Skip to main content

Advertisement

SpringerLink
Log in

Atorvastatin

A Review of its Pharmacology and Therapeutic Potential in the Management of Hyperlipidaemias

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Summary

Synopsis

Atorvastatin is a synthetic HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. It also reduces triglyceride levels through an as yet unproven mechanism.

Dose-dependent reductions in total cholesterol, low density lipoprotein (LDL)-cholesterol and triglyceride levels have been observed with atorvastatin in patients with hypercholesterolaemia and in patients with hypertriglyceridaemia. In large trials involving patients with hypercholesterolaemia, atorvastatin produced greater reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels than lovastatin, pravastatin and simvastatin. In patients with primary hypercholesterolaemia, the combination of atorvastatin and colestipol tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin monotherapy.

Although atorvastatin induced smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels than either fenofIbrate or nicotinic acid in patients with combined hyperlipidaemia, it produced larger reductions in total cholesterol and LDL-cholesterol.

As with other HMG-CoA reductase inhibitors, the most frequently reported adverse events associated with atorvastatin are gastrointestinal effects. In comparative trials, atorvastatin had a similar adverse event profile to that of other HMG-CoA reductase inhibitors.

Clinical data with atorvastatin are limited at present. However, with its ability to markedly reduce LDL-cholesterol levels, atorvastatin is likely to join other members of its class as a first-line agent for the treatment of patients with hypercholesterolaemia, if changes in lipid levels with atorvastatin convert to reductions in CHD mortality and morbidity. Atorvastatin may be particularly suitable for patients with heterozygous or homozygous familial hypercholesterolaemia because of the marked reductions in LDL-cholesterol experienced with the drug. Additionally, because of its triglyceride-lowering properties, atorvastatin appears to have the potential to become an appropriate treatment for patients with combined hyperlipidaemia or hypertriglyceridaemia.

Pharmacodynamic Properties

Like other members of its class, atorvastatin inhibits HMG-CoA reductase and impedes the formation of mevalonic acid, which is a rate-limiting step in the biosynthesis of cholesterol. The resulting effect is a reduction in intracellular cholesterol leading to an increase in the number of low density lipoprotein (LDL)-receptors and increase in LDL-cholesterol clearance from plasma. HMG-CoA reductase inhibitors may also lower plasma cholesterol levels by decreasing hepatic production of very low density lipoprotein (VLDL)- and LDL-cholesterol.

Atorvastatin inhibited cholesterol synthesis by 50% in human liver-derived cell line (Hep-G2) at a concentration of 73 nmol/L. Atorvastatin 80 mg/day reduced fasting plasma mevalonic acid levels by 59% in patients with heterozygous familial hypercholesterolaemia.

Patients with hypertriglyceridaemia receiving atorvastatin either 20 or 80 mg/day for 4 weeks experienced significant reductions in plasma levels of total cholesterol, triglycerides and apolipoproteins B, C-II, C-III and E.

Two indirect mechanisms have been suggested to explain the reduction in triglycéride levels with atorvastatin. Firstly, marked inhibition of cholesterol synthesis would impair the assembly and secretion of VLDL particles, of which cholesterol is an essential component, therefore causing reductions in triglyceride levels. Secondly, reductions in hepatocyte cholesterol levels caused by substantial inhibition of cholesterol synthesis would lead to increases in LDL-receptor expression and hence increased binding of VLDL particles and LDL, resulting in the reduction of both cholesterol and triglyceride levels.

There is some evidence that atorvastatin, like other drugs of its class, may have antiatherogenic effects. The drug inhibits smooth muscle cell proliferation and/or migration. Compared with untreated controls, atorvastatin 2.5 mg/kg significantly reduced rabbit atherosclerotic lesion size by 67%. Furthermore, in patients with hyperlipidaemia, atorvastatin 80 mg/day reduced plasma viscosity by 10%, factor VII activity by 8%, red blood cell sedimentation rate by 33% and arachidonic acid-induced whole blood aggregation by 11%.

Pharmacokinetic Properties

Multiple daily doses of atorvastatin 2.5 to 80mg produced steady-state maximum plasma concentrations (Cmax) of 1.95 to 252 µg/L within 2 to 4 hours after administration and area under the plasma concentration-time curve (AUC) values of 25.2 to 1293 |Ug/L · h. The drug has an absolute bioavailability of 12%. Atorvastatin is ≥98% protein-bound in plasma and has a mean elimination half-life of about 14 hours, but as a result of active metabolites the half-life of HMG-CoA reductase inhibition is 20 to 30 hours. Less than 2% of the parent drug and metabolites are excreted renally.

Atorvastatin Cmax and AUC values may be prolonged in patients with hepatic impairment. Renal impairment had no effect on atorvastatin pharmacokinetic parameters. Although some accumulation was evident in the elderly, this did not produce clinically significant changes in lipid reduction.

Therapeutic Efficacy

Currently, results of studies investigating the potential benefits of atorvastatin on mortality and morbidity in patients with or without coronary heart disease are not available. Therefore, clinical evaluation of atorvastatin at this time is based on lipid-lowering effects, a surrogate marker of clinical efficacy.

In placebo-controlled dose-response studies in patients with primary hyper-cholesterolaemia, atorvastatin 10 to 80 mg/day produced 35 to 61% reductions in LDL-cholesterol levels. 90% of the maximum observed reduction in LDL-cholesterol levels was attained after 2 weeks of treatment. In patients with hypertriglyceridaemia, atorvastatin 5,20 or 80 mg/day reduced triglyceride levels by 26 to 46%, LDL-cholesterol levels by 17 to 41% and total cholesterol levels by 20 to 43%.

In large double-blind trials of 1 year’s duration involving patients with hypercholesterolaemia, reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels were significantly greater with atorvastatin 10 to 20 mg/day than with lovastatin 20 to 40 mg/day, pravastatin 20 to 40 mg/day or simvastatin 10 to 20 mg/day. Atorvastatin, lovastatin, pravastatin and simvastatin all raised HDL-cholesterol levels by 7 to 10%. A greater number of patients tended to reach US National Cholesterol Education Program (NCEP) LDL-cholesterol goals with atorvastatin than with lovastatin, pravastatin or simvastatin. As a result, fewer patients receiving atorvastatin than these other agents tended to require upward dosage titration after 16 weeks of treatment.

In one study, the combination of atorvastatin 10 mg/day and colestipol 20 g/day tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin 10 mg/day monotherapy, in patients with primary hypercholesterolaemia.

In patients with combined hyperlipidaemia (elevated LDL-cholesterol and triglyceride levels), atorvastatin 10 mg/day produced larger reductions in total cholesterol and LDL-cholesterol than fenofibrate 100mg 3 times daily or nicotinic acid (niacin) 100 to 1000mg 3 times daily. However, smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels were achieved with atorvastatin than with both fenofibrate and nicotinic acid.

Atorvastatin 10 to 20 mg/day caused a greater reduction in triglyceride levels than simvastatin 10 to 20 mg/day in patients with raised cholesterol and triglyceride levels secondary to non-insulin-dependent diabetes mellitus (NIDDM).

Tolerability

Atorvastatin has been generally well tolerated in clinical studies of up to 52 weeks’ duration. Like other HMG-CoA reductase inhibitors, gastrointestinal effects (including flatulence, dyspepsia, constipation and abdominal pain) are the most frequently reported adverse events associated with atorvastatin. In total, <2% of 2502 patients withdrew from treatment with atorvastatin in clinical trials because of adverse events. In comparative trials, atorvastatin had a similar adverse event profile to that of lovastatin, pravastatin and simvastatin.

Hepatic dysfunction (raised serum aspartate or alanine aminotransferase levels) and myopathy (myalgia and abnormal creatine phosphokinase levels >10 times the normal limit) are the most serious tolerability concerns associated with HMG-CoA reductase inhibitors. To date, myopathy has not yet been reported with atorvastatin, although the drug has not been used as extensively as other HMG-CoA reductase inhibitors. 3% of the atorvastatin group (n=132) in one study reported myalgia, but no patients had persistent increases in creatine phosphokinase levels >10 times the normal limit.

Elevated serum transaminase levels were reported in 0.2, 0.6,0.6 and 2.3% of patients receiving atorvastatin 10, 20,40 and 80 mg/day, respectively. In patients receiving atorvastatin in clinical trials, the total incidence of persistent elevations in serum transaminases was 0.7%. After 52 weeks of treatment in a large study, the incidence of abnormal transaminase levels was similar with atorvastatin and lovastatin. Pancreatitis was reported in 1 of 1135 patients receiving atorvastatin in 3 trials.

Dosage and Administration

Atorvastatin 10 to 80 mg/day may be used to reduce the raised lipid levels in patients with primary hypercholesterolaemia (heterozygous familial, homozygous familial or nonfamilial) or combined dyslipidaemia

The dosage of atorvastatin should be adjusted according to response. Atorvastatin may be taken at any time of day with or without food. In patients with hepatic insufficiency dosage reductions may be required. The drug is contraindicated in patients with active hepatic disease or unexplained persistent elevations in serum transaminases.

Concomitant use of atorvastatin with cyclosporin, nicotinic acid, fibric acid derivatives, erythromycin or azole antifungals is likely to increase the risk of adverse events (e.g. myopathy or rhabdomyolysis), and these combinations should be avoided where possible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Blum CBB. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme Areductase. Am J Cardiol 1994; 73 Suppl. D: 3D–11D

    Article  PubMed  CAS  Google Scholar 

  2. Rackley CE. Monotherapy with HMG-CoA reductase inhibitors and secondary prevention in coronary artery disease. Clin Cardiol 1996 Sep; 19: 683–9

    Article  PubMed  CAS  Google Scholar 

  3. Alberts AW. Effects of HMG CoA reductase inhibitors on cholesterol synthesis. Drug Invest 1990; 2 Suppl. 2: 9–17

    Article  Google Scholar 

  4. O’Connor P, Feely J, Shepard J. Lipid lowering drugs. BMJ 1990 Mar 10; 300: 667–72

    Article  PubMed  Google Scholar 

  5. Haria M, McTavish D. Pravastatin: a reappraisal of its pharmacological properties and therapeutic use in the management of coronary heart disease. Drugs 1997; 53(2): 299–336

    Article  PubMed  CAS  Google Scholar 

  6. Conde K, Vergara-Jinenez M, Krause BR, et al. Hypercholesterolemic actions of atorvastatin are associated with alterations on hepatic cholesterol metabolism and lipoprotein composition in the guinea pig. J Lipid Res 1996; 37: 2372–82

    PubMed  CAS  Google Scholar 

  7. Lipitor™ (atorvastatin calcium) tablets. Data sheet. Parke-Davis, Division of Warner-Lambert Company, Morris Plains, NJ 07950, USA. 1996. (Data on file)

  8. Plosker GL, Wagstaff AJ. Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia. Drugs 1996 Mar; 51: 433–59

    Article  PubMed  CAS  Google Scholar 

  9. Kearney AS, Crawford LF, Mehta SC, et al. The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981. Pharm Res 1993 Oct; 10: 1461–5

    Article  PubMed  CAS  Google Scholar 

  10. Ferguson E, McNally W, Bocan TMA, et al. Measurement of sterol synthesis and tissue distribution of a liver selective HMG-CoA reductase inhibitor, CI-981 [abstract]. FASEB J 1991 Mar 15; 5: A1253

    Google Scholar 

  11. Newton RS. Are all HMG-CoA reductase inhibitors (vastatins) alike? [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–17; Florence (Italy), 31

  12. Shaw MK, Newton RS, Sliskovic DR, et al. Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase. Biochem Biophys Res Commun 1990; 170(2): 726–34

    Article  PubMed  CAS  Google Scholar 

  13. Auerbach BJ, Bousley RF, Stanfield RL, et al. Mechanism of cholesterol lowering in casein-fed rabbits treated with atorvastatin [abstract]. Atherosclerosis 1994 Sep 15; 109: 164–5

    Article  Google Scholar 

  14. Sliskovic DR, Roth BD, Bocan TMA. Tissue selectivity of HMG-CoA reductase inhibitors. Drug News Perspect 1992; 5(9): 517–33

    Google Scholar 

  15. Bocan TMA, Mazur MJ, Mueller SB, et al. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. Atherosclerosis 1994 Nov; 111: 127–42

    Article  PubMed  CAS  Google Scholar 

  16. Krause BR, Newton RS. Lipid-lowering activity of atorvastatin and lovastatin in rodent species: triglyceride-lowering in rat correlates with efficacy in LDL animal models. Atherosclerosis 1995 Oct; 117: 237–44

    Article  PubMed  CAS  Google Scholar 

  17. Auerbach BJ, Krause BR, Bisgaier CL. Comparative effects of HMG-CoA reductase inhibitors on apo B production in the casein-fed rabbit: atorvastatin versus lovastatin. Atherosclerosis 1995 Jun; 115: 173–80

    Article  PubMed  CAS  Google Scholar 

  18. Parker TS, McNamara DJ, Brown CD, et al. Plasma mevalonate as a measure of cholesterol biosynthesis in man. J Clin Invest 1984; 74: 795–804

    Article  PubMed  CAS  Google Scholar 

  19. Naoumova RP, Marais AD, Mountney J, et al. Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis 1996 Jan 26; 119: 203–13

    Article  PubMed  CAS  Google Scholar 

  20. Naoumova RP, Marais AD, Firth JC, et al. Apheresis plus atorvastatin: a hard act for gene therapy to follow? [abstract]. 66th Congress of the European Atherosclerosis Society Abstract Book. Jul 13–17, 1996. Florence Italy: 24

  21. Cilla Jr DD, Gibson DM, Whitfield LR, et al. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening. J Clin Pharmacol 1996 Jul; 36: 604–9

    PubMed  CAS  Google Scholar 

  22. Le N-A, Li X, Innis-Whitehouse W, et al. Lipid and apolipoprotein levels and distribution in patients with hypertriglyceridemia: effect of atorvastatin. Parke-Davis, Ann Arbor, Michigan, USA. (Data on file)

  23. Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996 Jan 10; 275: 128–33

    Article  PubMed  CAS  Google Scholar 

  24. Thompson GR, Naoumova RP, Watts GF, et al. Role of cholesterol in regulating apolipoprotein B secretion by the liver. J Lipid Res 1996; 37: 439–47

    PubMed  CAS  Google Scholar 

  25. Kasim SE, LeBoeuf RC, Khilnani S, et al. Mechanisms of triglyceride-lowering effect of HMG-CoA reductase inhibitors in a hypertriglyceridemic animal model, the Zucker obese rat. J Lipid Res 1992; 33: 1–7

    PubMed  CAS  Google Scholar 

  26. Goh EH, Heimburg M. Effects of free fatty acids on activity of hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase and on secretion of triglycéride and cholesterol by liver. J Biol Chem 1977 May 10; 252(9): 2822–6

    PubMed  CAS  Google Scholar 

  27. Watts GF, Cummings MH, Umpleby M, et al. Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications. Eur J Clin Invest 1995; 25: 559–67

    Article  PubMed  CAS  Google Scholar 

  28. Cianflone KM, Yasruel Z, Rodriguez MA, et al. Regulation of apoB secretion from HepG2 cells: evidence for a critical role for cholesteryl ester synthesis in the response to a fatty acid challenge. J Lipid Res 1990; 31: 2045–55

    PubMed  CAS  Google Scholar 

  29. Watts GF, Naoumova R, Cummings MH, et al. Direct correlation between cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidemic subjects. Metabolism 1995; 44(8): 1052–7

    Article  PubMed  CAS  Google Scholar 

  30. Schaefer EJ, Levy RI. Pathogenesis and management of lipoprotein disorders. N Engl J Med 1985 May 16; 312(20): 1300–10

    Article  PubMed  CAS  Google Scholar 

  31. McNeil JJ, Sloman JG. Cardiovascular Disorders. In: Speight TM, editor. Avery’s drug treatment. 3rd ed. Auckland: Adis International, 1987: 591–675

    Google Scholar 

  32. Grundy SM. HMG-CoA reductase inhibitors: clinical applications and therapeutic potential. In: Rifkind BM, editor. Drug treatment of hyperlipidemia. New York, New York: Mercel Dekker Inc, 1991: 139–67

    Google Scholar 

  33. Ma PTS, Gil G, Südhof TC, et al. Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits. Proc Natl Acad Sci USA 1986; 88: 8370–4

    Article  Google Scholar 

  34. Plosker GL, McTavish D. Simvastatin: a reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Drugs 1995 Aug; 50: 334–63

    Article  PubMed  CAS  Google Scholar 

  35. Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997; 79(1): 38–42

    Article  PubMed  CAS  Google Scholar 

  36. Merck to file for extended release Zocor in 1998; high dose is one strategy to combat atorvastatin launch: Zocor HMG-CoA market share is 29.9%. FDC Rep Pink Sheet 1996 Dec 23: 5

  37. Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996 Oct 19; 348: 1079–82

    Article  PubMed  CAS  Google Scholar 

  38. Corsini A, Raiteri M, Soma MR, et al. Simvastatin but not pravastatin has a direct inhibitory effect on rat and human myocyte proliferation. Clin Biochem 1992; 25: 399–400

    Article  PubMed  CAS  Google Scholar 

  39. Weissberg PL, Clesham GJ, Bennett MR. Is vascular smooth muscle cell proliferation beneficial? Lancet 1996 Feb 3; 347: 305–7

    Article  PubMed  CAS  Google Scholar 

  40. Negre-Aminou P, van Erck M, Cohen LH. Anti-proliferative potencies of 6 vastatins in cultured human cells; involvement of the ras-mediated signalling pathway [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–17; Florence (Italy), 120

  41. Ortego M, Bustos C, Hernández-Presa M, et al. The HMG-CoA reductase inhibitor atorvastatin reduces NF-kB activation and MCP-1 gene expression in vascular smooth muscle cells and mononuclear cells [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–17; Florence (Italy), 66

  42. Soma M, Piliego T, Seregni R, et al. Effect of atorvastatin on intimai carotid thickening induced by perivascular manipulation in normocholesterolemic rabbits [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 July 13–17, Florence Italy, 231

  43. Dujovne CA, Harris WS, Altman R, et al. Changes in hemorheology and atherothrombotic parameters by improving serum lipids in atorvastatin-treated hyperlipidemics [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–17; Florence (Italy), 169

  44. Alfón J, Pueyo C, Badimon L. Regulation by atorvastatin, a novel HMGCoA reductase inhibitor, of plasma lipids and thrombotic risk in atherosclerotic rabbits [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 July 13–17, Florence Italy, 201

  45. Dostal LA, Schardein JL, Anderson JA. Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 1994 Dec; 50: 387–94

    Article  PubMed  CAS  Google Scholar 

  46. Dostal LA, Whitfield LR, Anderson JA. Fertility and general reproduction studies in rats with the HMG-CoA reductase inhibitor, atorvastatin. Fundam Appl Toxicol 1996; 32: 285–92

    Article  PubMed  CAS  Google Scholar 

  47. Ciaravino V, Kropko ML, Rothwell CE, et al. The genotoxicity profile of atorvastatin, a new drug in the treatment of hypercholesterolemia. Mutat Res Genet Toxicol 1995 Jun; 343: 95–107

    Article  CAS  Google Scholar 

  48. Walsh KM, Albassam MA, Clarke DE. Subchronic toxicity of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, in beagle dogs. Toxicol Pathol 1996; 24(4): 468–76

    Article  PubMed  CAS  Google Scholar 

  49. Yang B-B, Smithers JA, Stern RH, et al. Pharmacokinetics and dose proportionality of atorvastatin and its active metabolites [abstract]. Pharm Res 1996; 13(9) Suppl.: S437

    Google Scholar 

  50. Radulovic LL, Cilla DD, Posvar EL. Effect of food on the bioavailability of atorvastatin, an HMG-CoA reductase inhibitor. J Clin Pharmacol 1995 Oct; 35: 990–4

    PubMed  CAS  Google Scholar 

  51. Davignon J, Dufour R, Montigny M. Atorvastatin: what do we know? [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–7: Florence (Italy), 31

  52. Cilla Jr DD, Radulovic LL, Whitfield LR, et al. Safety, tolerance and pharmacokinetic (PK) profiles following single-doses of CI-981, a potent HMG-CoA reductase inhibitor [abstract]. Pharm Res 1993; 10 Suppl.: S332

    Google Scholar 

  53. Henwood JM, Heel RC. Lovastatin: a preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. Drugs 1988; 36: 429–54

    Article  PubMed  CAS  Google Scholar 

  54. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202

    Article  PubMed  CAS  Google Scholar 

  55. Cilla Jr DD, Whitfield LR, Gibson DM, et al. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Pharmacol Ther 1996; 60: 687–95

    Article  CAS  Google Scholar 

  56. Whitfield LR, Cilla Jr DD, Posvar EL, et al. Single- and multiple-dose pharmacokinetics of CI-981, a potent HMG-CoA reductase inhibitor [abstract]. Pharm Res 1993; 10 Suppl.: S340

    Google Scholar 

  57. Michniewicz BM, Black AE, Sinz MW, et al. In vitro and in vivo metabolism of atorvastatin (CI-981) [abstract]. ISSX Proc 1994; 6: 93

    Google Scholar 

  58. Illingworth DR, Tobert JA. A review of clinical trials comparing HMG-CoA reductase inhibitors. Clin Ther 1994; 16(3): 366–85

    PubMed  CAS  Google Scholar 

  59. Davidson MM, McKenney JM, Stein EA, et al. Long-term efficacy and safety of atorvastatin compared to lovastatin in hypercholesterolemic patients. Am J Cardiol 1997. In press

  60. Gibson DM, Bron NJ, Richens A, et al. Effect of age and gender on pharmacokinetics of atorvastatin in humans [437340]. J Clin Pharmacol 1996; 36: 242–6

    PubMed  CAS  Google Scholar 

  61. Gibson DM, Yang B-B, Abel RB, et al. Effects of hepatic and renal impairment on pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin [abstract]. Pharm Res 1996; 13 (9 Suppl).: S428

    Google Scholar 

  62. Bocan TMA, Ferguson E, McNally W, et al. Hepatic and non-hepatic sterol synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981: comparison with selected HMG-CoA reductase inhibitors. Biochim Biophys Acta 1992 Jan 24; 1123: 133–44

    Article  PubMed  CAS  Google Scholar 

  63. Duggan DE, Vickers S. Physiological disposition of HMG-CoA-reductase inhibitors. Drug Metab Rev 1990; 22(4): 333–62

    Article  PubMed  CAS  Google Scholar 

  64. Yang B-B, Smithers JA, Siedlik PH, et al. Atorvastatin pharmacokinetic interactions with other CYP3A4 substrates: erythromycin and ethinyl estradiol [abstract]. Pharm Res 1996; 13(9) Suppl.: S437

    Google Scholar 

  65. Yang B-B, Smithers JA, Abel RB, et al. Effects of Maalox TC® on pharmacokinetics and pharmacodynamics of atorvastatin [abstract]. Pharm Res 1996; 13(9) Suppl.: S437

    Google Scholar 

  66. Oki JC. Dyslipidemias in patients with diabetes mellitus: classification and risks and benefits of therapy. Pharmacotherapy 1995; 15(3): 317–37

    PubMed  CAS  Google Scholar 

  67. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). I. Classification, prevalence, detection, and evaluation. Circulation 1994 Mar; 89: 1344–63, 1432–45

    Google Scholar 

  68. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II): IV. Special issues. Circulation 1994 Mar; 89: 1420–45

    Google Scholar 

  69. Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996 Sep 18; 276(11): 882–8

    Article  PubMed  CAS  Google Scholar 

  70. Pyörälä K, De Backer G, Graham I, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Atherosclerosis 1994 Oct; 110: 121–61

    Article  PubMed  Google Scholar 

  71. DiBianco R. Hypercholesterolaemia management guidelines. S Afr Med J 1992 Feb 15; 81 Suppl.: 4–9

    Google Scholar 

  72. Betteridge DJ, Dodson PM, Durrington PM, et al. Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association. Postgrad Med J 1993; 69: 359–69

    Article  PubMed  CAS  Google Scholar 

  73. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study Group (4S). Lancet 1994; 344: 1383–9

    Google Scholar 

  74. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9

    Article  PubMed  CAS  Google Scholar 

  75. Frick MH, Elo O, Haapa K, et al. Helsinki heart study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317(20): 1237–45

    Article  PubMed  CAS  Google Scholar 

  76. Sheperd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333(20): 1301–7

    Article  Google Scholar 

  77. West of Scotland Coronary Prevention Group. West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996 Nov 16; 348: 1339–42

    Article  Google Scholar 

  78. van Boven AJ, Brügemann J, de Graeff PA. The 4S study: implications for prescribing. Drugs 1996 Apr; 51: 507–14

    Article  PubMed  Google Scholar 

  79. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II): II. Dietary therapy and physical activity. Circulation 1994 Mar; 89: 1364–404, 1432–45

    Google Scholar 

  80. Gmerek A, Yang R, Bays H, et al. Atorvastatin causes a dose-dependent reduction in LDL-C and triglycerides [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–7: Florence (Italy), 212

  81. Nawrocki JW, Weiss SR, Davidson MH, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Art Thrombosis Vasc Biol 1995 May; 15: 678–82

    Article  CAS  Google Scholar 

  82. Heinonen TM, Stein E, Weiss SR, et al. The lipid-lowering effects of atorvastatin, a new HMG-CoA reductase inhibitor: results of a double-masked study. Clin Ther 1996; 18(5): 853–63

    Article  PubMed  CAS  Google Scholar 

  83. Bertolini S, Bittolo Bon G, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997. In press

  84. Dart A, Jerums G, Nicholson G, et al. A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997. In press

  85. Heinonen T, Stein E, Issacsohn J, et al. Atorvastatin in the treatment of severe hypercholesterolemia [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 July 13–17, Florence Italy, 214

  86. Heinonen T, Black D. Atorvastatin monotherapy and combination therapy in the treatment of severe hypercholesterolemia [abstract]. Atherosclerosis 1995 Jun; 115 Suppl.: S20

    Article  Google Scholar 

  87. Heinonen T, Schrott H, McKenney J, et al. The lipid-lowering effects of atorvastatin and colestipol used as monotherapies and in combination [abstract]. Atherosclerosis 1994 Sep 15; 109: 314

    Article  Google Scholar 

  88. Heinonen T, Schrott H, Broyles F, et al. The effects of atorvastatin in postmenopausal women [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–7; Florence (Italy), 56

  89. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II): III. Drug treatment. Circulation 1994 Mar; 89: 1405–19, 1432–45

    Google Scholar 

  90. Naoumova RP, Marais D, Firth JC, et al. Atorvastatin augments therapy of homozygous familial hypercholesterolemia by inhibiting upregulation of cholesterol synthesis after apheresis and bile acid sequestrants [abstract]. Circulation 1996; 94 (8 Suppl).: 1–583

    Article  Google Scholar 

  91. McKenney JM, McCormick LS, Kafonek S, et al. Lipid lowering effects of atorvastatin, a new HMG-CoA reductase inhibitor, and niacin in patients with combined or isolated hypertriglyceridemia. Parke-Davis, Ann Arbor, Michigan, USA. (Data on file)

  92. Ooi TC, Heinonen T, Alaupovic P, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate. Art Thrombosis Vasc Biol 1997. In press

  93. Best JD, Nicholson GC, O’Neal DN, et al. Atorvastatin and simvastatin reduce elevated cholesterol in non-insulin dependent diabetes]. Diabetes Nutr Metab 1996; 9(2): 74–80

    CAS  Google Scholar 

  94. Nawrocki J, Schwartz S, Fayyad R, et al. Atorvastatin, a new HMG-CoA reductase inhibitor is safe and effective in NIDDM patients with hyperlipidemia [abstract]. In: 66th Congress of the European Atherosclerosis Society Abstract Book: 1996 Jul 13–7; Florence (Italy), 222

  95. Gerson RJ, MacDonald JS, Alberts AW, et al. On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors. Exp Eye Res 1990; 50: 65–78

    Article  PubMed  CAS  Google Scholar 

  96. Warner-Lambert Lipitor is first statin indicated for reduction of triglycerides; co-promotions with Pfizer to tout head-to-head comparisons with competitors. FDC Rep Pink Sheet 1996 Dec 23: 3–4

  97. Newman TJ, Kassler-Taub KB, Gelarden RT, et al. Safety of pravastatin in long-term trials conducted in the United States. J Drug Dev 1990; 3 Suppl. 1: 275–81

    Google Scholar 

  98. Thompson GR. Adverse reactions profile: 10. Simvastatin and pravastatin. Prescr J 1990; 33: 217–20

    Google Scholar 

  99. Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health System Pharm 1995; 52: 1639–45

    CAS  Google Scholar 

  100. Schucker B, Wittes JT, Santanello NC, et al. Change in cholesterol awareness and action: results from national physician and public surveys. Arch Intern Med 1991; 151: 666–73

    Article  PubMed  CAS  Google Scholar 

  101. Thelle DS. Epidemiology of hypercholesterolemia and European management guidelines. Cardiology 1990; 77 Suppl. 4: 2–7

    Article  PubMed  Google Scholar 

  102. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial. JAMA 1982; 148(12): 1465–77

    Google Scholar 

  103. The Lipid Research Clinics Coronary Primary Prevention Trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 365–74

    Article  Google Scholar 

  104. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251: 351–64

    Article  Google Scholar 

  105. ASPIRE Steering Group. A British Cardiac Society survey of the potential for the secondary prevention of coronary disease: ASPIRE (Action on Secondary Prevention through Intervention to Reduce Events). Heart 1996; 75: 334–42

    Article  Google Scholar 

  106. Austin MA. Plasma triglyceride and coronary heart disease. Art Thrombosis Vasc Biol 1991; 11: 2–14

    Article  CAS  Google Scholar 

  107. Criqui MH, Heiss G, Cohn K, et al. Plasma triglyceride level and mortality from coronary artery disease. N Engl J Med 1993 Apr 29; 328: 1220–5

    Article  PubMed  CAS  Google Scholar 

  108. Carlson LA, Böttiger LE, Åhfeldt P-E. Risk factors for myocardial infarction in the Stockholm Prospective Study. A 14-year follow-up focusing on the role of plasma triglycerides and cholesterol. Acta Med Scand 1979; 206: 351–60

    Article  PubMed  CAS  Google Scholar 

  109. Tenkanen L, Pietilä K, Manninen V, et al. The triglyceride issue revisited. Findings from the Helsinki Heart Study. Arch Intern Med 1994 Dec 12–26; 154: 2714–20

    Article  PubMed  CAS  Google Scholar 

  110. Castelli WP. The triglycéride issue revisited: a view from Framingham. Am Heart J 1986; 112(2): 432–7

    Article  PubMed  CAS  Google Scholar 

  111. Hulley SB, Rosenman RH, Bawol RD, et al. Epidemiology as a guide to clinical decisions: the association between triglyceride and coronary heart disease. N Engl J Med 1980; 302: 1383–9

    Article  PubMed  CAS  Google Scholar 

  112. Pyörälä K, De Backer G, Graham I, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1994 Oct; 15: 1300–31

    PubMed  Google Scholar 

  113. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol 1992; 70: 733–7

    Article  PubMed  CAS  Google Scholar 

  114. Havel RJ, Rapaport E. Management of primary hyperlipidemia. N Engl J Med 1995; 332(22): 1491–8

    Article  PubMed  CAS  Google Scholar 

  115. Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein (a) are a risk for major coronary events in middle-aged men. Am J Cardiol 1996; 77: 1179–84

    Article  PubMed  CAS  Google Scholar 

  116. Byington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the pravastatin atherosclerosis intervention program. Circulation 1995; 92(9): 2419–25

    Article  PubMed  CAS  Google Scholar 

  117. Salonen R, Nyyssönen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995; 92(7): 1758–64

    Article  PubMed  CAS  Google Scholar 

  118. Pitt B, Ellis SG, Mancini GBJ, et al. Design and recruitment in the United States of a multicenter quantitative angiographic trial of pravastatin to limit atherosclerosis in the coronary arteries (PLAC I). Am J Cardiol 1993 Jul 1; 72: 31–5

    Article  PubMed  CAS  Google Scholar 

  119. Pitt B, Mancini BJ, Ellis SG, et al. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol 1995; 26(5): 1133–9

    Article  PubMed  CAS  Google Scholar 

  120. Byington RP, Furberg CD, Crouse III JR, et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 1995 Sep 28; 76: 54C–9C

    Article  PubMed  CAS  Google Scholar 

  121. Crouse III JR, Byington RP, Bond MG, et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 1995 Mar 1; 75: 455–9

    Article  PubMed  Google Scholar 

  122. Barth JD, Zonjee MMB, The REGRESS Research Group. Regression growth evaluation statin study (REGRESS): Study design and baseline characteristics in 600 patients. Can J Cardiol 1992 Nov; 8(9): 925–32

    PubMed  CAS  Google Scholar 

  123. de Groot E, Jukema JW, van Boven AJ, et al. Effect of pravastatin on progression and regression of coronary atherosclerosis and vessel wall changes in carotid and femoral arteries: a report from the Regression Growth Evaluation Statin Study. Am J Cardiol 1995 Sep 28; 76: 40C–6C

    Article  PubMed  Google Scholar 

  124. Jukema JW, Bruschke AVG, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91(10): 2528–40

    Article  PubMed  CAS  Google Scholar 

  125. Kroon AA, Aengevaeren WR, van der Werf T, et al. LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation 1996; 93(10): 1826–35

    Article  PubMed  CAS  Google Scholar 

  126. Hodis HN, Mack WJ, LaBree L, et al. Reduction of carotid arterial wall thickness using lovastatin and dietary therapy: a randomised controlled clinical trial. Ann Intern Med 1996; 124(6): 548–56

    PubMed  CAS  Google Scholar 

  127. Probstfield JL, Margitic SE, Byington RP, et al. Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Artery Progression Study. Am J Cardiol 1995; 76(9): 47C–53C

    Article  PubMed  CAS  Google Scholar 

  128. Furberg CD, Adams Jr HP, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events: Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1995; 90(4): 1679–87

    Article  Google Scholar 

  129. MAAS Investigators. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994 Sep 3; 344(8923): 633–8

    Article  Google Scholar 

  130. Water D, Higginson L, Gladstone P, et al. Effects of monotherapy with an HMG-CoAreductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atherosclerosis Intervention Trial. Circulation 1994; 89(3): 959–68

    Article  Google Scholar 

  131. Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS). The MARS Research Group. Ann Intern Med 1994; 119(10): 969–76

    Google Scholar 

  132. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous vein graft coronary artery bypass grafts. N Engl J Med 1997 Jan 16; 336: 153–62

    Article  Google Scholar 

  133. Parke-Davis, Ann Arbor, Michigan, USA. (Data on file)

Download references

Author information

Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Andrew P. Lea & Donna McTavish

Authors
  1. Andrew P. Lea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donna McTavish
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donna McTavish.

Additional information

Various sections of the manuscript reviewed by: J.D. Best, Department of Medicine, St Vincent’s Hospital, Fitzroy, Victoria, Australia; A. Dart, Alfred and Baker Medical Unit, The Alfred Hospital, Prahan, Victoria, Australia; P.D. Flynn, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, England; W.R. Garnett, Department of Pharmacy and Pharmaceutics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA; R.J. Havel, Cardiovascular Research Institute, University of California, San Francisco, California, USA; D.R. Illingworth, Department of Medicine, Oregon Health Services University, Portland, Oregon, USA; A.D. Marais, Department of Internal Medicine, University of Cape Town Medical School, Cape Town, South Africa; R. Naoumova, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, England; C.E. Rackley, Division of Cardiology, Georgetown University Medical Center, Washington, D.C., USA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lea, A.P., McTavish, D. Atorvastatin. Drugs 53, 828–847 (1997). https://doi.org/10.2165/00003495-199753050-00011

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199753050-00011

Keywords

Search

Navigation