Rosuvastatin Has Favorable Effects on Atherogenic Dyslipidemia in Patients with Metabolic Syndrome

NEW ORLEANS—In a comparison of statins, rosuvastatin had the most favorable effect on the atherogenic dyslipidemia associated with metabolic syndrome, said Prakash C. Deedwania, MD, at the 53rd Annual Scientific Session of the American College of Cardiology.

Metabolic syndrome has become more frequent as the prevalence of obesity has increased. "Approximately 25% of the adult population in the United States, and as many as 50% of adults older than 60 years, have metabolic syndrome," said Dr Deedwania, professor of medicine, chief, Cardiology Section, and director of cardiovascular research at the University of California, San Francisco. "With increasing prevalence of obesity, it is likely that in future years an even greater number of Americans will have metabolic syndrome."

Recent data indicate that the risk of cardiovascular disease increases in incremental fashion with the various components of metabolic syndrome. The risk of coronary heart disease is 2 to 3 times greater and the risk of stroke is 4 times greater in patients with metabolic syndrome compared with patients without metabolic syndrome.

Metabolic syndrome is associated with some specific types of dyslipidemia that increase the risk of atherosclerosis. Atherogenic dyslipidemia in patients with metabolic syndrome consists of a triad of elevated levels of low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol,and hypertriglyceridemia, each of which requires treatment for risk reduction.

"When treating patients with metabolic syndrome, clinicians may want to consider a statin that has the most positive effect on all components of atherogenic dyslipidemia," said Dr Deedwania.

The effect of the various statins on lipid abnormalities associated with metabolic syndrome was assessed in a subset of hypercholesterolemic subjects with metabolic syndrome enrolled in the Statin Therapies for Elevated Lipids Compared Across Doses to Rosuvastatin (STELLAR) trial. This trial was designed to compare the efficacy of rosuvastatin, atorvastatin, simvastatin, and pravastatin across their dose ranges in reducing LDL cholesterol in 2268 patients with hypercholesterolemia. The primary outcome of the STELLAR trial showed that LDL cholesterol reduction was significantly greater with rosuvastatin compared with the other statins at milligram-equivalent doses.

Participants in the STELLAR trial had LDL cholesterol levels of 160 to <250 mg/dL at baseline. Compared with the subjects in the STELLAR trial without metabolic syndrome, those with metabolic syndrome had higher mean values for triglycerides and lower mean values for HDL cholesterol.

The subjects were randomized to 1 of 14 open-label treatment arms for 6 weeks: rosuvastatin, 10, 20, or 40 mg/day; atorvastatin, 10, 20, 40, or 80 mg/day; simvastatin,10, 20, 40, or 80 mg/day; or pravastatin,10,20, or 40 mg/day. Doses of each drug were titrated to the highest dose allowed in patients who failed to meet their LDL cholesterol goals.

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HDL cholesterol increased by 10.4% with 40 mg/day of rosuvastatin, compared with 4.7% with 80 mg/day of atorvastatin ( <.002). Simvastatin increased HDL cholesterol by 8.3% to 10.0% across its dose range, and pravastatin was associated with increases in HDL cholesterol of 3.3% to 6.9% (Figure 1).

Non-HDL cholesterol, which is identified as a secondary target of therapy in the National Cholesterol Education Program Adult Treatment Panel III guidelines, was reduced by 52% with rosuvastatin, 40 mg/day; 46% with atorvastatin, 80 mg/day; 42% with simvastatin, 80 mg/day; and 27% with pravastatin, 40 mg/day (Figure 2).

Triglyceride values were reduced from baseline by 22% to 34% with rosuvastatin, 23% to 33% with atorvastatin, 15% to 23% with simvastatin, and 12% to 15% with pravastatin. The reduction in triglycerides with rosuvastatin, 40 mg, was significantly greater than that with simvastatin, 40 mg, and pravastatin, 40 mg, reported Dr Deedwania.

"This is the first study to assess in a randomized manner the comparative effect of 4 statins in patients with metabolic syndrome," he said. "The results from this STELLAR data analysis show that rosuvastatin has more favorable effects on the abnormal cholesterol levels associated with metabolic syndrome than other commonly prescribed statins."

Another result of the STELLAR trial is an indication that statins may arrest the progression of renal disease.¹

Study participants who were initially included in the 8-week STELLAR trial were permitted to enter an open-label extension trial and receive rosuvastatin treatment. This allowed investigators to assess the renal function of more than 10 000 patients, including 1929 patients with diabetes and 8722 patients without diabetes, who received rosuvastatin in its recommended dose range (5-40 mg) for up to 3.8 years.

Before the trial began, patients took a routine urine dipstick test and were periodically tested throughout the randomized and open-label treatment phases. The urine dipstick results were reported as none, trace, 1+, 2+, 3+, or 4+, and represented urinary protein concentrations that are <10, 10-20, —30, —100, —300, and =2000 mg/dL, respectively. The percentage of patients with urine dipstick protein results that were none, trace, 1+, 2+, 3+, or 4+ was similar at baseline and at the last visit.

The low percentage of patients who developed dipstick-positive proteinuria during rosuvastatin treatment were retested and usually had normal urine dipstick results.

Serum creatinine levels were measured using the alkaline picrate method of Jaffe. Mean serum creatinine concentrations were lower when compared with baseline in the course of rosuvastatin treatment, but concentrations were unchanged in the placebo groups.

The participants also had baseline and posttreatment assessments of their glomerular filtration rates (GFR) which were predicted using the Modification of Diet in Renal Disease equation. The mean (standard deviation [SD]) increased 0.4 (9) mL/min/1.73 m² in patients with diabetes and 2 (8) mL/min/1.73 m² in patients without diabetes. GFR was either unchanged or tended to increase with rosuvastatin treatment; mean (SD) GFR increased 1 (9) mL/min/1.73 m² and 5 (8) mL/min/1.73 m² in the patients with diabetes and without diabetes, respectively.

Because the majority of patients are started on a dosage of 10 mg, investigators paid special attention to this group during the study. In the trial, 893 patients were receiving the 10-mg dose after 96 weeks of treatment. The group had an increase in estimated GFR from 64 (10) at baseline to 69 (12) mL/min/1.73 m² (Table).

The findings of this trial support the concept of a renoprotective effect of statin treatment because GFR did not decrease during long-term rosuvastatin treatment. This suggests that certain statins, including rosuvastatin, may not only reduce cardiovascular risk but renal risk as well. Further studies are needed, however, to clarify the renoprotective effects of rosuvastatin.

Cardiology

1. Vidt DG, Cressman MD, Harris S, et al. Rosuvastatin-induced arrest in progression of renal disease. . 2004;102:52-60.