Further reduction of low-density lipoprotein cholesterol and C-reactive protein with the addition of ezetimibe to maximum-dose rosuvastatin in patients with severe hypercholesterolemia

Stein, Evan A.; Ose, Leiv; Retterstøl, Kjetil; Tonstad, Serena; Schleman, Margo; Harris, Susan S.; Sager, Philip T.

doi:10.1016/j.jacl.2007.07.003

Cited by 26 publications

(11 citation statements)

References 23 publications

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“…The similar reductions in apolipoprotein B, lipoprotein(a), and LDL cholesterol are in contrast with those obtained with other commonly used LDL cholesterol-reducing agents, such as statins, ezetimibe, and bile acid sequestrants, with which apolipoprotein B reductions are usually 6% below the LDL cholesterol decrease and lipoprotein(a) is reduced minimally if at all. 4,5,22 Although the clinical significance of this enhanced apolipoprotein B reduction with mipomersen remains to be evaluated, studies suggest that apolipoprotein B levels predict initial and residual CAD risk better than LDL cholesterol. 23 On the basis of such evidence, treatment targets for apolipoprotein B have been incorporated into several guidelines.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia

et al. 2012

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Background— Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease. Methods and Results— This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (−28.0% [−34.0% to −22.1%] compared with 5.2% [−0.5% to 10.9%] increase with placebo; P <0.001). Mipomersen significantly reduced apolipoprotein B (−26.3%), total cholesterol (−19.4%), and lipoprotein(a) (−21.1%) compared with placebo (all P <0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo ( P <0.001). Conclusions— Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00706849.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia

et al. 2012

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“…6 -8 However, despite the ability of these drugs in combination to reduce LDL-C levels by 50% to 65%, many HeFH patients are still unable to achieve recommended LDL-C targets. 9,10 The role of PCSK9, a secreted protease involved in regulating hepatic LDL receptor activity, is now well established through human genetic and animal models. 11 Blocking PCSK9 binding to the LDL receptor with a monoclonal antibody has recently been shown to be effective in lowering LDL-C in humans.…”

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Low-Density Lipoprotein Cholesterol–Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia

Raal

Scott²,

Somaratne³

et al. 2012

Circulation

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Background-Despite statin treatment, many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol (LDL-C) targets. AMG 145, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease, demonstrated significant reductions in LDL-C in phase 1 studies. This phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients. Methods and Results-Patients

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“…However, the majority of patients on statins still suffer from cardiovascular events (27). In many patients, statin treatment fails to achieve target LDL-C levels (1,45). Some patients with familial hypercholesterolemia respond poorly, or not at all, to statin therapy (34).…”

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New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism

Miyosawa

Watanabe

Murakami

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Despite significant reduction of cardiovascular events by statin treatment, substantial residual risk persists, driving emerging needs for the development of new therapies. We identified a novel cholesteryl ester transfer protein (CETP) inhibitor, K-312, that raises HDL and lowers LDL cholesterol levels in animals. K-312 also suppresses hepatocyte expression of proprotein convertase subtilisin/kexin 9 (PCSK9), a molecule that increases LDL cholesterol. We explored the underlying mechanism for the reduction of PCSK9 expression by K-312. K-312 inhibited in vitro human plasma CETP activity (IC50; 0.06 M). Administration of K-312 to cholesterol-fed New Zealand White rabbits for 18 wk raised HDL cholesterol, decreased LDL cholesterol, and attenuated aortic atherosclerosis. Our search for additional beneficial characteristics of this compound revealed that K-312 decreases PCSK9 expression in human primary hepatocytes and in the human hepatoma cell line HepG2. siRNA silencing of CETP in HepG2 did not compromise the suppression of PCSK9 by K-312, suggesting a mechanism independent of CETP. In HepG2 cells, K-312 treatment decreased the active forms of sterol regulatory element-binding proteins (SREBP-1 and -2) that regulate promoter activity of PCSK9. Chromatin immunoprecipitation assays demonstrated that K-312 decreased the occupancy of SREBP-1 and SREBP-2 on the sterol regulatory element of the PCSK9 promoter. PCSK9 protein levels decreased by K-312 treatment in the circulating blood of cholesterol-fed rabbits, as determined by two independent mass spectrometry approaches, including the recently developed, highly sensitive parallel reaction monitoring method. New CETP inhibitor K-312 decreases LDL cholesterol and PCSK9 levels, serving as a new therapy for dyslipidemia and cardiovascular disease. cholesteryl ester transfer protein; proprotein convertase subtilisin/ kexin 9; atherosclerosis; sterol regulatory element-binding protein; lipoproteins; mass spectrometry; parallel reaction monitoring

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Further reduction of low-density lipoprotein cholesterol and C-reactive protein with the addition of ezetimibe to maximum-dose rosuvastatin in patients with severe hypercholesterolemia

Cited by 26 publications

References 23 publications

Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia

Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia

Low-Density Lipoprotein Cholesterol–Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia

New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism

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