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Statins and low-density lipoprotein cholesterol levels

      To the Editor:
      It is well known that the types of patients, clinical presentations, and treatment outcomes in everyday medical practice can vary greatly from those in controlled clinical studies. Thus, it is not surprising that Frolkis et al (
      • Frolkis J.P.
      • Pearce G.L.
      • Nambi V.
      • Minor S.
      • Sprecher D.L.
      Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.
      ) found that statins in clinical practice were associated with low-density lipoprotein (LDL) cholesterol reductions that were 20% less than the reductions projected by package insert guidelines (
      • Frolkis J.P.
      • Pearce G.L.
      • Nambi V.
      • Minor S.
      • Sprecher D.L.
      Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.
      ). Although I agree with the authors’ conclusion that physicians should be aware of this disparity, I am concerned that this will lead physicians to prescribe stronger initial doses of statins. This would be a mistake for several reasons.
      It should be noted that 38% of patients in this study had LDL cholesterol reductions that were greater than 100% of the expected reductions. This explains the substantial number of patients who cannot tolerate standard initial statin doses, but who achieve their target LDL cholesterol levels without adverse effects with lower doses. This is not unusual because 5 mg of atorvastatin and 10 mg of simvastatin (doses that are 50% lower than recommended initially by package inserts) reduce LDL cholesterol levels by 28% to 30% on average, which is enough for many patients with mild-to-moderate LDL cholesterol elevations (
      • Bakker-Arkema R.G.
      • Davidson M.H.
      • Goldstein R.J.
      • et al.
      Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.
      ,
      ). Indeed, dose-related adverse effects, such as myalgia and gastrointestinal discomfort, are major reasons why 50% of patients quit statin treatment within months of starting (
      • Jackevicius C.A.
      • Mamdani M.
      • Tu J.V.
      Adherence with statin therapy in elderly patients with and without acute coronary syndromes.
      ,
      • Benner J.S.
      • Glynn R.J.
      • Mogun H.
      • Newmann P.J.
      • Weinstein M.C.
      • Avorn J.
      Long-term persistence in use of statin therapy in elderly patients.
      ), and the incidence of liver enzyme elevations and liver toxicities are known to increase directly with the statin dosage (
      • Roberts W.C.
      The rule of 5 and the rule of 7 in lipid-lowering by statin drugs.
      ,
      • Pasternak R.C.
      • Smith S.C.
      • Bairey-Merz C.N.
      • et al.
      ACC/AHA/NHLBI clinical advisory on the use and safety of statins.
      ). Thus, statin doses must be gauged to individual response and tolerance.
      Moreover, that the majority of patients in the Frolkis study did not achieve expected LDL cholesterol reductions reflects a failure of the system, not of the drugs. Many of the patients required upward adjustments in their statin dosages but did not receive them. In everyday practice, clinicians must recognize that the projected LDL cholesterol reductions in package inserts are based on statistical means from studies, and that even in these studies individual responses vary considerably (
      • Tuomilehto J.
      • Guimaraes A.C.
      • Kettner H.
      • et al.
      Dose-response of simvastatin in primary hypercholesterolemia.
      ,
      • Steinhagen-Thiessen E.
      Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group.
      ). Similar and even greater variability is seen with everyday patients. The key is for physicians to anticipate this variability and to adjust statin doses according to each patient’s response. This often means an upward adjustment of dosage. In the 38% of patients who, because of genetic variations in metabolic enzyme functioning or other factors, have greater than expected reductions in LDL cholesterol levels, downward adjustments in dosage may sometimes be necessary to reduce dose-related adverse effects and maintain adherence.

      References

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        • Pearce G.L.
        • Nambi V.
        • Minor S.
        • Sprecher D.L.
        Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.
        Am J Med. 2002; 113: 625-629
        • Bakker-Arkema R.G.
        • Davidson M.H.
        • Goldstein R.J.
        • et al.
        Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.
        JAMA. 1996; 275: 128-133
      1. Physicians’ Desk Reference. 57th ed. Medical Economics Company, Montvale, New Jersey2003
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        • Mamdani M.
        • Tu J.V.
        Adherence with statin therapy in elderly patients with and without acute coronary syndromes.
        JAMA. 2002; 288: 462-467
        • Benner J.S.
        • Glynn R.J.
        • Mogun H.
        • Newmann P.J.
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        Long-term persistence in use of statin therapy in elderly patients.
        JAMA. 2002; 288: 455-461
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        The rule of 5 and the rule of 7 in lipid-lowering by statin drugs.
        Am J Cardiol. 1997; 80: 106-107
        • Pasternak R.C.
        • Smith S.C.
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        J Am Coll Cardiol. 2002; 40: 567-572
        • Tuomilehto J.
        • Guimaraes A.C.
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        Dose-response of simvastatin in primary hypercholesterolemia.
        J Cardiovasc Pharmacol. 1994; 24: 941-949
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        Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group.
        Cardiology. 1994; 85: 244-254