Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin

ORIGINAL ARTICLE

Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statinirene F. Gazi, Stella S. daskalopoulou, devaki R. nair and dimitri p. MikhailidisDepartment of Clinical Biochemistry (Vascular Disease Prevention Clinics),

Royal Free Hospital (and University College of Medicine), London, UK

Address for correspondence: Dr Dimitri P. Mikhailidis MD, FFPM, FRCP, FRCPath, Reader and Honorary Consultant, Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College of Medicine, University of London, Pond Street, London NW3 2QG, UK. Tel.: +44 207 830 2258; Fax: +44 207 830 2235; e-mail: [email protected]

Key words: Creatinine – Ezetimibe – High density lipoprotein cholesterol – Low density lipoprotein cholesterol – Safety – Statins – Triglycerides – Vascular disease

0300-7995

doi:10.1185/030079907X226267

All rights reserved: reproduction in whole or part not permitted

CuRREnT MEdiCAL RESEARCh And OpiniOn®

VOL. 23, NO. 9, 2007, 2183–2192

© 2007 LiBRAphARM LiMiTEd

Paper 4035 2183

Background: Recent guidelines underline the need for high-risk patients to reach strict low density lipoprotein cholesterol (LDL-C) targets (1.8–2.6 mmol/L; 70–100 mg/dL), and specifically mention the possible use of combination therapy (e.g. statin + ezetimibe) to achieve these goals.

Methods: A retrospective case-note audit was carried out to assess the response to administering ezetimibe in patients unable to tolerate statins (Group 1), or high dose of statins (Group 2) and patients who cannot achieve the LDL-C target (2.6 mmol/L; 100 mg/dL) despite taking a statin (Group 3).

Results: Ezetimibe lowered LDL-C levels by 20–29% across the 3 patient groups after 2–3 months of treatment. High density lipoprotein cholesterol (HDL-C) levels tended to remain unchanged, although there was a consistent trend for a fall if baseline values were ‘high’. However, the LDL-C/HDL-C ratio changed significantly and favourably in all groups. The fall in fasting triglyceride levels in all groups

was greater (reaching 19–25%) when baseline levels were ≥ 1.5 or 1.7 mmol/L (136–150 mg/dL). There were no marked abnormalities in liver function tests or creatine kinase activity. In Group 3 there was a significant trend for a fall in serum creatinine levels across the tertiles of baseline creatinine values.

Limitations of the present study include the small sample size (especially in Groups 1 and 2), its short-term duration and the absence of event-based end-points. Therefore, the results are hypothesis-generating rather than conclusive.

Conclusions: When used alone or added to a statin, ezetimibe favourably altered the LDL-C/HDL-C ratio and lowered triglyceride levels. Ezetimibe was well tolerated in patients with statin intolerance and was associated with a 26% fall in LDL-C. An additional action may be some degree of improved renal function. Further studies are needed to confirm these findings.

A B S T R A C T

Introduction

Current t reatment guidel ines (2005–2006) recommend strict low density lipoprotein cholesterol (LDL-C) targets (1.8–2.6 mmol/L; 70–100 mg/dL) for high-risk individuals1,2. These guidelines are based on the findings of several trials that support the concept that ‘lower is better’ for cholesterol3–6. In 2006 the

American Heart Association/American College of Cardiology (AHA/ACC) guidelines7 for secondary prevention stated that ‘it is reasonable to further reduce LDL-C levels to 1.8 mmol/L (70 mg/dL)’ in very high-risk patients. These guidelines also state that combination therapy (statin with ezetimibe, niacin or bile acid sequestrants) may be required to achieve this target.

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2184 Ezetimibe: efficacy and safety © 2007 LiBRAphARM LTd – Curr Med Res Opin 2007; 23(9)

For patients failing to achieve their LDL-C targets, dual inhibition of the 2 main sources of cholesterol – synthesis (with statins) and absorption (with ezetimibe, a selective cholesterol absorption inhibitor that acts at the intestinal level) – is an appealing option8.

Ezetimibe monotherapy results in a reduction in LDL-C levels by approximately 18%9–11, while high density lipoprotein cholesterol (HDL-C) levels increase and triglyceride (TG) levels usually decrease slightly8. Ezetimibe added to a statin provides an additional decrease in LDL-C levels by 12–30%12–17. Most studies have shown that the addition of ezetimibe to a statin provides further increase in HDL-C and decrease in TG levels12–18, although these changes were not always significant when compared with the placebo groups. The side effect profile of ezetimibe, in terms of liver, renal and muscle safety, is comparable to that of placebo4,8,19.

The present study evaluated the effects of ezetimibe in patients who cannot tolerate any statin, who cannot tolerate high doses of statins and in patients who cannot get to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)1 LDL-C goal (2.6 mmol/L; 100 mg/dL) despite being on a statin. We also assessed the effect of ezetimibe on renal function as well as on liver and muscle enzymes.

Materials and methods

Study population

The records of consecutive eligible patients (n = 154) attending the Outpatient Lipid and Vascular Disease Prevention Clinic at the Royal Free Hospital were retrieved in this retrospective clinical audit. All of these patients had:

(a) established coronary heart disease (CHD; previous vascular event, coronary intervention or angiographic evidence) or,

(b) a CHD equivalent according to the NCEP ATP III criteria (peripheral arterial disease, symptomatic carotid artery disease, abdominal aortic aneurysm or diabetes mellitus)1 or,

(c) familial hypercholesterolaemia based on clinical criteria1 or,

(d) a calculated 10-year Framingham risk1 of a vascular event ≥ 20%.

The selected patients were categorised into 3 groups: patients who could not tolerate statins (Group 1), patients who could not tolerate high doses of statins (Group 2) and patients who could not reach the NCEP ATP III LDL-C target1 despite being on a statin (Group 3). All the patients fulfilled certain criteria (see below).

Exclusion criteria were: abnormal liver function tests (LFTs) (serum aminotransferase activity greater than 40 IU/L), impaired renal function (serum creatinine levels greater than 120 µmol/L; 1.35 mg/dL), impaired thyroid function [thyroid stimulating hormone (TSH) reference range 0.27–4.2 IU/L] (whether or not on thyroxine) and abnormal creatine kinase (CK) activity (> 220 U/L). Also patients were not included in this clinical audit if they had: a recent (within the preceding 3 months) major vascular event or other severe illness, angioplasty, or surgery, psychiatric conditions (involving medication or not) and chronic inflammatory disease (e.g. rheumatoid arthritis, Crohn’s disease, ulcerative colitis, collagen diseases) or cancer. Declared or determined history of alcohol or other drug abuse was also an exclusion criterion. For alcohol consumption, the limit was 21 units/week for men and 14 units/week for women. Peri-menopausal women (6 months without a period were required to define a woman as post-menopausal) were excluded, as well as women with current or recent (within the previous 4 months) pregnancy.

Baseline values and those after short-term (2–3 months) treatment with ezetimibe were retrieved.

The eligible study population consisted of the following:

Group 1: patients who cannot tolerate statins

Ezetimibe (10 mg/day) was administered to patients (n = 27) who had tried statins (and occasionally other lipid-lowering drugs) and had adverse events (AEs) that resulted in discontinuation of treatment.

Group 2: patients who cannot tolerate higher doses of statins

Ezetimibe (10 mg/day) was administered to 12 patients who developed an AE when the dose of statin was increased. This AE resulted in a return to a lower dose of statin. Ezetimibe (10 mg/day) was then added to the current dose of statin which is shown in the Results section below.

Group 3: patients who cannot get to the NCEP ATP III LDL-C target (2.6 mmol/L; 100 mg/dL) despite taking a statin

Ezetimibe (10 mg/day) was added to 115 patients who were already on a statin but could not get to the NCEP ATP III LDL-C target (2.6 mmol/L; 100 mg/dL)1.

Biochemical profile

All non-diabetic (n = 25 in Group 1, n = 10 in Group 2 and n = 100 in Group 3) patients had a blood sample

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© 2007 LiBRAphARM LTd – Curr Med Res Opin 2007; 23(9) Ezetimibe: efficacy and safety Gazi et al. 2185

collected after an overnight (12 h) fast. Serum total cholesterol (TC), HDL-C and TG were assayed by standard enzymatic methods (Boehringer Mannheim, Sussex, England) adapted for the Hitachi 911 analyser (HDL was measured after precipitating Apo B lipoprotein by a phosphotungstate procedure). Serum LDL-C was calculated by the Friedewald formula. Since this formula is not valid for samples with serum TG > 4.5 mmol/L (398 mg/dL), we did not include patients with this degree of hypertriglyceridaemia. Liver, thyroid and renal function profiles and serum glucose concentration were determined by standard methods in routine use in our department. The Department of Clinical Biochemistry, Royal Free Hospital Hampstead Trust, participates in several quality assurance programs and has full Clinical Pathology (CPA) Accreditation.

Statistical analysis

Our analyses include data from patients who completed the study period (2–3 months) without discontinuing ezetimibe. During the study period, the patients did not have any changes (other than the introduction of ezetimibe) in their drug treatment, in glycaemic, smoking or thyroid status, or weight gain/loss of > 5%. Thus, any AE and the changes in biochemical variables can be attributed to the use of ezetimibe.

The Shapiro–Wilk test was used to evaluate whether each variable followed a Gaussian distribution. Data are expressed as mean ± standard deviation (SD), except for parameters not following a Gaussian distribution, which are expressed as median (range). The paired samples t-test and Wilcoxon test were used to assess the effect of ezetimibe on serum metabolic parameters for Gaussian and non-Gaussian variables, respectively. The unpaired t-test or Mann–Whitney U test was used to assess differences in changes in serum metabolic parameters when the patients in Group 3 were divided according to median baseline HDL-C and TG levels and initial LDL-C response to statins, as well as the dose of statins (high vs. low dose). The Kruskal–Wallis test was used to assess differences between Gaussian and non-Gaussian results, respectively, when the patients in Group 3 were divided into tertiles according to initial LDL-C response to statins, the type of statin and baseline creatinine.

We report the number of patients initially recruited in each group and any reason why they were not included in the final analysis. We compared several biochemical variables (lipids, liver function tests, creatine kinase activity and creatinine levels) before and after treatment with ezetimibe. We also report the number of patients reaching the NCEP ATP III1 and AHA/ACC guideline LDL-C targets7 (2.6 and 1.8 mmol/L; 100 and 70 mg/dL, respectively).

A p value of < 0.05 was considered significant. All analyses were carried out using the SPSS for Windows (version 13.0; SPSS Inc., Chicago, IL, USA).

Results

patient subgroup analysis

Group 1: patients who cannot tolerate statins (n = 27)

In this group, 25 (93%) patients completed the study period (2–3 months). Two patients were excluded from the analysis due to a change in other drugs during the study period. Table 1 shows the biochemical profile of the 25 patients in Group 1 before and after the administration of ezetimibe. TC was reduced by 18% and LDL-C by 26% ( p < 0.001 for both); 20% of the patients achieved the NCEP ATP III LDL-C goal of ≤ 2.6 mmol/L (100 mg/dL)1, while none achieved the AHA/ACC LDL-C target of ≤ 1.8 mmol/L (70 mg/dL)7. Ezetimibe did not affect HDL-C and TG levels ( p = NS). The LDL-C/HDL-C ratio decreased by a median of 22% ( p < 0.001). All the other biochemical parameters were not significantly affected by ezetimibe, except for alkaline phosphatase (ALP) which decreased by a median 7% ( p = 0.017).

Group 2: patients who cannot tolerate higher doses of statins (n = 12)

Ten (83%) patients in this group completed the study period (2–3 months). Two patients discontinued ezetimibe due to muscle aches (without serum CK elevation). Of the 10 patients, 4 were receiving atorvastatin (dose range: 10–20 mg/day), 3 pravastatin (20 mg/day), 2 fluvastatin (dose range: 20–40 mg/day) and 1 simvastatin (20 mg/day). The addition of ezetimibe significantly decreased TC (–10%, p = 0.005) and LDL-C (–20%, p < 0.001) levels, as well as the LDL-C/HDL-C ratio (–23%, p < 0.001) (Table 2). In this group, 50% of the patients achieved the NCEP ATP III LDL-C goal of ≤ 2.6 mmol/L (100 mg/dL)1, while 10% achieved the AHA/ACC LDL-C target of ≤ 1.8 mmol/L (70 mg/dL)7. All other biochemical parameters were not significantly affected by ezetimibe. We do not show the alkaline phosphatase results because we only had 3 paired values.

Group 3: patients who cannot get to the NCEP ATP III LDL-C target (2.6 mmol/L; 100 mg/dL) despite taking a statin (n = 115)

In this group, 108 (94%) completed the follow-up (2–3 months) and were included in the analysis; 7 patients

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Table 1. Changes in measured variables in Group 1: cannot tolerate statins (n = 25 for paired samples except otherwise indicated)

Table 2. Changes in measured variables in Group 2: cannot tolerate higher doses of statins (n = 10 for paired samples except otherwise indicated)

Pre-ezetimibe Post-ezetimibe Change % p

Age (years) 66 ± 10

Sex (male/female) 11/14

TC (mmol/L) 6.8 ± 1.3 5.5 ± 0.8 –18 [(–46)–(+17)] < 0.001

HDL-C (mmol/L) 1.6 ± 0.5 1.6 ± 0.4 0 [(–26)–(+29)] NS

LDL-C (mmol/L) 4.4 ± 1.0 3.2 ± 0.7 –26 [(–60)–(+13)] < 0.001

TG (mmol/L) 1.5 (0.6–3.6) 1.6 (0.7–4.1) –11 [(–52)–(+93)] NS

LDL-C/HDL-C 3.0 ± 1.1 2.2 ± 0.8 –22 [(–60)–(+35)] < 0.001

Urea (mmol/L) (n = 15) 5.6 ± 1.5 5.8 ± 1.1 2 [(–20)–(+33)] NS

Creatinine (µmol/L) (n = 16) 80 ± 18 83 ± 16 0 [(–9)–(+68)] NS

Uric acid (mmol/L) (n = 9) 0.41 ± 0.1 0.41 ± 0.1 –2 [(–11)–(+31)] NS

ALP (U/L) (n = 9) 79 ± 16 74 ± 19 –7 [(–22)–(+6)] 0.017

AST (U/L) (n = 21) 24 ± 5 24 ± 4 4 [(–36)–(+29)] NS

ALT (U/L) (n = 21) 23 ± 7 23 ± 6 5 [(–41)–(+46)] NS

γGT (U/L) (n = 20) 22 (14–39) 24 (12–60) –6 [(–29)–(+77)] NS

Creatine kinase (U/L) (n = 19) 114 ± 42 113 ± 53 –10 [(–66)–(+207)] NS

Results are expressed as mean ± standard deviation for parametric variables or as median (range) for non-parametric variables. The treatment period was 2–3 months. None of the patients had diabetes

TC: total cholesterol, HDL-C: high density lipoprotein cholesterol, LDL-C: low density lipoprotein cholesterol, TG: triglycerides, ALP: alkaline phosphatase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γGT: gamma-glutamyl aminotransferase NS: not significant

To convert: mmol/L of total cholesterol, LDL-C, HDL-C to mg/dL, multiply by 38.6; mmol/L of triglycerides to mg/dL, multiply by 88.5; μmol/L of creatinine to mg/dL, multiply by 0.0113; mmol/L of urea to mg/dl, multiply by 2.8; mmol/L of uric acid to mg/dl, multiply by 16.95




TC (mmol/L) 5.5 ± 0.8 4.9 ± 0.9 –10 [(–26)–(+5)] 0.005

HDL-C (mmol/L) 1.5 (1.1–2.5) 1.4 (1.1–3) 0 [(–21)–(+20)] NS

LDL-C (mmol/L) 3.2 ± 0.6 2.6 ± 0.6 –20 [(–38)–(–9)] < 0.001

TG (mmol/L) 1.3 (1–2.8) 1.5 (1.1–3.2) 12 [(–22)–(+146)] NS

LDL-C/HDL-C 2.2 ± 0.7 1.8 ± 0.7 –23 [(–37)–(–2)] < 0.001

Urea (mmol/L) (n = 4) 5.5 ± 0.8 5.3 ± 1.2 –7 [(–11)–(+10)] NS

Creatinine (µmol/L) (n = 4) 88 ± 10 89 ± 10 1 [(–6)–(+5)] NS


AST (U/L) (n = 7) 23 ± 4 24 ± 6 11 [(–21)–(+20)] NS

ALT (U/L) (n = 6) 26 ± 5 32 ± 2 20 [(–6)–(+63)] NS

γGT (U/L) (n = 6) 25 ± 7 30 ± 15 12 [(–17)–(+72)] NS

Creatine kinase (U/L) (n = 6) 117 ± 28 167 ± 96 0 [(–23)–(+340)] NS

Results are expressed as mean ± standard deviation for parametric variables or as median and (range) for non-parametric variables. The treatment period was 2–3 months. None of the patients had diabetes

For abbreviations and conversion factors, see Table 1

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developed an AE while on ezetimibe (2 muscle aches without CK elevation, 2 gastrointestinal disorders like bloating and increased frequency of bowel motions, 1 rash, 1 ‘dry mouth’ and 1 headache). Of the 108 patients, 55 received atorvastatin (dose range: 10–80 mg/day), 31 simvastatin (dose range: 10–80 mg/day), 7 fluvastatin (dose range: 20–80 mg/day), 7 pravastatin (dose range: 20–40 mg/day) and 8 rosuvastatin (dose range: 10–30 mg/day).

TC was reduced by 19%, LDL-C by 29% and TG by 12% ( p < 0.001 for all comparisons). Ezetimibe did not affect HDL-C ( p = NS). The LDL-C/HDL-C ratio decreased by 29% ( p < 0.001). In this group, 67.6% of the patients achieved the NCEP ATP III LDL-C goal of ≤ 2.6 mmol/L (100 mg/dL)1, while 24.1% achieved the AHA/ACC LDL-C target of ≤ 1.8 mmol/L (70 mg/dL) target7. There was a significant increase in aspartate (AST) and alanine (ALT) aminotransferase activities (+5% and +9%, respectively, p < 0.001 for both) (Table 3).

None of the patients in all 3 study groups reached an increase in AST, ALT or CK activity greater than 3-fold the upper limit of normal (ULN) of the reference range for these tests.

Subgroup analysis of responses for the measured biochemical variables

Some analyses were not carried out in Groups 1 and 2 due to the small sample sizes.

HDL-C response to ezetimibe administration

We divided the patients in Group 1 according to median HDL-C levels before the administration of ezetimibe: HDL-C < 1.5 mmol/L (n = 12) and ≥ 1.5 mmol/L (n = 13). In the subgroup with baseline HDL < 1.5 mmol/L ezetimibe did not affect HDL-C levels (1.2 ± 0.2 vs. 1.2 ± 0.2, p = NS), while it produced a significant decrease (by approximately 10%) in HDL-C levels in the group with higher baseline HDL-C (2.0 ± 0.4 vs. 1.8 ± 0.4, respectively, p = 0.028). The LDL-C/HDL-C ratio decreased by 27% [(–50)–(+35%), p = 0.001] in the group with the lower baseline HDL-C levels, and by 17% [(–60)–(+7), p = 0.004] in the group with the higher HDL-C levels (between groups p = NS).

Group 2 was not analysed because of the small number of patients.

We divided the patients in Group 3 according to median HDL-C levels before the addition of ezetimibe: HDL-C ≤ 1.4 (n = 54) and > 1.4 mmol/L (n = 54). In the subgroup with baseline HDL-C ≤ 1.4 mmol/L, ezetimibe did not affect HDL-C levels [1.3 (0.9–1.4) vs. 1.3 (0.8–1.7), p = NS], while it produced a significant decrease (by approximately 6%) in HDL-C in the group with a higher baseline HDL-C [1.7 (1.5–2.6) vs. 1.6 (1.1–2.7), p = 0.014]. The LDL-C/HDL-C ratio decreased by 32% [(–54)–(+17), p < 0.001] in the group with the lower baseline HDL-C levels and

Table 3. Changes in measured variables in Group 3: patients who cannot get to the NCEP ATP III LDL-C target (2.6 mmol/L; 100 mg/dL) despite taking a statin (n = 108 for paired samples except where otherwise indicated)




TC (mmol/L) 5.6 ± 0.8 4.5 ± 0.9 –19 ± 12 < 0.001

HDL-C (mmol/L) 1.4 (0.9–2.6) 1.4 (1.2–2.7) 0 [(–32)–(+40)] NS

LDL-C (mmol/L) 3.3 (2.0–6.0) 2.3 (1.2–4.8) –29 [(–57)–(+20)] < 0.001

TG (mmol/L) 1.4 (0.5–3.4) 1.2 (0.5–3.5) –12 [(–57)–(+218)] < 0.001

LDL-C/HDL-C 2.3 ± 0.7 1.7 ± 0.7 –29 [(–60)–(+27)] < 0.001

Urea (mmol/L) (n = 68) 5.5 (3.0–10.7) 5.5 (2.8–11.9) –3 [(–45)–(+68)] NS

Creatinine (µmol/L) (n = 70) 83 (59–120) 82 (60–158) 1 [(–23)–(+44)] NS


ALP (U/L) (n = 36) 70 ± 16 70 ± 17 –3 [(–18)–(+28)] NS

AST (U/L) (n = 98) 24 (13–40) 26 (14–44) 5 [(–36)–(+62)] < 0.001

ALT (U/L) (n = 101) 25 (10–40) 28 (12–72) 9 [(–41)–(+106)] < 0.001

γGT (U/L) (n = 86) 24 (6–52) 24 (7–77) 0 [(–39)–(+126)] NS

Creatine kinase (U/L) (n = 88) 110 (48–220) 107 (17–328) –6 [(–85)–(+122)] NS

Results are expressed as mean ± standard deviation for parametric variables or as median and (range) for non-parametric variables. The treatment period was 2–3 months. A total of 8 patients had type 2 diabetes For abbreviations and conversion factors, see Table 1

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by 27% [(–60)–(+27), p < 0.001] in the group with the higher HDL-C levels (between groups p = NS).

TG response to the administration of ezetimibe

We divided the patients in Group 1 into 2 subgroups according to baseline TG levels using 1.7 mmol/L as the cut-off point (i.e. the TG criterion for the NCEP ATP III diagnosis of the metabolic syndrome)1. There were no diabetic patients in this group. The subgroup of patients with the lower baseline TG levels (< 1.7 mmol/L; n = 15) had a non-significant increase by 13% [(–40%)–(+93%)] and those with the higher baseline TG levels (≥ 1.7 mmol/L; n = 10) had a non-significant decrease by 19% [(–52%)–(+24%)] in TG levels. The reductions in TC (–21% vs. –16%) and LDL-C (–28% vs. –24%) levels were greater (but not significantly so) in the group with higher compared with lower baseline TG levels. However, HDL-C changes were significantly different between the 2 subgroups ( p = 0.041). In the subgroup with the lower baseline TG levels, HDL-C (median baseline value = 1.8 mmol/L) decreased by 7% [(–18%)–(+21%)] ( p = 0.033) while HDL-C (median baseline value = 1.4 mmol/L) did not change in the subgroup with high baseline TG levels ( p = NS).

We divided the non-diabetic patients in Group 3 into 2 subgroups according to baseline TG levels using the cut-off point of 1.7 mmol/L (see above): TG < 1.7 mmol/L (n = 71) and ≥ 1.7 mmol/L (n = 29). The subgroup of patients with the lower baseline TG levels had a non-significant decrease by 7% and those with high baseline TG levels had a significant ( p < 0.001) decrease by 25% in TG levels (comparison between the 2 subgroups p = 0.023). TC (–21% vs. –17%) and LDL-C (–31% vs. –27%) reductions were greater (but not significantly so) in the subgroup with the higher compared with lower TG levels. HDL-C levels decreased by 2% ( p = NS) in the group with the lower TG levels (median baseline HDL-C = 1.5 mmol/L) and did not change in the group with high TG levels (median baseline HDL-C = 1.3 mmol/L).

We then divided the population of Group 3 into 2 subgroups using the TG cut-off point of 1.5 mmol/L (the value at which it has been proposed that LDL becomes more dense and, therefore, more atherogenic20): TG < 1.5 mmol/L (n = 53) and ≥ 1.5 mmol/L (n = 47). TG concentration decreased by 7% [1.1(0.5–1.4) vs. 1.0 (0.5–3.5), p = NS] in the subgroup with the lower baseline TG levels and by 20% [1.9 (1.5–3.4) vs. 1.6 (0.7–3.5), p < 0.001] in the subgroup with the higher TG levels. TC (–19% vs. –18%) and LDL-C (–29% vs. –28%) decreased more (but not significantly so) in the subgroup with the higher baseline TG levels compared with the subgroup with the lower baseline TG levels. The effect of ezetimibe on HDL-C levels was marginally different ( p = 0.05) between the 2 subgroups: in the subgroup with the lower baseline TG levels HDL-C decreased by 5% ( p = 0.013) (median baseline HDL-C = 1.6 mmol/L) and HDL-C did not change in the subgroup with higher baseline TG levels ( p = NS) (median baseline HDL-C = 1.4 mmol/L).

Response to ezetimibe according to initial LDL-C decrease achieved with statins

We divided the patients in Group 3 into 2 subgroups according to the median initial decrease in LDL-C levels achieved after the administration of a statin: LDL-C decrease < 39% (n = 30) and ≥ 39% (n = 31) (Table 4). Pre-statin treatment values were not available for 47 patients in this group because they were already on treatment at the time of referral and we could not access these results. Moreover, most of these tests were conducted in other laboratories.

No significant differences in the changes induced by ezetimibe in TC (–17% vs. –13%), LDL-C (–24% vs. –26%), HDL-C (no change vs. +5%) and TG (–17% vs. –8%) levels were observed.

Response to ezetimibe according to the statin used

We divided the patients in Group 3 into 5 subgroups according to the type of statin they received:

Table 4. Response to ezetimibe according to initial response to statins

Initial LDL-C reduction < 39% after statin use (n = 30)

Initial LDL-C reduction ≥ 39% after statin use (n = 31)

p

Δ-TC (%) –17 ± 9 –13 ± 11 NS

Δ-HDL-C (%) 0 [(–24)–(+18)] 5 [(–21)–(+28)] NS

Δ-LDL-C (%) –24 ± 13 –26 ± 17 NS

Δ-TG (%) –17 [(–55)–(+100)] –8 [(–54)–(+218)] NS

LDL-C: low density lipoprotein cholesterol, Δ: change, TC: total cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglycerides NS: not significant

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atorvastatin (n = 55), simvastatin (n = 31), fluvastatin (n = 7), pravastatin (n = 7) and rosuvastatin (n = 8). The changes in TC, LDL-C, HDL-C and TG levels as well as in the LDL-C/HDL-C ratio induced by the addition of ezetimibe did not differ between the subgroups ( p = NS for all).

Response to ezetimibe according to the dose of statin used (Table 5)

We divided the atorvastatin-receiving patients (n = 55) in Group 3 according to the dose of atorvastatin co-administered: lower dose (AL) 10–20 mg/day (n = 33) versus higher dose of atorvastatin (AH) 40–80 mg/day (n = 22). The median decrease in LDL-C levels achieved with ezetimibe was greater (but not significantly so) in the AH (–35%) compared with the AL subgroup (–30%).

We divided the simvastatin-receiving patients (n = 31) in Group 3 according to the dose of simvastatin co-administered: lower dose (SL) 10–20 mg/day (n = 11) versus higher dose of simvastatin (SH) 40–80 mg/day (n = 20). The median decrease in LDL-C levels achieved with ezetimibe was similar in the SL (–31%) and the SH (–30%) subgroups ( p = NS).

Renal function response to ezetimibe

In order to evaluate the effect of ezetimibe on serum creatinine levels, we divided the patients in Group 3 into 3 equal subgroups, as follows: baseline creatinine ≤ 73 µmol/L (n = 23), 73–86 µmol/L (n = 23) and > 86 µmol/L (n = 24). There was a significant trend for a fall in creatinine levels across these tertiles ( p = 0.001).

To investigate the possible relationship between the changes in creatinine levels and those in LDL-C levels following ezetimibe administration, we divided the patients in Group 3 into 2 subgroups according to their median LDL-C change (∆-LDL-C): ∆-LDL-C < 33% (n = 35) and ∆-LDL-C ≥ 33% (n = 35). The 2 subgroups did not differ regarding the creatinine response following the addition of ezetimibe {1% [(–12%)–(+28%)] vs. 2% [(–23%)–(+44%)], p = NS}.

No analysis was conducted for Groups 1 and 2 due to the small sample sizes.

Discussion

This is the first published study to have categorised patients into three groups (cannot tolerate statins, cannot tolerate higher doses of statins and cannot get to the NCEP ATP III LDL-C target of 2.6 mmol/L (100 mg/dL) despite being on a statin). Our results are broadly in agreement with several studies14,21,22 that assessed the efficacy of ezetimibe in patients with primary dyslipidaemia. We showed that ezetimibe, either as monotherapy or when added to a statin, significantly reduces the levels of TC and LDL-C over a period of 2–3 months. Moreover, the atherogenic index LDL-C/HDL-C23 ratio decreased significantly ( p < 0.001) in all groups.

HDL-C levels are inversely associated with the risk of vascular events24–26. In Groups 1 and 3, HDL-C levels were significantly reduced (by 10% and 6%, respectively) in patients with higher baseline HDL-C levels. This is in contrast with the majority of studies, which reported an increase in HDL-C levels9,11. However, the LDL-C/HDL-C ratio always decreased significantly in our study. None of the ezetimibe studies in primary dyslipidaemia specifically evaluated the effect of ezetimibe in patients with ‘high’ baseline HDL-C levels. In 3 studies involving the use of ezetimibe in renal transplant patients27–29, HDL-C concentration fell (significantly in one study29). In all these studies the HDL-C levels were 1.66–1.92 mmol/L (i.e. levels similar to those where a fall in HDL-C was noted in our study).

TG levels are considered an independent risk factor for vascular events30. TG levels were not significantly affected by ezetimibe in Groups 1 and 2, whereas there was a significant 12% decrease in Group 3. When Groups 1 and 3 were divided into 2 subgroups according to the cut-off point of 1.7 mmol/L for baseline TG levels, the higher baseline TG levels decreased by 19% ( p = NS) in Group 1 and by 25% ( p < 0.001) in Group 3. When Group 3 was divided according to a baseline

Table 5. LDL-C response to ezetimibe according to dose of statin co-administered

AL (n = 33) AH (n = 22) p

Δ-LDL-C (%) –30 [(–57)–(+7)] –35 [(–57)–(0)] NS

SL (n = 11) SH (n = 20)

Δ-LDL-C (%) –31 [(–53)–(–10)] –30 [(–47)–(+4)] NS

LDL-C: low density lipoprotein cholesterol, Δ-LDL-C: LDL-C change, AL: low dose (10–20 mg/day) of atorvastatin, AH: high dose (40–80 mg/day) of atorvastatin, SL: low dose (10–20 mg/day) of simvastatin, SH: high (40–80 mg/day) dose of simvastatin NS: not significant

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TG cut-off point of 1.5 mmol/L, a significant decrease in TG levels was maintained (–20%, p < 0.001) in the higher TG group. A TG concentration of 1.5 mmol/L has been proposed as the threshold above which atherogenic small, dense LDL (sdLDL) particles predominate20,31. Patients with TG levels above this ‘threshold’ level had a favourable shift in the LDL subfraction profile when TG levels were reduced by ezetimibe32. A brief report did not find a change in LDL size in 3 patients with ezetimibe33; however, only 1 of these 3 patients had a baseline TG > 1.5 mmol/L. Another study showed that ezetimibe did not change the LDL distribution in 20 patients treated with statins and LDL-apheresis but the median pre-apheresis TG levels were approximately 1.4 mmol/L34.

HDL-C and TG levels are inversely related35,36. We showed that HDL-C levels decreased [by 2%, p = NS (Group 1) and by 5%, p = 0.013 (Group 3)] in patients with the lower baseline TG levels and therefore ‘higher’ HDL-C levels. In contrast, HDL-C levels were not affected in patients with ‘high’ baseline TG levels (who experienced the greatest fall in TG), suggesting that ezetimibe may be useful in patients with elevated TG and low HDL-C levels.

It has been proposed that the initial LDL-C response to a statin predicts the subsequent response to ezetimibe37, hence patients with high rates of cholesterol synthesis and low rates of cholesterol absorption may benefit more from statins and less by ezetimibe38. There was no difference in the LDL-C response to the addition of ezetimibe when our patients were divided according to their initial response to statins.

High doses of statins can induce an increase in cholesterol absorption39, suggesting that ezetimibe may be a more effective cholesterol lowering drug in patients receiving high doses of statins. We found that when higher doses of statins (atorvastatin and simvastatin) were administered, ezetimibe produced a greater decline in LDL-C levels but this difference was not significant possibly due to the small sample size.

The GREek Atorvastatin in Coronary-heart-disease Evaluation (GREACE) study40,41 showed that LDL-C lowering with atorvastatin had favourable effects on renal function. This effect depended on baseline creatinine levels and the extent of fall in LDL-C. In the present study the effect of ezetimibe on serum creatinine levels was dependent on baseline serum creatinine concentration ( p for trend = 0.001). However, no difference was observed in creatinine concentration for different LDL-C reductions after adding ezetimibe. This may be attributed to the small sample size (n = 70) with available paired serum creatinine levels. Because of the limited numbers, we only regard these renal function findings as hypothesis generating.

In terms of side effects, no elevations in AST/ALT > 3-fold ULN were observed in any group. In Group 3 a significant increase was noted by 5% ( p < 0.001) for AST and by 9% ( p < 0.001) for ALT. The clinical relevance of these changes is unclear. CK activity in all 3 groups was not significantly affected by ezetimibe.

Our results showed a large variation in the LDL-C response to ezetimibe possibly due to several factors. These include genetic variations in the Niemann-Pick C1 Like-1 (NPC1L1) protein42–45 responsible for the extraction of cholesterol and phytosterols into enterocytes. Thereafter a small amount of cholesterol and the majority of phytosterols are transported back into the gastrointestinal lumen by ABCG5 and ABCG8 proteins46. Ezetimibe does not influence ABCG5 and ABCG8; however, the efficacy of these transporter proteins (possibly partly genetically determined) may influence the net influx of cholesterol47. Other factors that may interfere with cholesterol absorption are body weight and dietary plant sterols48. Cholesterol absorption efficacy is lower in type 2 diabetic patients compared with obese subjects48. Low cholesterol absorption efficiency and high synthesis may be part of the insulin resistance syndrome48. Our study only included a small number of diabetic patients (n = 8 in the final analysis) to allow subgroup analysis. There is no evidence showing if ezetimibe works more efficiently in the young or elderly49.

The NCEP ATP III guidelines published in 20011 recommended an LDL-C target of 2.6 mmol/L (100 mg/dL) for high-risk individuals. More recently, an optional target of 1.8 mmol/L (70 mg/dL) was set for very high-risk patients2. We showed that ezetimibe achieved the 2.6 mmol/L (100 mg/dL) target in 20% of the patients in Group 1 (as monotherapy), 50% in Group 2 and 67.6% in Group 3. The ‘strict’ 1.8 mmol/L (70 mg/dL) goal was reached by 10% of the Group 2 patients and 24% of the Group 3 patients; none of the patients reached this target in Group 1. Similar findings were reported in other studies8. However, at the time our study started the recommended target for LDL-C was < 2.6 mmol/L (100 mg/dL)1.

Limitations of the present study include the small sample size (especially in Groups 1 and 2), the fact that it is short-term (2–3 months) and that it does not include event-based end-points. Therefore, the results are hypothesis-generating rather than conclusive. Also in Group 3 not all patients were on the highest dose of a statin before administering ezetimibe. This was because in patients with LDL-C values far from the LDL-C value (2.6 mmol/L; 100 mg/dL) used to define inclusion in Group 3, doubling the dose was expected to only provide an approximate 6% additional reduction in LDL-C (the ‘rule of six’)50; it was, therefore, more cost-effective and convenient for the patients to initiate ezetimibe at this stage.

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Conclusions

Ezetimibe can decrease LDL-C levels (–26%) in patients who cannot tolerate statins, in patients who cannot tolerate higher doses of statins (–20%), as well as in patients who cannot get to the LDL-C target despite being on a statin (–29%). A recent meta-analysis (n = 5039 patients) evaluated the decrease in LDL-C after adding ezetimibe to ongoing statin treatment51. It estimated the additional fall in LDL-C to be 23.6% which is compatible with the present findings. Ezetimibe was well tolerated in both our study and the meta-analysis1.

In our study, the reductions in LDL-C resulted in 67.6% of the patients in Group 3 to reach the NCEP ATP III LDL-C target (≤ 2.6 mmol/L; 100 mg/dL). The corresponding percentages for Group 1 and 2 were 20% and 50%, respectively. The remaining biochemical profile of ezetimibe is favourable, especially in patients with ‘high’ TG levels, who experienced a significant decrease (by 19–25%) in TG concentration. Although a fall in HDL-C was seen when baseline values were ‘high’, the LDL-C/HDL-C ratio always improved significantly. Finally, it appears that the addition of ezetimibe to on-going statin treatment may be beneficial to renal function. These findings need to be evaluated in larger and appropriately designed studies.

Acknowledgements

Declaration of interest: This study was conducted independently; no company or institution supported it financially. The authors have attended conferences, participated in advisory boards and trials and given talks sponsored by various pharmaceutical companies.

Dr I. Gazi is supported by a grant from the Hellenic Atherosclerosis Society.

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CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper CMRO-4035_3, Accepted for publication: 18 July 2007Published Online: 09 August 2007doi:10.1185/030079907X226267

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Documents

Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin