Efficacy of Colestimide Coadministered With Atorvastatin in Japanese Patients With Heterozygous Familial Hypercholesterolemia (FH)

Abstract

amilial hypercholesterolemia (FH), is an autosomal dominant disorder that is attributable to a mutated low-density-lipoprotein (LDL) receptor gene, and is characterized by excessively high concentrations of LDL cholesterol (LDL-C), tendon xanthomas, and premature coronary artery disease (CAD). 1 If cholesterol lowering therapy is ineffective, as it is in more than 70% of cases of heterozygous FH in Japan, the patient dies from atherosclerotic cardiovascular disease. The mean age at death is 54 years for men, and 69 years for women. 2 FH is one of the most common disorders causing coronary artery disease at the age of 40 years or less in Japan. 3 Many clinical trials have proven the efficacy of cholesterol-lowering therapy using 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, statins, for the primary and secondary prevention of CAD. [4][5][6][7][8][9] It is also recognized that the increased use of cholesterol-lowering drugs, especially statins, is associCirculation Journal Vol.69, May 2005 ated with improved cardiovascular prognosis of FH. 10 The administration of statins increases the activity of LDL receptors, 11 thus for heterozygous FH patients whose LDL receptor activity is partially impaired, statins are the most effective cholesterol-lowering drugs. Recently, statins such as pravastatin and simvastatin have been superceded in Japan by atorvastatin, which is even more effective in reducing LDL-C. However, because FH is highly refractory to cholesterol-lowering drugs, monotherapy using atorvastatin frequently fails to achieve the target concentrations of LDL-C recommended by the Japan Atherosclerosis Society, 12 the Joint Task Force of European and other Societies 13 and the National Cholesterol Education Program in the United States of America 14 for the primary and secondary prevention of atherosclerotic cardiovascular disorders.Bile-acid-sequestering resins interrupt the enterohepatic circulation of bile acids, resulting in the upregulation of LDL receptors on hepatocytes, especially when used in conjunction with statins. 15,16 Colestimide, a 2-methylimidazoleepichlorohydrin polymer, is a new bile-acid-sequestering resin produced by the Mitsubishi Chemical Corporation, Tokyo, Japan (Fig 1). Its in vitro bile-acid-binding capacity is 4-fold greater than that of the conventionally used bileacid-sequestering resin, cholestyramine. 17 In addition, the clinical use of cholestyramine is limited because of poor patient compliance, mainly because the drug has to be dissolved in water before being taken. In the present study, we examined for the first time the combined effects of

Effects of Late Administration of Immunoglobulin on Experimental Atherosclerosis in Apolipoprotein E-Deficient Mice

“…The therapy was first demonstrated to be effective for an autoimmune disorder (idiopathic thrombocytopenic purpura) 8 and since then, it has been established as effective in the treatment of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki's syndrome, and in the prevention of graft-vs-host disease in recipients of allogenic bone marrow transplants. [8][9][10][11][12][13][14][15][16][17] Benefits have been reported for many other autoimmune and systemic inflammatory conditions, but controlled trials are often lacking.…”

“…16 Accordingly, it may be that plaque is stabilized by this inhibitory receptor. To date, there are no immunomodulating agents available for the prevention of atherosclerosis in the clinical setting, 17,18 even though immune abnormalities are postulated as part of the disease's pathogenesis. Although there are some difficulties in the practical application of this therapy, exploration of the efficacy of this agent in human atherosclerosis appears warranted.…”

Characteristics and Vascular Complications of Familial Hypercholesterolemia in Korea

“…Meanwhile, probucol is more commonly used in Japanese FH patients 46) , with supportive evidence of long-term cardiovascular benefits 49) . In addition, a combination of statins, ezetimibe, and resins showed further lowering of LDL-C levels without serious safety issues in Japan 50,51) . In the future, novel therapeutic agents may improve prognosis in FH patients.…”

Marked Aortic Valve Stenosis Progression After Receiving Long-Term Aggressive Cholesterol-Lowering Therapy Using Low-Density Lipoprotein Apheresis in a Patient With Familial Hypercholesterolemia

“…4-6 FH is highly resistant to conventional drug therapy and high-dose statin combined with other cholesterol-lowering drugs, such as cholesterol-sequestering resin, is frequently needed. 7 Although 2 prospective studies of the prevention of progression of AVS by aggressive cholesterol-lowering therapy using high-dose statin have been reported, 8,9 the results are conflicting.We report a female heterozygous FH patient with marked progression of AVS requiring surgical replacement, despite her LDL-cholesterol level having been controlled by LDL apheresis combined with drug therapy, and her coronary atherosclerosis and saphenous vein graft (SVG) disease have progressed minimally over 20 years. …”

“…[4][5][6] FH is highly resistant to conventional drug therapy and high-dose statin combined with other cholesterol-lowering drugs, such as cholesterol-sequestering resin, is frequently needed. 7 Although 2 prospective studies of the prevention of progression of AVS by aggressive cholesterol-lowering therapy using high-dose statin have been reported, 8,9 the results are conflicting.…”