosuvastatin/ezetimibe

Fibrates - other than fenofibrate

• The safety and efficacy of ezetimibe, as in rosuvastatin/ezetimibe, administered with fibrates, have not been established

Fenofibrate

• If cholelithiasis is suspected in a patient receiving rosuvastatin/ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered
• Co-administration of rosuvastatin/ezetimibe and fenofibrate is not recommended in patients with pre-existing gallbladder disease

Anticoagulants

• There have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe, as in rosuvastatin/ezetimibe, added to warfarin. Most of these patients were also on other medicines
• If rosuvastatin/ezetimibe is added to warfarin or another coumarin anticoagulant, the INR should be appropriately monitored

Statins

• No clinically significant pharmacokinetic interactions were seen when ezetimibe, as in rosuvastatin/ezetimibe, was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin

Ciclosporin

• Caution should be exercised when initiating ezetimibe, as in rosuvastatin/ezetimibe, in the setting of ciclosporin
• Ciclosporin concentrations should be monitored in patients receiving ezetimibe, as in rosuvastatin/ezetimibe, and ciclosporin

Excipients

• Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine

Ability to drive and use machines

• Pharmacology testing revealed no evidence of a sedative effect of rosuvastatin, as in rosuvastatin/ezetimibe. From the safety profile, rosuvastatin, as in rosuvastatin/ezetimibe, is not expected to adversely affect the ability to drive or use machines
• Certain side effects that have been reported, such as dizziness, may affect some patients' ability to drive or operate machinery
• Individual responses may vary. Patients should not drive, use machinery or perform any tasks that require concentration until they are certain that rosuvastatin/ezetimibe do not adversely affect their ability to do so safely

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Primary hypercholesterolaemia
- As adjunctive therapy to diet, when response to diet and exercise is inadequate, for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C), in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia
Homozygous familial hypercholesterolaemia (HoFH)
- As adjunctive therapy to diet for the reduction of elevated total-C and LDL-C levels in patients with HoFH
Prevention of cardiovascular events
- To reduce the increased risk of atherosclerotic cardiovascular disease based on the presence of cardiovascular disease markers such as an elevated high sensitivity C-reactive protein level, age, hypertension, low HDL-C, smoking or family history of premature coronary heart disease
- To reduce the risk of non-fatal stroke, non-fatal myocardial infarction and the need for arterial revascularisation in patients who are adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate products

Rosuvastatin Calcium/ Ezetimibe
5/10 (mg)
10/10 (mg)
20/10 (mg)
40/10 (mg)

• Oral (fct, tab): 1 tab, daily; Dosage of rosuvastatin should be individualised according to the goal of therapy and patient response; Majority of patients are controlled at the start dose; Dose adjustment, if necessary can be made after 4 weeks

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Rosuvastatin calcium/ ezetimibe can be taken as substitution therapy in adult patients adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate medicines

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Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should be continued during treatment

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Rosuvastatin/ ezetimibe is not suitable for initial therapy. Treatment initiation or dose adjustment if necessary should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Rosuvastatin/ ezetimibe 10mg/10mg and 20mg/10mg tablets are not suitable for the treatment of patients requiring a 40mg dose of rosuvastatin

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Specific doses based on individual indications:

Primary hypercholesterolaemia
- As substitution therapy in adult patients adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate medicines

• Oral (fct, tab): Usual start dose: 10mg rosuvastatin/ 10mg ezetimibe, once daily; For patients with severe hypercholesterolaemia (including heterozygous familial hypercholesterolaemia): Start dose of 20mg of rosuvastatin may be considered

Homozygous familial hypercholesterolaemia
- As substitution therapy in adult patients adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate medicines

• Oral (fct, tab): Patients should be established on a dose of 20mg rosuvastatin/ 10mg ezetimibe, once daily

Prevention of cardiovascular events
- As substitution therapy in adult patients adequately controlled with the individual medicines given concurrently at the same dose level as in the fixed dose combination, but as separate medicines

• Oral (fct, tab): Usual dose: 20mg rosuvastatin and 10mg ezetimibe, once daily

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For dosing when rosuvastatin/ ezetimibe is coadministered with other medicines see Additional Prescribing Points

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For oral administration. Rosuvastatin/ ezetimibe may be given at any time of the day, with or without food

• Contraindicated

Pregnancy

South African recommendations

• Contraindicated
• No studies on the effect on embryo-foetal development have been conducted with ezetimibe and rosuvastatin in combination, as in rosuvastatin/ ezetimibe
• Atherosclerosis is a chronic process and discontinuation of lipid-lowering medicines during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia
• Cholesterol and other products of cholesterol biosynthesis are essential components for foetal development (including synthesis of steroids and cell membranes)

Women of childbearing potential

• Women of child-bearing potential should use appropriate contraceptive measures. Rosuvastatin/ ezetimibe should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential
• If the patient becomes pregnant while taking rosuvastatin/ ezetimibe, therapy should be discontinued, and the patient apprised of the potential hazard to the foetus

Breastfeeding

South African recommendations

• Contraindicated
• No studies in lactating animals have been conducted with the combination of ezetimibe and rosuvastatin, as in rosuvastatin/ ezetimibe
• Studies in rats have shown that ezetimibe and rosuvastatin are excreted in milk. It is not known whether ezetimibe or rosuvastatin is excreted into human breast milk. Therefore, rosuvastatin/ ezetimibe is contraindicated in breastfeeding women
• Ezetimibe had no effects on pup development in rats treated with up to 1000mg/kg/day of ezetimibe during late pregnancy and lactation
• Medicine exposures (based on AUC) in pups were approximately 1.5% and 50% of maternal exposures for ezetimibe and total ezetimibe respectively. A study in rats treated with rosuvastatin showed that unchanged medicine and metabolites are excreted in milk at concentrations up to 3 times greater than those in maternal plasma

Fertility

South African recommendations

• No studies on the effect on fertility have been conducted with ezetimibe and rosuvastatin in combination

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Contraindicated

South African recommendations

• Mild (Child Pugh score 5-6): No dose adjustment recommended
• Moderate (Child Pugh score 7-9) to Severe (Child Pugh score >9): Contraindicated
  Treatment with rosuvastatin/ ezetimibe is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score > 9) liver dysfunction
• Active liver disease: Contraindicated

South African recommendations

• Caution; no dose adjustment recommended
  A starting dose of 5mg rosuvastatin is recommended in patients over 70 years of age

Rosuvastatin Calcium and Ezetimibe (each administered alone)

Immune System Disorders

Less frequent

• Hypersensitivity reactions including angioedema

Nervous System Disorders

Frequent

• Headache
• Dizziness

Psychiatric Disorders

Less frequent

• Parasomnias, including abnormal dreaming, nightmares, sleepwalking

Gastrointestinal Disorders

Frequent

• Abdominal pain
• Constipation
• Nausea

Less frequent

• Pancreatitis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Pruritus
• Rash
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Frequent

• Myalgia
• Arthralgia

Less frequent

• Myopathy
• Rhabdomyolysis

General Disorders and Administration Site Conditions

Less frequent

• Asthenia
• Peripheral oedema

Investigations

Frequent

• Abnormal liver function test

Rosuvastatin Calcium (administered alone)

Metabolism and Nutrition Disorders

Frequent

• Diabetes mellitus

Renal and Urinary Disorders

Less frequent

• Proteinuria, which decreases or disappears spontaneously on reduction of dose

Ezetimibe (administered alone)

Infections and Infestations

Frequent

• Viral infection
• Pharyngitis
• Sinusitis

Metabolism and Nutrition Disorders

Less frequent

• Decreased appetite

Vascular Disorders

Less frequent

• Hot flush
• Hypertension

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Cough

Gastrointestinal Disorders

Frequent

• Diarrhoea
• Flatulence

Less frequent

• Dyspepsia
• Gastroesophageal reflux disease

Hepatobiliary Disorders

Frequent

• Increased alanine transaminase (ALT)
• Increased aspartate transaminase (AST)

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Back pain
• Pain in extremity
• Muscle spasms
• Neck pain

General Disorders and Administration Site Conditions

Frequent

• Fatigue

Less frequent

• Chest pain
• Pain

Investigations

Frequent

• Increased gamma-glutamyltransferase

Post marketing adverse reactions (Rosuvastatin Calcium and Ezetimibe (each administered alone))

Blood and the Lymphatic System Disorders

Less frequent

• Thrombocytopenia

Immune System Disorders

Less frequent

• Hypersensitivity reactions (including anaphylaxis, rash, urticaria)

Very rare

• Angio-oedema

Psychiatric Disorders

Less frequent

• Depression

Nervous System Disorders

Less frequent

• Dizziness

Gastrointestinal Disorders

Less frequent

• Nausea
• Pancreatitis
• Constipation

Hepato-biliary Disorders

Less frequent

• Hepatitis
• Increased hepatic transaminases

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Myalgia
• Arthralgia
• Myopathy/rhabdomyolysis

General Disorders and Administration Site Conditions

Less frequent

• Asthenia

Investigations

Less frequent

• Increased transaminases
• Increased CPK

Post marketing adverse reactions (Rosuvastatin Calcium administered alone)

Psychiatric Disorders

Frequency unknown

• Sleep disorders
• Insomnia
• Nightmares

Nervous System Disorders

Less frequent

• Memory loss

Hepato-biliary Disorders

Less frequent

• Jaundice

Frequency unknown

• Hepatic failure

Musculoskeletal and Connective Tissue Disorders

Frequency unknown

• Immune-mediated necrotising myopathy

Reproductive System and Breast Disorders

Frequency unknown

• Gynaecomastia

Post marketing adverse reactions (Ezetimibe administered alone)

Nervous System Disorders

Less frequent

• Paraesthesia

Hepato-biliary Disorders

Less frequent

• Cholelithiasis
• Cholecystitis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Erythema multiforme

Rosuvastatin Calcium/ Ezetimibe

• OATP1B1 transporter protein inhibitors
• Colestyramine
• Fibrates (other than fenofibrate)
• Fusidic acid
• Ciclosporin

Rosuvastatin Calcium

• Antacid suspension (containing aluminium and magnesium hydroxide)
• Ciclosporin
• Gemfibrozil
• Vitamin K antagonists
• Warfarin
• OATP1B1 transporter protein inhibitors
• BCRP efflux transporter protein inhibitors
• Protease inhibitors/ HCV antivirals
• Simeprevir
• Atazanavir/ ritonavir
• Lopinavir/ritonavir
• Grazoprevir
• Elbasvir
• Ticagrelor
• Colchicine
• Daptomycin

Ezetimibe

• Ciclosporin
• Colestyramine

• Lipid panel (total cholesterol, HDL, LDL, triglycerides)
  - Baseline lipid panel; fasting lipid profile within 4-12 weeks after initiation or dose adjustment and every 3-12 months (as clinically indicated) thereafter
  If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose
• Hepatic transaminase levels
  - Baseline measurement of hepatic transaminase levels (AST and ALT)
  - Measure AST, ALT, total bilirubin, and alkaline phosphatase if symptoms suggest hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-coloured urine, yellowing of skin or sclera) during therapy

Specific cases may require

• Creatine phosphokinase (CPK)
  - Baseline CPK measurement is reasonable for some individuals (e.g., family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy)
  - May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalised fatigue)
  - CPK should not be routinely measured
• Evaluate for new-onset diabetes mellitus during therapy
  - If diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation

Additional observations

• Consider neuromuscular and serologic testing if immune-mediated necrotizing myopathy is suspected
• Monitor for signs/symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-coloured urine, yellowing of skin or sclera)
• Monitor for symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalised fatigue)
• If patient develops a confusional state or memory impairment, evaluate for non-statin causes (e.g., exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy

Rosuvastatin

Rosuvastatin is a selective fully synthetic competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated, with apolipoprotein B (ApoB), into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. VLDL particles are TG-rich. Cholesterol-rich low-density lipoprotein (LDL) is formed from VLDL and is cleared primarily through the high affinity LDL receptor in the liver. Rosuvastatin produces its lipid-modifying effects in two ways; it increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles. High density lipoprotein (HDL), which contains ApoA-I, is involved, amongst other functions, in transport of cholesterol from tissues back to the liver (reverse cholesterol transport). 

The involvement of LDL-C in atherogenesis has been well documented. Epidemiological studies have established that high LDL-C and TG, and low HDL-C and ApoA-I have been linked to a higher risk of cardiovascular disease. Intervention studies have shown the benefits on mortality and CV event rates of lowering LDL-C and TG or raising HDL-C. More recent data has linked the beneficial effects of HMG-CoA reductase inhibitors to the lowering of non-HDLC (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ApoA-I ratio. 

Ezetimibe

In human studies, ezetimibe inhibited the intestinal absorption of cholesterol and related plant sterols. Ezetimibe has a mechanism of action that differs from other classes of cholesterol reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives, and plant sterols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols. Ezetimibe therefore inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe does not increase bile acid excretion (like bile acid sequestrants) and does not inhibit cholesterol synthesis in the liver (like statins). Statins reduce cholesterol synthesis in the liver. Together these distinct mechanisms provide complementary cholesterol reduction. Ezetimibe, administered with a statin, reduces total-C, LDL-C, Apo B, and TG and increases HDL-C in patients with hypercholesterolaemia, beyond either treatment alone. 

Clinical studies demonstrate that elevated levels of total C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. Ezetimibe in experimental animals inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat soluble vitamins A and D.