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Rosuvastatin

A Review of its Effect on Atherosclerosis

American Journal of Cardiovascular Drugs volume 8, pages 127–146 (2008)Cite this article

Summary

Abstract

The HMG-CoA reductase inhibitor (statin) rosuvastatin (Crestor®) is widely available for use in the management of dyslipidemia, and was recently approved in the US to slow the progression of atherosclerosis as part of a strategy to lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) to target levels. Rosuvastatin has greater lipid-lowering efficacy than any of the other currently available statins, and significantly more patients receiving rosuvastatin than other statins achieve LDL-C goals. Rosuvastatin delayed the progression of carotid atherosclerosis in patients with subclinical carotid atherosclerosis, moderately elevated cholesterol levels, and a low risk of cardiovascular disease in a primary prevention trial (METEOR). The results of METEOR suggest a possible role for the earlier use of rosuvastatin in primary prevention, although more data are needed from trials examining the effects of the drug on cardiovascular endpoints. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in patients with established coronary heart disease (CHD) in the ASTEROID trial, supporting the use of intensive lipid lowering in secondary prevention patients (although it should be noted that it has not yet been established that atherosclerotic regression translates into improved cardiovascular outcomes). Rosuvastatin is generally well tolerated, with a similar tolerability profile to that of other currently available statins. Thus, rosuvastatin is an important lipid-lowering treatment option that has been shown to cause regression of atherosclerosis in secondary prevention patients, and has a potential future role in delaying atherosclerosis in primary prevention patients.

Pharmacologic Properties

Rosuvastatin is relatively hydrophilic and highly selective for hepatic cells. The uptake of rosuvastatin is mediated by the liver-specific organic anion transporter OATP-C; in vitro, the affinity of rosuvastatin for OATP-C was significantly higher than that of pravastatin or simvastatin.

In numerous large, well designed trials, rosuvastatin reduced LDL-C levels to a significantly greater extent than simvastatin, pravastatin, or atorvastatin in patients with hypercholesterolemia, including patients at high risk of CHD and special patient groups, such as patients with the metabolic syndrome or diabetic dyslipidemia, African-American patients, Hispanic-American patients at moderate or high risk of CHD, and South-Asian patients at high risk of CHD. TC levels were generally reduced to a significantly greater extent with rosuvastatin than with simvastatin, pravastatin, or atorvastatin. Significantly greater improvements in high-density lipoprotein-cholesterol levels were seen with rosuvastatin than with simvastatin, pravastatin, or atorvastatin in most studies, and few studies reported significant between-group differences in triglyceride levels.

Significantly more patients receiving rosuvastatin than atorvastatin achieved National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), 2003 European, or 1998 European LDL-C goals. Similarly, in a series of trials conducted in a clinical practice setting, LDL-C goals were achieved by significantly more patients receiving rosuvastatin 10 mg/day than those receiving atorvastatin 10 mg/day, simvastatin 20 mg/day, or pravastatin 40 mg/day. In addition, switching studies demonstrated that the 1998 European or NCEP ATP III LDL-C goals were generally achieved in significantly more patients who switched to rosuvastatin 10 or 20 mg/ day than in those who remained on atorvastatin, simvastatin, or pravastatin.

Rosuvastatin has pleiotropic effects beyond its lipid-lowering effects. For example, rosuvastatin had anti-inflammatory effects in patients with dyslipidemia or CHD; significant reductions from baseline in C-reactive protein levels, fibrinogen levels, and in plasma levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interferon-γ occurred in rosuvastatin recipients. Rosuvastatin also demonstrated antioxidant effects and beneficial effects on endothelial function and platelets.

Therapeutic Efficacy

Results are available from three trials (METEOR, ORION, and ASTEROID) examining the effect of rosuvastatin on atherosclerosis.

METEOR was a randomized, double-blind, placebo-controlled, multicenter, 2-year, primary prevention trial. Patients (984 randomized patients) were middle-aged and had subclinical carotid atherosclerosis with moderately elevated cholesterol levels and a low risk of cardiovascular disease. In METEOR, rosuvastatin 40 mg/day significantly slowed the progression of carotid atherosclerosis. The change from baseline in maximum carotid intima-media thickness (CIMT) for all 12 carotid artery sites (primary endpoint) significantly favored rosuvastatin over placebo with a between-group difference of −0.0145 mm/year (95% CI −0.0196, −0.0093). Superiority of rosuvastatin over placebo was also seen for the change in maximum CIMT for the segment-specific sites and for the change in mean CIMT for the common carotid artery sites.

ORION was a small (33 evaluable patients) randomized, double-blind, multicenter, 2-year, primary prevention trial conducted in patients aged ≥18 years with asymptomatic carotid disease and moderate hypercholester-olemia. Patients were initially randomized to receive low-dose rosuvastatin (5 mg/day) or high-dose rosuvastatin (40 mg/day titrated to 80 mg/day) for 2 years; however, following a protocol amendment, patients receiving rosuvastatin 80 mg/day were back titrated to receive 40 mg/day for the remainder of the trial. Rosuvastatin 5 and 40 mg/day were not associated with significant changes from baseline in carotid artery wall volume (primary endpoint). However, the proportion of the plaque comprising lipid-rich necrotic core was significantly reduced by a mean 41.4% and fibrous tissue was significantly increased by a mean 1.8%.

ASTEROID was a noncomparative, multicenter, 2-year, secondary prevention trial in which all patients received rosuvastatin 40 mg/day (349 evaluable patients). Patients were aged ≥18 years, had a clinical indication for coronary angiography, and had at least one obstruction in any coronary vessel with >20% narrowing in the angiographic luminal diameter. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in ASTEROID. The percent atheroma volume (primary endpoint) was significantly reduced from baseline with rosuvastatin. According to this endpoint, 63.6% of rosuvastatin recipients showed regression of atherosclerosis. Moreover, there was a significant reduction from baseline in the atheroma volume in the most diseased 10-mm segment (primary endpoint). According to this endpoint, 78.1% of rosuvastatin recipients showed regression of atherosclerosis. A significant reduction from baseline in the normalized total atheroma volume was also seen with rosuvastatin, with 77.9% of patients showing regression.

Tolerability

In a pooled safety analysis of an integrated clinical trial database that included 16 876 patients who had received rosuvastatin 5–40 mg/day, the most commonly occurring adverse events (occurring in ≥2% of rosuvastatin recipients) included myalgia, headache, nasopharyngitis, arthralgia, nausea, and upper respiratory tract infection. Clinically significant ALT elevations (>3 times the upper limit of normal [ULN] on at least two consecutive measurements) occurred in 0.6%, 0.2%, 0.2%, and 0.4% of patients receiving rosuvastatin 5, 10, 20, and 40 mg/ day. ALT elevations were generally transient and either resolved or improved with continued treatment (with or without dosage reduction). The proportion of rosuvastatin 5, 10, 20, and 40 mg/day recipients with creatine kinase elevations to >10 times ULN was 0.4%, 0.2%, 0.3%, and 0.6%, respectively. Myalgia occurred in 3.5% of rosuvastatin 5–40 mg/day recipients; five rosuvastatin recipients had myopathy that was considered possibly related to treatment. A shift from no or trace proteinuria at baseline to >2+ dipstick proteinuria occurred in <1% of patients receiving rosuvastatin 5–20 mg/day and in 1.5% of rosuvastatin 40 mg/day recipients.

Rosuvastatin 40 mg/day was generally well tolerated in the METEOR and ASTEROID trials, with a tolerability profile similar to that seen in the pooled safety analysis. The most commonly reported adverse event in METEOR was myalgia (12.7% of rosuvastatin recipients and 12.1% of placebo recipients). Muscle pain or weakness was the most common adverse event leading to drug discontinuation in ASTEROID (3.7% of rosuvastatin recipients). There were no cases of rhabdomyolysis in either trial. ALT elevations to >3 times ULN on two consecutive measurements, creatine kinase elevations to >10 times ULN, and a shift from no or trace proteinuria at baseline to ≥2+ dipstick proteinuria each occurred in ≤0.6% of rosuvastatin recipients and ≤0.7% of placebo recipients in METEOR and in ≤0.2% of rosuvastatin recipients in ASTEROID.

Several large retrospective analyses revealed no significant differences between rosuvastatin and other statins in the incidence rates of hospitalization for rhabdomyolysis, myopathy, renal dysfunction, or hepatic dysfunction.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Affiliations

  1. Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand

    Gillian M. Keating & Dean M. Robinson

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Gillian M. Keating & Dean M. Robinson

Authors
  1. Gillian M. Keating
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  2. Dean M. Robinson
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Corresponding author

Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: A.S. Binbrek, Department of Cardiology, Rashid Hospital, Dubai, United Arab Emirates; J.K. Ghali, Wayne State University, Detroit, Michigan, USA; A. Vogt, Lipidambulanz, Lipidapherese und Ernährungsmedizin, Interdisziplinäres Stoffwechsel-Centrum, Charité, Virchow-Klinikum, Humboldt-Universität zu Berlin, Berlin, Germany; K.E. Watson, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; G.F. Watts, School of Medicine and Pharmacology, Royal Perth Hospital, Perth, Western Australia, Australia; R.J. Weiss, Androscoggin Cardiology Research, Auburn University, Auburn, Maine, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘rosuvastatin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘rosuvastatin’ and ‘atherosclerosis’. Searches were last updated 3 March 2008.

Selection: Studies in patients with atherosclerosis who received rosuvastatin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Rosuvastatin, atherosclerosis, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Keating, G.M., Robinson, D.M. Rosuvastatin. Am J Cardiovasc Drugs 8, 127–146 (2008). https://doi.org/10.1007/BF03256589

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Keywords

  • Simvastatin
  • Atorvastatin
  • Pravastatin
  • Rosuvastatin
  • Atheroma Volume