Safety and efficacy of ezetimibe monotherapy in 1624 primary hypercholesterolaemic patients for up to 2 years.

AIMS: This report examined the safety and efficacy of treatment for up to 2 years with the cholesterol absorption inhibitor, ezetimibe (EZE). METHODS: Two identical, randomised, double-blind trials (starting with 827 and 892 patients), evaluated the efficacy and safety of EZE 10 mg/day vs. placebo for 12 weeks in patients with primary hypercholesterolaemia [low-density lipoprotein cholesterol (LDL-C) 3.3-5.1 mmol/l]. Upon completion of these base studies, patients were offered a 2-year, open-label extension study. Adverse event (AE) reports for EZE monotherapy-treated patients were summarised for 3-month intervals to allow for comparison with the placebo group of the 3-month base studies. The primary end-point for this analysis was the evaluation of the long-term safety and tolerability of EZE 10 mg monotherapy dosed daily for up to 24 months. RESULTS: The incidences of new AEs, treatment-related (TR) AEs, serious AEs (SAEs), TRSAEs and discontinuations as a result of AEs during any 3-month interval were comparable with the respective observations in the placebo group of the base studies. The incidences of AEs, TRAEs, SAEs, TRSAEs and discontinuations as a result of AEs decreased in almost every interval compared with earlier intervals throughout the 2-year study. In addition, the incidences of > or = 3-fold consecutive elevations of liver transaminases (0.7%) or > or = 10-fold increases in creatine phosphokinase (0.4%) for the entire 2-year treatment period were comparable with those of the placebo group (0.7% and 0.2% respectively). LDL-C reductions of approximately 18% were maintained throughout the study. CONCLUSIONS: Compared with placebo, treatment with EZE for up to 2 years in 1624 patients showed no evidence of increased incidence of AEs with increased treatment duration, while showing sustained effects on LDL-C reduction.

Evaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies.

Ezetimibe is a novel cholesterol absorption inhibitor that blocks intestinal absorption of dietary and biliary cholesterol. Data from 1719 patients who participated in two multicentre, double-blind studies of ezetimibe were pooled to evaluate the drug's efficacy and safety in patients with primary hypercholesterolaemia. Following dietary stabilisation, a two- to 12-week washout period, and a four-week, single-blind, placebo lead-in period, patients were randomised to ezetimibe 10 mg or placebo once daily in the morning for 12 consecutive weeks. The primary efficacy endpoint was percent reduction in plasma low-density lipoprotein (LDL)-cholesterol from baseline at endpoint. Ezetimibe reduced LDL-cholesterol by a mean of 18.2% compared with an increase of 0.9% with placebo (p<0.01) and resulted in favourable, statistically significant changes in HDL-cholesterol, triglycerides and apo B. The response to ezetimibe was consistent across all subgroups analysed. Ezetimibe was well tolerated, with a safety profile similar to placebo.

Long-term efficacy and safety of cerivastatin 0.8 mg in patients with primary hypercholesterolemia.

BACKGROUND: Statins are the agents of choice in reducing elevated plasma low-density lipoprotein cholesterol (LDL-C). HYPOTHESIS: Cerivastatin 0.8 mg has greater long-term efficacy in reducing LDL-C than pravastatin 40 mg in primary hypercholesterolemia. METHODS: In this double-blind, parallel-group, 52-week study, patients (n = 1,170) were randomized (4:1:1) to cerivastatin 0.8 mg, cerivastatin 0.4 mg, or placebo daily. After 8 weeks, placebo was switched to pravastatin 40 mg. Patients with insufficient LDL-C lowering after 24 weeks were allowed open-labeled resin therapy. RESULTS: Cerivastatin 0.8 mg reduced LDL-C versus cerivastatin 0.4 mg (40.8 vs. 33.6%, p <0.0001) or pravastatin 40 mg (31.5%, p<0.0001), and brought 81.8% of all patients, and 54.1% of patients with atherosclerotic disease, to National Cholesterol Education Program (NCEP) goals. Cerivastatin 0.8 mg improved mean total C (-29.0%), triglycerides (-18.3%), and high-density lipoprotein cholesterol (HDL-C) (+9.7%) (all p < or = 0.013 vs. pravastatin 40 mg). Higher baseline triglycerides were associated with greater reductions in triglycerides and elevations in HDL-C with cerivastatin. Cerivastatin was well tolerated; the most commonly reported adverse events were arthralgia, headache, pharyngitis, and rhinitis. Symptomatic creatine kinase > 10x the upper limit of normal (ULN) occurred in 1, 1.5, and 0% of patients receiving cerivastatin 0.8 mg, cerivastatin 0.4 mg, and pravastatin 40 mg, respectively. Repeat hepatic transaminases >3 x ULN occurred in 0.3-0.5, 0.5, and 0% of patients, respectively. CONCLUSION: In long-term use, cerivastatin 0.8 mg effectively and safely brings the majority of patients to NCEP goal.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Effects of sibutramine on body weight and serum lipids: a double-blind, randomized, placebo-controlled study in 322 overweight and obese patients with dyslipidemia.

BACKGROUND: Cardiovascular risk factors associated with obesity, including dyslipidemia, can be improved by weight loss. The main dyslipidemia associated with obesity is elevated serum triglyceride and decreased serum high-density lipoprotein cholesterol (HDL-C) levels. METHODS: A total of 322 obese patients (body mass index > or = 27) with serum triglyceride levels > or = 250 mg/dL and < or = 1000 mg/dL and serum HDL-C levels < or = 45 mg/dL (women) and < or = 40 mg/dL (men) were placed on a step I American Heart Association diet and subsequently randomized to sibutramine 20 mg (n = 162) or placebo (n = 160) once daily for 24 weeks. RESULTS: Patients taking sibutramine had significantly greater mean weight loss than those receiving placebo (-4.9 kg vs -0.6 kg, P < or = .05). Forty-two percent of the sibutramine group lost > or = 5% of baseline weight and 12% lost > or = 10% compared with 8% and 3%, respectively, of the placebo group (P < or = .05). Mean decreases in serum triglyceride levels among 5% and 10% weight-loss responders in the sibutramine group were 33.4 mg/dL and 72.3 mg/dL, respectively, compared with an increase of 31.7 mg/dL among all patients receiving placebo (P < or = .05). Mean increases in serum HDL-C levels for 5% and 10% weight-loss responders in the sibutramine group were 4.9 mg/dL and 6.7 mg/dL, respectively, compared with an increase of 1.7 mg/dL among all patients in the placebo group (P < or = .05). Adverse events and discontinuation rates were similar in the sibutramine and placebo groups, although sibutramine-treated patients had mean increases in systolic and diastolic blood pressure of 2 to 3 mm Hg relative to placebo. CONCLUSIONS: In overweight and obese patients with high serum triglyceride levels and low serum HDL-C levels, treatment with sibutramine was associated with significant improvements in body weight and in serum triglyceride and HDL-C levels.

Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia.

Although acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce lipid levels in several animal models, the safety and lipid modifying activity of any single agent in this class has not been demonstrated in humans. The safety and efficacy of avasimibe (CI-1011), a new, unique, wholly synthetic ACAT inhibitor, was evaluated in the treatment of 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia (low levels of high-density lipoprotein cholesterol [HDL-C]). Following an 8-week placebo and dietary-controlled baseline period, patients were randomly assigned to double-blind treatment with placebo, 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks. At all evaluated doses, avasimibe treatment resulted in prompt and significant reductions (P<0.05) in plasma levels of total triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) with mean reductions of up to 23% and 30% respectively, apparently independent of dose. No statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C or apolipoprotein (apo) B were detected. ApoAI levels were also unchanged on all doses of avasimibe apart from the 500 mg dosage, which was associated with a significant decrease in plasma apoAI. The relevance of this latter finding in only one dosage group is not known. All doses of avasimibe were well tolerated with no resulting significant abnormalities of biochemical, hematological, or clinical parameters.

Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study.

SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2- to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p < or = 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461- or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia.

Probucol.

The purpose of this review article is twofold. It seeks to present an overview of research studies conducted on the many effects of probucol, and it demonstrates the interest in pursuing studies on probucol"s multiple specific actions and its future as a therapeutic agent. Within this article, the results of animal studies, experimental human studies, and clinical human studies are detailed, as is information on toxicology studies and on the side effects of the drug.

Randomized comparison of the efficacy and safety of cerivastatin and pravastatin in 1,030 hypercholesterolemic patients. The Cerivastatin Study Group.

OBJECTIVE: To determine the relative efficacy and safety of cerivastatin and pravastatin in patients with type II hypercholesterolemia. PATIENTS AND METHODS: In this prospective, double-blind, parallel-group study, hypercholesterolemic patients were randomized to treatment with cerivastatin, 0.3 mg (n=250) or 0.4 mg (n=258), or pravastatin, 20 mg (n=266) or 40 mg (n=256), for 8 weeks. RESULTS: Cerivastatin, 0.3 mg, was significantly more effective than pravastatin, 20 mg, in reducing low-density lipoprotein (LDL) cholesterol from baseline (-29.6% vs -26.8%; P=.008). Cerivastatin, 0.4 mg, was significantly more effective than pravastatin, 40 mg, in reducing LDL cholesterol (-34.2% vs -30.3%; P<.001). A larger proportion of cerivastatin-treated patients had greater than 40% reductions in LDL cholesterol than those receiving pravastatin (11.1% vs 6.0%). The percentage of patients who achieved the National Cholesterol Education Program (NCEP) target was 71.3% with cerivastatin, 0.3 mg, compared with 67.5% with pravastatin, 20 mg, and 74.0% with cerivastatin, 0.4 mg, compared with 71.1% with pravastatin, 40 mg (no significant difference). Cerivastatin, 0.3 mg, reduced total cholesterol to a greater extent than did pravastatin, 20 mg (P<.03). Both agents reduced triglycerides and increased high-density lipoprotein cholesterol to a similar degree (no significant differences). Cerivastatin and pravastatin were well tolerated. CONCLUSIONS: Cerivastatin, 0.3 mg and 0.4 mg, showed greater efficacy than pravastatin, 20 mg and 40 mg, respectively, in lowering LDL cholesterol. Cerivastatin is safe and effective for patients with hypercholesterolemia who require aggressive LDL cholesterol lowering to achieve NCEP-recommended targets.

Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients.

Plasma fibrinogen and hemorheologic-hemostatic factors contribute to dyslipidemia-induced morbidity. Some of these parameters can be favorably affected when abnormal serum lipoprotein levels are corrected. Thus, we investigated whether treatment with atorvastatin would result in changes in plasma viscosity and other hemorheologic and hemostatic parameters. Twenty-two hyperlipidemic men at a university lipid clinic were treated single-blinded with atorvastatin 80 mg/day for 12 weeks to determine hemostatic-hemorheologic parameters including blood viscosity, fibrinogen levels, whole blood platelet aggregation, tissue plasminogen activator antigen, hematocrit, plasminogen activator inhibitor activity, factor VII activity, red blood cell (RBC) deformity and lipid ratio, sedimentation rate, and fasting serum lipoprotein levels. Atorvastatin treatment provided significant lowering of serum lipoprotein levels: low-density lipoprotein -53% (p = 0.0001), very low density lipoprotein -43% (p = 0.0001), and triglycerides -35% (p < 0.0001). These effects were accompanied by changes in plasma viscosity -10% (p = 0.0007), arachidonic acid-induced whole blood platelet aggregation -11% (p = 0.006), factor VII -8% (p = 0.001), RBC lipid composition +5% (p = 0.0003), and RBC sedimentation -33% (p = 0.0002). Plasma fibrinogen levels were not affected. Thus, atorvastatin 80 mg/day produced marked reductions in serum low-density lipoprotein cholesterol (-53%), very low density lipoprotein cholesterol (-43%), and triglycerides levels (-35%), and significant changes in plasma viscosity as well as other hemorheologic-hemostatic parameters, but no changes in plasma fibrinogen levels.

Lipid-altering efficacy and safety of simvastatin 80 mg/day: worldwide long-term experience in patients with hypercholesterolemia.

BACKGROUND AND AIM: Clinical data suggesting that larger decreases in low density lipoprotein cholesterol (LDL-C) result in greater reductions in coronary heart disease events have led to the establishment of aggressive LDL-C targets for the treatment of hypercholesterolemia. In view of this, the efficacy and safety of a new maximum dose of simvastatin, 80 mg, were evaluated in 9 studies involving 2819 hypercholesterolemic patients. This report focuses on the combined results from the 4 main or Pivotal studies in which a total of 1936 patients received simvastatin 40 or 80 mg for 36 to 48 weeks. METHODS AND RESULTS: The Pivotal studies had similar randomized, multicenter, controlled, double-blind, parallel-group designs. Their combined results demonstrated a significant advantage in the LDL-C-lowering effect for the 80 mg dose. At week 24, the mean percentage reductions (95% confidence intervals) from baseline in LDL-C for the 40 and 80 mg groups were -39.8% (-40.9, -38.7) and -45.7% (-46.5, -45.0) respectively (p < 0.001, between groups), and larger reductions in total cholesterol and triglycerides were also observed in the 80 mg group. Both doses were well tolerated. No new or unexpected adverse events were observed and the overall clinical event profiles were similar in the two groups. Clinically significant hepatic transaminase increases (> 3 times the upper limit of normal/ULN) and myopathy (muscle symptoms plus creatine kinase increase > 10 times ULN) occurred infrequently with both doses. Simvastatin 80 mg had a comparable efficacy and safety profile in women and men as well as in non-elderly and elderly patients. CONCLUSIONS: Simvastatin 80 mg provides additional LDL-C and triglyceride reductions compared to the 40 mg dose and has an excellent safety and tolerability profile.

Lipid-altering drugs in development.

Although currently available lipid lowering therapies are effective and well tolerated, the search continues for additional treatments with even better efficacy and tolerability profiles. As well as refinements to existing strategies (new HMG-CoA reductase inhibitors, fibrates and combination therapies) new avenues are being explored. These include inhibitors of enzymes other than HMG-CoA reductase involved in cholesterol regulation and drugs which affect absorption of lipids from the gastrointestinal tract. In the case of the latter, it has been shown that the new antiobesity treatment orlistat can favourably affect the blood lipid profile. In line with an increasing emphasis on improving high density lipoprotein-cholesterol (HDL-C) levels, the potential therapeutic roles of niacin and drugs which inhibit enzymes involved in the metabolism of HDL-C are also being researched.

Long-term blood cholesterol-lowering effects of a dietary fiber supplement.

BACKGROUND: The study evaluated the blood cholesterol-lowering effects of a dietary supplement of water-soluble fibers (guar gum, pectin) and mostly non-water-soluble fibers (soy fiber, pea fiber, corn bran) in subjects with mild to moderate hypercholesterolemia (LDL cholesterol, 3.37-4.92 mmol/L). METHODS: After stabilization for 9 weeks on a National Cholesterol Education Program Step 1 Diet, subjects were randomly assigned to receive 20 g/d of the fiber supplement (n = 87) or matching placebo (n = 82) for 15 weeks and then receive the fiber supplement for 36 weeks. The efficacy analyses included the 125 subjects (58 fiber; 67 placebo) who were treatment and diet compliant. One hundred two (52 fiber; 50 placebo) completed the 15-week comparative phase. Of these subjects 85 (45 fiber; 40 placebo) elected to continue in the 36-week noncomparative extension phase. RESULTS: The mean decreases during the 15-week period for LDL cholesterol (LDL-C), total cholesterol (TC), and LDL-C/HDL-C ratio were greater (P < 0.001) in the fiber group. The mean changes from pre-treatment values in LDL-C, TC, and LDL-C/HDL-C ratio for subjects in the fiber group were -0.51 mmol/L (-12.1%), -0.53 mmol/L (-8.5%), and -0.30 (-9.4%), respectively. The corresponding changes in the placebo group were -0.05 mmol/L (-1.3%), -0.05 mmol/L (-0.8%), and 0.05 (1.5%), respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol (HDL-C), triglyceride, iron, ferritin, or vitamin A or E levels. Similar effects were seen over the subsequent 36-week noncomparative part of the study. CONCLUSIONS: The fiber supplement provided significant and sustained reductions in LDL-C without reducing HDL-C or increasing triglycerides over the 51-week treatment period.

Drug interactions of lipid-altering drugs.

The use of lipid-altering drugs has been shown to reduce the progression of atherosclerotic lesions and reduce the risk of atherosclerotic events (such as myocardial infarction and stroke). In general, these lipid-altering drugs are well tolerated but there is the potential for drug interactions. For example, HMG-CoA reductase inhibitors may interact with macrolides, azalides, azole antifungals and cyclosporin. Resins (such as cholestyramine and colestipol) may impair the absorption of many concurrent medications. Fibrates have potential drug interactions with warfarin, furosemide (frusemide), oral hypoglycaemics and probenecid. Nicotinic acid (niacin) may have potential drug interactions with high dose aspirin (acetylsalicylic acid), uricosuric agents (such as sulfapyrazone) and alcohol (ethanol). Finally, probucol may have potential drug interactions with antidysrhythmics, tricyclic antidepressants and phenothiazines. In addition, lipid-altering drugs, used in combination, may have the potential for drug interactions, enhancing some of the risks of adverse effects, such as myositis and hepatotoxicity. Therefore, in order to use lipid-altering drugs in the most effective, and safest manner, it is important for the clinician to have an understanding of the mechanisms of potential drug interactions, which drug interactions may theoretically occur, and specifically, which spe cific drug interactions have already been described.

Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group.

This randomized, multicenter, double-blind parallel-group study was performed to evaluate the lipid-altering efficacy and safety of simvastatin 80 mg/day, a dose twice the current maximum recommended dose. At 20 centers in the United States, 521 male and female hypercholesterolemic patients were randomly assigned in a ratio of 2:3 to receive simvastatin 40 or 80 mg once daily, respectively, for 24 weeks in conjunction with a lipid-lowering diet. Patients met National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol averaged at weeks 18 and 24 were 38% (-40 to -36) and 46% (-47 to -45) for the 40- and 80-mg groups, respectively (p <0.001 between groups). One third of patients on the 40- and 80-mg doses achieved an LDL cholesterol reduction of 46% and > or = 53%, respectively. Decreases in apolipoprotein B, total cholesterol, and triglycerides were also significantly greater among patients receiving 80 mg/day. Simvastatin was well tolerated in both groups. Two patients (0.6%) in the 80-mg group developed myopathy. Consecutive, clinically significant hepatic transaminase elevations occurred in 3 (1.0%) and 6 (1.9%) patients in the 40- and 80-mg groups, respectively (p= 0.486). In conclusion, simvastatin 80 mg/day provided substantial reductions in LDL cholesterol, allowing most patients to reach their NCEP target levels; it also had an excellent safety and tolerability profile.