Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study

被引：579

作者：

Cuchel, Marina ^{[1
,2
]}

Meagher, Emma A. ^{[2
]}

Theron, Hendrik du Toit ^{[3
]}

Blom, Dirk J. ^{[4
,6
]}

Marais, A. David ^{[5
,6
]}

Hegele, Robert A. ^{[7
,8
]}

Averna, Maurizio R. ^{[9
]}

Sirtori, Cesare R. ^{[10
]}

Shah, Prediman K. ^{[11
,12
]}

Gaudet, Daniel ^{[13
]}

Stefanutti, Claudia ^{[14
]}

Vigna, Giovanni B. ^{[15
]}

Du Plessis, Anna M. E. ^{[16
]}

Propert, Kathleen J. ^{[2
]}

Sasiela, William J. ^{[17
]}

Bloedon, LeAnne T. ^{[2
,17
]}

Rader, Daniel J. ^{[2
]}

机构：

[1] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Cardiovasc Inst, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Med, Philadelphia, PA 19104 USA

[3] Netcare Private Hosp, Bloemfontein, South Africa

[4] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa

[5] Univ Cape Town, Dept Chem Pathol, ZA-7925 Cape Town, South Africa

[6] Cape Heart Grp, Med Res Council S Africa, Cape Town, South Africa

[7] Univ Western Ontario, Robarts Res Inst, London, ON, Canada

[8] Univ Western Ontario, Schulich Sch Med & Dent, London, ON, Canada

[9] Univ Palermo, Palermo, Italy

[10] Osped Maggiore Niguarda, Milan, Italy

[11] Cedars Sinai Heart Inst, Div Cardiol, Los Angeles, CA USA

[12] Cedars Sinai Heart Inst, Atherosclerosis Res Ctr, Los Angeles, CA USA

[13] Univ Montreal, Dept Med, Chicoutimi, PQ, Canada

[14] Univ Roma La Sapienza, Extracorporeal Therapeut Tech Unit, Dept Mol Med, Rome, Italy

[15] Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy

[16] Univ Pretoria, Clin Res Unit, ZA-0002 Pretoria, South Africa

[17] Aeger Pharmaceut, Cambridge, MA USA

来源：

LANCET | 2013年 / 381卷 / 9860期

基金：

英国医学研究理事会;

关键词：

LDL-APHERESIS; LIVER-TRANSPLANTATION; ATORVASTATIN; SIMVASTATIN; EZETIMIBE;

D O I：

10.1016/S0140-6736(12)61731-0

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8.7 mmol/L [SD 2.9]) to week 26 (4.3 mmol/L [2.5]; p<0.0001). Levels of LDL cholesterol were lower than 2.6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0.0001) at week 56 and 38% (-52 to -24; p<0.0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia.

引用

页码：40 / 46

页数：7

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