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Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering.

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely effective at reducing low-density lipoprotein (LDL) cholesterol and have been demonstrated to reduce mortality and the risk of major cardiovascular events in a number of large primary and secondary prevention studies. The linear relationship between LDL-cholesterol and cardiovascular risk suggests statins work solely by reducing LDL-cholesterol, and that ancillary properties do not contribute to cardiovascular risk reduction. In recent years, however, a number of additional non-lipid-lowering, or 'pleiotropic', effects of statins have been suggested to contribute to their efficacy in cardiovascular disease. The first data to suggest that statins may have benefits beyond lipid lowering came from the Heart Protection Study, in which simvastatin reduced mortality and morbidity even in patients with 'normal' LDL-cholesterol levels (2.6 mmol/L or 100 mg/dL). It has since been demonstrated, however, that cardiovascular risk remains high at this LDL concentration, but is substantially reduced in those achieving levels below 2.0 mmol/L (77 mg/dL). Evidence for the pleiotropic effects of statins in heart failure comes largely from retrospective and subgroup analyses of large studies. When statin therapy is compared with placebo, or when high-dose statin therapy is compared with low-dose treatment, a lower incidence of heart failure or hospitalization is observed. Despite promising retrospective data, however, two prospective studies of rosuvastatin in the treatment of patients with New York Heart Association class II-IV heart failure showed no impact on the primary endpoint and only one of the studies showed a lower rate of hospitalization favouring rosuvastatin. A number of small studies has shown evidence for mechanisms of action of statins outside of LDL-cholesterol lowering, including improvements in endothelial function, halting or retardation of atheroma development, reduction in inflammation and antithrombotic effects. The linear relationship between LDL-cholesterol lowering and reduction in coronary heart disease risk, as well as a lack of conclusive evidence for other mechanisms of action raise the question of whether any cholesterol-lowering agent is equally effective for reducing cardiovascular risk, but recent data from the torcetrapib clinical trial programme suggest this is not the case. Future cholesterol-lowering modalities must be able to demonstrate efficacy and good tolerability in large-scale clinical trials.

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  • Publisher Full Text
  • Authors+Show Affiliations

    Centre for Preventative Medicine, Ullevål University Hospital, University of Oslo, Oslo, Norway. t.r.pedersen@medisin.uio.no

    Source

    MeSH

    Animals
    Anticholesteremic Agents
    Cardiovascular Diseases
    Cholesterol, LDL
    Heart Failure
    Humans
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Myocardial Ischemia

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    21391729

    Citation

    Pedersen, Terje R.. "Pleiotropic Effects of Statins: Evidence Against Benefits Beyond LDL-cholesterol Lowering." American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions, vol. 10 Suppl 1, 2010, pp. 10-7.
    Pedersen TR. Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs. 2010;10 Suppl 1:10-7.
    Pedersen, T. R. (2010). Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering. American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions, 10 Suppl 1, pp. 10-7. doi:10.2165/1158822-S0-000000000-00000.
    Pedersen TR. Pleiotropic Effects of Statins: Evidence Against Benefits Beyond LDL-cholesterol Lowering. Am J Cardiovasc Drugs. 2010;10 Suppl 1:10-7. PubMed PMID: 21391729.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering. A1 - Pedersen,Terje R, PY - 2011/3/12/entrez PY - 2010/1/1/pubmed PY - 2011/5/25/medline SP - 10 EP - 7 JF - American journal of cardiovascular drugs : drugs, devices, and other interventions JO - Am J Cardiovasc Drugs VL - 10 Suppl 1 N2 - 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely effective at reducing low-density lipoprotein (LDL) cholesterol and have been demonstrated to reduce mortality and the risk of major cardiovascular events in a number of large primary and secondary prevention studies. The linear relationship between LDL-cholesterol and cardiovascular risk suggests statins work solely by reducing LDL-cholesterol, and that ancillary properties do not contribute to cardiovascular risk reduction. In recent years, however, a number of additional non-lipid-lowering, or 'pleiotropic', effects of statins have been suggested to contribute to their efficacy in cardiovascular disease. The first data to suggest that statins may have benefits beyond lipid lowering came from the Heart Protection Study, in which simvastatin reduced mortality and morbidity even in patients with 'normal' LDL-cholesterol levels (2.6 mmol/L or 100 mg/dL). It has since been demonstrated, however, that cardiovascular risk remains high at this LDL concentration, but is substantially reduced in those achieving levels below 2.0 mmol/L (77 mg/dL). Evidence for the pleiotropic effects of statins in heart failure comes largely from retrospective and subgroup analyses of large studies. When statin therapy is compared with placebo, or when high-dose statin therapy is compared with low-dose treatment, a lower incidence of heart failure or hospitalization is observed. Despite promising retrospective data, however, two prospective studies of rosuvastatin in the treatment of patients with New York Heart Association class II-IV heart failure showed no impact on the primary endpoint and only one of the studies showed a lower rate of hospitalization favouring rosuvastatin. A number of small studies has shown evidence for mechanisms of action of statins outside of LDL-cholesterol lowering, including improvements in endothelial function, halting or retardation of atheroma development, reduction in inflammation and antithrombotic effects. The linear relationship between LDL-cholesterol lowering and reduction in coronary heart disease risk, as well as a lack of conclusive evidence for other mechanisms of action raise the question of whether any cholesterol-lowering agent is equally effective for reducing cardiovascular risk, but recent data from the torcetrapib clinical trial programme suggest this is not the case. Future cholesterol-lowering modalities must be able to demonstrate efficacy and good tolerability in large-scale clinical trials. SN - 1175-3277 UR - https://www.unboundmedicine.com/medline/citation/21391729/Pleiotropic_effects_of_statins:_evidence_against_benefits_beyond_LDL_cholesterol_lowering_ L2 - https://dx.doi.org/10.2165/1158822-S0-000000000-00000 DB - PRIME DP - Unbound Medicine ER -