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Clinical Papers

Rosuvastatin is more effective than atorvastatin in the treatment of dyslipidaemic patients with the metabolic syndrome

Background

The metabolic syndrome is a multiplex risk factor for cardiovascular disease that is characterised by abdominal obesity, atherogenic dyslipidaemia, impaired glucose regulation and hypertension.(1) A recent survey found that this syndrome is present in 24% of American adults,(2) and even higher prevalences have been reported in other populations.(3) The metabolic syndrome is likely to become more common in the future as a consequence of the rising prevalence of obesity and diabetes and greater longevity.

Therapeutic lifestyle changes form the basis of treatment for the metabolic syndrome, but many patients also require pharmacological intervention for treatment of hypertension, hyperglycaemia and dyslipidaemia. The atherogenic dyslipidaemia that typically occurs in patients with the metabolic syndrome is characterised by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglyceride (TG).(1) Increased levels of small, dense low-density lipoprotein cholesterol (LDL-C) are commonly present,(4) and affected patients may also have increased total LDL-C levels.

Statins improve many aspects of the lipid profile. Although their primary action is to lower LDL-C, these agents also increase HDL-C and lower TG levels.(5) Furthermore, the ‘pleiotropic’ actions of this class of agents (e.g., reducing oxidative stress, modulating the inflammatory response) (5,6) may provide added benefits for patients at increased cardiovascular risk, such as those with the metabolic syndrome.

In the Comparative study with rosuvastatin in subjects with METabolic Syndrome (COMETS), Stalenhoef et al. compared the effects of rosuvastatin and atorvastatin on the lipid profile of patients with the metabolic syndrome. COMETS is the first large, international, prospective, randomised trial of statin therapy in patients with this condition.

Method

The investigators recruited adult patients who met the following inclusion criteria:

a diagnosis of the metabolic syndrome, defined by the presence of = 3 of the following factors: abdominal obesity^a, elevated triglyceride levels^b, low HDL-C levels^c, hypertension^d, elevated fasting blood glucose levels^e
LDL-C = 3.36 mmol/L (130 mg/dL)
additional multiple risk factors conferring a 10-year coronary heart disease risk > 10%.

All patients were required to follow the National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) therapeutic lifestyle-change diet during a 4-week run-in period prior to treatment. Patients were then randomised in a 2:2:1 ratio to 6 weeks of treatment with rosuvastatin 10 mg/day, atorvastatin 10 mg/day or placebo. At the end of this period, the rosuvastatin 10 mg and placebo groups were allocated to treatment with rosuvastatin 20 mg/day and the atorvastatin 10 mg group received atorvastatin 20 mg/day. This second treatment phase was also of 6 weeks duration.

Primary efficacy variable:

percentage change in LDL-C after 6 weeks (rosuvastatin 10 mg vs atorvastatin 10 mg)

Secondary efficacy variables included:

percentage change in LDL-C after 12 weeks (combined placebo/rosuvastatin 20 mg and rosuvastatin 10/20 mg groups vs the atorvastatin 10/20 mg group)
percentage change from baseline in HDL-C, TG, total cholesterol, non-HDL-C, apolipoprotein B (apo B) and apolipoprotein A-1 (apo A-1) at 6 and 12 weeks (rosuvastatin vs atorvastatin, treatment groups as above)
percentage change in lipid and lipoprotein ratios (total cholesterol:HDL-C, LDL-C:HDL-C, non-HDL-C:HDL-C and apo B:apo A-1) at 6 and 12 weeks (rosuvastatin vs atorvastatin, treatment groups as above)
percentage of patients achieving 2003 European and NCEP ATP III LDL-C goals at 6 and 12 weeks (rosuvastatin vs atorvastatin, treatment groups as above)
percentage change in high sensitivity C-reactive protein (hsCRP) at 6 and 12 weeks.

Results

A total of 401 patients were randomised to treatment. After 6 weeks of treatment, LDL-C reductions were significantly greater with rosuvastatin (42.7%) than with atorvastatin (36.6%, P < 0.001), and rosuvastatin remained significantly more effective than atorvastatin at 12 weeks (LDL-C reduction: 48.9% vs. 42.5%, P < 0.001). Compared with the atorvastatin group, significantly more rosuvastatin-treated patients achieved European and NCEP ATP III LDL-C goals at both 6 and 12 weeks. For example, after 12 weeks of treatment, 91% of rosuvastatin-treated patients had achieved their NCEP ATP III LDL-C goal whereas this target was achieved by 79% of atorvastatin-treated patients (P < 0.001).

At both 6 and 12 weeks, rosuvastatin achieved significantly greater reductions in plasma levels of total cholesterol, non-HDL-C and apo B, and significantly greater increases in HDL-C and apo A-1. For example, after 12 weeks of treatment, rosuvastatin had increased HDL-C levels by 10.4%, whereas atorvastatin was associated with an HDL-C increase of 5.8% (P < 0.01). Compared with atorvastatin, rosuvastatin also led to significantly greater reductions in all the lipid ratios examined. The two statins were associated with similar decreases in TG levels from baseline (combined rosuvastatin; -22.9%, atorvastatin 10/20 mg; -25.2%) at 12 weeks. After the same time period hsCRP levels were also significantly reduced compared with baseline in both the combined rosuvastatin (-28.6%; P < 0.001) and 10/20 mg atorvastatin (-27.7%; P < 0.01) groups. (7)

Both rosuvastatin 10/20 mg and atorvastatin 10/20 mg were well tolerated, and the incidence of adverse events was similar in the two active treatment groups.

Conclusions

COMETS is the first prospectively designed study to evaluate the comparative efficacy of statin treatment in patients with the metabolic syndrome. The results of COMETS show that rosuvastatin was consistently superior to atorvastatin in reducing LDL-C levels and allowing patients with the metabolic syndrome to achieve their LDL-C goals. Moreover, rosuvastatin achieved substantial reductions in plasma TG levels, and was significantly more effective than atorvastatin in increasing HDL-C.

Low HDL-C and elevated TG levels are included in the diagnostic criteria for metabolic syndrome and it is important to use agents that provide optimal improvements in these variables when selecting appropriate therapeutic options in this patient group. Although LDL-C levels do not form part of the diagnostic criteria for the metabolic syndrome, the NCEP ATP III guidelines regard this lipoprotein as the primary target of antidyslipidaemic therapy in all patients, including those with the metabolic syndrome.(1) Rosuvastatin thus fulfils all the criteria for a lipid-modifying agent that is effective in this population, since it is capable of achieving substantial beneficial changes in LDL-C, HDL-C and TG levels.

The finding that rosuvastatin is generally superior to milligram-equivalent doses of atorvastatin is consistent with analyses from other studies. For example, in the Measuring Effective Reductions in Cholesterol Using rosuvastatin therapY (MERCURY) I study, rosuvastatin 10 mg was significantly more effective than atorvastatin 10 mg in reducing LDL-C, total cholesterol and non-HDL-C in patients with the metabolic syndrome, and significantly more effective in reducing LDL-C, total cholesterol, non-HDL-C and TGs than simvastatin 20 mg and pravastatin 40 mg.(8) The STELLAR trial showed that rosuvastatin is superior to atorvastatin, pravastatin and simvastatin in reducing LDL-C, non-HDL-C and apo B in patients with hypercholesterolaemia.(9,10) Rosuvastatin 10 mg has similar antidyslipidaemic effects in patients with and without the metabolic syndrome.(11)

The beneficial effects of rosuvastatin and atorvastatin on levels of the inflammatory marker hsCRP are likely to be of therapeutic and prognostic importance. Inflammation is known to play an important role in the pathogenesis of atherosclerosis (12) and hsCRP is a strong predictor of future cardiovascular risk.(13,14) Moreover, statin-induced reductions in hsCRP levels are associated with substantial lowering of cardiovascular risk.(14)

In conclusion, COMETS has shown that rosuvastatin is significantly more effective than atorvastatin in reducing LDL-C levels in patients with the metabolic syndrome, and in allowing these patients to achieve their LDL-C goals. The superiority of rosuvastatin in increasing HDL-C levels and its highly beneficial effect on TG levels further demonstrate its potential for reducing cardiovascular risk in this population.

Footnotes

^a Waist circumference > 102 cm for men, > 88 cm for women
^b Triglycerides = 1.70 mmol/L (150 mg/dL)
^c HDL-C < 1.04 mmol/L (40 mg/dL) for men, < 1.30 mmol/L (50 mg/dL) for women
^d Blood pressure = 130/85 mm Hg or receiving antihypertensive treatment
^e Fasting blood glucose = 6.11 mmol/L (110 mg/dL)

References

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Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356-9.
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Jones PH, Hunninghake DB, Ferdinand KC, et al. Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: additional results from the STELLAR trial. Clin Ther 2004; 26:1388-99.
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