Simvastatin

(BAN, USAN, rINN)
Simvastatin Chemical formula
Synonyms: L-644128-000U; MK-733; Simvastatiini; Simvastatina; Simvastatinas; Simvastatine; Simvastatinum; Sinvinolina; Synvinolin; Szimvasztatin; Velastatin; Velastatina. (1S,3R,7S,8S,8aR)-1,2,3,7,8,8aHexahydro-3,7-dimethyl-8-{2-[(2R,4R)-tetrahydro-4-hydroxy-6oxo-2H-pyran-2-yl]ethyl}-1-naphthyl 2,2-dimethylbutyrate.
Cyrillic synonym: Симвастатин.

💊 Chemical information

Chemical formula: C25H38O5 = 418.6.
CAS — 79902-63-9.
ATC — C10AA01.
ATC Vet — QC10AA01.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Simvastatin). A white or almost white crystalline powder. Practically insoluble in water; freely soluble in alcohol; very soluble in dichloromethane. Store under nitrogen in airtight containers. Protect from light.

USP 31

(Simvastatin). A white to off-white powder. Practically insoluble in water; freely soluble in alcohol, in chloroform, and in methyl alcohol; sparingly soluble in propylene glycol; very slightly soluble in petroleum spirit. Store at a temperature between 15° and 30°, or at 2° to 8°.

💊 Adverse Effects

The commonest adverse effects of therapy with simvastatin and other statins are gastrointestinal disturbances. Other adverse effects reported include headache, skin rashes, dizziness, blurred vision, insomnia, and dysgeusia. Reversible increases in serum-aminotransferase concentrations may occur and liver function should be monitored (see Precautions, below). Hepatitis and pancreatitis have been reported. Hypersensitivity reactions including anaphylaxis and angioedema have also occurred. Myopathy, characterised by myalgia and muscle weakness and associated with increased creatine phosphokinase concentrations, has been reported, especially in patients also taking ciclosporin, fibric acid derivatives, or nicotinic acid. Rarely, rhabdomyolysis with acute renal failure may develop.
1. Farmer JA, Torre-Amione G. Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Safety 2000; 23: 197–213
2. Davidson MH. Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust. Drugs 2001; 61: 197–206
3. Pasternak RC, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002; 106: 1024–8. Also available at: http://circ.ahajournals.org/cgi/reprint/106/8/ 1024.pdf (accessed 29/05/08
4. Karthikeyan VJ. Adverse effects of statins: an update. Adverse Drug React Bull 2005; (Aug): 895–8
5. McKenney JM, et al. Final conclusions and recommendations of the National Lipid 1389, respectively.
Statins may also have effects on other drugs. Bleeding and increases in prothrombin time have been reported in patients taking simvastatin or other statins with coumarin anticoagulants.
1. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002; 41: 343–70
2. Martin J, Krum H. Cytochrome P450 drug interactions within the HMG-CoA reductase inhibitor class: are they clinically relevant? Drug Safety 2003; 26: 13–21
3. Committee on Safety of Medicines/Medicines and Healthcare Products Regulatory Agency. Statins and cytochrome P450 interactions. Current Problems 2004; 30: 1–2. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON007448&RevisionSelectionMethod= LatestReleased (accessed 30/05/08
4. Rätz Bravo AE, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Safety 2005; 28: 263–75
5. Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol 2006; 97 (suppl 8A): 27C–31C
6. Neuvonen PJ, et al. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006; 80: 565–81.

Antiarrhythmics.

Amiodarone is an inhibitor of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma concentrations of statins metabolised by this enzyme, increasing the risk of toxicity. There have been reports1-3 of myopathy and rhabdomyolysis in patients taking amiodarone and simvastatin (in some cases with other CYP3A4 inhibitors), and a pharmacokinetic study4 found that amiodarone increased plasma-simvastatin concentrations in healthy subjects. High doses of simvastatin are not recommended in patients taking amiodarone (see Uses and Administration, below). An asymptomatic increase in serum aminotransferases in a patient receiving rosuvastatin and amiodarone may have been the result of an interaction between the drugs.5
1. Roten L, et al. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004; 38: 978–81
2. Chouhan UM, et al. Simvastatin interaction with clarithromycin and amiodarone causing myositis. Ann Pharmacother 2005; 39: 1760–1
3. Ricaurte B, et al. Simvastatin–amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006; 40: 753–7
4. Becquemont L, et al. Amiodarone interacts with simvastatin but not with pravastatin disposition kinetics. Clin Pharmacol Ther 2007; 81: 679–84
5. Merz T, Fuller SH. Elevated serum transaminase levels resulting from concomitant use of rosuvastatin and amiodarone. Am J Health-Syst Pharm 2007; 64: 1818–21.

Antibacterials.

Erythromycin and other macrolides are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma concentrations and the risk of myopathy with some statins. Increased plasma concentrations of simvastatin have been reported with erythromycin,1 and increased plasma concentrations of atorvastatin have been found with erythromycin2 and clarithromycin,3 but not with azithromycin.3There have been reports of myopathy or rhabdomyolysis in patients receiving simvastatin with clarithromycin,4 and in patients receiving lovastatin with azithromycin,5 clarithromycin,5 or erythromycin.6 Rifampicin, an inducer of CYP2C9 and CYP3A4, may reduce the bioavailability of fluvastatin, and has also been reported to reduce the plasma concentration of simvastatin7 and atorvastatin.8 There have been reports of rhabdomyolysis in patients receiving atorvastatin9 or simvastatin10 with fusidic acid.
1. Kantola T, et al. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177–82
2. Siedlik PH, et al. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999; 39: 501–4
3. Amsden GW, et al. A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers. J Clin Pharmacol 2002; 42: 444–9
4. Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother 2001; 35: 26–31
5. Grunden JW, Fisher KA. Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin. Ann Pharmacother 1997; 31: 859–63
6. Ayanian JZ, et al. Lovastatin and rhabdomyolysis. Ann Intern Med 1988; 109: 682–3
7. Kyrklund C, et al. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 2000; 68: 592–7
8. Backman JT, et al. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther 2005; 78: 154–67
9. Wenisch C, et al. Acute rhabdomyolysis after atorvastatin and fusidic acid therapy. Am J Med 2000; 109: 78
10. Yuen SLS, McGarity B. Rhabdomyolysis secondary to interaction of fusidic acid and simvastatin. Med J Aust 2003; 179: 172.

Anticoagulants.

For reports of bleeding and increased prothrombin time in patients receiving oral anticoagulants with statins, see Lipid Regulating Drugs.

Antidepressants.

Myositis and rhabdomyolysis, with raised liver enzyme values, have been reported1-4 in patients given simvastatin with nefazodone; in one case3 the reaction appeared to be precipitated by the addition of azithromycin. Increased creatine kinase concentrations also occurred in a patient given pravastatin with nefazodone.5 A study6 in healthy subjects found that St John’s wort reduced the plasma concentration of simvastatin but had no effect on pravastatin.
1. Jacobson RH, et al. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA 1997; 277: 296
2. Thompson M, Samuels S. Rhabdomyolysis with simvastatin and nefazodone. Am J Psychiatry 2002; 159: 1607
3. Skrabal MZ, et al. Two cases of rhabdomyolysis associated with high-dose simvastatin. Am J Health-Syst Pharm 2003; 60: 578–81
4. Karnik NS, Maldonado JR. Antidepressant and statin interactions: a review and case report of simvastatin and nefazodoneinduced rhabdomyolysis and transaminitis. Psychosomatics 2005; 46: 565–8
5. Alderman CP. Possible interaction between nefazodone and pravastatin. Ann Pharmacother 1999; 33: 871
6. Sugimoto K-i, et al. Different effects of St John’s Wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 2001; 70: 518–24.

Antifungals.

Itraconazole and ketoconazole are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma concentrations and the risk of myopathy with some statins. Raised plasma concentrations of simvastatin,1,2 lovastatin,3,4and atorvastatin5 have been reported with itraconazole, whereas the effect on pravastatin,1 rosuvastatin,6 or fluvastatin4 appears to be minimal. Myopathy and rhabdomyolysis have been reported with simvastatin and itraconazole2,7 or ketoconazole,8 and with lovastatin and itraconazole.9 Fluconazole inhibits CYP2C9 and has been reported10 to increase the plasma concentration of fluvastatin. There has also been a report11 of rhabdomyolysis in a patient taking fluconazole and simvastatin.
1. Neuvonen PJ, et al. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41
2. Segaert MF, et al. Drug-interaction-induced rhabdomyolysis. Nephrol Dial Transplant 1996; 11: 1846–7
3. Neuvonen PJ, Jalava K-M. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 54–61
4. Kivistö KT, et al. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49–53
5. Kantola T, et al. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65
6. Cooper KJ, et al. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2003; 73: 322–9
7. Horn M. Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals. Arch Dermatol 1996; 132: 1254
8. Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22: 295–7
9. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995; 333: 664–5
10. Kantola T, et al. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000; 56: 225–9
11. Shaukat A, et al. Simvastatin–fluconazole causing rhabdomyolysis. Ann Pharmacother 2003; 37: 1032–5.

Antiplatelet drugs.

For discussion of a possible interaction between statins and clopidogrel

Antivirals.

HIV-protease inhibitors are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may affect the metabolism of simvastatin and other statins. Studies have shown increased plasma concentrations of both simvastatin and atorvastatin with nelfinavir,1 and with ritonavir-boosted saquinavir,2 whereas the plasma concentration of pravastatin was reduced with ritonavir-boosted saquinavir.2 Rhabdomyolysis has been reported3 in a patient taking simvastatin when ritonavir was added to her therapy. Although rosuvastatin is not significantly metabolised, increased plasma concentrations have been reported with ritonavir-boosted lopinavir.4,5 There has also been a report6 of rhabdomyolysis in a patient receiving atorvastatin with the non-nucleoside reverse transcriptase inhibitor delavirdine. Efavirenz is an inducer of CYP3A4 and a study in healthy subjects7 found that it could reduce plasma concentrations of atorvastatin and simvastatin; plasma concentrations of pravastatin were also reduced, although it is not metabolised by CYP3A4.
1. Hsyu P-H, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45: 3445–50
2. Fichtenbaum CJ, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569–77
3. Cheng CH, et al. Rhabdomyolysis due to probable interaction between simvastatin and ritonavir. Am J Health-Syst Pharm 2002; 59: 728–30
4. van der Lee M, et al. Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIVinfected patients. Antivir Ther 2007; 12: 1127–32
5. Kiser JJ, et al. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 2008; 47: 570–8
6. Castro JG, Gutierrez L. Rhabdomyolysis with acute renal failure probably related to the interaction of atorvastatin and delavirdine. Am J Med 2002; 112: 505
7. Gerber JG, et al. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr 2005; 39: 307–12.

Calcium-channel blockers.

Calcium-channel blockers may increase plasma concentrations of some statins, probably by inhibition of the cytochrome P450 isoenzyme CYP3A4. Pharmacokinetic studies have reported increased plasma concentrations of simvastatin with verapamil,1 and with diltiazem,2 and of lovastatin with diltiazem;3 the small increase with simvastatin and lacidipine was not considered clinically relevant.4 The interaction between statins and diltiazem has also been reported in patients. A retrospective study5 found that the cholesterol-lowering effect of simvastatin was greater in patients who were also receiving diltiazem, and there have also been reports6-8of rhabdomyolysis, associated with hepatitis in 1 case,6 in patients receiving simvastatin and diltiazem together. Rhabdomyolysis8,9 and hepatitis9 have also been reported in patients receiving atorvastatin with diltiazem.
1. Kantola T, et al. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177–82
2. Mousa O, et al. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267–74
3. Azie NE, et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64: 369–77
4. Ziviani L, et al. The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects. Br J Clin Pharmacol 2001; 51: 147–52
5. Yeo KR, et al. Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999; 48: 610–615
6. Kanathur N, et al. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. Tenn Med 2001; 94: 339–41
7. Peces R, Pobes A. Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem. Nephron 2001; 89: 117–118
8. Gladding P, et al. Potentially fatal interaction between diltiazem and statins. Ann Intern Med 2004; 140: W31. Available at: http:// www.annals.org/cgi/reprint/140/8/W-31.pdf (accessed 14/11/07
9. Lewin JJ, et al. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother 2002; 36: 1546–9.

Colchicine.

For reports of additive muscle toxicity with statins and colchicine, see Cardiovascular Drugs under Interactions of Colchicine.

Danazol.

Rhabdomyolysis has been reported1 in a patient receiving lovastatin with a number of other drugs; it was considered that an interaction with danazol was the most likely cause. A similar reaction has been reported2 with simvastatin.
1. Dallaire M, Chamberland M. Rhabdomyolyse sévère chez un patient recevant lovastatine, danazol et doxycycline. Can Med Assoc J 1994; 150: 1991–4
2. Andreou ER, Ledger S. Potential drug interaction between simvastatin and danazol causing rhabdomyolysis. Can J Clin Pharmacol 2003; 10: 172–4.

Endothelin receptor antagonists.

Bosentan is an inducer of the cytochrome P450 isoenzyme CYP3A4 and has been reported1 to reduce plasma-simvastatin concentrations in healthy subjects.
1. Dingemanse J, et al. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet 2003; 42: 293–301.

Fruit juices.

Grapefruit juice inhibits the cytochrome P450 isoenzyme CYP3A4 and studies using concentrated grapefruit juice have reported increased plasma concentrations of simvastatin,1 lovastatin,2 and atorvastatin.3 A study4 using less concentrated grapefruit juice found only minimal effect on the activity of lovastatin, but the conclusions of this study have been criticised;5 studies using normal strength grapefruit juice have found considerable increases in plasma concentrations of atorvastatin6and simvastatin.7 There is also a case report8 of a woman receiving simvastatin who developed symptoms of rhabdomyolysis 4 days after she started eating one grapefruit each day. Statins that are not significantly metabolised by CYP3A4, such as pitavastatin6 and pravastatin,3,9 do not appear to be affected. Rhabdomyolysis has also been reported10 in a patient taking rosuvastatin and ezetimibe when he started drinking pomegranate juice regularly.
1. Lilja JJ, et al. Grapefruit juice–simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477–83
2. Kantola T, et al. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998; 63: 397–402
3. Lilja JJ, et al. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118–27
4. Rogers JD, et al. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Clin Pharmacol Ther 1999; 66: 358–66
5. Bailey DG, Dresser GK. Grapefruit juice–lovastatin interaction. Clin Pharmacol Ther 2000; 67: 690
6. Ando H, et al. Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin. Br J Clin Pharmacol 2005; 60: 494–7
7. Lilja JJ, et al. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004; 58: 56–60
8. Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004; 62: 670
9. Fukazawa I, et al. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. Br J Clin Pharmacol 2004; 57: 448–55
10. Sorokin AV, et al. Rhabdomyolysis associated with pomegranate juice consumption. Am J Cardiol 2006; 98: 705–6.

Immunosuppressants.

Myopathy and rhabdomyolysis have been reported in patients receiving atorvastatin,1 lovastatin,2-4 or simvastatin5-7 with immunosuppressant regimens including ciclosporin. The mechanism of the interaction may be additive toxicity, since both statins and ciclosporin are known to cause myopathy, but effects on plasma concentrations may also be involved. Pharmacokinetic studies have shown that ciclosporin increases the plasma concentrations of atorvastatin,8,9 fluvastatin,10,11 lovastatin,12 pravastatin,12,13 rosuvastatin,14 and simvastatin.15 For the effects of statins on plasma-ciclosporin concentrations.
1. Maltz HC, et al. Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 1999; 33: 1176–9
2. Norman DJ, et al. Myolysis and acute renal failure in a hearttransplant recipient receiving lovastatin. N Engl J Med 1988; 318: 46–7
3. East C, et al. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med 1988; 318: 47–8
4. Corpier CL, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA 1988; 260: 239–41
5. Blaison G, et al. Rhabdomyolyse causée par la simvastatine chez un transplanté cardiaque sous ciclosporine. Rev Med Interne 1992; 13: 61–3
6. Meier C, et al. Rhabdomyolyse bei mit Simvastatin und Ciclosporin behandelten Patienten: Rolle der aktivität des Cytochrom-P450-Enzymsystems der Leber. Schweiz Med Wochenschr 1995; 125: 1342–6
7. Gumprecht J, et al. Simvastatin-induced rhabdomyolysis in a CsA-treated renal transplant recipient. Med Sci Monit 2003; 9: CS89–CS91
8. Åsberg A, et al. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am J Transplant 2001; 1: 382–6
9. Hermann M, et al. Substantially elevated levels of atorvastatin and metabolites in cyclosporine-treated renal transplant recipients. Clin Pharmacol Ther 2004; 76: 388–91
10. Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation 1996; 62: 1559–64
11. Park J-W, et al. Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant recipients taking cyclosporine A. J Cardiovasc Pharmacol Ther 2001; 6: 351–61
12. Olbricht C, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62: 311–21
13. Regazzi MB, et al. Altered disposition of pravastatin following concomitant drug therapy with cyclosporin A in transplant recipients. Transplant Proc 1993; 25: 2732–4
14. Simonson SG, et al. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther 2004; 76: 167–77
15. Arnadottir M, et al. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993; 65: 410–13.

Levothyroxine.

For reference to the effect of lovastatin and simvastatin in patients receiving levothyroxine, see Lipid Regulating Drugs.

Lipid regulating drugs.

Myopathy and myositis are recognised adverse effects of both statins and fibric acid derivatives, including fibrates and gemfibrozil, and the risk is increased if they are given together. There has also been a report1 of both hepatotoxicity and rhabdomyolysis in a patient given a statin and gemfibrozil together. The interaction between gemfibrozil and statins may also have a pharmacokinetic basis; studies have shown increased plasma concentrations of atorvastatin,2 lovastatin,3 pravastatin,4 rosuvastatin,5 and simvastatin6 when given with gemfibrozil. Myopathy has also been reported7,8 in patients given statins with nicotinic acid, although a study9 of adverse effects reported to the FDA found no increase in reports for lovastatin given with nicotinic acid compared with either drug alone. For reports of increased hepatotoxicity when statins were given with ezetimibe see Effects on the Liver.
1. Akoglu H, et al. Combined organ failure with combination antihyperlipidemic treatment: a case of hepatic injury and acute renal failure. Ann Pharmacother 2007; 41: 143–7
2. Backman JT, et al. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther 2005; 78: 154–67
3. Kyrklund C, et al. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001; 69: 340–5
4. Kyrklund C, et al. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther 2003; 73: 538–44
5. Schneck DW, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2004; 75: 455–63
6. Backman JT, et al. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 2000; 68: 122–9
7. Reaven P, Witztum JL. Lovastatin, nicotinic acid, and rhabdomyolysis. Ann Intern Med 1988; 109: 597–8.
8. Hill MD, Bilbao JM. Case of the month: February 1999—54 year old man with severe muscle weakness. Brain Pathol 1999; 9: 607–8
9. Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol 2007; 99: 379–81.

Proton pump inhibitors.

There is a report1 of rhabdomyolysis causing AV block in a patient receiving atorvastatin when esomeprazole and clarithromycin were added to her treatment. As symptoms started before the introduction of clarithromycin, it was thought that a possible contributory mechanism for the interaction was a reduction in the first-pass metabolism of atorvastatin due to the inhibition of p-glycoprotein by esomeprazole.
1. Sipe BE, et al. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother 2003; 37: 808–11.

Ranolazine.

A study1 in healthy subjects showed that ranolazine moderately increased plasma concentrations of simvastatin but it was not thought that the interaction would be clinically significant.
1. Jerling M, et al. Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. J Clin Pharmacol 2005; 45: 422–33.

💊 Pharmacokinetics

Simvastatin is absorbed from the gastrointestinal tract and must be hydrolysed to its active β-hydroxyacid form. Other active metabolites have been detected and a number of inactive metabolites are also formed. Simvastatin is a substrate for the cytochrome P450 isoenzyme CYP3A4 and undergoes extensive first-pass metabolism in the liver, its primary site of action. Less than 5% of the oral dose has been reported to reach the circulation as active metabolites. Both simvastatin and its β-hydroxyacid metabolite are about 95% bound to plasma proteins. Simvastatin is mainly excreted in the faeces via the bile as metabolites. About 10 to 15% is recovered in the urine, mainly in inactive forms. The half-life of the active β-hydroxyacid metabolite is 1.9 hours.
1. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202
2. Desager J-P, Horsmans Y. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet 1996; 31: 348–71
3. Lennernäs H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors: similarities and differences. Clin Pharmacokinet 1997; 32: 403–25.

Genetic variation.

The pharmacokinetics of statins are influenced not only by metabolising enzymes but also by their affinity for organ-specific transporter proteins responsible for their uptake and efflux from cells, in particular in the intestine and liver.1,2 Statins differ not only in their affinity for cytochrome P450 isoenzymes, but also in their affinity for transporter proteins such as organic anion transporting polypeptides (OATPs) and P-glycoprotein (multi-drug resistance 1; MDR1). Both metabolising enzymes and transporter proteins may be subject to ethnic and genetic variation, and it has been suggested that this may explain some of the variability in the efficacy and the risk of adverse effects in different populations.
1. Kim RB. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) and genetic variability (single nucleotide polymorphisms) in a hepatic drug uptake transporter: what’s it all about? Clin Pharmacol Ther 2004; 75: 381–5
2. Tirona RG. Ethnic differences in statin disposition. Clin Pharmacol Ther 2005; 78: 311–16.

💊 Uses and Administration

Simvastatin is a lipid regulating drug; it is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the ratedetermining enzyme for cholesterol synthesis. Inhibition of HMG-CoA reductase leads to reduced cholesterol synthesis in the liver and lower intracellular cholesterol concentrations; this stimulates an increase in low-density-lipoprotein (LDL)-cholesterol receptors on hepatocyte membranes, thereby increasing the clearance of LDL from the circulation. HMG-CoA reductase inhibitors (also called statins) reduce total cholesterol, LDL-cholesterol, and very-low-density lipoprotein (VLDL)-cholesterol concentrations in plasma. They also tend to reduce triglycerides and to increase high-density lipoprotein (HDL)-cholesterol concentrations. Simvastatin is used to reduce LDL-cholesterol, apolipoprotein B, and triglycerides, and to increase HDLcholesterol in the treatment of hyperlipidaemias. It is used in hypercholesterolaemias, combined (mixed) hyperlipidaemia (type IIa or IIb hyperlipoproteinaemias), hypertriglyceridaemia (type IV), and primary dysbetalipoproteinaemia (type III), and may also be used as adjunct therapy in patients with homozygous familial hypercholesterolaemia who have some LDL-receptor function. Simvastatin is also used for cardiovascular risk reduction. Simvastatin is given orally and doses range from 5 to 80 mg daily. For the treatment of hyperlipidaemias, the usual initial dose is 10 to 20 mg in the evening; an initial dose of 40 mg may be used in patients who require a large reduction in cholesterol or who are at high cardiovascular risk. The dose may be adjusted at intervals of not less than 4 weeks up to a maximum of 80 mg once daily in the evening. Patients with homozygous familial hypercholesterolaemia may be treated with 40 mg once daily in the evening, or 80 mg daily in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. For cardiovascular risk reduction in high-risk patients, such as those with atherosclerotic cardiovascular disease or diabetes mellitus, the usual dose is 20 to 40 mg once daily. Patients who are at moderate risk may be given a dose of 10 mg once daily. The dose of simvastatin should be reduced in patients at risk of myopathy, including patients with severe renal impairment (see below). For patients taking drugs that interact with simvastatin, dose reduction is also advised, as follows:
patients taking ciclosporin or danazol, initial dose 5 mg once daily and maximum dose 10 mg once daily
patients taking gemfibrozil or other fibrates, or nicotinic acid, maximum dose 10 mg once daily
patients taking amiodarone or verapamil, maximum dose 20 mg once daily
patients taking diltiazem, maximum dose 40 mg once daily For the use of simvastatin in children, see below.
1. Mauro VF, MacDonald JL. Simvastatin: a review of its pharmacology and clinical use. DICP Ann Pharmacother 1991; 25: 257–64
2. Plosker GL, McTavish D. Simvastatin: a reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Drugs 1995; 50: 334–63
3. Schectman G, Hiatt J. Dose–response characteristics of cholesterol-lowering drug therapies: implications for treatment. Ann Intern Med 1996; 125: 990–1000
4. White CM. Pharmacological effects of HMG CoA reductase inhibitors other than lipoprotein modulation. J Clin Pharmacol 1999; 39: 111–18
5. Mata P, et al. Benefits and risks of simvastatin in patients with familial hypercholesterolaemia. Drug Safety 2003; 26: 769–86.

Action.

The effects of statins on plasma lipids are well established.1-4 Their primary action is to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Cholesterol is an important precursor for synthesis of a number of substances by the liver, and reduced intracellular concentrations stimulate an increase in the expression of low-density lipoprotein (LDL) receptors in the liver. This leads to increased uptake of LDL-cholesterol from the plasma into liver cells, with a subsequent reduction in both LDL and total cholesterol. Triglycerides are also decreased, due to decreased synthesis of very-low-density lipoprotein (VLDL), while high-density lipoprotein (HDL)-cholesterol is either modestly increased or unchanged, leading to an improvement in the LDL:HDL ratio. An effect on LDL-cholesterol may also occur independent of the effect on receptors; some statins have been shown to lower LDL-cholesterol in patients with homozygous familial hypercholesterolaemia, despite their lack of functional LDL receptors. Statins generally provide a greater reduction in LDL-cholesterol than other classes of lipid regulating drugs, but where large reductions are required combination therapy may be necessary. Statins have been used with bile-acid binding resins and with ezetimibe; they have also been given with fibrates or nicotinic acid, although the increased risk of adverse effects needs to be considered. Cholesterol synthesis in the liver peaks during the early morning (midnight to 3 a.m.) and there is some evidence that statins with short half-lives, such as simvastatin, should be taken in the evening.5 Statins have a number of additional (pleiotropic) actions,1-4,6,7 although whether these contribute to their cardiovascular effects is controversial.8 In atherosclerosis they have beneficial effects on endothelial function, which may be partly independent of their effect on lipids, and also appear to stabilise atherosclerotic plaques. A number of studies9,10 have also shown that statins reduce concentrations of C-reactive protein (CRP), a marker of inflammation that is raised in atherosclerosis, and there is some evidence that the reduction in CRP is independently associated with a reduction in cardiovascular events11 and regression of atherosclerotic lesions,12 although results have been mixed in a related condition, calcific aortic stenosis.13 Statins have a number of actions that may be beneficial in heart failure,14 but detrimental effects are also possible and their role specifically for heart failure is unclear.15 Evidence from cohort studies16-18 suggests statins may improve mortality in heart failure, and analyses of cardiovascular risk reduction studies19,20 also suggest benefit. However, a randomised study21 of rosuvastatin in patients with heart failure of ischaemic origin failed to show an effect on mortality, although there were fewer hospitalisations in patients given the active drug. Statins may also have antihypertensive22 and antiarrhythmic effects; they reduce the incidence of atrial fibrillation,23 and have also been associated with a reduced risk of ventricular arrhythmias,24,25 although this requires confirmation. Beneficial effects have also been reported on some measures of haemostasis,26 and a reduced incidence of venous thromboembolism has been noted in some studies.27 Statins also appear to have anti-inflammatory and immunomodulatory actions and these may contribute to their beneficial effects. There is evidence from epidemiological studies that they reduce the risk of bacterial infections, although this has been attributed to a ‘healthy-user’ effect,28,29 and they may also reduce mortality in patients with sepsis.29 Benefit has also been reported in rheumatoid arthritis and other inflammatory arthropathies.30-33 In patients with organ transplantation, both cardiovascular and immunomodulatory actions may be of benefit (see below). However, the use of statins in these diseases remains to be confirmed. For discussion of the use of statins in other non-cardiovascular disorders, including dementia, kidney disorders, malignant neoplasms, and osteoporosis, see below.
1. Maron DJ, et al. Current perspectives on statins. Circulation 2000; 101: 207–13
2. Shepherd J. The statin era: in search of the ideal lipid regulating agent. Heart 2001; 85: 259–64
3. Chong PH, et al. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med 2001; 111: 390–400
4. Igel M, et al. Pharmacology of 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin. J Clin Pharmacol 2002; 42: 835–45
5. Plakogiannis R, Cohen H. Optimal low-density lipoprotein cholesterol lowering—morning versus evening statin administration. Ann Pharmacother 2007; 41: 106–10
6. Sotiriou CG, Cheng JWM. Beneficial effects of statins in coronary artery disease—beyond lowering cholesterol. Ann Pharmacother 2000; 34: 1432–9
7. Balk EM, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med 2003; 139: 670–82
8. Robinson JG, et al. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005; 46: 1855–62
9. Ridker PM, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 1959–65
10. Albert MA, et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286: 64–70
11. Ridker PM, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20–8
12. Nissen SE, et al. Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352: 29–38
13. Chua D, Kalb K. Statins and progression of calcified aortic stenosis. Ann Pharmacother 2006; 40: 2195–9
14. Laufs U, et al. HMG-CoA reductase inhibitors in chronic heart failure: potential mechanisms of benefit and risk. Drugs 2006; 66: 145–54
15. van der Harst P, et al. Statins in the treatment of chronic heart failure: a systematic review. PLoS Med 2006; 3: e333
16. Horwich TB, et al. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004; 43: 642–8
17. Foody JM, et al. Statins and mortality among elderly patients hospitalized with heart failure. Circulation 2006; 113: 1086–92
18. Go AS, et al. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA 2006; 296: 2105–11
19. Scirica BM, et al. PROVE IT-TIMI 22 Investigators. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol 2006; 47: 2326–31
20. Khush KK, et al. Effect of high-dose atorvastatin on hospitalizations for heart failure: subgroup analysis of the Treating to New Targets (TNT) study. Circulation 2007; 115: 576–83
21. Kjekshus J, et al. CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248–61
22. Strazzullo P, et al. Do statins reduce blood pressure? A metaanalysis of randomized, controlled trials. Hypertension 2007; 49: 792–8
23. Patel AA, et al. The relationship between statin use and atrial fibrillation. Curr Med Res Opin 2007; 23: 1177–85.
24. Mitchell LB, et al. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 2003; 42: 81–7
25. Vyas AK, et al. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol 2006; 47: 769–73
26. Krysiak R, et al. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs 2003; 63: 1821–54
27. Ray JG, et al. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 2001; 161: 1405–10
28. Majumdar SR, et al. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ 2006; 333: 999–1001
29. Falagas ME, et al. Statins for infection and sepsis: a systematic review of the clinical evidence. J Antimicrob Chemother 2008; 61: 774–85
30. Kanda H, et al. Antiinflammatory effect of simvastatin in patients with rheumatoid arthritis. J Rheumatol 2002; 29: 2024–6
31. McCarey DW, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004; 363: 2015–21
32. ten Cate R, et al. Therapy-refractory systemic juvenile idiopathic arthritis successfully treated with statins. Rheumatology (Oxford) 2004; 43: 934–5
33. van Denderen JC, et al. Statin therapy might be beneficial for patients with ankylosing spondylitis. Ann Rheum Dis 2006; 65: 695–6.

Administration in children.

The management of hyperlipidaemias in children and adolescents is controversial and is usually reserved for those with familial hyperlipidaemias who have a high risk of premature cardiovascular disease. Dietary measures and bile-acid binding resins have traditionally been first-line therapy in children, but may be poorly tolerated or inadequate. Studies with statins in children aged 8 to 18 years with familial hypercholesterolaemia have shown1,2 that they effectively lower total cholesterol and low-density lipoprotein (LDL)-cholesterol and they are now increasingly preferred where drug therapy is indicated.3,4 However, there have been concerns about the potential adverse effects of statins on growth and sexual development, since these patients require life-long treatment. Although this does not appear to be a problem, most studies have been relatively short-term, and longer follow-up is needed to confirm statin safety.3,4 Preliminary evidence suggests that statins may also be effective in children with hyperlipidaemia related to nephrotic syndrome5 or organ transplantation.3,4 US licensed product information for simvastatin allows its use in children aged 10 to 17 years with familial heterozygous hypercholesterolaemia in an initial oral dose of 10 mg at night, increased at intervals of 4 weeks as required to a maximum dose of 40 mg daily. A placebo-controlled study6 in 173 such children found that simvastatin given orally in a dose of up to 40 mg daily for 48 weeks effectively reduced LDL-cholesterol and was well tolerated, with no effect on growth or sexual development. The BNFC recommends the following doses for children with hyperlipidaemia:
age 5 to 10 years: initial dose 5 mg at night, increased if necessary at intervals of at least 4 weeks to a maximum dose of 20 mg at night
age 10 to 18 years: initial dose 10 mg at night, increased if necessary at intervals of at least 4 weeks to a maximum dose of 40 mg at night Doses should be reduced in children who are taking drugs that may interact with simvastatin (see Interactions, above).
1. Shafiq N, et al. A meta-analysis to evaluate the efficacy of statins in children with familial hypercholesterolemia. Int J Clin Pharmacol Ther 2007; 45: 548–55
2. Avis HJ, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2007; 27: 1803–10
3. McCrindle BW, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation 2007; 115: 1948–67. Available at: http://circ.ahajournals.org/cgi/reprint/115/ 14/1948.pdf (accessed 30/05/08
4. Belay B, et al. The use of statins in pediatrics: knowledge base, limitations, and future directions. Pediatrics 2007; 119: 370–80
5. Prescott WA, et al. The potential role of HMG-CoA reductase inhibitors in pediatric nephrotic syndrome. Ann Pharmacother 2004; 38: 2105–14
6. de Jongh S, et al. Simvastatin in Children Study Group. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 2002; 106: 2231–7.

Administration in renal impairment.

Statins appear to be safe and effective in patients with dyslipidaemia and renal impairment, and there is some evidence that they may have beneficial effects on renal function (see Kidney Disorders, below). However, patients with severe renal impairment may be at increased risk of developing myopathy or rhabdomyolysis and lower doses may be appropriate in such patients. Dose reduction may also be needed for statins that are excreted by the kidneys. Simvastatin does not undergo significant renal excretion and no dose modification is required in patients with mild or moderate renal impairment. However, in patients with severe renal impairment the recommended initial dose is 5 mg once daily and doses above 10 mg once daily should be used with caution.

Cardiovascular risk reduction.

Lipid regulating drugs have an important role in cardiovascular risk reduction, and statins are widely used for both primary and secondary prevention. The rationale for their use has been the established link between hypercholesterolaemia and atherosclerosis, but they may have additional actions that contribute to their effect (see Action, above). The efficacy of statins in reducing cardiovascular events has been established in a wide range of patient groups and is generally believed to be a class effect, although outcome studies have not been performed for all the statins in every case. In patients with established ischaemic heart disease, statins reduce the risk of further cardiovascular events, and also reduce both cardiovascular and overall mortality.1 Statins shown to be effective for secondary prevention in large, randomised studies include simvastatin,2 pravastatin,3,4 and fluvastatin.5,6 For primary prevention in patients at high risk but without prior cardiovascular events, statins similarly reduce the risk of cardiovascular events, although an effect on mortality has not been shown.7Benefit has been established in studies using pravastatin,8,9 lovastatin,10 simvastatin,11 and atorvastatin;12 the negative results of the ALLHAT-LLT study13 with pravastatin were attributed to the substantial use of statins in the control group. Although the main benefit of statins is to reduce mortality and major coronary events, there may also be a reduction in the incidence14-17 and severity18 of stroke (although there may be an increase in haemorrhagic stroke16), and the incidence of peripheral vascular disease;19 some studies have also shown a reduction in coronary19,20 and peripheral19,21 ischaemic symptoms. Observational studies have suggested that statins may also reduce postoperative mortality in patients with high cardiovascular risk undergoing surgery, although this remains to be confirmed,22 and there is some evidence that statins may reduce the risk of myocardial damage in patients undergoing percutaneous interventions,23 although they have not been shown to affect restenosis.24,25 Early use of statins may also have a role in patients with acute coronary syndromes; one meta-analysis26 found no evidence of benefit at 1 or 4 months after the initial event, but another27 reported a reduction in cardiovascular events with statin therapy for 6 months or longer, and some studies28 have suggested earlier benefit with high-dose regimens. The main effect of statins appears to relate to their action on lipid concentrations, and increased benefit has been reported29 with the use of intensive lipid lowering regimens, including a reduction in mortality in patients with acute coronary syndromes.30However, studies have shown that statins improve outcomes in patients with both raised8,26 and average3,4,10,12 cholesterol concentrations, and meta-analyses31,32 have concluded that the absolute benefit of statin treatment depends on both the initial cardiovascular risk and the degree of cholesterol reduction achieved. Most benefit has been reported in patients at the highest risk; subgroups in whom particular benefit has been reported include patients with metabolic syndrome compared with those without,33and diabetics compared with non-diabetics,34 although a study35with atorvastatin in diabetics undergoing haemodialysis found no benefit. Early studies included mainly middle-aged men, but later studies11 and meta-analyses9,31 have confirmed that statins also improve outcomes in women and in the elderly. Observational studies36,37 have confirmed that these benefits extend to the clinical situation. Statins differ in potency,38-40 but evidence that they differ in efficacy for cardiovascular risk reduction when given at comparable lipid-lowering doses is limited.41 Patients who do not achieve target lipid concentrations or who experience adverse effects with one statin may find an alternative statin effective and tolerable, although recurrence of myalgia is not uncommon.42
1. Wilt TJ, et al. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med 2004; 164: 1427–36
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9
3. Sacks FM, et al. The Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9
4. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57
5. Riegger G, et al. The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis 1999; 144: 263–70
6. Serruys PWJC, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 287: 3215–22
7. Thavendiranathan P, et al. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166: 2307–13
8. Shepherd J, et al. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7
9. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623–30
10. Downs JR, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615–22
11. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22
12. Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149–58
13. The ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288: 2998–3007
14. Briel M, et al. Effects of statins on stroke prevention in patients with and without coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med 2004; 117: 596–606
15. Amarenco P, et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004; 35: 2902–9
16. Henyan NN, et al. Impact of statins on risk of stroke: a metaanalysis. Ann Pharmacother 2007; 41: 1937–45
17. O’Regan C, et al. Statin therapy in stroke prevention: a metaanalysis involving 121,000 patients. Am J Med 2008; 121: 24–33
18. Elkind MSV, et al. Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology 2005; 65: 253–8
19. Pedersen TR, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998; 81: 333–5
20. Fathi R, et al. A randomized trial of aggressive lipid reduction for improvement of myocardial ischemia, symptom status, and vascular function in patients with coronary artery disease not amenable to intervention. Am J Med 2003; 114: 445–53
21. Mondillo S, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med 2003; 114: 359–64
22. Kapoor AS, et al. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. Abridged version: BMJ 2006; 333: 1149–52.. Full version: http://www.bmj.com/cgi/reprint/333/7579/ 1149.pdf (accessed 30/05/08
23. Cahoon WD, Crouch MA. Preprocedural statin therapy in percutaneous coronary intervention. Ann Pharmacother 2007; 41: 1687–93
24. Serruys PW, et al. A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty: final results of the fluvastatin angiographic restenosis (FLARE) trial. Eur Heart J 1999; 20: 58–69
25. Weintraub WS, et al. Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med 1994; 331: 1331–7
26. Briel M, et al. Effects of early treatment with statins on shortterm clinical outcomes in acute coronary syndromes: a metaanalysis of randomized controlled trials. JAMA 2006; 295: 2046–56
27. Hulten E, et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166: 1814–21
28. Ray KK, et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46: 1405–10
29. Cannon CP, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48: 438–45
30. Afilalo J, et al. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative metaanalysis of randomised controlled trials. Heart 2007; 93: 914–21
31. Cheung BMY, et al. Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes. Br J Clin Pharmacol 2004; 57: 640–51
32. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78. Correction. ibid.; 1358
33. Pyörälä K, et al. Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: subgroup analyses of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 2004; 27: 1735–40
34. Costa J, et al. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ 2006; 332: 1115–8
35. Wanner C, et al. German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–48
36. Wei L, et al. Statin use in the secondary prevention of coronary heart disease in primary care: cohort study and comparison of inclusion and outcome with patients in randomised trials. BMJ 2005; 330: 821–4
37. Hippisley-Cox J, Coupland C. Effect of statins on the mortality of patients with ischaemic heart disease: population based cohort study with nested case-control analysis. Heart 2006; 92: 752–8
38. Hippisley-Cox J, et al. Cross sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices. Abridged version: BMJ 2003; 326: 689–92. Full version: http://www.bmj.com/cgi/ reprint/326/7391/689.pdf (accessed 30/05/08
39. Edwards JE, Moore RA. Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Fam Pract 2003; 4: 18
40. Insull W, et al. Achieving low-density lipoprotein cholesterol goals in high-risk patients in managed care: comparison of rosuvastatin, atorvastatin, and simvastatin in the SOLAR trial. Mayo Clin Proc 2007; 82: 543–50. Correction. ibid.; 890
41. Zhou Z, et al. Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J 2006; 151: 273–81
42. Krasuski RA, et al. Conversion to atorvastatin in patients intolerant or refractory to simvastatin therapy: the CAPISH study. Mayo Clin Proc 2005; 80: 1163–8.

Dementia.

There is conflicting evidence on the link between statin use and dementia. Epidemiological studies have reported1,2 that the prevalence of dementia is lower in patients taking statins, although it has been suggested that this may be due to bias in prescribing.3 (Prevalence may also be reduced in patients taking fibrates.2) Some longitudinal studies have reported4,5 that statins also reduce the incidence of dementia, but others have found no evidence of a reduction in risk,6-8and it has been suggested6 that inappropriate analysis may explain the positive results. Prospective, randomised trials are therefore needed to determine their role, if any, in the prevention of dementia.3 There is also some evidence that statins9-11 and other lipid regulating drugs11 may reduce the progression of cognitive decline in patients with dementia, although the effect has generally been small. However, negative effects on mental function have been reported with some statins (see under Adverse Effects, above) and their use in the management of dementia is not established.
1. Wolozin B, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000; 57: 1439–43
2. Dufouil C, et al. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology 2005; 64: 1531–8
3. Scott HD, Laake K. Statins for the prevention of Alzheimer’s disease. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2001 (accessed 30/05/08)
4. Jick H, et al. Statins and the risk of dementia. Lancet 2000; 356: 1627–31. Correction. ibid.; 357: 562
5. Wolozin B, et al. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med 2007; 5: 20
6. Li G, et al. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology 2004; 63: 1624–8
7. Zandi PP, et al. Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry 2005; 62: 217–24
8. Rea TD, et al. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch N
Published May 08, 2019.