Int J Angiol 2013; 22(02): 075-082
DOI: 10.1055/s-0033-1343358
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Problems and Possible Solutions for Therapy with Statins

Thomas F. Whayne Jr.
1   Division of Cardiovascular Medicine, Department of Medicine (Cardiology), Gill Heart Institute, University of Kentucky, Lexington, Kentucky
› Author Affiliations
Further Information

Publication History

Publication Date:
17 May 2013 (online)

Abstract

Despite issues about the value of statins, benefit for high cardiovascular (CV) risk outweighs problems. However, the practitioner must be aware of concerns, be prepared to respond, and justify statin usage. Symptoms of statin-related myopathy are of more concern than stated by pharmaceutical companies. Occurrence of myopathy symptoms, estimated to be up to 10.4%, can decrease statin adherence of high CV risk patients. Dosage modification, or use of pitavastatin, may help the problematic patient. There are concerns that there may be little benefit of statins for primary prevention in women. However, evidence appears to support statin use in women at high CV risk, both in primary and secondary prevention. Abandoning low-density lipoprotein cholesterol (LDL-C) as a valid target is unwarranted; there is much evidence to support “lower is better.” The practitioner must be aware of the complicated processes causing atherosclerosis and when to incorporate new approaches to disease management. Tailoring therapy for CV risk, when indicated, may contribute further to LDL-C reduction. Liver inflammation can occur with statins but is of minimal concern; frequently, statins alleviate the problem. Unless liver transaminases are over three times normal, a statin should be prescribed, if indicated. The net effect of statins on cognition appears to be zero—no harm, no benefit. Despite reports of improved cognition, statins should not be prescribed for this. With diabetes mellitus (DM), statins can increase incidence, but the CV benefit far outweighs any risk. Therefore, statins should be prescribed in DM to reduce CV risk. Statins are a major medical contribution when used appropriately.

 
  • References

  • 1 Whayne Jr TF. Statin myopathy: significant problem with minimal awareness by clinicians and no emphasis by clinical investigators. Angiology 2011; 62 (5) 415-421
  • 2 Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clin Ther 2006; 28 (1) 26-35
  • 3 Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004; 291 (18) 2243-2252
  • 4 Hayward RA, Krumholz HM. Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes 2012; 5 (1) 2-5
  • 5 Whayne Jr TF. Assessment of low-density lipoprotein targets. Angiology 2012; Jun 25. [Epub ahead of print], PMID: 22734087 [PubMed- as supplied by publisher].
  • 6 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106 (25) 3143-3421
  • 7 McGuinness B, O'Hare J, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Cochrane Database Syst Rev 2010; (8) CD007514
  • 8 Sattar N, Preiss D, Murray HM , et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375 (9716) 735-742
  • 9 Ghatak A, Faheem O, Thompson PD. The genetics of statin-induced myopathy. Atherosclerosis 2010; 210 (2) 337-343
  • 10 Phillips PS, Haas RH, Bannykh S , et al; Scripps Mercy Clinical Research Center. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002; 137 (7) 581-585
  • 11 Nissen SE, Tuzcu EM, Schoenhagen P , et al; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291 (9) 1071-1080
  • 12 Cannon CP, Braunwald E, McCabe CH , et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350 (15) 1495-1504
  • 13 Nissen SE, Nicholls SJ, Sipahi I , et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295 (13) 1556-1565
  • 14 Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008; 178 (5) 576-584
  • 15 Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 2005; 19 (6) 403-414
  • 16 Pablos-Méndez A, Barr RG, Shea S. Run-in periods in randomized trials: implications for the application of results in clinical practice. JAMA 1998; 279 (3) 222-225
  • 17 Gazi IF, Daskalopoulou SS, Nair DR, Mikhailidis DP. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin 2007; 23 (9) 2183-2192
  • 18 Sager PT, Melani L, Lipka L , et al; Ezetimibe Study Group. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003; 92 (12) 1414-1418
  • 19 Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr 2001; 20 (6) 591-598
  • 20 Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5.  mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol 2008; 101 (12) 1747-1748
  • 21 Kawashiri MA, Nohara A, Tada H , et al. Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study. Clin Pharmacol Ther 2008; 83 (5) 731-739
  • 22 Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis 2011; 215 (1) 23-29
  • 23 LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282 (24) 2340-2346
  • 24 Culver AL, Ockene IS, Balasubramanian R , et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 2012; 172 (2) 144-152
  • 25 Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59 (6) 572-582
  • 26 Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med 2012; 172 (12) 909-919
  • 27 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344 (8934) 1383-1389
  • 28 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 (19) 1349-1357
  • 29 Shepherd J, Cobbe SM, Ford I , 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 (20) 1301-1307
  • 30 Downs JR, Clearfield M, Weis S , et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279 (20) 1615-1622
  • 31 Ray KK, Seshasai SR, Erqou S , et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 2010; 170 (12) 1024-1031
  • 32 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414) 557-560
  • 33 Redberg RF. Update in cardiology: evidence published in 2010. Ann Intern Med 2011; 154 (8) 549-553
  • 34 Ridker PM, Danielson E, Fonseca FA , et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21) 2195-2207
  • 35 de Lorgeril M, Salen P, Abramson J , et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med 2010; 170 (12) 1032-1036
  • 36 Whayne Jr TF. Astronomical science or astronomical marketing?. Clin Geriatrics 2009; 17: 36
  • 37 Green LA. Cholesterol-lowering therapy for primary prevention: still much we don't know. Arch Intern Med 2010; 170 (12) 1007-1008
  • 38 Brugts JJ, Yetgin T, Hoeks SE , et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009; 338: b2376
  • 39 The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251 (3) 351-364
  • 40 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 (3) 365-374
  • 41 Blankenhorn DH, Johnson RL, Nessim SA, Azen SP, Sanmarco ME, Selzer RH. The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results. Control Clin Trials 1987; 8 (4) 356-387
  • 42 Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987; 257 (23) 3233-3240
  • 43 Buchwald H, Stoller DK, Campos CT, Matts JP, Varco RL. Partial ileal bypass for hypercholesterolemia. 20- to 26-year follow-up of the first 57 consecutive cases. Ann Surg 1990; 212 (3) 318-329 , discussion 329–331
  • 44 Buchwald H, Varco RL, Boen JR , et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med 1998; 158 (11) 1253-1261
  • 45 Moriarty PM. LDL-apheresis therapy. Curr Treat Options Cardiovasc Med 2006; 8 (4) 282-288
  • 46 Schonfeld G. The hypobetalipoproteinemias. Annu Rev Nutr 1995; 15: 23-34
  • 47 Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. PROVE IT-TIMI 22 Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol 2005; 46 (8) 1411-1416
  • 48 Athyros VG, Papageorgiou AA, Mercouris BR , et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 2002; 18 (4) 220-228
  • 49 Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol 2011; 57 (16) 1666-1675
  • 50 Grundy SM, Cleeman JI, Merz CN , et al; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110 (2) 227-239
  • 51 Pascale A, Pais R, Ratziu V. An overview of nonalcoholic steatohepatitis: past, present and future directions. J Gastrointestin Liver Dis 2010; 19 (4) 415-423
  • 52 Athyros VG, Tziomalos K, Gossios TD , et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756) 1916-1922
  • 53 Han KH, Rha SW, Kang HJ , et al. Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage). J Clin Lipidol 2012; 6 (4) 340-351
  • 54 Wierzbicki AS, Oben J. Nonalcoholic fatty liver disease and lipids. Curr Opin Lipidol 2012; 23 (4) 345-352
  • 55 Henninger C, Huelsenbeck J, Huelsenbeck S , et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Appl Pharmacol 2012; 261 (1) 66-73
  • 56 Rzouq FS, Volk ML, Hatoum HH, Talluri SK, Mummadi RR, Sood GK. Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians. Am J Med Sci 2010; 340 (2) 89-93
  • 57 Biondi E. Prescription of lipophilic statins to Alzheimer's disease patients: some controversies to consider. Neurol Sci 2011; 32 (2) 195-201
  • 58 Rojas-Fernandez CH, Cameron JC. Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother 2012; 46 (4) 549-557
  • 59 Li G, Shofer JB, Rhew IC , et al. Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc 2010; 58 (7) 1311-1317
  • 60 Trompet S, van Vliet P, de Craen AJ , et al. Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol 2010; 257 (1) 85-90
  • 61 Glasser SP, Wadley V, Judd S , et al. The association of statin use and statin type and cognitive performance: analysis of the reasons for geographic and racial differences in stroke (REGARDS) study. Clin Cardiol 2010; 33 (5) 280-288
  • 62 Sabbagh MN, Sparks DL. Statins to treat Alzheimer's disease: an incomplete story. Expert Rev Neurother 2012; 12 (1) 27-30
  • 63 Freeman DJ, Norrie J, Sattar N , et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103 (3) 357-362
  • 64 Dalla Nora E, Passaro A, Zamboni PF, Calzoni F, Fellin R, Solini A. Atorvastatin improves metabolic control and endothelial function in type 2 diabetic patients: a placebo-controlled study. J Endocrinol Invest 2003; 26 (1) 73-78
  • 65 Huptas S, Geiss HC, Otto C, Parhofer KG. Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome. Am J Cardiol 2006; 98 (1) 66-69
  • 66 Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380 (9841) 565-571
  • 67 Colbert JD, Stone JA. Statin use and the risk of incident diabetes mellitus: a review of the literature. Can J Cardiol 2012; 28 (5) 581-589
  • 68 Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S. The controversies of statin therapy: weighing the evidence. J Am Coll Cardiol 2012; 60 (10) 875-881
  • 69 Navarese EP, Buffon A, Andreotti F , et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol 2013; Jan 24 [Epub ahead of print]. PMID: 23352266 [PubMed-as supplied by publisher].
  • 70 Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation 2012; 126 (18) e282-e284
  • 71 Rocco MB. Statins and diabetes risk: fact, fiction, and clinical implications. Cleve Clin J Med 2012; 79 (12) 883-893