This 6-week, multicenter, randomized, open-label, parallel-group, single-dose trial (NCT00335699) was designed to compare the efficacy of a single dose of rosuvastatin and atorvastatin in patients having nondiabetic metabolic syndrome with dyslipidemia (Fig. 1). The study was conducted from August 2005 to January 2006 at 20 medical centers in Korea. The study included a 6-week dietary run-in period before randomization, followed by a 6-week treatment phase. Subjects entering the run-in period were asked to follow the NCEP Step I diet and required to discontinue any previous lipid lowering therapy. Following the dietary lead-in period, patients with fasting LDL-C levels ≥ 130 mg/dL to < 220 mg/dL were selected and randomly assigned to two parallel treatment groups. At baseline, eligible subjects were randomized 1 : 1 to receive either rosuvastatin (Astra-Zeneca Korea, Seoul, Korea) 10 mg or atorvastatin (Pfizer Pharmaceuticals Korea, Seoul, Korea) 10 mg once daily at bedtime for 6 weeks. The study drug was discontinued and subjects were removed from the study if they withdrew informed consent, became pregnant, or developed creatine kinase levels greater than 10 times the upper normal limit.

The ethics committees and institutional review boards at each participating hospital approved the study protocol. All patients provided informed consent to participate in this study.

Patients were ≥ 18 years of age and had nondiabetic metabolic syndrome. Metabolic syndrome was defined according to the modified NCEP ATP III criteria [11], which requires at least three of the following: abdominal obesity (waist circumference): men > 90 cm (36 inches), women > 80 cm (32 inches); triglyceride levels ≥ 150 mg/dL (1.70 mmol/L); HDL-C levels: men < 40 mg/dL (1.04 mmol/L) and women < 50 mg/dL (1.3 mmol/L); BP ≥ 130 / ≥ 85 mmHg or subject receiving antihypertensive treatment; and fasting blood glucose 110 mg/dL (6.11 mmol/L) to 125 mg/dL (6.94 mmol/L). Patients were excluded if they were pregnant or had malignancy. Additional exclusion criteria included diabetes, and active arterial disease such as unstable angina, myocardial infarction, cerebrovascular accident, coronary artery bypass surgery, or angioplasty within 2 months prior to enrollment. After completing the 6-week dietary run-in period, fasting LDL-C concentrations were required to be ≥ 130 mg/dL (3.36 mmol/L) to < 220 mg/dL (5.69 mmol/L) and fasting triglyceride levels were required to be < 400 mg/dL (4.52 mmol/L).

Sample analysis for efficacy endpoints was performed in the Green Cross Reference Laboratory, Yongin, Korea, which was certified by the American College of Pathology (LAP No. 6708401) and the National Committee for Clinical Laboratory Standards. Blood samples from patients who had fasted for 12 hours were collected at all investigational sites and delivered by courier to the central laboratory within 24 hours of blood draw. To assess the primary efficacy endpoint, lipid parameters such as total cholesterol, LDL-C, HDL-C, and triglyceride levels were measured during the dietary lead-in period, at randomization, and 6 weeks after treatment. Additionally, levels of apolipoprotein A-1 and B, high-sensitivity C-reactive protein (hsCRP), insulin, glucose, and hemoglobin A1c (HbA1c) were measured at randomization and at 6 weeks after treatment. LDL-C levels were calculated using the Friedewald equation (LDL-C = total cholesterol - (HDL-C + triglyceride/5). The insulin resistance index was estimated using the homeostasis model assessment (HOMA) for insulin resistance based on the following formula: fasting serum insulin (µU/mL) × fasting plasma glucose (mmol/L)/22.5. According to the NCEP ATP III guidelines, the goal LDL-C level for each patient and the proportion of patients achieving the goal in each group was assessed. Persons with CHD or CHD risk equivalent (Framingham 10-year CHD risk > 20%) had a LDL-C level goal of < 100 mg/dL. Those with multiple risk factors had a LDL cholesterol level goal of < 130 mg/dL and those with 0 - 1 risk factor (s) had a goal LDL cholesterol of < 160 mg/dL.

Individual demographic data, physical findings, vital signs, and adverse events were evaluated and recorded in the given case record form. To evaluate adverse events, various laboratory assessments including blood counts, and hemoglobin, aspartate aminotransferase, alanine aminotransferase, creatine kinase, electrolyte, and creatinine levels were performed at each time point.

One-hundred and forty-three evaluable subjects per treatment group were required to achieve 95% power for detecting a clinically significant difference of 6% at the 5% two-sided level in percentage change from baseline in LDL-C levels at 6 weeks with an assumed standard deviation of 14% [12]. Assuming a dropout rate of 20% during the randomized treatment period, approximately 180 subjects were recruited to each active treatment group. To obtain the required number of randomized subjects (360 in total), approximately 900 subjects were assumed to be needed for screening based on a screening failure rate of 60%.

The primary analysis population was the last observation carried forward on the intention-to-treat population. This included all subjects with a baseline and at least one post-baseline lipid level measurement. All numeric variables were expressed as the mean ± SEM (standard error of the mean). Efficacy endpoints were analyzed using the unpaired t-test for continuous variables and Pearson's chi-square test for frequencies with 95% confidence intervals. Multivariate logistic regression analysis was used to evaluate the predictors for reaching target NCEP ATP III LDL-C levels after treatment. Variables used for analysis included the statin used, presence of coronary artery disease and hypertension, body mass index, gender, age, waist circumference, and lipid parameters.

On the basis of the actual treatment received, safety data were evaluated for all patients who received at least one dose of study medication.

In total, 645 subjects were screened for participation in this study. Of them, 370 patients entered the dietary lead-in phase and 351 patients met the inclusion criteria and were randomly assigned to treatment with either rosuvastatin 10 mg or atorvastatin 10 mg (Fig. 1). One patient was lost to follow-up and had no safety assessment. Table 1 shows demographic data and baseline characteristics of all 350 subjects who took at least one dose of the study drug at baseline. In terms of demographic data and baseline characteristics, no statistically significant differences existed between the two treatment groups. Patients had a mean age of 60 years in the rosuvastatin group and 58 years in the atorvastatin group. Mean body weights were 66 kg in the rosuvastatin group and 66 kg in the atorvastatin group. Mean systolic and diastolic BP and waist circumstance were comparable between the two groups (Table 1).

A total of five patients dropped out before efficacy assessment. Data from 346 patients were analyzed for efficacy in the intention-to-treat population defined as those who took at least one dose of study drug and had lipid levels checked at baseline and follow-up. Safety assessments were performed in 350 patients who were randomized and available for follow-up.

Lipid levels, glucose levels, insulin resistance indices, and hsCRP levels at baseline and 6 weeks are shown in Table 2. In each group, atherogenic lipid parameters including total cholesterol, LDL-C, triglyceride, non-HDL-C, and apolipoprotein B had significantly decreased after 6 weeks of treatment (p < 0.001 vs. baseline). Only the atorvastatin treatment produced a modest decrease in HDL-C. Rosuvastatin treatment significantly increased HbA1c and the HOMA index; however, no significant change occurred in the atorvastatin group.

Data from two groups were analyzed for an efficacy comparison in the intention-to-treat population. Baseline values of all parameters were similar between the two groups. At 6 weeks after treatment, rosuvastatin 10 mg produced a significantly greater reduction in total cholesterol, LDL-C, non-HDL-C, and apolipoprotein B levels. Otherwise, no significant differences were detected in HDL-C and apolipoprotein A-1 levels between the two groups. In addition, no significant differences were observed with respect to glucose, HbA1c, and hsCRP levels, and HOMA index between the rosuvastatin and atorvastatin groups at 6 weeks (Table 2). At 6 weeks, LDL-C absolute values decreased by 48.04 ± 14.45 mg/dL in the rosuvastatin group and by 39.52 ± 14.42 mg/dL in the atorvastatin group; the former reduction associated with rosuvastatin use was significantly larger than that with atorvastatin (p < 0.0001).

Percent changes from baseline in lipid profiles after treatment for 6 weeks, including LDL-C, are shown in Fig. 2. Reductions in total cholesterol (- 35.94 ± 11.38 vs. - 30.07 ± 10.46%, p < 0.0001), non-HDL-C (- 42.93 ± 13.15 vs. - 35.52 ± 11.76%, p < 0.0001), and apolipoprotein B (- 38.7 ± 18.85 vs. - 32.57 ± 17.56%, p = 0.0019) levels were larger in the rosuvastatin group as compared to the atorvastatin group (Fig. 2).

According to the reported CHD or/and CHD risk equivalents and/or number of risk factors and/or Framingham 10-year risk, the NCEP ATP III LDL-C target goal was determined in each patient and the success rate in reaching their target goal was analyzed after 6 weeks in each group.

The percentage of patients who reached their ATP III LDL-C level goals was higher in the rosuvastatin group (87.6 vs. 69.9%, p < 0.001). Among them, patients having LDL-C target cholesterol level goals of < 100 mg and < 130 mg reached their LDL-C target level goals more frequently in the rosuvastatin group as compared to the atorvastatin group. In contrast, in patients with a LDL-C target level goal < 160 mg, more than 96% reached their target goal without a significant difference between the rosuvastatin- and atorvastatin-treated groups (Fig. 3). The overall achievement rate for NCEP non-HDL-C level target goals after 6 weeks of treatment was 76.08% in the rosuvastatin group and 58.92% in the atorvastatin group (p = 0.067).

Percent changes in glucose levels and insulin resistance at 6 weeks are summarized in Table 3. Changes in glucose and insulin levels were not significantly different between the two groups; however, HbA1c levels were slightly higher in the rosuvastatin group with marginal significance. To evaluate insulin resistance in the two groups, the HOMA index was calculated. At 6 weeks, the HOMA index increased in both groups and the difference between groups was not significant.

Both rosuvastatin 10 mg and atorvastatin 10 mg were well tolerated, with similar incidences of adverse events. During the treatment period, 13 subjects in the rosuvastatin group and 9 subjects in the atorvastatin group reported adverse events (Table 4). The most frequent adverse events in the rosuvastatin group were edema and dizziness, both with incidences of 1.16%. Only five adverse events were reported in the atorvastatin group as related to the study drug; myalgia was reported in one case (0.56%). All adverse events were mild, developed within 2 weeks after starting treatment, had no action taken, and resolved spontaneously. No drug-related adverse effects were observed in the rosuvastatin group. Also, no patient had an increase in alanine aminotransferase level > 3 times the upper limit of normal or rhabdomyolysis.

Overall, the percentage of patients who reached NCEP ATP III LDL-C target level goals was higher in the rosuvastatin group as compared to the atorvastatin group. Univariate analysis showed that patients with target LDL-C levels at 6 weeks tended to be rosuvastatin-treated and have coronary artery disease. Multivariate logistic regression analyses that included age, gender, statin, coronary artery disease, hypertension, body mass index, waist circumference, baseline total cholesterol levels, and triglyceride levels showed that rosuvastatin treatment, the presence of coronary artery disease, female gender, lower total cholesterol level, and lower LDL-C levels at baseline were independent predictors for achievement of target LDL-C levels at 6 weeks (Table 5).