Ezetimibe: cholesterol lowering and beyond

Figures & data

Figure 1. Overview of cholesterol metabolism.

ApoB: Apolipoprotein B; CE: Cholesterol ester; CETP: Cholesteryl ester transfer protein; chol: Cholesterol; CM: Chylomicron;

CMr: Chylomicron remnant; IDL: Intermediate-density lipoprotein; LCAT: Lecithin-cholesterol acetyltranferase; NPC1L1: Niemann–Pick C1-like 1 protein; SR-BI: Scavenger receptor type BI; TG: Triglyceride; VLDL: Very-low-density lipoprotein.

Figure 2. Hepatic cholesterol synthesis and lipoprotein packaging.

Adapted with permission from [2].

Figure 3. Analogy of free cholesterol packaging into apolipoprotein B-containing lipoproteins in peripheral tissue, liver and intestine.

The esterification and lipoprotein packaging of cholesterol by the liver (hepatocyte) and intestine (enterocyte), occur intracellularly. Peripheral cholesterol transport via HDL particles occurs in the plasma.

ACAT: Acyl-CoA:cholesterol acyl transferase; CETP: Cholesteryl ester transfer protein; LCAT: Lecithin-cholesterol acyltransferase; MTP: Microsomal triglyceride transfer protein; VLDL: Very-low-density lipoprotein.

Reproduced with permission from [2].

Figure 4. Peripheral cholesterol transport.

ABCA1: Adenosine triphosphate-binding cassette transporter; ApoA-I : Apolipoprotein A-I; B100: Apolipoprotein B-100-containing lipoproteins; B48: Apolipoprotein B-48-containing lipoproteins; CE: Cholesterol ester; CETP: Cholesteryl ester transfer protein; CM: Chylomicron; CMr: Chylomicron remnant; FC: Free cholesterol; IDL: Intermediate-density lipoprotein; LCAT: Lecithin-cholesterol acyltransferase; LDLR: LDL receptor; NPC1L1: Niemann–Pick C1-like 1 protein; SR-BI: Scavenger receptor type BI; TG: Triglyceride; VLDL: Very-low-density lipoprotein.

Figure 5. NPC1L1 controls cholesterol absorption in the intestine and is the target of ezetimibe.

ACAT: Acyl-CoA:cholesterol acyltransferase; NPC1L1: Niemann–Pick C1-like 1 protein.

Figure 6. Complementary mechanisms of action lead to broader lipid control.

ApoA-I: Apolipoprotein A-I; B100: Apolipoprotein B-100-containing lipoproteins; B48: Apolipoprotein B-48-containing lipoproteins; CE: Cholesterol ester; CETP: Cholesteryl ester transfer protein; chol: Cholesterol; CM: Chylomicron; CMr: Chylomicron remnant; IDL: Intermediate-density lipoprotein; LCAT: Lecithin-cholesterol acetyltransferase; LDLR: LDL receptor; NPC1L1: Niemann–Pick C1-like 1 protein; SR-BI: Scavenger receptor type BI; TG: Triglyceride; VLDL: Very-low-density lipoprotein.

Figure 7. Dose–response effect of ezetimibe monotherapy.

*p < 0.05 versus placebo.

EZE: Ezetimibe.

Reproduced with permission from [51].

Figure 8. Ezetimibe add-on to statin therapy.

^*p < 0.001; ^**p < 0.05; ^***p < 0.01.

HDL-C: High-density lipoprotein-cholesterol; LDL-C: Low-density lipoprotein-cholesterol; TG: Triglyceride.

Reproduced with permission from [54].

Figure 9. C-reactive protein and inflammation.

CRP: C-reactive protein.

Figure 10. Effect of ezetimibe, simvastatin and ezetimibe/simvastatin on RLP-C.

^*p < 0.001 EZE/SIMVA versus same dose SIMVA.

^**p < 0.05 EZE/SIMVA versus same dose SIMVA.

^‡p < 0.05 EZE/SIMVA versus next highest dose SIMVA.

EZE: Ezeteimibe; RLP-C: Remnant-like particle cholesterol; SIMVA: Simvastatin.

Adapted with permission from [65].

Figure 11. Cardiovascular disease risk factors and association with phytosterols and cholesterol synthesis precursors.

Adapted with permission from [122].

Figure 12. Ezetimibe and statin effect on phytosterol concentrations.

^* p < 0.001 versus placebo.

^‡p < 0.001 versus pooled SIMVA.

^§p < 0.05 versus EZE.

^¶p < 0.001 versus EZE.

^#p < 0.001 versus pooled ATORVA.

ATORVA: Atorvastatin; EZE: Ezetimibe; SIMVA: Simvastatin.

Adapted with permission from [129].

Figure 13. Ezetimibe and statin effects on cholesterol precursors.

^*p < 0.001 versus placebo.

^‡p < 0.05 versus placebo.

^§p < 0.05 versus EZE.

^¶p < 0.001 versus EZE

ATORVA: Atorvastatin; EZE: Ezetimibe; SIMVA: Simvastatin.

Adapted with permission from [129].

Table 1. ABC transporters and disease.

Transporter	Location	Function	Disease/disorder caused by dysfunction of transporter
ABC A1	Plasma membranes of multiple body tissues including macrophages, liver, placenta, adipose tissue and spleen	Transports phospholipids and cholesterol, and is believed to be a rate-limiting step in cholesterol transport from the peripheral tissue to the liver	Tangier disease Familial HDL deficiency
ABC G5	Liver and intestine	Transports intestinally absorbed cholesterol and plant sterols/stanols	Sitosterolemia
ABC G8	Liver and intestine	Transports intestinally absorbed cholesterol and plant sterols/stanols	Sitosterolemia

ABC: Adenosine-binding cassette.

Adapted with permission from [2].

Table 2. Ezetimibe monotherapy studies.

Study (year)	Treatment			% difference compared with placebo^* (mg/dl)				Ref.
	n	Weeks	mg	LDL-C	TG	HDL-C	ApoB
Sudhop et al. (2002)	18	2	E 10	-22.3^‡	-2.7	2.2	ND	[47]
Bays et al. (2001)	432	6	E 5 E 10	-15.7^§ -18.5^§#	ND	2.9^¶ 3.5^¶	ND	[48]
Dujovne et al. (2002)	816	12	E 10	-17.2^§	-11.4^§	2.9^§	-14.1^§	[49]
Knopp et al. (2003)	827	12	E 10	-18.5^§	-4.1	2.3^§	-14.3^§	[50]

^*Based on difference of individual LS means for LDL-C, HDL-C and Apo B, and on difference of individual medians for TG.

^‡p < 0.001 versus placebo.

^§p < 0.01.

^¶p < 0.05.

^#p < 0.05 versus 5 mg ezetimibe.

Apo B: Apolipoprotein B; E: Ezetimibe; HDL-C: HDL-cholesterol; LDL-C: LDL-cholesterol; ND: Not determined; TG: Triglyceride.

Table 3. Ezetimibe combination studies.

Study (year)	Treatment			% difference compared with placebo or indicated statin^### (mg/dl)						Ref.
	n	Weeks	mg	LDL-C	TG	HDL-C	Non-HDL-C	ApoB	hsCRP (mg/l)
Add-on studies^*
Gagne et al. (2002)	769	8	All E/Stat^** vs placebo	-21.3^#	-11.4^#	1.7^§	-19.9^#	-15.6^#	-9.7^§	[54]
Pearson et al. (2005)	3030	6	All E/Stat^‡‡ vs placebo	-23.1^#	-11.5^#	2.1^#	-20.6^#	-16.3^#	-10.0^#	[55]
Masana et al. (2005) (extension of [54])	433	12	All E/S^§§ vs placebo	-27.0^#	-13.8^#	2.6	-25.3^#	-13.9^¶¶¶	-14.3^¶¶¶	[56]
Combination studies^‡
Davidson et al. (2004)	2382	12	All E/Stat^¶¶ vs All Stat^¶¶	-13.3^¶	-9.0^¶	2.9^¶	-13.0^¶	-10.6^¶	ND	[57]
Davidson et al. (2002)	668	12	All E/S^## vs All S^##	-13.8^¶	-7.4^¶	2.4^§	-13.5^¶	-10.9^¶	ND	[58]
Goldberg et al. (2004)	887	12	All E/S^## vs All S^##	-14.8^#	-12.8^#	0.6	-14.4^#	-12.9^#	-24.6^#	[59]
Feldman et al. (2004)	710	5	E/S10 vs S 20	-9.0^#	-0.0	1.1	-8.0^#	-6.0^#	ND	[60]
		5	E/S 20 vs S 20	-15.0^#	-6.0^§	2.9^§	-14.0^#	-11.0^#	ND
		5	E/S 40 vs S 20	-21.0^#	-11.0^#	2.3	-19.0^#	-17.0^#	ND
Ballantyne et al. (2004)	788	6	E/S 10 vs A 10	-8.9^§	-3.3	2.9^§	-7.6^§	-6.0^§	ND	[61]
		6	E/S 20 vs A 10	-13.1^§	-2.6	4.4^§	-11.1^§	-9.5^§	ND
		12	E/S 20 vs A20	-5.9^§	0.9	2.1	-4.6^§	-2.9^§	ND
		12	E/S 40 vs A20	-10.0^§	-3.1	5.5^§	-8.7^§	-7.2^§	ND
		18	E/S 40 vs A 40	-6.5^§	0.7	3.6^§	-5.1^§	-3.0^§	ND
		24	E/S 80 vs A 80	-6.9^§	-0.9	5.8^§	-5.0^§	-3.4^§	ND
Sager et al. (2003) (Post hoc of [58])	575	12	All E 10 vs placebo	-17.8^§	-12.4^¶	4.5^¶	ND	-15.7^¶	-10.3	[62]
			All E/S^## vs All S^##	-14.3^¶	-9.8^¶	2.5^¶	ND	-11.5^¶	-16.6^¶
Sager et al. (2005) (Post hoc of [58] and [59])	575	12	All E/S^## vs All S^##	-14.8^¶	-10.5^¶	1.5	ND	-12.0^¶	-19.0^¶	[63]
Ballantyne et al. (2003)	1703	12	All E/A^*** vs All A^***	-12.1^¶	8.0^¶	3.0^¶	-11.2^¶	-9.3^¶	-10.0^¶	[64]
Combination tablet^‡
Bays et al. (2004)	1528	12	All E/S^## vs All S^##	-14.0^#	-3.5^#	0.4	-12.7^#	-10.7^#	-14.3^#	[65]
Ballantyne et al. (2005)	1902	6	All E/S^## vs All A^***	-8.1^#	-1.4	3.6^#	ND	ND	-0.3	[66]
Catapano et al. (2006)	2959	6	All E/S^‡‡‡ vs All R^§§§	-4.2^#	-2.7^#	0.0	-4.1^#	-2.9^#	-2.9	[67]

^*Baseline measured at time of ezetimibe or placebo add-on to ongoing stable statin therapy.

^‡Baseline measured following placebo run-in prior to active treatment.

^§p < 0.05.

^¶p < 0.01.

^#p < 0.001 for ezetimibe or ezetimibe/statin vs placebo or indicated statin.

^**Simvastatin (10, 20, 40, 80 mg), atorvastatin (10, 20, 40, 80 mg), lovastatin (10, 20, 40 mg), pravastatin (10, 20, 40 mg), fluvastatin (20, 40, 80 mg), cerivastatin (0.2, 0.3, 0.4, 0.8 mg).

^‡‡Atorvastatin (10, 20, 40, 80 mg), simvastatin (10, 20, 40, 80 mg), pravastatin (20, 40 mg), other statins.

^§§Dose of simvastatin equipotent to patient’s current statin therapy.

^¶¶10, 20, 40 mg of atorvastatin, simvastatin, pravastatin or lovastatin.

^##Simvastatin (10, 20, 40, 80 mg).

^***Atorvastatin (10, 20, 40, 80 mg).

^‡‡‡Simvastatin (20, 40, 80 mg).

^§§§Rosuvastatin (10, 20, 40 mg).

^¶¶¶48 weeks.

^###Based on difference of individual LS means for LDL-C, HDL-C, non-HDL-C and Apo B, and on difference of individual medians or nonparametric analysis for TG and hsCRP.

A: Atorvastatin; Apo B: Apolipoprotein B; E: Ezetimibe10 mg; HDL-C: HDL-cholesterol; hsCRP: High-sensitivity C-reactive protein; LDL-C: LDL-cholesterol; ND: Not determined; R: Rosuvastatin; S: Simvastatin; Stat: Statins; TG: Triglyceride.

Table 4. Clinical outcome studies.

Study	Treatment	Clinical end points	Population	Ref.
SEAS	Combination ezetimibe 10 mg plus simvastatin 40 mg vs placebo	Composite of major CVD events and progression of existing aortic stenosis	n = 1873 pateints with asymptomatic aortic stenosis	[135]
SHARP	Combination ezetimibe 10 mg plus simvastatin 20 mg vs placebo	Incidence of stroke, myocardial infarction and revascularization	n = 9000 patients with chronic kidney disease	[136]
IMPROVE-IT	Ezetmibe/simvastatin 10/40 mg combination tablet vs simvastatin 40 mg	CVD outcomes	n = 10,000 patients with acute coronary syndrome	[137]

CVD: Cardiovascular disease; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SEAS: Simvastatin and Ezetimibe in Patients with Aortic Stenosis; SHARP: Study of Heart and Renal Protection.

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