ZIENT Tablet Ref.[50664] Active ingredients: Ezetimibe

Mechanism of action

ZIENT (ezetimibe) is in a class of lipid-modifying compounds that inhibit the intestinal absorption of cholesterol and related plant sterols.

Ezetimibe has a mechanism of action that differs from other classes of cholesterol reducing compounds (eg 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).

In a 2-week clinical study in 18 hypercholesterolaemic patients, ZIENT inhibited intestinal cholesterol absorption by 54%, compared with placebo. By inhibiting the absorption of intestinal cholesterol, ZIENT reduces the delivery of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Together these distinct mechanisms provide complementary cholesterol reduction. ZIENT, 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 triglyceriderich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis.

A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe 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.

Clinical trials

Controlled clinical studies of varying designs were conducted with ZIENT either as monotherapy or co-administration with a statin. ZIENT significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia.

Primary Hypercholesterolemia

Monotherapy

In two, multicentre, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolaemia, ZIENT 10 mg significantly lowered total-C, LDL-C, Apo B, and TG and increased HDL-C compared to placebo (see Table 2). Reduction in LDL-C was consistent across age, sex, race, and baseline LDL-C. In addition, ZIENT had no effect on the plasma concentrations of the fat-soluble vitamins A, D, and E, had no effect on prothrombin time, and did not impair adrenocortical steroid hormone production.

Table 2. Response to ZIENT in Patients with Primary Hypercholesterolaemia (Absolute and Percent Change from Baseline):

^a Mean absolute change from baseline, expressed as mmol/L
^b Mean percent change from baseline
^c Mean absolute change from baseline, expressed as g/L
^d Median absolute change from baseline, expressed as mmol/L
^e Median percent change from baseline

Co-Administration with a Statin

ZIENT Initiated Concurrently with a Statin:

In four, multicentre, double-blind, placebo-controlled, 12-week trials, in 1187 patients with hypercholesterolaemia, ZIENT 10 mg was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin. The greatest LDL-C reducing effect is seen with the lowest dose of each statin, with only a further 2-9% incremental reduction in LDL-C with each doubling of the dose. Comparatively, adding 10mg of ZIENT to a given dose of a statin is shown to achieve a greater reduction in LDL-C than that achieved with statin dose doubling.

Table 3. Mean Absolute and Percent Change from Baseline in Plasma Concentration of Calculated LDL-C for ZIENT Administered with Statins:

^a Mean absolute change from baseline, expressed as mmol/L
^b Mean percent change from baseline

In a pooled analysis of all ZIENT + statin doses, ZIENT had a beneficial effect on total-C, Apo B, TG, and HDL-C (Table 4).

Table 4. Pooled Analysis of Absolute and Percent Change from Baseline in Total-C, ApoB, TG, and HDL-C:

^a Mean absolute change from baseline, expressed as mmol/L
^b Mean percent change from baseline
^c Mean absolute change from baseline, expressed as g/L
^d Median absolute change from baseline, expressed as mmol/L
^e Median percent change from baseline

ZIENT Added to On-going Statin Therapy:

In a multicentre, double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.59 to 4.14 mmol/L, depending on baseline characteristics) were randomised to receive either ZIENT 10 mg or placebo in addition to their on-going statin therapy.

Among statin-treated patients not at LDL-C goal at baseline (~82 ), LDL-C goal at study endpoint was achieved by 72 and 19% of patients randomised to ZIENT and placebo, respectively.

ZIENT, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, and TG and increased HDL-C, compared with placebo (Table 5). LDL-C reductions were consistent across all statins.

Table 5. Response to Addition of ZIENT to On-going Statin Therapya in Patients with Hypercholesterolaemia (Absolute and Percent Change from Baseline):

^a Percentages of patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin)
^b Mean absolute change from baseline, expressed as mmol/L
^c Mean percent change from baseline
^d Mean absolute change from baseline, expressed as g/L
^e Median absolute change from baseline, expressed as mmol/L
^f Median percent change from baseline

ZIENT or placebo added to statin therapy reduced median C-reactive protein by 10% or 0% from baseline, respectively.

In a multicentre, double-blind, 14 week study, 621 patients with hypercholesterolaemia receiving atorvastatin 10 mg daily with an LDL-C >3.36 mmol/L were randomised to receive atorvastatin 20 mg or ZIENT 10 mg added to atorvastatin 10 mg therapy. The atorvastatin dose could be titrated up to 80 mg in the atorvastatin arm and up to 40 mg in the ZIENT plus atorvastatin co-administration arm, based on patients not attaining LDL-C goal (<2.59 mmol/L). The mean baseline LDL-C was 4.84 mmol/L and approximately 60% of the patients had heterozygous familial hypercholesterolaemia (HeFH). At study end, there was a significant difference in attainment of LDL-C goal between patients in the ZIENT coadministration arm (22%) and patients on atorvastatin monotherapy (7%). At week 4, there was a significant difference in LDL-C reductions between co-administration patients (24%; ZIENT + atorvastatin 10 mg) and monotherapy patients (9%; atorvastatin 20 mg). In the sub-group of patients with HeFH, similar results for LDL-C goal attainment and LDL-C reductions were achieved.

In a similarly designed study in 100 patients with hypercholesterolaemia receiving simvastatin 20 mg and not at LDL-C goal, the addition of ZIENT 10 mg to simvastatin titration compared to titration of simvastatin alone produced similar advantages to those observed in the atorvastatin study described above. For example, significant differences in LDL-C goal attainment (27% for ZIENT + simvastatin vs. 3% for simvastatin alone) and LDL-C reductions (24% for ZIENT + simvastatin vs. 11% for simvastatin alone) were achieved.

Other Studies

The use of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia demonstrated a numerically higher incidence of cholecystectomies in patients in the co-administration group compared with those in the monotherapy groups (see Section 4.3 Contraindications and Section 4.8 Adverse Effects (Undesirable Effects)). Each drug contributed to lowering LDL-C, but the effects on triglycerides and HDL-C were related to fenofibrate and were not enhanced by co-administration. Longer term clinical outcomes such as mortality and morbidity were not investigated.

Clinical Studies in Paediatric (6 to 17 Years of Age) Patients

Paediatric Patients 10 to 17 Years of Age:

In a multicentre, double-blind, controlled study, 142 boys and 106 post-menarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% Multiracial) with heterozygous familial hypercholesterolaemia (HeFH) were randomised to receive either ZIENT co-administered with simvastatin or simvastatin alone. Inclusion in this study required 1) a baseline LDL-C level between 4.1 and 10.4 mmol/L (160 and 400 mg/dL) and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 5.8 mmol/L (range: 4.2-9.1 mmol/L) in the ezetimibe coadministered with simvastatin group compared to 5.7 mmol/L (range: 3.9-8.7 mmol/L) in the simvastatin monotherapy group. The patients received co-administered ZIENT and simvastatin (10 mg, 20 mg or 40 mg) or simvastatin alone (10 mg, 20 mg or 40 mg) for 6 weeks, co-administered ZIENT and simvastatin 40 mg or 40 mg simvastatin alone for the next 27 weeks, and openlabel co-administered ZIENT and simvastatin (10 mg, 20 mg or 40 mg) for 20 weeks thereafter.

The primary hypothesis was that the percent change in LDL-C from baseline to Week 6 in the pooled ZIENT and simvastatin groups would be greater than in the pooled simvastatin monotherapy groups. At Week 6, co-administered ZIENT and simvastatin (all doses) lowered LDL-C significantly more than simvastatin (all doses) alone (49% vs 34% respectively). The results of the study at Week 6 are summarised in Table 6 and 6a. Results at Week 33 were consistent with those at Week 6. At Week 53, the end of the open-label extension, the effects on lipid parameters were maintained.

Table 6. Response to ZIENT Co-administered with Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolaemia:

^* Mean (or median) absolute change from baseline (units are mmol/L for all parameters except Apo B, which is in g/L).
^† For triglycerides, median absolute change from baseline.

Table 6a. Mean Percent Difference at Week 6 Between Pooled ZIENT and Simvastatin Group and Pooled Simvastatin Group in Adolescent Patients with Heterozygous Familial Hypercholesterolaemia:

^* For triglycerides, median % change from baseline

From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe coadministered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.

The clinical safety and efficacy of ZIENT co-administered with simvastatin in children and adolescents (10-17 years old) with hypercholesterolaemia other than Heterozygous Familial Hypercholesterolaemia have not been studied.

The safety and efficacy of ZIENT co-administered with doses of simvastatin above 40 mg daily have not been studied in children and adolescents (10-17 years old) and are not recommended.

The long-term efficacy of therapy with ZIENT in children and adolescents (10-17 years old) to reduce morbidity and mortality in adulthood has not been studied.

Paediatric Patients <10 Years of Age:

In a multicentre, double-blind, controlled study, 138 patients [59 boys (51 Tanner stage I and 6 Tanner stage II) and 79 girls (52 Tanner stage I, 22 Tanner stage II and 1 Tanner stage III)], 6 to 10 years of age (mean age 8.3 years) with heterozygous familial or non-familial hypercholesterolaemia were randomised to either ZIENT 10 mg or placebo for 12 weeks. Inclusion in the study required 1) a baseline LDL-C >4.1 and <10.4 mmol/L (>159 and <400 mg/dL) and 2) a medical history and clinical presentation consistent with HeFH.

At week 12, ZIENT significantly reduced total-C, LDL-C, Apo-B and non-HDL-C compared to placebo. Results for the two treatment groups were similar for TG and HDL-C.

Table 7. Response to ZIENT in Paediatric Patients with Heterozygous Familial Hypercholesterolaemia:

^a Baseline – on no lipid-lowering drug
^b For triglycerides, median absolute and geometric median % change from baseline
^c Absolute change from baseline expressed as mmol/L for all parameters except Apo B, which is in g/L
^d Mean percent change from baseline

ZIENT has not been studied in patients younger than 6 years of age.

Homozygous Familial Hypercholesterolaemia (HoFH)

A study was conducted to assess the efficacy of ZIENT in the treatment of HoFH. This double-blind, randomised, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40mg). Patients were randomised to one of three treatment groups, atorvastatin or simvastatin (80mg), ZIENT 10mg administered with atorvastatin or simvastatin (40mg), or ZIENT 10mg administered with atorvastatin or simvastatin (80mg). Results are shown in Table 8. ZIENT, administered with atorvastatin (40 or 80mg) or simvastatin (40 or 80mg), significantly reduced LDL-C compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80mg.

Table 8. Mean Response to ZIENT in Patients with HoFH (Mean Absolute and Percent Change from Baseline):

^a Mean absolute change from baseline, expressed as mmol/L
^b Mean percent change from baseline

Prevention of Cardiovascular Disease

ZIENT in combination with simvastatin has been shown in the IMPROVE-IT trial (details below) to reduce the major cardiovascular events of non-fatal myocardial infarction and stroke in patients with coronary heart disease and a history of Acute Coronary Syndrome. Total mortality, cardiovascular mortality and rates of unstable angina requiring hospitalization and all coronary revascularization were unchanged. There was a small increase in the rate of haemorrhagic stroke that was not statistically significant. The incremental benefit is expected to be similar with co-administration of other statins shown to be effective in reducing the risk of cardiovascular events but this has not been demonstrated in studies similar to IMPROVEIT.

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was a multicenter, randomized, double-blind, active-control study of 18,144 patients enrolled within 10 days of hospitalization for acute coronary syndrome (ACS; either acute myocardial infarction [MI] or unstable angina [UA]). Patients had an LDL-C ≤3.2 mmol/L (≤125 mg/dL) at the time of presentation with ACS if they had not been taking lipid-lowering therapy, or ≤2.6 mmol/L (≤100 mg/dL) if they had been receiving lipid-lowering therapy. All patients were randomized in a 1:1 ratio to receive either ezetimibe/simvastatin 10/40 mg (n=9067) or simvastatin 40 mg (n=9077) and followed for a median of 6.0 years.

Patients had a mean age of 63.6 years; 76% were male, 84% were Caucasian, and 27% were diabetic. The average LDL-C value at the time of study qualifying event was 2.1 mmol/L (80 mg/dL) for those on lipid-lowering therapy (n=6390) and 2.6 mmol/L (101 mg/dL) for those not on previous lipid-lowering therapy (n=11594). Prior to the hospitalization for the qualifying ACS event, 34% of the patients were on statin therapy. At one year, the average LDL-C for patients continuing on therapy was 1.4 mmol/L (53.2 mg/dL) for the ezetimibe/simvastatin group and 1.8 mmol/L (69.9 mg/dL) for the simvastatin monotherapy group. Lipid values were generally obtained for patients who remained on study therapy.

The primary endpoint was a composite consisting of cardiovascular death, major coronary events (MCE; defined as non-fatal myocardial infarction, documented unstable angina that required hospitalization, or any coronary revascularization procedure occurring at least 30 days after randomized treatment assignment) and non-fatal stroke. The study demonstrated that treatment with ezetimibe when added to simvastatin provided incremental benefit in reducing the primary composite endpoint of cardiovascular death, MCE, and non-fatal stroke compared with simvastatin alone (relative risk reduction of 6.4%, p=0.016). The primary endpoint occurred in 2572 of 9067 patients (7-year Kaplan-Meier [KM] rate 32.72%) in the ezetimibe/simvastatin group and 2742 of 9077 patients (7-year KM rate 34.67%) in the simvastatin alone group. (See Figure 1 and Table 9.) This incremental benefit is expected to be similar with coadministration of other statins shown to be effective in reducing the risk of cardiovascular events. Total mortality was unchanged in this high risk group (see Table 9).

There was an overall benefit for all strokes; however there was a small non-significant increase in heamorrhagic stroke in the ezetimibe-simvastatin group compared with simvastatin alone (see Table 9). The risk of haemorrhagic stroke for ezetimibe co-administered with higher potency statins in long-term outcome studies has not been evaluated.

The treatment effect of ezetimibe/simvastatin was generally consistent with the overall results across many subgroups, including sex, age, race, medical history of diabetes mellitus, baseline lipid levels, prior statin therapy, prior stroke, and hypertension.

Figure 1. Effect of ZIENT and simvastatin 40 mg or 80 mg on the Primary Composite Endpoint of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke:

Table 9. Major Cardiovascular Events by Treatment Group in All Randomized Patients in IMPROVEIT:

^* 6% were uptitrated to ezetimibe/simvastatin 10/80 mg.
^† 27% were uptitrated to simvastatin 80 mg.
^‡ Kaplan-Meier estimate at 7 years.
^§ includes ischemic stroke or stroke of undetermined type.

Prevention of Major Vascular Events in Chronic Kidney Disease (CKD)

The Study of Heart and Renal Protection (SHARP) was a multinational, randomised, placebocontrolled, double-blind study conducted in 9,438 patients with chronic kidney disease, a third of whom were on dialysis at baseline. Patients with a definite history of myocardial infarction (MI) or coronary revascularisation procedure, existing or planned renal transplant, recent acute uraemic emergency, evidence of active inflammatory muscle disease or creatine kinase (CK) >3xULN were excluded. For the first year, patients were randomised in a ratio of 4:4:1, respectively, to a fixed dose combination of ZIENT 10 mg with simvastatin 20 mg, placebo, or simvastatin 20 mg daily. The 1-year simvastatin arm was included to enable the comparison of ZIENT combined with simvastatin to simvastatin alone with regard to safety and lipids. At 1 year the simvastatin-only arm was re-randomised 1:1 to a fixed dose combination of ZIENT 10 mg with simvastatin 20 mg or placebo. A total of 4,650 patients were allocated to ZIENT 10 mg combined with simvastatin 20 mg and 4,620 to placebo, and followed for a median of 4.9 years. Patients had a mean age of 62 (ranging in age from 39 to 94.5 years old); 63% were male, 72% were Caucasian and 23% were diabetic; and, for those not on dialysis, the median serum creatinine was 0.22 mmol/L and the mean estimated glomerular filtration rate (eGFR) was 26.5 mL/min/1.73 m², with 94% of patients having an eGFR <45 mL/min/1.73 m². There were no lipid entry criteria. Mean LDL-C at baseline was 2.8 mmol/L. As of the 1- year measurement, LDL-C was reduced 26% relative to placebo by simvastatin 20 mg alone and 38% for ZIENT 10 mg combined with simvastatin 20 mg. At the midpoint of the study (2.5 years) mean LDL-C reduction in all randomised patients for ZIENT combined with simvastatin relative to placebo was 32%. All lipid measurements included patients no longer taking study medication.

The SHARP protocol-specified primary comparison was an intention-to-treat analysis of “major vascular events” (MVE; defined as nonfatal MI or cardiac death, stroke, or any revascularisation procedure) in only those patients initially randomised to the ZIENT combined with simvastatin (n=4,193) or placebo (n=4,191) groups. Secondary analyses included the same composite analysed for the full cohort randomised (at study baseline or at year 1) to ZIENT combined with simvastatin (n=4,650) or placebo (n=4,620) as well as the components of this composite.

The primary endpoint analysis showed that ZIENT combined with simvastatin significantly reduced the risk of MVE (749 patients with events in the placebo group vs. 639 in the ZIENT combined with simvastatin group) with an absolute risk reduction of 2.3% (number needed to treat, 43) and a relative risk reduction of 16% (p=0.001) (see Figure 2). An analysis of major atherosclerotic events (MAE, a subset of the MVE composite that excluded non-coronary cardiac deaths and haemorrhagic stroke) showed that ZIENT combined with simvastatin significantly reduced the risk of MAE (526 (11.3%) of 4650 patients ever allocated to ZIENT combined with simvastatin and 619 (13.4%) of 4620 patients ever allocated to placebo), corresponding to an absolute risk reduction of 2.1% (number needed to treat, 48) and a relative risk reduction of 17% (p=0.002).

The risk reduction for the MVE composite was directionally consistent (i.e., ZIENT combined with simvastatin numerically superior to placebo) with that of the entire cohort of patients for the following key baseline predefined subgroups: age, gender, dialysis vs. non-dialysis, eGFR, diabetes, pre-existing atherosclerotic disease, blood pressure, or tertiles of baseline LDL-C.

Compliance rates with placebo and study medication declined over the course of the study. For example, at 20-25 months of follow-up, 68% of patients allocated to ezetimibe/simvastatin and 67% of patients allocated to placebo were taking 80% or more of the study medication, while at 44-49 months, compliance had fallen to 60% and 56%, respectively.

Figure 2. Effect of ZIENT Combined with Simvastatin on the Primary Endpoint of Risk of Major Vascular Events:

The individual components of MVE in all randomised patients are presented in Table 10. ZIENT combined with simvastatin significantly reduced the risk of stroke and any revascularisation, with non-significant numerical differences favouring ZIENT combined with simvastatin for nonfatal MI and cardiac death.

Table 10. Major Vascular Events by Treatment Group in All Randomised Patients in SHARP^a:

^a Intention-to-treat analysis on all SHARP patients randomised to ZIENT combined with simvastatin or placebo either at baseline or year 1.
^b MAE defined as the composite of nonfatal myocardial infarction, coronary death, non-haemorrhagic stroke, or any revascularisation.

No significant treatment effect of ZIENT combined with simvastatin on MVE was found in the subgroup of patients on dialysis at baseline compared with those not on dialysis at baseline.

Among 3023 patients on dialysis at baseline, ZIENT combined with simvastatin reduced the risk of MVE by 6% (RR 0.94: 95% CI 0.80-1.09) compared with 22% (RR 0.78: 95% CI 0.69-0.89) among 6247 patients not on dialysis at baseline (interaction P=0.08). Among patients not on dialysis at baseline, ZIENT combined with simvastatin did not reduce the risk of progressing to end-stage renal disease compared with placebo.

There were no significant differences between the ZIENT combined with simvastatin and placebo groups on all cause mortality, or on any specific cause of death.

The study design precluded drawing conclusions regarding the independent contribution of either ezetimibe or simvastatin to the observed effect, and was not able to provide evidence of efficacy for the combination of ZIENT 10 mg with simvastatin 20 mg compared to either the lower dose combination (i.e. ZIENT 10 mg with simvastatin 10 mg) or to treatment with statin alone (i.e. simvastatin 20 mg).

The effect of ezetimibe taken in combination with other statins in patients with CKD has not been studied.

Homozygous Sitosterolaemia (Phytosterolaemia)

A study was conducted to assess the efficacy of ZIENT in the treatment of homozygous sitosterolaemia. In this multicentre, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolaemia were randomised to receive ZIENT 10 mg (n=30) or placebo (n=7). ZIENT significantly lowered the two major plant sterols, sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ZIENT, the reduction in plant sterols was progressive over the course of the study.

Reductions in sitosterol and campesterol were consistent between patients taking ZIENT concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).