Treatment Drug Therapy

Journal of Atherosclerosis and Thrombosis Vol.15, No.4 167 Committee Report 8

Treatment─Drug Therapy

Tamio Teramoto, Jun Sasaki, Hirotsugu Ueshima, Genshi Egusa, Makoto Kinoshita, Kazuaki Shimamoto, Hiroyuki Daida, Sadatoshi Biro, Kazuhiko Hirobe, Tohru Funahashi, Koutaro Yokote, and Masayuki Yokode

Committee for Epidemiology and Clinical Management of Atherosclerosis

J Atheroscler Thromb, 2008; 15:167-178.

The basis of treatment either for primary or sec- menopausal female, they may be treated with lifestyle ondary prevention is through the modification of life- modification alone, even if target management lipid style such as correction of dietary habits, increase in levels are not attained. Drug therapy should be con- physical activities, maintenance of an appropriate body sidered only if management targets cannot be attained weight, and smoking cessation. Concerning primary even after the continuation of guidance aimed to prevention, in particular, it is necessary to perform improve lifestyle for 3-6 months depending on the treatments by accurately evaluating risk factors of ath- level of risk. erosclerosis and stratifying patients according to their On the basis of the results of many overseas risk. For this purpase, it is important to evaluate not large-scale clinical trials using statins, the effectiveness only the presence or absence of coronary artery disease of lipid-lowering therapy targeted to dyslipidemia, par- (CAD) and the LDL-C level, but also other coexisting ticularly high-LDL-cholesterolemia, for the primary2-7) major risk factors, i.e., atherosclerotic disorders other and secondary8-14) prevention of CAD has been dem- than CAD such as cerebrovascular diseases and arte- onstrated (Table 1). In HPS (partially including riosclerosis obliterans, and to perform risk stratifica- secondary prevention)4, 15), ASCOT-LLA6), CARDS7), tion and lipid management based on the guideline. and other studies, LDL-C-lowering therapy using However, for secondary prevention, stringent inter- statins showed significant preventive effects against vention is always required, and the necessity of drug stroke as well as CAD in high-risk groups. These trials therapy is greater than for primary prevention. have also demonstrated that lipid lowering therapy were equally effective regardless of age, gender, and the presence or absence of diabetes or hypertention. 1. Primary Prevention In Japan (Table 2), KLIS16) in males with hyer- 1) LDL-C Lowering cholesterolemia and PATE17) in elderly subjects (par- The relationship between the LDL-C level and tially including secondary prevention) were reported relative risk of CAD is similar among Japan and West- as studies using pravastatin for primary prevention. ern countries, but there was controversy regarding the While these studies suggested the effectiveness of LDL- effectiveness of LDL-C-lowering therapy for the pre- C-lowering therapy for primary prevention, problems vention, particularly primary prevention, of CAD in such as the inadequate randomization for KLIS and Japanese population, because their absolute risk was the insufficient size of the cohort for PATE have been lower than those in Western populations. However, raised. As mentioned earlier, MEGA1), a large-scale MEGA (Management of Elevated Cholesterol in the study on primary prevention, was also reported in Primary Prevention Group of Adult Japanese)1), a Japan, showing a 33% decrease in CAD though an large-scale clinical trial conducted in Japan, confirmed 18% reduction in the LDL-C level. In this study, 68% the significance of LDL-C-reducing therapy using of the subjects were female, but no significant gender statin for primary prevention in Japanese, as men- difference was noted in any endpoint concerning the tioned below. However, drug therapy for primary pre- therapeutic effect, and the statin treatment was con- vention should not be performed without adequate firmed to be effective in females as well as males. In risk evaluation. Drug therapy for LDL-C lowering addition, the data during the first 5 years indicated should be performed in those at high risk. Because the significant decreases in stroke morbidity and total mor- risk is low particularly in young patients and pre- tality rates. 168 Teramoto et al. Treatment ─ Drug Therapy 169

Table 1. Representative foreign large-scale clinical studies using statins

Dose Number of subjects Mean age Females Diabetics History of myocardial Duration Study name Drug used (mg/day) (treated group/control group) (years) (%) (%) infarction (%) (years)

WOSCOPS Pravastatin 40 3,302/3,293 55 0 1 0 4.9 AFCAPS/TexCAPS Lovastatin 20-40 3,304/3,301 58 15 2 0 5.2 ALLHAT-LLT Pravastatin 40 5,170/5,185 66 49 35 0 4.8 ASCOT-LLA Atorvastatin 10 5,168/5,137 63 19 25 0 3.3 CARDS Atorvastatin 10 1,428/1,410 61 32 100 0 3.9 HPS Simvastatin 40 10,269/10,267 (40-80) 25 29 41 5 PROSPER Pravastatin 40 2,891/2,913 75 52 11 13 3.2 4S Simvastatin 20-40 2,221/2,223 59 19 5 79 5.4 CARE Pravastatin 40 2,081/20,78 59 14 14 100 5 LIPID Pravastatin 40 4,512/4,502 62 17 9 64 6.1 CCLA 45,054/45,002 24 21 32 4.7

Table 2. Representative large-scale clinical studies in Japan

Dose Number of subjects Mean age Females Diabetics History of myocardial Duration Study name Drug used (mg/day) (treated group/control group) (years) (%) (%) infarction (%) (years)

KLIS Pravastatin 10-20 2,219/1,634 58 0 23 0 5 PATE Pravastatin 10-20 331/334＊ 73 79 30 3 3.9 MEGA Pravastatin 10-20 3,966/3,866 58 68 21 0 5.3 JELIS Ethyl icosapentate 1,800 9,326/9,319 61 68 16 20 4.6 ＊: A low-dose group at 5 mg/day

Table 3. Representative foreign large-scale clinical studies using fibrates

Dose Number of subjects Mean age Females Diabetics History of myocardial Duration Study name Drug used (mg/day) (treated group/control group) (years) (%) (%) infarction (%) (years)

Helsinki Heart study Gemfibrozil 1,200 2,051/2,030 47 0 2.6 0 5 FIELD Fenofibrate 200 4,895/4,900 62 37 100 5 5 VA-HIT Gemfibrozil 1,200 1,264/1,267 64 0 24 61 5.1 BIP Bezafibrate 400 1,548/1,542 60 9 10 79 6.2

LDL-C-lowering therapy using statins has also of cerebral infarction in hyperlipidemic patients, was been suggested to have a primary preventive effect initiated in 2004 and is currently in progress. The Jap- against stroke similar to that against CAD15, 18-24). anese guidelines for the treatment of stroke27) recom- SPARCL25), intended to evaluate the preventive effect mend the administration of statins for the prevention of atorvastatin against stroke recurrence in patients of cerebral infarction in patients with CAD. with no history of CAD. It was shown to be effective for the prevention of cerebral infarction. However, 2) Treatment of Dyslipidemia other than High increase in cerebral hemorrhage indicated by the same LDL-C study warrants further evaluation in the future. Large-scale clinical studies trials in patients with In Japan, also, J-STARS26), aimed to evaluate the hypertriglyceridemia and low HDL-cholesterol not preventive effect of pravastatin against the recurrence accompanied by high LDL-cholesterolemia have not 168 Teramoto et al. Treatment ─ Drug Therapy 169

NS: not significant, NA: not available TC (mg/dL) LDL-C (mg/dL) Relative risk of CVD (% reduction) Year of Before After treatment Before After treatment Major cardiovascular Stroke Cardiovascular Total publication treatment (% decrease) treatment (% decrease) events (lethal/non-lethal) deaths deaths

272 218 (－20) 192 142 (－26) －32 NS －32 －22 1995 221 184 (－17) 150 115 (－25) －37 NA －32 NS 1998 224 184 (－17) 146 105 (－28) NS NS NS NS 2002 213 163 (－24) 131 90 (－31) －36 －27 NS NS 2003 207 159 (－23) 118 82 (－31) －37 －48 NA NS 2004 226 NA 130 89 (－32) －27 －25 －17 －13 2002 220 NA 147 98 (－33) －19 NS NS NS 2002 261 196 (－25) 188 123 (－35) －34 －30 －42 －30 1994 209 167 (－20) 139 97 (－32) －24 －31 NS NS 1996 218 179 (－18) 150 112 (－25) －24 －19 －34 －22 1998 －23 －17 －19 －12 2005

254 215 (－15) 169 132 (－22) NS NS NS NS 2000 253 209 (－16) 166 125 (－25) NS NA NA NS 2001 243 215 (－12) 157 128 (－18) －33 NS NS NS 2005 275 182 －19 NS －24 NS 2005

270 247 (－9) 189 173 (－9) －34 NA NS NS 1987 195 164 (－15) 119 94 (－21) NS NS NS NS 2005 175 170 (－4) 111 111 (0) －22 －29 NS NS 1999 212 202 (－5) 148 139 (－7) NS NS NS NS 2000

provided evidence as reliable as that supporting LDL- CAD, but it was effective for the prevention of non- C-lowering therapy (Table 3)28-32). As for fibrates, fatal cardiovascular events. which most effectively reduce the TG level as well as In JELIS35), performed in Japan to evaluate the increase the HDL-C level, the Helsinki Heart Study 83) effect of ethyl icosapentate (EPA), in which the sub- showed that Gemfibrozil (not approved in Japan) was jects were patients with high LDL-cholesterol (14,981 effective for the primary prevention of cardiovascu- primary prevention and 3,664 secondary prevention lar events. In FIELD34), in which the subjects were case), the incidence of major coronary artery events patients with type 2 diabetes mellitus (7,664 primary after 5 years was 19% lower in the group administered prevention and 2,131 secondary prevention cases), a statin with EPA than in the group administered a fibrates were not shown to be effective for the preven- statin alone. No difference was noted in the mortality tion of the primary endpoint including death due to rate from CAD. The treatment was significantly effec- 170 Teramoto et al. Treatment ─ Drug Therapy 171

Table 4. Representative clinical studies which aggressive lipid-reducing therapy

Dose Mean age Females Diabetics History of myocardial Duration Study name Drug used Number of subjects (mg/day) (years) (%) (%) infarction (%) (years)

Pravastatin 40 2,063 PROVE-IT 58 22 18 100 2 Atorvastatin 80 2,099 Atorvastatin 10 5,006 TNT 61 19 15 58 4.9 Atorvastatin 80 4,995 Simvastatin 20 4,449 IDEAL 62 81 12 17 4.8 Atorvastatin 80 4,439

tive for the prevention of major coronary artery events tion of the progression of coronary atherosclerosis by in the secondary-prevention or high-risk group but LDL-C-lowering therapy was reported. Their meta- was not significantly effective for primary prevention, analyses indicated that a lower LDL-C level during although an 18% decrease in the incidence of major treatment is associated with larger degree of prevention coronary artery events was noted. These results suggest of the progression of coronary atherosclerosis43, 44). that the use of EPA may be recommended for the Furthermore, REVERSAL45) and ASTEROID46), in treatment of high-risk group as well as the use of statin which coronary plaques were examined using intravas- in Japan. cular ultrasonography (IVUS), suggested that aggressive LDL-C-lowering therapy leads to prevention of the progression, and induction of the regression, of 2. Secondary Prevention coronary plaques. The combined use of statins and 1) LDL-Cholesterol nicotinates shows to have a potent LDL-C-reducing Among large-scale clinical trials in secondary and HDL-C-increasing effects. HATS47) showed a prevention, those including 4S, CARE, and LIPID 42% decrease in the LDL-C level and a 26% increase established the effectiveness of statin therapy. Recently, in the HDL-C level after combined therapy in patients the safety and effectiveness of statin administration in with CAD. This combination therapy has also revealed acute coronary syndrome (ACS), which had been to prevent the progression of atherosclerotic lesions by excluded from large-scale clinical trials in the past, also quantitative coronary angiography (QCA). have been demonstrated, gradually establishing the As for evidence of secondary prevention in a Jap- importance of strict lipid management early after the anese population evaluating the regression of coronary onset of ACS36-40). PROVE-IT TIMI-2236) compared atherosclerosis by coronary angiography, LDL-C-low- moderate and intensive LDL-C-lowering therapies for ering therapy was reported to prevent the progression ACS, showed the effectiveness of intensive LDL-C- of coronary atherosclerosis similarly to overseas stud- lowering therapy for secondary prevention. Moreover, ies48, 49). Among intervention studies using IVUS, the TNT41) also indicated the effectiveness of intensive one by Takagi et al. was reported first in the world50), LDL-C-lowering therapy for the treatment of chronic showing prevention of the progression of coronary CAD compared with conventional lipid-lowering atherosclerosis. Recently, ESTABLISH51) reported that therapy (Table 4). However, IDEAL42), which also the progression of coronary plaques was prevented, or evaluated the effects of aggressive treatment in patients its regression was promoted, by aggressive LDL-C- with stable CAD in the stable phase, could not estab- lowering therapy in patients with ACS. Concerning lish the effectiveness of the therapy at the primary the secondary preventive effect of statins against acute endpoint including death due to CAD. Thus, no suf- myocardial infarction, MUSASHI-AMI10) was report- ficient consensus has been reached concerning inten- ed, and the effectiveness of LDL-C-lowering therapy sive LDL-C-lowering therapy, and sufficient consider- against CAD is being established in Japan as well as in ation of medical cost as well as the safety and effective- Western countries. ness is necessary. Many clinical studies using coronary angiography have been performed since the 1990s, and inhibi- 170 Teramoto et al. Treatment ─ Drug Therapy 171

NS: not significant LDL-C (mg/dL) Refative risk of CVD (% redactum) (% decrease) Year of Major cardiovascular Stroke Cardiovascular Total Before treatment After treatment publication events (lethal/non-lethal) deaths deaths 106 95 －16 NS NS NS 2004 106 62 158 101 －22 －25 NS NS 2005 158 77 121 104 NS NS NS NS 2006 122 81

Table 5. Characteristics of the drugs for dyslipidemia Classification LDL-C TC TG HDL-C Generic names of major drugs Statins ↓↓↓ ↓↓ ↓ ↑ Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, Pitavastatin, Rosuvastatin Anion exchange resin ↓↓ ↓ － ↑ Cholestyramine, Cholestimide Fibrates ↓ ↓ ↓↓↓ ↑↑ Clofibrate, Clinofibrate, Bezafibrate, Fenofibrate Nicotinates ↓ ↓ ↓↓ ↑ Tocopherol nicotinate, Nicomol, Niceritrol Probucol ↓ ↓ － ↓↓ Probucol EPA －－ ↓ － Ethyl icosapentate

↓↓↓: ≦－25%, ↓↓: －20-25%, ↓: －10-20%, ↑: 10-20%, ↑↑: 20-30%, ↑↑↑: ≧30%, －: －10-10%

2) Treatment of Dyslipidemia other than High for dyslipidemia are described below. LDL-C In BIP, a secondary prevention study using bezaf- 1) HMG-CoA Reductase Inhibitors (Statins): Prava- ibrate, the effectiveness of treatment concerning the statin, Simvastatin, Fluvastatin, Atorvastain, primary endpoint could not be established. However, Pitavastatin, Rosuvastatin when subjects were limited to those with a TG level Type Ⅱa and Ⅱb hyperlipidemia, in which the of 200 mg/dL or higher, the therapeutic effect was LDL-C level increases, and type Ⅲ hyperlipidemia, in dependent on the TG level. Sub-analysis of BIP30) also which remnant lipoproteins increase, are indications. showed that bezafibrate was effective for the secondary Since statins were shown to be effective for the prevention of myocardial infarction in patients with treatment of familial hypercholesterolemia52), they have metabolic syndrome. Therefore, bezafibrate is expected been the most effective drugs to reduce the LDL-C to be effective for the secondary prevention in high- level. Statins antagonistically inhibit HMG-CoA re- risk patients. Also, VA-HIT28) reported a significant ductase, which is a rate-limmiting enzyme involved in secondary preventive effect of Gemfibrozil in patients cholesterol synthesis, suppress cholesterol synthesis53), with CAD showing low HDL-cholesterol. promote LDL receptor synthesis, and cause decreases in the blood LDL-C level54) of 20-50%. They also cause a decrease in TG55) of about 10-20% by reduc- 3. Characteristics of the Drugs ing IDL and VLDL remnants56) and inhibiting VLDL for Dyslipidemia synthesis and secretion due to reduced cholesterol Table 5 shows the classification of the drugs for synthesis in the liver. As for adverse effects, liver dys- dyslipidemia according to their effects. These effects function, an increase in CK (CPK), myopathy-like have also been confirmed in Japan by double-blind symptoms such as muscle weakness, and rare instances trials, in principle. Safe and effective drugs must be of rhabdomyolysis, which is characterized by increases selected by understanding the characteristics and effects in blood and urinary myoglobin levels, have been of various drugs and in consideration of complications reported. The risk of adverse effects increases by the and drug interactions. The characteristics of the drugs concomitant use of drugs including fibrates, nicotin- 172 Teramoto et al. Treatment ─ Drug Therapy 173

ates, cyclosporine, and erythromycin. bile, is considered to be the mechanism of this effect. There has also been a report suggesting teratoge- The mechanism of the decrease in the HDL-C level nicity of statins on their accidental use during early is considered to be the inhibition of ABCA-1, a cho- pregnancy57), and the use of statins should be avoided lesterol transporter present on the cell surface 61-68), and at present in women desiring as well as those in early an enhancement of the activity of cholesterol ester pregnancy. transfer protein (CETP) and SR-B1, which is a HDL receptor, has also been suggested to be involved. LDL 2) Anion Exchange Resins (Resins): Cholestryra- oxidation is considered to be important in the patho- mine, Cholestimide genic mechanism of atherosclerosis by various lines Type Ⅱa hyperlipidemia with a high LDL-C level of evidence such as cell biological69, 70) and immuno- is an indication. Although statins are the first choice histological71, 72) findings. Probucol is made up of 2 for high-LDL-cholesterol, resins may be an alternative molecules of BHT, which is an antioxidant, bound first choice if drug therapy is necessary for patients together and is lipid-soluble, so that it exhibits a in whom doctors are hesitant to prescribe statins due potent antioxidant activity when taken up by lipopro- to renal dysfunction, statins are not tolerated due to teins. It has been shown to prevent atherosclerosis in causes such as adverse reactions, and women who are, WHHL rabbits73), and has been clinically confirmed or may be, pregnant. However, the greatest significance to significantly suppress re-stenosis after PTCA74, 75). of resin administration is in combination therapy with In PQRST76), however, probucol administration in statins. addition to dietary therapy and cholestyramine ther- Cholestyramine was the first drug proven to be apy showed no suppressive effect against the progres- effective for the prevention of CAD by large-scale clin- sion of artherosclerosis in the femoral artery. At any ical studies58, 59). Resins promote the catabolism of rate, probucol has limited uses, which include the cholesterols into bile acids by adsorbing bile acids in treatment of patients who do not tolerate statins and the intestine and inhibiting the enterohepatic circula- concomitant administration with statins, because no tion of bile acids by their reabsorption. Through this large-scale clinical study has been performed. Adverse effect, resins cause a decrease in the sterol pool and effects include occasional QT prolongation and tors- promote LDL receptor synthesis in the liver, with a ade de pointes on ECG as well as gastrointestinal consequent decrease in the LDL-C level60). However, symptoms, liver dysfunction, and rash. resins may simultaneously cause the activation of HMG-CoA reductase in the liver and promote choles- 4) Nicotinates: Niceritrol, Nicomol, Tocopherol terol synthesis. Therefore, their concomitant use with Nicotinate statins, which are HMG-CoA reductase inhibitors, Conditions such as high LDL-cholesterol, hyper- is theoretically very reasonable. Adverse reactions to triglyceridemia, and dyslipidemia with increased rem- resins are primarily gastrointestinal symptoms such as nant lipoproteins are indications. constipation and abdominal distension, but no serious Nicotinates inhibit lipoprotein synthesis in the ones have been reported, because resins are non-absorb- liver by preventing the activation of hormone-sensitive able. Also, as resins have been reported to adsorb con- lipase, inhibiting triglyceride hydrolyzation in periph- comitant medications such as statins, digitalis, warfa- eral adipose tissues, and reducing the influx of free rin, thiazides, and thyroid preparations, medication fatty acids into the liver. It also increases HDL-C guidance such as taking resins and other drugs at a by inhibiting apoprotein A-Ⅰ catabolism. The percent sufficient interval is necessary when they are used con- decrease in TG by the administration of a nicotinate comitantly. alone (3.0 g/day) is 26%77). A preventive effect of nicotinates against CAD has also been demonstrated by 3) Probucol a large-scale clinical study78). Nicotinates also reduce Type Ⅱa hyperlipidemia with a high LDL-C level Lp(a), which is an atherogenic lipoprotein79-81). Pri- is an indication. Regression of xanthoma is a charac- mary adverse effects are itching and flashing due to teristic effect of this drug. However, as it reduces the peripheral vasodilation. They may also exacerbate HDL-C as well as LDL-C level, caution is necessary insulin resistance, and their administration to diabetic when it is administered to patients with low-HDL- patients requires caution. cholesterol. The LDL-C-reducing effect of probucol is 5) Fibrates: Bezafibrate, Fenofibrate 15-25%, and the promotion of LDL catabolism, par- Fibrates are drugs most effective for the treat- ticularly the promotion of cholesterol excretion into ment of hypertriglyceridemia. Since they also enhance 172 Teramoto et al. Treatment ─ Drug Therapy 173

remnant lipoprotein catabolism, they are markedly about 78% is excreted in stools. As it selectively inhib- effective in patients with type Ⅲ hyperlipidemia. They its cholesterol absorption, it exerts no effect on the also have a strong HDL-C-elevating effect. absorption of lipid-soluble vitamins such as vitamins Their major action mechanism is through the A and D. While it reduces the LDL-C level by about activation of PPAR-α as they serve as ligands of 18% at an ordinary oral dose (10 mg/day), it also pro- PPAR-α of nuclear receptors82, 83). This results in: (i) motes cholesterol synthesis in the liver similarly to res- the promotion of β oxidation of fatty acids and a ins, so that its concomitant use with statins is advis- decrease in TG production in the liver, (ii) an increase able. Compound preparations of Ezetimibe and statins in LPL synthesis, (iii) promotion of TG hydrolyzation have been developed overseas. Synergic effect can be and conversion of VLDL into LDL by a decrease in obtained by their concomitant use, and an approxi- apo C-Ⅲ production and an enhancement of LPL mate 35-50% decrease in the LDL-C level, an effect activity, and (iv) increases in apoprotein A-Ⅰ and A-Ⅱ similar to that obtained through the administration synthesis and a consequent increase in the HDL level. of a statin at its maximum dose, is obtained by a Bezafibrate decreases the TG level by 30-40%, reduces combination of 10 mg Ezemitibe and a normal dose the TC level by about 10%, and increases the HDL-C of statin85-87). This combination also increases the level by 35-45%. Fenofibrate is characterized by a long HDL-C level by 8-9% and decreases the TG level by half-life, and it has uric acid-reducing as well as anti- 20-30%. Ezetimibe is expected to be an effective drug dyslipidemic effects. Its major adverse effect is the to be used with statins if the management target of the increased occurrence of rhabdomyolysis in patients LDL-C level cannot be attained with a statin alone. with renal dysfunction, and its frequency increases Gastrointestinal symptoms have often been reported when it is used with statins. as adverse reactions, but their frequency did not differ significantly compared with the control group. An 6) EPA: Ethyl Icosapentate increase in CK (CPK) and myopathy-like symptoms Dyslipidemia with an increase in TG, particularly such as muscle weakness have been reported infre- type Ⅱb and type Ⅳ hyperlipidemia, is an indication. quently, similarly to statins, but intensification of these EPA not only inhibits VLDL synthesis in the adverse effects by its concomitant use with statins has liver and reduces the TG level but also slightly not been reported. increases the HDL-C level. While intakes of fish oil and n-3 polyunsaturated fatty acids have been known 4. Combination Therapies to lead to a preventive effect against cardiovascular events by epidemiological studies and studies of sec- If the management target level cannot be attained ondary prevention, there has been no report on drug with a single anti-dyslipidemic drug, an increase in the therapy for primary prevention. JELIS 35) performed dose of the drug or combination therapy should be in Japan, in which about 80% of the subjects were considered. Particularly in secondary prevention, the primary prevention cases, reported that major coro- LDL-C level cannot be reduced to less than 100 nary events were significantly prevented in a group mg/dL in some patients with a single drug. In combi- administered EPA in addition to a statin compared nation therapies, a method that would optimize the with a group administered a statin alone, and con- characteristics of the drugs described above and has firmed the effectiveness of EPA itself. EPA is also been confirmed to be safe must be selected. Preven- expected to prevent atherosclerosis by antiplatelet and tion of the progression or regression of atherosclerotic anti-inflammatory activities in addition to its anti- lesions by such combination therapies has been dyslipidemic effect. As for its major adverse effects, reported abroad. In one report, the cholesterol level attention to hemorrhagic tendency is necessary other was reduced by 34% using the combination of a statin than gastrointestinal symptoms such as diarrhea. and a resin85). In Japanese studies of combination therapy using pravastatin and cholestimide86, 88), a 26% 7) Ezetimibe decrease in the TC level, 37% decrease in the LDL-C Ezetimibe is resently approved by the Ministry of level, and 21% increase in the HDL-C level were Health, Labor and Welfare in Japan. It decreases serum observed, confirming the effectiveness of this combi- cholesterol levels by directly inhibiting the absorption nation therapy. Combination therapies using a resin of dietary and bile-derived cholesterol in the small and a nicotinate85, 89) have been reported to reduce the intestine via the NPC1L1 pathway (cholesterol trans- LDL-C level by 43% and TG level by 22% at high porter) in the intestinal mucosa 84). Unlike resins, it doses. is absorbed, enters the enterohepatic circulation, and Combination therapies that have been reported 174 Teramoto et al. Treatment ─ Drug Therapy 175

in Japan to be effective for improving the serum lipid Group: Primary prevention of cardiovascular disease with profile include: (1) statin and resin88, 90, 91), (2) statin pravastatin in Japan (MEGA Study): a prospective ran- and fibrate92, 93), (3) statin and probucol94), (4) statin domised controlled trial. Lancet, 2006; 368:1155-1163 and nicotinate95), (5) probucol and nicotinate96), and 2) Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, 97, 98) MacFarlane PW, McKillop JH, and Packard CJ: Preven- (6) statin, probucol, and resin . The combination tion of coronary heart disease with pravastatin in men of statin and resin is theoretically the most effective with hypercholesterolemia. West of Scotland Coronary for reducing the LDL-C level, and the combination of Prevention Study Group. N Engl J Med, 1995; 333:1301- statin and nicotinate not only reduces the cholesterol 1307 level but also increases the HDL-C level. Among these 3) Downs JR, Clearfield M, Weis S, Whitney E, Shapiro combination therapies, greatest attention must be paid DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, and to the rare occurrence of rhabdomyolysis on the con- Gotto AM Jr.: Primary prevention of acute coronary events with lovastatin in men and women with average comitant use of a statin and a fibrate. Rhabdomyolysis cholesterol levels: results of AFCAPS/TexCAPS. Air caused by the concomitant use of pravastatin and Force/Texas Coronary Atherosclerosis Prevention Study. bezafibrate was accompanied by renal disorders in JAMA, 1998; 279:1615-1622 more than half of Japanese patients. If abnormal val- 4) Heart Protection Study Collaborative Group: MRC/BHF ues are noted on laboratory tests related to renal func- Heart Protection Study of cholesterol lowering with simv- tion, the use of this combination should be limited astatin in 20,536 high-risk individuals: a randomised pla- to situations in which it is judged to be absolutely cebo-controlled trial. Lancet, 2002; 360:7-22 5) ALLHAT Officers and Coordinators for the ALLHAT necessary. Collaborative Research Group: Major outcomes in moderately hypercholesterolemic, hypertensive patients ran- 5. Follow-Up of Drug Therapies domized to pravastatin vs usual care: The Antihyper- tensive and Lipid-Lowering Treatment to Prevent Heart After the initiation of drug therapies, adverse as Attack Trial (ALLHAT-LLT). JAMA, 2002; 288:2998- well as therapeutic effects must be evaluated. Gener- 3007 ally, these examinations should be performed monthly 6) Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, during the first 3 months and every 3 months thereaf- Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Oster- ter. gren J, and ASCOT investigators: Prevention of coronary Therapeutic effects of anti-dyslipidemic medica- and stroke events with atorvastatin in hypertensive tion are evaluated by measuring the TC, TG, and patients who have average or lower-than-average choles- HDL-C levels. However, as LDL is the most impor- terol concentrations, in the Anglo-Scandinavian Cardiac tant lipoprotein in CAD, diagnostic and management Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a criteria should be based on the LDL-C rather than TC multicentre randomised controlled trial. Lancet, 2003; level. The LDL-C level is calculated using the Friede- 361:1149-1158 7) Colhoun HM, Betteridge DJ, Durrington PN, Hitman wald formula, in principle. Direct measurement of the GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness LDL-C level, which has recently become possible, is MI, Charlton-Menys V, Fuller JH, and on behalf of the useful when the TG level is 400 mg/dL or above, or CARDS investigators: Primary prevention of cardiovascu- the blood sample has been obtained without fasting. lar disease with atorvastatin in type 2 diabetes in the Col- Consciousness of the importance of the management laborative Atorvastatin Diabetes Study (CARDS): multi- of the non HDL-C (TC - HDL-C) level is also nec- centre randomised placebo-controlled trial. Lancet, 2004; essary. Measurements of Lp(a), remnant cholesterol 364:685-696 (RLP-C), and high-sensitivity CRP are also recom- 8) Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun mended depending on the patient. CC, Davis BR, and Braunwald E: The effect of pravas- For the checking of adverse effects, examinations tatin on coronary events after myocardial infarction in of liver function [AST (GOT), ALT (GPT), LDH, patients with average cholesterol levels. Cholesterol and ALP, γGTP, and total bilirubin], renal function (uri- Recurrent Events Trial investigators. N Engl J Med, 1996; nalysis, serum creatinine, and BUN), CK (CPK), and 335:1001-1009 blood cell counts are necessary. 9) The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol Reference levels. The Long-Term Intervention with Pravastatin in 1) Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Ischaemic Disease (LIPID) Study Group. N Engl J Med, Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, 1998; 339:1349-1357 Yamamoto A, Mizuno K, Ohashi Y, and MEGA Study 10) Sakamoto T, Kojima S, Ogawa H, Shimomura H, Kimura 174 Teramoto et al. Treatment ─ Drug Therapy 175

K, Ogata Y, Sakaino N, Kitagawa A, and Multicenter 20) Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Study for Aggressive Lipid-Lowering Strategy by HMG- Bernstein V, Cuddy TE, Moyé LA, Piller LB, Rutherford CoA Reductase Inhibitors in Patients With Acute J, Simpson LM, and Braunwald E: Reduction of stroke Myocardial Infarction (MUASASHI-AMI) Investigators: incidence after myocardial infarction with pravastatin: Effects of early statin treatment on symptomatic heart the Cholesterol and Recurrent Events (CARE) study. The failure and ischemic events after acute myocardial infarc- Care Investigators. Circulation, 1999; 99:216-223 tion in Japanese. Am J Cardiol, 2006; 97:1165-1171 21) White HD, Simes RJ, Anderson NE, Hankey GJ, Watson 11) Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon S, VV, Symeonidis AN, Basayannis EO, Demitriadis DS, Kirby AC, West MJ, and Tonkin AM: Pravastatin therapy and Kontopoulos AG: Treatment with atorvastatin to the and the risk of stroke. N Engl J Med, 2000; 343:317-326 National Cholesterol Educational Program goal versus 22) Di Mascio R, Marchioli R, and Tognoni G: Cholesterol ‘usual’ care in secondary coronary heart disease preven- reduction and stroke occurrence: an overview of random- tion. The GREek Atorvastatin and Coronary-heart-dis- ized clinical trials. Cerebrovasc Dis, 2000; 10:85-92 ease Evaluation (GREACE) study. Curr Med Res Opin, 23) Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, 2002; 18:220-228 and Lechat P: Differential effects of lipid-lowering thera- 12) Jukema JW, Bruschke AV, van Boven AJ, Reiber JH, Bal pies on stroke prevention: a meta-analysis of randomized ET, Zwinderman AH, Jansen H, Boerma GJ, van Rap- trials. Arch Intern Med, 2003; 163:669-676 pard FM, Lie KI, et al: Effects of lipid lowering by pravas- 24) Law MR, Wald NJ, and Rudnicka AR: Quantifying effect tatin on progression and regression of coronary artery dis- of statins on low density lipoprotein cholesterol, ischaemic ease in symptomatic men with normal to moderately ele- heart disease, and stroke: systematic review and meta- vated serum cholesterol levels. The Regression Growth analysis. BMJ, 2003; 326:1423-1429 Evaluation Statin Study (REGRESS). Circulation, 1995; 25) Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein 91:2528-2540 LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, 13) Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Szarek M, Welch KM, Zivin JA, and Stroke Prevention Title LM, Eisenberg D, Shurzinske L, and McCormick by Aggressive Reduction in Cholesterol Levels (SPARCL) LS: Aggressive lipid-lowering therapy compared with Investigators: High-dose atorvastatin after stroke or tran- angioplasty in stable coronary artery disease. Atorvastatin sient ischemic attack. N Engl J Med, 2006; 355:549-559 versus Revascularization Treatment Investigators. N Engl 26) Nomura E, Kohriyama T, Matsumoto M, and Kobayashi J Med, 1999; 341:70-76 S: Clinical characteristics of first-ever atherothrombotic 14) Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, infarction or lacunar infarction with hyperlipidemia (J- Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, STARS-C): an analysis of data from the stroke data bank Meier B, and Lescol Intervention Prevention Study (LIPS) of Japan. Intern Med, 2005; 44:1252-1257 Investigators: Fluvastatin for prevention of cardiac events 27) The Joint Committee on Guidelines for the Management following successful first percutaneous coronary inter- of Stroke: Japanese Guidelines for the management of vention: a randomized controlled trial. JAMA, 2002; Stroke (2004) in Japanese 287:3215-3222 28) Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, 15) Collins R, Armitage J, Parish S, Sleight P, Peto R, and Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Heart Protection Study Collaborative Group: Effects of Wilt TJ, and Wittes J: Gemfibrozil for the secondary pre- cholesterol-lowering with simvastatin on stroke and other vention of coronary heart disease in men with low levels major vascular events in 20536 people with cerebrovascu- of high-density lipoprotein cholesterol. Veterans Affairs lar disease or other high-risk conditions. Lancet, 2004; High-Density Lipoprotein Cholesterol Intervention Trial 363:757-767 Study Group. N Engl J Med, 1999; 341:410-418 16) Pravastatin use and risk of coronary events and cerebral 29) Secondary prevention by raising HDL cholesterol and infarction in japanese men with moderate hypercholester- reducing triglycerides in patients with coronary artery olemia: the Kyushu Lipid Intervention Study (KLIS). J disease: the Bezafibrate Infarction Prevention (BIP) study. Atheroscler Thromb, 2000; 7:110-121 Circulation, 2000; 102:21-27 17) Ito H, Ouchi Y, Ohashi Y, Saito Y, Ishikawa T, Nakamura 30) Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko H, and Orimo H: A comparison of low versus standard V, and Behar S: Bezafibrate for the secondary prevention dose pravastatin therapy for the prevention of cardiovas- of myocardial infarction in patients with metabolic syn- cular events in the elderly: the pravastatin anti-atheroscle- drome. Arch Intern Med, 2005; 165:1154-1160 rosis trial in the elderly (PATE). J Atheroscler Thromb, 31) Tanne D, Koren-Morag N, Graff E, and Goldbourt U: 2001; 8:33-44 Blood lipids and first-ever ischemic stroke/transient isch- 18) Briel M, Studer M, Glass TR, and Bucher HC: Effects of emic attack in the Bezafibrate Infarction Prevention (BIP) statins on stroke prevention in patients with and without Registry: high triglycerides constitute an independent risk coronary heart disease: a meta-analysis of randomized factor. Circulation, 2001; 104:2892-2897 controlled trials. Am J Med, 2004; 117:596-606 32) Bloomfield Rubins H, Davenport J, Babikian V, Brass 19) Amarenco P, Labreuche J, Lavallée P, and Touboul PJ: LM, Collins D, Wexler L, Wagner S, Papademetriou V, Statins in stroke prevention and carotid atherosclerosis: Rutan G, Robins SJ, and VA-HIT Study Group: Reduc- systematic review and up-to-date meta-analysis. Stroke, tion in stroke with gemfibrozil in men with coronary 2004; 35:2902-2909 heart disease and low HDL cholesterol: The Veterans 176 Teramoto et al. Treatment ─ Drug Therapy 177

Affairs HDL Intervention Trial (VA-HIT). Circulation, 42) Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, 2001; 103:2828-2833 Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lin- 33) Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, dahl C, Szarek M, Tsai J, and Incremental Decrease in Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Man- End Points Through Aggressive Lipid Lowering (IDEAL) ninen V, et al: Helsinki Heart Study: primary-prevention Study Group: High-dose atorvastatin vs usual-dose simv- trial with gemfibrozil in middle-aged men with dyslipid- astatin for secondary prevention after myocardial infarc- emia. Safety of treatment, changes in risk factors, and tion: the IDEAL study: a randomized controlled trial. incidence of coronary heart disease. N Engl J Med, 1987; JAMA, 2005; 294:2437-2445 317:1237-1245 43) Rossouw JE: Lipid-lowering interventions in angiographic 34) Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen trials. Am J Cardiol, 1995; 76:86C-92C MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, 44) Ballantyne CM, Herd JA, Dunn JK, Jones PH, Farmer Kesäniemi YA, Sullivan D, Hunt D, Colman P, d’Emden JA, and Gotto AM Jr.: Effects of lipid lowering therapy M, Whiting M, Ehnholm C, Laakso M, and FIELD study on progression of coronary and carotid artery disease. investigators: Effects of long-term fenofibrate therapy on Curr Opin Lipidol, 1997; 8:354-361 cardiovascular events in 9795 people with type 2 diabetes 45) Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, mellitus (the FIELD study): randomised controlled trial. Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Lancet, 2005; 366:1849-1861 Grines CL, DeMaria AN, and REVERSAL Investigators: 35) Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Effect of intensive compared with moderate lipid-lower- Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Ita- ing therapy on progression of coronary atherosclerosis: a kura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shi- randomized controlled trial. JAMA, 2004; 291:1071-1080 mada K, Shirato K; Japan EPA lipid intervention study 46) Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, (JELIS) Investigators: Effects of eicosapentaenoic acid Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif (EPA) on major copatients: The Japan EPA Lipid Inter- JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goor- vention Study (JELIS). Lancet, 2007; 369:1090-10987 mastic M, Tuzcu EM, and ASTEROID Investigators: 36) Cambien F, Jacqueson A, Richard JL, Warnet JM, Ducim- Effect of very high-intensity statin therapy on regression etiere P, and Claude JR: Is the level of serum triglyceride a of coronary atherosclerosis: the ASTEROID trial. JAMA, significant predictor of coronary death in “normocholes- 2006; 295:1556-1565 terolemic” subjects? The Paris Prospective Study. Am J 47) Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Epidemiol, 1986; 124:624-632 Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic 37) Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver P, Frohlich J, and Albers JJ: Simvastatin and niacin, anti- MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, oxidant vitamins, or the combination for the prevention and Myocardial Ischemia Reduction with Aggressive Cho- of coronary disease. N Engl J Med, 2001; 345:1583-1592 lesterol Lowering (MIRACL) Study Investigators: Effects 48) Mizuno K, Nakamura H, Ohashi Y, Kaburagi T, Kita- of atorvastatin on early recurrent ischemic events in acute batake A, Tochihara T, Hosoda S, and JUST Study Inves- coronary syndromes: the MIRACL study: a randomized tigators: A randomized, open-label, comparative study of controlled trial. JAMA, 2001; 285:1711-1718 simvastatin plus diet versus diet alone on angiographic 38) Thompson PL, Meredith I, Amerena J, Campbell TJ, retardation of coronary atherosclerosis in adult Japa- Sloman JG, Harris PJ, and Pravastatin in Acute Coronary nese patients: Japanese utilization of simvastatin therapy Treatment (PACT) Investigators: Effect of pravastatin (JUST) study. Clin Ther, 2004; 26:878-888 compared with placebo initiated within 24 hours of onset 49) Makuuchi H, Furuse A, Endo M, Nakamura H, Daida H, of acute myocardial infarction or unstable angina: the Watanabe M, Ohashi Y, Hosoda Y, Hosoda S, Yamaguchi Pravastatin in Acute Coronary Treatment (PACT) trial. H, and Yasui H: Effect of pravastatin on progression of Am Heart J, 2004; 148:e2 coronary atherosclerosis in patients after coronary artery 39) de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox bypass surgery. Circ J, 2005; 69:636-643 KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, 50) Takagi T, Yoshida K, Akasaka T, Hozumi T, Morioka S, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, and Yoshikawa J: Intravascular ultrasound analysis of Pfeffer MA, Califf RM, Braunwald E, and A to Z Investi- reduction in progression of coronary narrowing by treat- gators: Early intensive vs a delayed conservative simvas- ment with pravastatin. Am J Cardiol, 1997; 79:1673-1676 tatin strategy in patients with acute coronary syndromes: 51) Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata phase Z of the A to Z trial. JAMA, 2004; 292:1307-1316 T, Sato H, and Daida H: Early statin treatment in patients 40) Stenestrand U, Wallentin L, and Swedish Register of Car- with acute coronary syndrome: demonstration of the diac Intensive Care (RIKS-HIA): Early statin treatment beneficial effect on atherosclerotic lesions by serial volu- following acute myocardial infarction and 1-year survival. metric intravascular ultrasound analysis during half a year JAMA, 2001; 285:430-436 after coronary event: The ESTABLISH Study. Circula- 41) LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, tion, 2004; 110:1061-1068 Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shep- 52) Mabuchi H, Haba T, Tatami R, Miyamoto S, Sakai Y, herd J, Wenger NK, and Treating to New Targets (TNT) Wakasugi T, Watanabe A, Koizumi J, and Takeda R: Investigators: Intensive lipid lowering with atorvastatin Effect of an inhibitor of 3-hydroxy-3-methyglutaryl coen- in patients with stable coronary disease. N Engl J Med, zyme A reductase on serum lipoproteins and ubiquinone- 2005; 352:1425-1435 10-levels in patients with familial hypercholesterolemia. 176 Teramoto et al. Treatment ─ Drug Therapy 177

N Engl J Med, 1981; 305:478-482 Acta, 1999; 1438:85-98 53) Endo A: The discovery and development of HMG-CoA 67) Favari E, Zanotti I, Zimetti F, Ronda N, Bernini F, reductase inhibitors. J Lipid Res, 1992; 33:1569-1582 and Rothblat GH: Probucol inhibits ABCA1-mediated 54) Bilheimer DW, Grundy SM, Brown MS, and Goldstein cellular lipid efflux. Arterioscler Thromb Vasc Biol, 2004; JL: Mevinolin and colestipol stimulate receptor-mediated 24:2345-2350 clearance of low density lipoprotein from plasma in famil- 68) Duong M, Collins HL, Jin W, Zanotti I, Favari E, and ial hypercholesterolemia heterozygotes. Proc Natl Acad Rothblat GH: Relative contributions of ABCA1 and Sci USA, 1983; 80:4124-4128 SR-BI to cholesterol efflux to serum from fibroblasts 55) Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davi- and macrophages. Arterioscler Thromb Vasc Biol, 2006; gnon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, 26:541-547 Miller VT, Shurzinske LJ, and Black DM: Efficacy and 69) Kodama T, Reddy P, Kishimoto C, and Krieger M: Purifi- safety of a new HMG-CoA reductase inhibitor, atorvas- cation and characterization of a bovine acetyl low den- tatin, in patients with hypertriglyceridemia. JAMA, 1996; sity lipoprotein receptor. Proc Natl Acad Sci USA, 1988; 275:128-133 85:9238-9242 56) Broyles FE, Walden CE, Hunninghake DB, Hill-Williams 70) Kita T, Ishii K, Yokode M, Kume N, Nagano Y, Arai H, D, and Knopp RH: Effect of fluvastatin on intermediate and Kawai C: The role of oxidized low density lipoprotein density lipoprotein (remnants) and other lipoprotein in the pathogenesis of atherosclerosis. Eur Heart J, 1990; levels in hypercholesterolemia. Am J Cardiol, 1995; 11:122-127 76:129A-135A 71) Itabe H, Takeshima E, Iwasaki H, Kimura J, Yoshida Y, 57) Edison RJ and Muenke M: Central nervous system and Imanaka T, and Takano T: A monoclonal antibody against limb anomalies in case reports of first-trimester statin oxidized lipoprotein recognizes foam cells in athero- exposure. N Engl J Med, 2004; 350:1579-1582 sclerotic lesions. Complex formation of oxidized phos- 58) The Lipid Research Clinics Coronary Primary Prevention phatidylcholines and polypeptides. J Biol Chem, 1994; Trial results. Ⅰ. Reduction in incidence of coronary heart 269:15274-15279 disease. JAMA, 1984; 251:351-364 72) Itabe H, Yamamoto H, Suzuki M, Kawai Y, Nakagawa Y, 59) The Lipid Research Clinics Coronary Primary Prevention Suzuki A, Imanaka T, and Takano T: Oxidized phosphati- Trial results. Ⅱ. The relationship of reduction in incidence dylcholines that modify proteins. Analysis by monoclonal of coronary heart disease to cholesterol lowering. JAMA, antibody against oxidized low density lipoprotein. J Biol 1984; 251:365-374 Chem, 1996; 271:33208-33217 60) Rudling MJ, Reihnér E, Einarsson K, Ewerth S, and Ange- 73) Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima lin B: Low density lipoprotein receptor-binding activity in A, Yoshida H, and Kawai C: Probucol prevents the pro- human tissues: quantitative importance of hepatic recep- gression of atherosclerosis in Watanabe heritable hyperlip- tors and evidence for regulation of their expression in idemic rabbit, an animal model for familial hypercholes- vivo. Proc Natl Acad Sci USA, 1990; 87:3469-3473 terolemia. Proc Natl Acad Sci USA, 1987; 84:5928-5931 61) Tsujita M and Yokoyama S: Selective inhibition of free 74) Tardif JC, Cöté G, Lespérance J, Bourassa M, Lambert J, apolipoprotein-mediated cellular lipid efflux by probucol. Doucet S, Bilodeau L, Nattel S, and de Guise P: Probucol Biochemistry, 1996; 35:13011-13020 and multivitamins in the prevention of restenosis after 62) Tsujita M, Tomimoto S, Okumura-Noji K, Okazaki M, coronary angioplasty. Multivitamins and Probucol Study and Yokoyama S: Apolipoprotein-mediated cellular Group. N Engl J Med, 1997; 337:365-372 cholesterol/phospholipid efflux and plasma high density 75) Yokoi H, Daida H, Kuwabara Y, Nishikawa H, Takatsu F, lipoprotein level in mice. Biochim Biophys Acta, 2000; Tomihara H, Nakata Y, Kutsumi Y, Ohshima S, Nishi- 1485:199-213 yama S, Seki A, Kato K, Nishimura S, Kanoh T, and 63) Tomimoto S, Tsujita M, Okazaki M, Usui S, Tada T, Yamaguchi H: Effectiveness of an antioxidant in prevent- Fukutomi T, Ito S, Itoh M, and Yokoyama S: Effect of ing restenosis after percutaneous transluminal coronary probucol in lecithin-cholesterol acyltransferase-deficient angioplasty: the Probucol Angioplasty Restenosis Trial. J mice: inhibition of 2 independent cellular cholesterol- Am Coll Cardiol, 1997; 30:855-862 releasing pathways in vivo. Arterioscler Thromb Vasc Biol, 76) Walldius G, Erikson U, Olsson AG, Bergstrand L, Hådell 2001; 21:394-400 K, Johansson J, Kaijser L, Lassvik C, Mölgaard J, Nilsson 64) Wu CA, Tsujita M, Hayashi M, and Yokoyama S: Probu- S, et al: The effect of probucol on femoral atherosclero- col inactivates ABCA1 in the plasma membrane with sis: the Probucol Quantitative Regression Swedish Trial respect to its mediation of apolipoprotein binding and (PQRST). Am J Cardiol, 1994; 74:875-883 high density lipoprotein assembly and to its proteolytic 77) Alderman JD, Pasternak RC, Sacks FM, Smith HS, Mon- degradation. J Biol Chem, 2004; 279:30168-30174 rad ES, and Grossman W: Effect of a modified, well-toler- 65) Tsujita M, Wu CA, Abe-Dohmae S, Usui S, Okazaki M, ated niacin regimen on serum total cholesterol, high den- and Yokoyama S: On the hepatic mechanism of HDL sity lipoprotein cholesterol and the cholesterol to high assembly by the ABCA1/apoA-Ⅰ pathway. J Lipid Res, density lipoprotein ratio. Am J Cardiol, 1989; 64:725-729 2005; 46:154-162 78) Clofibrate and niacin in coronary heart disease. JAMA, 66) Sakr SW, Williams DL, Stoudt GW, Phillips MC, and 1975; 231:360-381 Rothblat GH: Induction of cellular cholesterol efflux to 79) Teramoto T, Yamada N, Shimano H, Oka Y, Itakura H, lipid-free apolipoprotein A-Ⅰ by cAMP. Biochim Biophys Saito Y, Morisaki N, Shirai K, Ishikawa T, Tada N, Ito H, 178 Teramoto et al.

Yamanouchi T, Matsushima T, Kawakami M, Murase T, ME, Azen SP, and Cashin-Hemphill L: Beneficial effects Okubo M, Totsuka Y, and Kikuchi M: Dose-dependent of combined colestipol-niacin therapy on coronary ath- effect of niceritrol on plasma lipoprotein-a. Scand J Clin erosclerosis and coronary venous bypass grafts. JAMA, Lab Invest, 1996; 56:359-365 1987; 257:3233-3240 80) Carlson LA, Hamsten A, and Asplund A: Pronounced 90) Diabetes Atherosclerotic Intervention Study Investigators: lowering of serum levels of lipoprotein Lp(a) in hyperlipi- Effect of fenofibrate on progression of coronary-artery daemic subjects treated with nicotinic acid. J Intern Med, disease in type 2 diabetes: the Diabetes Atherosclerosis 1989; 226:271-276 Intervention Study, a randomised study. Lancet, 2001; 81) Matsunaga A, Handa K, Mori T, Moriyama K, Hidaka K, 357:905-910 Yuki M, Sasaki J, and Arakawa K: Effects of niceritrol on 91) Mabuchi H, Sakai T, Sakai Y, Yoshimura A, Watanabe A, levels of serum lipids, lipoprotein(a), and fibrinogen in Wakasugi T, Koizumi J, and Takeda R: Reduction of patients with primary hypercholesterolemia. Atherosclero- serum cholesterol in heterozygous patients with familial sis, 1992; 94:241-248 hypercholesterolemia. Additive effects of compactin and 82) Schoonjans K, Staels B, and Auwerx J: Role of the peroxi- cholestyramine. N Engl J Med, 1983; 308:609-613 some proliferator-activated receptor (PPAR) in mediating 92) Inadera H: Clinical efficacy of Clinofibrate in combina- the effects of fibrates and fatty acids on gene expression. J tion with pravastatin in patients with hyperlipidemia The Lipid Res, 1996; 37:907-925 Journal of medicine; Journal of medicine and pharmaceu- 83) Fruchart JC, Brewer HB Jr., and Leitersdorf E: Consensus tical science, 1994; 31:1021-1029 in Japanese for the use of fibrates in the treatment of dyslipopro- 93) Kumagai H: The Japanese journal of clinical and experi- teinemia and coronary heart disease. Fibrate Consensus mental medicine, 1993; 70:2012-2016 in Japanese Group. Am J Cardiol, 1998; 81:912-917 94) Otsuji S, Tanaka N, Takesako K, Kawahira K, Tomari T, 84) Gagné C, Gaudet D, Bruckert E, and Ezetimibe Study Tanaka H, Nakao S, Arima T, Sanada J, Osame M, Kuri- Group: Efficacy and safety of ezetimibe coadministered yama M, Kmada T, Toda H, Kuroiwa Y, and Fukuoka T: with atorvastatin or simvastatin in patients with homo- The Effects of Single and Combined Pravastatin and Pro- zygous familial hypercholesterolemia. Circulation, 2002; bucol Therapy in Hypercholesterolemia. J Jpn Atheroscler 105:2469-2475 Soc, 1994; 22:509-516 in Japanese 85) Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, 95) Kinoshita M, Suzuki H, Matsushima T, and Teramoto Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, and T: Evaluation of niceritrol and pravastatin combination Dodge HT: Regression of coronary artery disease as a therapy for hyperlipidemia. J Jpn Atheroscler Soc, 1995; result of intensive lipid-lowering therapy in men with 26:95-102 in Japanese high levels of apolipoprotein B. N Engl J Med, 1990; 96) Yamamoto K, Sasaki J, Saku K, Hiromatu Y, Kobori S, 323:1289-1298 Nakanishi T, Ikeda Y, Fukushima N, and Ageta M: 86) Mabuchi H: Journal of clinical therapeutics & medicine, Benefical Effects of Combined Niceritrol-Probucol Ther- 1996; 12:1435-1462 in Japanese apy on Type Ⅱ Hyperlipoproteinemia. J Jpn Atheroscler 87) Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka Soc, 1991; 19:63-70 in Japanese LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, and Veltri EP; 97) Nakamura T, Matsuzawa Y, Nagai Y, Funahashi T, Sakai N, Ezetimibe Study Group: Effect of ezetimibe coadminis- Ueyama Y, Yamashita S, Takemura K, Kubo M, Hirobe K, tered with atorvastatin in 628 patients with primary hyper- and Tarui S: Significance of Combined Treatment with cholesterolemia: a prospective, randomized, double-blind Pravastatin (CS-514), Probucol and Cholestyramine for trial. Circulation, 2003; 107:2409-2415 Cholesterol Reduction and Regression of Achilles Tendon 88) Mabuchi H: Journal of clinical therapeutics & medicine, Xanthoma in Patients with familial Hypercholesterolemia. 1996; 12:1463-1489 in Japanese J Jpn Atheroscler Soc, 1990; 18:73-79 in Japanese 89) Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco 98) Miita T: Shinzo, 1995; 27:1070-1076 in Japanese