A Multicenter, Placebo-Controlled, Dose-Ranging Study of Atorvastatin. Safety and efficacy of atorvastatin in patients with severe renal dysfunction. A randomized, double-blind, placebo-controlled, 8-week study to evaluate the efficacy and safety of once daily atorvastatin (10 mg) in patients with elevated LDL-cholesterol. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Efficacy and safety of a new hydroxymethylglutaryl-coenzyme A reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate. Efficacy and safety of rosuvastatin and atorvastatin in patients with hypercholesterolemia and a high risk of coronary heart disease: a randomized, controlled trial. Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia. Efficacy and tolerability of a generic and a branded formulation of atorvastatin 20 mg/d in hypercholesterolemic Korean adults at high risk for cardiovascular disease: a multicenter, prospective, randomized, double-blind, double-dummy clinical trial. Atorvastatin increases low-density lipoprotein size and enhances high-density lipoprotein cholesterol concentration in male, but not in female patients with familial hypercholesterolemia.
BACKGROUND: Coronary heart disease (CHD) is the number one cause of death in Western societies. Elevated levels of plasma low-density lipoprotein (LDL) cholesterol and triglycerides (TG) increase the risk for CHD. 3-Hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase inhibitors effectively reduce plasma cholesterol levels in patients with hypercholesterolemia. This study assesses the safety and dose-related effects of atorvastatin calcium on lipoprotein fractions in patients with LDL cholesterol levels between 160 mg/dL (4.1 mM) and 250 mg/dL (6.5 mM) or less and TG levels of 400 mg/dL (4.5 mM) or less. METHODS AND RESULTS: Sixty-five patients were enrolled in a 6-week, randomized, placebo-controlled, parallel-group study. Patients received placebo or atorvastatin 10, 20, 40, 60, or 80 mg once daily. Adjusted mean decreases in LDL cholesterol for patients receiving atorvastatin 10, 20, 40, 60, and 80 mg were 37%, 42%, 50%, 52%, and 59%, respectively, compared with a mean increase of 0.3% for patients receiving placebo; the differences between each of the atorvastatin dose groups and placebo were statistically significant (P =.0001). Total cholesterol, triglycerides, and apolipoprotein B were significantly reduced in atorvastatin groups (P =.0001). Adverse events were similar in the placebo and atorvastatin treatment groups. No patient had a serious adverse event or withdrew because of an adverse event during this study. CONCLUSIONS: Atorvastatin effectively lowered plasma LDL cholesterol, triglycerides, and apoB levels in a dose-related manner. Atorvastatin was well tolerated in hyperlipidemic patients over a 6-week period. To investigate the efficacy and safety of a daily dose of 10 mg of atorvastatin in patients with chronic kidney disease (CKD) stages 4 and 5 and a glomerular filtration rate of <30 ml/min.
                This was an open, prospective, randomized study. A total of 143 patients were included: 73 were controls and 70 were prescribed 10 mg/day of atorvastatin. As efficacy variables, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels were determined at the start of the study and at 1, 3, 6, 12, 18, 24, 30 and 36 months.
                The follow-up period was a mean of 20+/-14.4 months (range 1-36 months) for those on atorvastatin versus 22+/-12.7 months (range 0.5-36 months) for the controls. Compared with baseline values, patients treated with atorvastatin had significantly lower concentrations of total cholesterol at Month 36 (5.8 vs 4.4 mmol/l; -23%; p<0.001), of LDL cholesterol at Month 36 (3.6 vs 2.2 mmol/l; -35%; p<0.001) and of triglycerides at Months 24 (2.5 vs 1.9 mmol/l) and 36 (2.5 vs 1.8 mmol/l). The controls had significantly reduced levels of total cholesterol at Month 36 (p<0.21) and of LDL cholesterol at Months 30 and 36. Compared with the controls, the atorvastatin group had lower levels of total cholesterol and LDL cholesterol at Months 1-30. Fifteen patients (21%) stopped taking their medication as they could not tolerate the side-effects, the most frequent complaints being gastrointestinal discomfort and headache.
                Although the medication caused no severe adverse events, we recommend caution when using atorvastatin for severe CKD patients until further evidence of its safety and efficacy is verified. Lowering of serum cholesterol levels by pharmacologic intervention with statins reduces the incidence of cardiovascular events in subjects with and without atherosclerotic manifestations. In an 8-week, randomized, double-blind study we compared the efficacy and safety of the new compound atorvastatin for reducing LDL-cholesterol (LDL-C) with placebo in an Asian patient cohort. Patients with LDL-C between 160 mg/dl and 250 mg/dl were randomly assigned to treatment with 10 mg atorvastatin or placebo once daily for 8 weeks. At the end of weeks 4 and 8 of the randomized phase, the serum concentrations of lipid parameters as well as safety parameters were determined. Fifty-four patients (32 males and 22 females) were enrolled. Twenty-six patients were assigned to the treatment group. The primary end-point, LDL-C, was reduced by 40% and 42% after 4 and 8 weeks of treatment in the atorvastatin treated patients (p<0.001). The reductions in total cholesterol and triglycerides were up to 31% and 23%, respectively. The HDL-C levels increased up to 11% (p=0.043). There were no significant adverse events. Transient increases in CPK levels (10 times) without myalgia were identified in 1 patient. Atorvastatin, 10 mg/day produced significant reductions in LDL-C, total cholesterol and triglycerides and an elevation of HDL-C levels when used as an adjunct to diet in hyperlipidemic patients. The majority of the clinical effects could be attained by week 4. The overall safety profile of atorvastatin was similar to that of placebo. Atorvastatin was considered to be well tolerated in this patient cohort. The lipid-lowering effects of rosuvastatin and atorvastatin were determined across their dose ranges in a 6-week, randomized, double-blind trial. Three hundred seventy-four hypercholesterolemic patients with fasting low-density lipoprotein (LDL) cholesterol > or =160 but <250 mg/dl (> or =4.14 but <6.47 mmol/L) and fasting triglycerides <400 mg/dl (<4.52 mmol/L) and without active arterial disease within 3 months of entry received once-daily rosuvastatin (5, 10, 20, 40, or 80 mg [n = 209]) or atorvastatin (10, 20, 40, or 80 mg [n = 165]). The percentage decrease in plasma LDL cholesterol versus dose was log-linear for each drug, ranging from -46.6% to -61.9% for rosuvastatin 10 and 80 mg, compared with -38.2% to -53.5% for atorvastatin 10 and 80 mg. The dose curve for rosuvastatin yielded an 8.4% greater decrease in LDL cholesterol compared with atorvastatin at any given dose (p <0.001). Similarly greater decreases were observed for rosuvastatin across the dose range in total cholesterol (-4.9%), non-high-density lipoprotein (non-HDL) cholesterol (-7.0%), apolipoprotein B (-6.3%), and related ratios versus atorvastatin (all p <0.001). Because dose responses for HDL cholesterol, triglycerides, and apolipoprotein A-I were non-log-linear and nonparallel between the 2 drugs, percentage changes from baseline were compared at each dose. Significantly greater increases for rosuvastatin compared with atorvastatin were observed for HDL cholesterol at 40 and 80 mg, and for apolipoprotein A-I at 80 mg. Significantly greater triglyceride decreases were seen at 80 mg with atorvastatin over rosuvastatin. Both rosuvastatin and atorvastatin were well tolerated over 6 weeks. This 24-week, randomized, open-label multicenter study evaluated the efficacy and safety of atorvastatin compared with fenofibrate in the treatment of patients with combined hyperlipidemia (CHL). Following a 6-week baseline period, 84 patients with CHL were randomly assigned to either atorvastatin treatment, 10 mg QD for 12 weeks increasing to 20 mg QD for 12 weeks, or fenofibrate treatment, 100 mg TID for 24 weeks. Changes from baseline in lipid parameters were evaluated at weeks 12 and 24. At both 10- and 20-mg doses, atorvastatin treatment resulted in significantly greater reductions in LDL cholesterol, apolipoprotein (apo) B, total cholesterol, LDL-apoB, and lipoprotein-B compared to 300-mg fenofibrate treatment (P < .05). While atorvastatin also resulted in clinically significant reductions in triglyceride, VLDL cholesterol, apoB in VLDL, triglyceride in VLDL, and apoC-III and significant increases in HDL cholesterol and apoA-I levels, fenofibrate was more effective than atorvastatin in altering all these parameters. However, by significantly affecting both the cholesterol-rich and triglyceride-rich particles, atorvastatin holds promise as a lipid-regulator able to adequately treat a broad range of patients that includes those with CHL. This double-blind, multicenter, randomized trial compared rosuvastatin and atorvastatin for reducing low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia and a high risk of coronary heart disease.
                After a 6-week dietary lead-in period, patients with LDL-C levels > or =160 and <250 mg/dL and triglyceride levels < or =400 mg/dL were randomly assigned to 24 weeks' treatment in 1 of 3 groups, each with forced dose titrations at 12 and 18 weeks. Starting and titrated doses for each group were rosuvastatin 5, 20, and 80 mg (n = 127); rosuvastatin 10, 40, and 80 mg (n = 128); and atorvastatin 10, 40, and 80 mg (n = 128).
                At 24 weeks, LDL-C was reduced significantly more with 80 mg rosuvastatin (combined rosuvastatin group) than with atorvastatin 80 mg (60% vs 52% [P <.001]). At 12 weeks, rosuvastatin 5 and 10 mg reduced LDL-C significantly more than atorvastatin 10 mg (40% [P <.01], 47% [P <.001] vs 35%). At 18 weeks, LDL-C reductions were also significantly greater in both rosuvastatin groups than in the atorvastatin group (52% [P <.01], 59% [P <.001] vs 47%). Consequently, more patients receiving rosuvastatin achieved LDL-C goals. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoproteins B and A-I, and all lipid ratios were more favorably modified by rosuvastatin at 24 weeks (P <.01). Effects of the 2 agents on triglycerides were similar.
                Rosuvastatin was more efficacious than atorvastatin in modifying lipids in patients with hypercholesterolemia and a high coronary heart disease risk. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of ischemic heart disease. An open-label study was conducted to test the efficacy and safety of atorvastatin, a new synthetic HMG-CoA reductase inhibitor in proven FH. After a 4-week placebo phase, 22 subjects were randomized to either 80 mg atorvastatin at night (n = 11) or 40 mg twice a day for 6 weeks. The two dosage groups were well matched and had no difference in lipoprotein responses. After 6 weeks, the LDL cholesterol concentration was reduced by 57%, from 8.16 +/- 1.15 to 3.53 +/- 0.99 mmol/L (P < .001). The total cholesterol concentration decreased from 9.90 +/- 1.32 to 5.43 mmol/L (P < .001). HDL cholesterol concentration increased from 1.19 +/- 0.31 to 1.49 +/- 0.43 mmol/L (P < .001). Triglyceride concentrations decreased from 1.34 +/- 0.66 to 0.88 +/- 0.36 mmol/L (P < .01). Three subjects had single, transient increases of serum transaminase of up to twice the upper limit of normal. Apolipoprotein B concentration decreased significantly by 42%. Changes in apolipoproteins AI and (a) were not statistically significant. Nondenaturing gradient gel electrophoresis revealed increases in the size of smaller LDL particles in four subjects. Plasma fibrinogen concentration increased by 44%. The drug was well tolerated. One subject withdrew for personal reasons. Atorvastatin is a powerful and safe lipid-modifying agent for LDL cholesterol; it also modifies HDL cholesterol and triglyceride concentrations, and may suffice as a single agent for many subjects with heterozygous FH. The reduction in plasma LDL-C concentrations with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has been reported to reduce cardiovascular risk and mortality in individuals with or without preexisting coronary artery disease and elevated LDL-C concentrations. Atorvastatin is a statin used for lowering LDL-C concentrations. A generic formulation of atorvastatin is being developed in Korea. This study was undertaken for the purposes of marketing the generic formulation.
                This study was designed to compare the efficacy and tolerability of a generic formulation of atorvastatin 20 mg/d versus a branded formulation at the same dosage in hypercholesterolemic Korean adults at high risk for cardiovascular events.
                This 8-week, multicenter, randomized, double-blind, double-dummy study was conducted at 10 clinical centers in Korea between September 2008 and May 2009. Male and female patients aged 20 to 85 years at high risk for cardiovascular events (defined as an elevated LDL-C concentration [≥100 mg/dL]) were enrolled. Eligible patients were randomly assigned to receive generic or branded atorvastatin 20 mg once daily for 8 weeks. The primary end point was the percentage change from baseline to 8 weeks in LDL-C concentration. Secondary end points were the percentage changes from baseline in total cholesterol (TC), triglycerides (TG), HDL-C, apolipoprotein (apo) A1 and B, and high-sensitivity C-reactive protein concentrations; small, dense LDL (sdLDL) fraction; and tolerability. Tolerability was assessed using physical examination, laboratory testing, and by recording adverse events (AEs) at each visit. An additional secondary end point was the proportion of patients who achieved an LDL-C goal of <100 mg/dL.
                A total of 244 patients were randomized to treatment, and 33 patients were withdrawn from the study (9 patients did not receive the study medication, 11 patients due to AEs, and 13 patients due to withdrawal of consent). A total of 211 patients completed the study (50.7% male; 100% Asian; mean [SD] age, 61.7 [9.2] years) (106 patients in the group that received Accepted for publication October 5, 2010. the generic formulation and 105 patients in the group that received the branded formulation). LDL-C concentrations were reduced from the baseline by 44% and 46% after 8 weeks of treatment with the generic and branded formulations, respectively (P = NS). The percentage changes from baseline to study end in HDL-C, TC, TG, apo A1, apo B, and hsCRP concentrations and sdLDL fraction the proportions of patients who achieved the LDL-C goal between the 2 groups did not reach statistical significance. The most commonly reported events were hepatobiliary laboratory abnormality (1.7%), general somatic discomfort (1.7%), and epigastric pain (0.8%) in the group that received the generic formulation, and myalgia (1.7%), epigastric pain (0.9%), and elevation of creatinine phosphokinase (0.9%) in the group that received the branded formulation. No serious AEs were reported in either group.
                After 8 weeks of treatment, the differences in the LDL-C-lowering effects between the generic and branded formulations of atorvastatin 20 mg/d did not reach statistical significance in these Korean patients at high risk for cardiovascular events. Both formulations were generally well tolerated.
                Copyright © 2010 Excerpta Medica Inc. All rights reserved. The effects of atorvastatin (Lipitor) were evaluated in 40 patients with familial hypercholesterolemia (FH). Following a 6 week drug-free baseline period 20 male and 20 female patients were treated with atorvastatin 40 mg once daily (QD) for the initial 6 weeks increasing to 80 mg QD during the following 6 weeks. Atorvastatin 40 and 80 mg resulted in a dose related reduction in LDL cholesterol of 44 and 50% (P<0.001), respectively. The reduction of triglycerides (TG) was 35% (P<0.001) with 40 and 80 mg atorvastatin. The lipoprotein lipase and the hepatic lipase activity decreased dose independently by 13% (P<0.05) and 18% (P<0.01), respectively. In males, a dose independent increase in high-density lipoprotein (HDL) cholesterol concentration was observed of 8%, (P<0.05). In females, the HDL cholesterol concentration did not change. Baseline LDL size in the females was significantly larger than in the males, being 268+/-6 A and 264+/-8 A (P<0.05), respectively. In males LDL size increased significantly from 264+/-8 A at baseline to269+/-6 A at 40 mg (P<0.05) and to 270+/-5 A (P<0.05) at 80 mg atorvastatin. In females LDL size did not change upon treatment with atorvastatin 40 and 80 mg QD. In conclusion, atorvastatin has the ability to decrease cholesterol and triglyceride concentrations as well as the activity of both lipoprotein and hepatic lipase activity. Additionally it has a favorable effect on LDL size and HDL cholesterol concentration in male, but not in female FH patients.
Blood total cholesterol, LDL-cholesterol and triglyceride lowering effect of atorvastatin was dependent on dose. Log dose-response data was linear over the commonly prescribed dose range. Manufacturer-recommended atorvastatin doses of 10 to 80 mg/day resulted in 36% to 53% decreases of LDL-cholesterol. The review did not provide a good estimate of the incidence of harms associated with atorvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 37% of the placebo-controlled trials.