Hypercholesterolemia is a major contributor to atherosclerosis and its clinical sequelae, myocardial infarction, ischemic stroke, and peripheral vascular diseases. Our Council Member, Dr. Andrea Kwa, reviews the safety of statins.

During the past two decades, cholesterol lowering by a variety of drugs has yielded a significant reduction of cardiovascular mortality, but none of these agents have been as efficacious as statins.  Statins inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway through which cells synthesize cholesterol. To compensate for decreased synthesis and to maintain cholesterol homeostasis, cells, particularly hepatocytes, increase the expression of LDL receptors, which increases the uptake of plasma LDL, the main carrier of extracellular cholesterol, resulting in lower plasma LDL concentrations. Decreased plasma LDL levels reduce the progression of atherosclerosis and may even lead to the regression of preexisting atherosclerotic lesions. 

HMG-CoA reductase inhibitors are among the most frequently prescribed medications with proven efficacy and infrequent side effects1.  Any incidence of hypersensitivity is unknown with these drugs.  Manufacturers of statin drugs report the combined incidence of rash and allergic reactions to be 7.7% (data on file; Parke-Davis; Schaumburg, IL). Drug-induced hypersensitivity reactions are immunologically mediated and share the following characteristics: (1) they occur in small numbers of patients; (2) they require previous exposure to the same or chemically related drugs (3); they develop rapidly after re-exposure; and (4) they produce clinical syndromes that are commonly associated with immunologic reactions.2  Hypotension, Eosinophila, Hypersensitivity Pneumonitis, Urticaria, Angioedema, Dyspnea, Dermatomyositis with lung involvement, Interstitial Lung Disease with pleural effusion, Lichenoid drug eruption with HMG-CoA reductase inhibitors, Lupus Erythematosus were the frequent reported hypersensitivity symptoms of statins 3-8.  The finding of hypersensitivity pneumonitis is confirmed by normal chest radiographs and yet very abnormal High Resolutions CTs. As such, a normal chest radiograph should not preclude clinical suspicion of disease caused by these medications. The findings on HRCT were alveolitis with ground-glass haziness. The rapid improvement in the HRCT, only after withdrawal of the statin medication, despite steroid treatment, reaffirm the hypersensitivity pneumonitis by statins 8.  Worsening of left ventricular systolic function secondary to polymyalgia is infrequent but has been reported 8.  The above hypersensitivity reactions of statins are usually accompanied by an increase in Erythrocyte Sedimentation Rate (ESR) and positive Antinuclear Antibody (ANA) test.  The risk of revealing porphyria with the use of HMG CoA reductase inhibitors in patients with Porphyria cutanea tarda is emphasized and HMG CoA reductase inhibitors is absolutely contraindicated in patients with Porphyria 9.  Since statins are frequently prescribed and the above contraindication is not indicated in product information leaflet, we need to be mindful of this fact.  All hypersensitivity reactions will resolve upon discontinuation of statins and they should not result in mortality if withdrawal is early.

Data for incidence of cross-reactivity in hypersensitivity reactions among statins is severely lacking.  For patients who had any previous hypersensitivity reactions to any statin and are fully justified and in need of a statin, the physician may switch from one statin to another, monitor the patient closely, according to his own clinical judgement.  Ezetimibe, fibrates, cholestyramine, high dose niacin in sustained release are alternatives for patients who cannot tolerate statins, but they are not as effective as statins in many clinical trials and does not improve mortality and outcomes .

It is important for clinicians and pharmacists to recognize these manifestations of hypersensitivity because they have not been commonly associated with these medications. The symptoms could be insidious in onset and were frequently delayed for years, with delays lasting 6 months to 6 years.  Clinicians may attribute cough and dyspnea to other causes.  However, suspicions should be heightened, and when a careful search fails to find a cause for complaints in patients taking these medications, HMG-CoA inhibitors should be considered as a possible cause.  Also, pharmacists and clinicians should be aware that the likelihood of  having an adverse drug event from Statins can be dependent of the type of Statin involved and the interindividual differences in the body’s ability in handling Statins, accounted by genetic polymorphism.

The cytochrome P450 enzymes, which can be divided into families, subfamilies, and isoenzymes, act as a major catalyst for drug oxidation in the liver. CYP3A4 is a major enzyme, accounting for about 60% of drug metabolic capacity in the liver and 70% of such function in the intestine. Lovastatin, simvastatin, and atorvastatin are substrates of CYP3A4, whereas fluvastatin is metabolized by CYP2C9. Pravastatin is not extensively metabolized by either of these isoenzymes; rather, it is transported into hepatocytes by a sodium-independent, carrier-mediated uptake system that normally transports bile acids. Compared with other statins, pravastatin thus has a reduced potential for drug interactions with other substrates, inhibitors, or inducers of the CYP3A4 and CYP2C9 systems.

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There is evidence that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition, metabolism, or excretion. Despite the good tolerability of HMG-CoA reductase inhibitors, there are two uncommon but potentially serious adverse effects related to HMG-CoA reductase inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhabdomyolysis in patients treated with cerivastatin has raised heightened concern by physicians and patients regarding the tolerability of HMG-CoA reductase inhibitors.  Apart from pravastatin and rosuvastatin, HMG-CoA reductase inhibitors are metabolized by the phase I cytochrome P450 (CYP) superfamily of drug metabolizing enzymes.  The best-characterized pharmacogenetic polymorphisms are those within this enzyme family.  One of these enzymes, CYP2D6, plays an important role in the metabolism of simvastatin.  It has been shown that the cholesterol-lowering effect as well as the efficacy and tolerability of simvastatin is influenced by CYP2D6 genetic polymorphism 10.  Because the different HMG-CoA reductase inhibitors differ, with respect to the degree of metabolism by the different CYP enzymes, genotyping may help to select the appropriate HMG-CoA reductase inhibitor and the optimal dosage during the start of the treatment and will allow for more efficient individual therapy.  Hence, the incidence and occurrence of hypersensitivity reactions of statins maybe dependent of pharmacogenetic polymorphisms in patients.  A detailed knowledge of the genetic basis of individual drug response is potentially of major clinical and economic importance.

Pharmacists must understand the functions of these enzymes and be well-versed of the adverse reactions of statins to identify potential drug interactions, especially in high-risk patient populations, and to make appropriate therapeutic recommendations that prevent or minimize adverse clinical outcomes.

1. Hebert, PR, Gaziano, JM, Chan, KS, et al (1997) Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 278,313-321
2. deShazo, RD, Kemp, SF (1997) Allergic Reactions to Drugs and Biologic Agents. JAMA 278,1895-1906
   Hampson JP, Smith D, Cowell R, Baker A.  Hypotension and eosinophilia with atorvastatin. Pharm World Sci. 2005 Aug;27(4):279-80.
3. Hill C, Zeitz C, Kirkham B.  Dermatomyositis with lung involvement in a patient treated with simvastatin.  Aust N Z J Med. 1995 Dec;25(6):745-6
4. De Groot RE, Willems LN, Dijkman JH.  Interstitial lung disease with pleural effusion caused by simvastin.  Intern Med 239,361-363.
5. Sebok B, Toth M, Anga B, Harangi F, Schneider I.Lichenoid drug eruption with HMG-CoA reductase inhibitors (fluvastatin and lovastatin).  Acta Derm Venereol. 2004;84(3):229-30.
6. Ahmad, S (1991) Lovastatin-induced lupus erythematosus. Arch Intern Med 151,1667-1668
7. Liebhaber MI, Wright RS, Gelberg HJ, Dyer Z, Kupperman JL.  Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten cases.  Chest. 1999;115:886-889
8. Perrot JL, Guy C, Bour Guichenez G, Amigues O, Servoz J, Cambazard F.  Porphyria cutanea tarda induced by HMG CoA reductase inhibitors: simvastatin, pravastatin.  Ann Dermatol Venereol. 1994;121(11):817-9
9. Vermes A, Vermes I.  Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors.  Am J Cardiovasc Drugs. 2004;4(4):247-55.

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