The Ugly Side of Statins. Systemic Appraisal of the Contemporary Un-Known Unknowns

Sherif Sultan, Niamh Hynes

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Department of Vascular and Endovascular Surgery, Western Vascular Institute, University College Hospital Galway, Galway, Ireland.

DOI: 10.4236/ojemd.2013.33025                

Abstract

Cardio-vascular specialists have witnessed and actively participated in the revolutionary developments that have occurred in their field of specialization over the last few years. Cutting-edge technologies have led to dramatic improvements in life-expectancy and quality of life. An open-mind and pioneering attitude are necessary when exploring new frontiers to improve our patients’ health. However, naive indiscriminate acceptance of novel mainstream therapies is not always advisable and prudence is required in unearthing harmful, covert side effects. An objective review of contemporary vascular research was performed and industrial bias was sifted out for a fresh prospective on how to promote primary cardiovascular prevention with attainable lifestyle adjustments [1]. A comprehensive review of Pubmed, EM-BASE and Cochrane review databases was undertaken for articles relating to cardiovascular primary prevention and statin side effects with the aim of harmonising their roles within contemporary clinic practice. Particular attention was paid to large-scale randomised controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular primary prevention and regenerative programmes. There is a categorical lack of clinical evidence to support the use of statin therapy in primary prevention. Not only is there a dearth of evidence for primary cardiovascular protection, there is ample evidence to show that statins actually augment cardiovascular risk in women, patients with Diabetes Mellitus and in the young. Furthermore statins are associated with triple the risk of coronary artery and aortic artery calcification. Cardiovascular primary prevention and regeneration programmes, through life style changes and abstaining from tobacco use have enhanced clinical efficacy and quality of life over any pharmaceutical or other conventional intervention.

Keywords

Statin; Primary Prevention; Side-Effects; Diabetes Mellitus

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	S. Sultan and N. Hynes, “Cardiovascular Disease: Primary Prevention, Disease Modulation and Regenerative Therapy,” Vascular, Vol. 20, No. 5, 2012, pp. 243-250. doi:10.1258/vasc.2012.ra0062
[2]	S. Ebrahim, F. Taylor, K. Ward, A. Beswick, M. Burke and G. Davey, “Smith Multiple Risk Factor Interventions for Primary Prevention of Coronary Heart Disease,” Cochrane Database of Systematic Reviews, Vol. 19, 2011, Article ID: CD001561. doi:10.1002/14651858.CD001561.pub3
[3]	F. Taylor, K. Ward, T. H. Moore, M. Burke, G. Davey Smith, J. P. Casas and S. Ebrahim, “Statins for the Primary Prevention of Cardiovascular Disease,” Cochrane Database of Systematic Reviews, Vol. 19, No. 1, 2011, Article ID: CD004816. doi:10.1002/14651858.CD004816.pub4
[4]	V. Prasad and A. Vandross, “Cardiovascular Primary Prevention: How High Should We Set the Bar?” Archives of Internal Medicine, Vol. 172, No. 8, 2012, pp. 656-659. doi:10.1001/archinternmed.2012.812
[5]	A. A. Bartolucci, M. Tendera and G. Howard, “Meta-Analysis of Multiple Primary Prevention Trials of Cardiovascular Events Using Aspirin,” American Journal of Cardiology, Vol. 107, No. 12, 2011, pp. 1796-1801. doi:10.1016/j.amjcard.2011.02.325
[6]	J. Hippisley-Cox and C. Coupland, “Unintended Effects of Statins in Men and Women in England and Wales: Population Based Cohort Study Using the Q Research Database,” British Medical Journal, Vol. 340, 2010, Article ID: c2197.
[7]	K. El-Salem, B. Ababneh, S. Rudnicki, A. Malkawi, A. Alrefai, Y. Khader, R. Saadeh and M. Saydam, “Prevalence and Risk Factors of Muscle Complications Secondary to Statins,” Muscle Nerve, Vol. 44, No. 6, 2011, pp. 877-881. doi:10.1002/mus.22205
[8]	Y. Vinogradova, C. Coupland and J. Hippisley-Cox, “Exposure to Statins and Risk of Common Cancers: A Series of Nested Case-Control Studies,” BMC Cancer, Vol. 11, No. 1, 2011, p. 409. doi:10.1186/1471-2407-11-409
[9]	B. A. Parker, A. L. Augeri, J. A. Capizzi, K. D. Ballard, C. Troyanos, A. L. Baggish, P. A. D’Hemecourt and P. D. Thompson, “Effect of Statins on Creatine Kinase Levels before and after a Marathon Run,” American Journal of Cardiology, Vol. 109, No. 2, 2012, pp. 282-287. doi:10.1016/j.amjcard.2011.08.045
[10]	G. Fernandez, E. S. Spatz, C. Jablecki and P. S. Phillips, “Statin Myopathy: A Common Dilemma Not Reflected in Clinical Trials,” Cleveland Clinic Journal of Medicine, Vol. 78, No. 6, 2011, pp. 393-403.
[11]	A. B. Fernandez, R. H. Karas, A. A. Alsheikh-Ali and P. D. Thompson, “Statins and Interstitial Lung Disease. A Systematic Review of the Literature and of Food and Drug Administration Adverse Event Reports,” Chest, Vol. 134, No. 4, 2008, pp. 824-830. doi:10.1378/chest.08-0943
[12]	R. Sukhija, S. Prayaga, M. Marashdeh, Z. Bursac, P. Kakar, D. Bansal, R. Sachdeva, S. H. Kesan and J. L. Mehta, “Effect of Statins on Fasting Plasma Glucose in Diabetic and Nondiabetic Patients,” Journal of Investigative Medicine, Vol. 57, No. 3, 2009, pp. 495-499.
[13]	“Jupiter Subanalysis Rosuvastatin for Cardiovascular Prevention: Too Many Uncertainties,” Prescrire International, Vol. 18, No. 102, 2009, p. 176.
[14]	S. Ahmed, C. P. Cannon, S. A. Murohy and E. Braunwald, “Acute Coronary Syndromes and Diabetes: Is Intensive Lipid Lowering Beneficial? Results of the PROVE IT-TIMI 22 Trial,” European Heart Journal, Vol. 27, No. 19, 2006, pp. 2323-2329. doi:10.1093/eurheartj/ehl220
[15]	S. Huptas, H. C. Geiss, C. Otto and K. G. Parhofer, “Effect of Atorvastatin (10 mg/day) on Glucose Metabolism in Patients with the Metabolic Syndrome,” American Journal of Cardiology, Vol. 98, No. 1, 2006, pp. 66-69. doi:10.1016/j.amjcard.2006.01.055
[16]	A. L. Culver, I. S. Ockene, R. Balasubramanian, B. C. Olendzki, D. M. Sepavich, J. Wactawski-Wende, J. E. Manson, Y. Qiao, S. Liu, P. A. Merriam, C. Rahilly-Tierny, F. Thomas, J. S. Berger, J. K. Ockene, J. D. Curb and Y. Ma, “Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women’s Health Initiative,” Archives of Internal Medicine, Vol. 172, No. 2, 2012, pp. 144-152. doi:10.1001/archinternmed.2011.625
[17]	M. de Lorgeril, P. Salen, J. Abramson, S. Dodin, T. Hamazaki, W. Kostucki, H. Okuyama, B. Pavy and M. Rabeaus, “Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy: A Critical Reappraisal,” Archives of Internal Medicine, Vol. 170, No. 12, 2010, pp. 1032-1036. doi:10.1001/archinternmed.2010.184
[18]	N. Sattar, D. Preiss, H. M. Murray, P. Welsh, B. M. Buckley, A. J. de Craen, S. R. Seshasai, J. J. McMurray, D. J. Freeman, J. W. Jukema, P. W. Macfarlane, C. J. Packard, D. J. Stott, R. G. Westendorp, J. Shepherd, B. R. Davis, S. L. Pressel, R. Marchioli, R. M. Marfisi, A. P. Maggioni, L. Tavazzi, G. Tognoni, J. Kjekshus, T. R. Pedersen, T. J. Cook, A. M. Gotto, M. B. Clearfield, J. R. Downs, H. Nakamura, Y. Ohashi, K. Mizuno, K. K. Ray and I. Ford, “Statins and Risk of Incident Diabetes: A Collaborative Meta-Analysis of Randomised Statin Trials,” Lancet, Vol. 375, No. 9716, 2010, pp. 735-742.
[19]	D. Preiss, S. R. Seshasai, P. Welsh, S. A. Murphy, J. E. Ho, D. D. Waters, D. A. DeMicco, P. Barter, C. P. Cannon, M. S. Sabatine, E. Braunwald, J. J. Kastelein, J. A. de Lemos, M. A. Blazing, T. R. Pedersen, M. J. Tikkanen, N. Sattar and K. K. Ray, “Risk of Incident Diabetes with Intensive-Dose Compared With Moderate-Dose Statin Therapy: A Meta-Analysis,” Journal of the American Medical Association, Vol. 305, No. 24, 2011, pp. 2556-2564.
[20]	K. K. Koh, I. Sakuma and M. J. Quon, “Differential Metabolic Effects of Distinct Statins,” Atherosclerosis, Vol. 2015, No. 1, 2011, pp. 1-8.
[21]	M. B. Westover, M. T. Bianchi, M. H. Eckman and S. M. Greenberg, “Statin Use Following Intracerebral Hemorrhage: A Decision Analysis,” Archives of Neurology, Vol. 68, No. 5, 2011, pp. 573-579.
[22]	P. Amarenco, O. Benavente, L. B. Goldstein, A. Callahan 3rd, H. Sillesen, M. G. Hennerici, S. Gilbert, A. E. Rudolph, L. Simunovic, J. A. Zivin and K. M. Welch, “Stroke Prevention by Aggressive Reduction in Cholesterol Levels Investigators. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SP-ARCL) Trial by Stroke Subtypes,” Stroke, Vol. 40, No. 4, 2009, pp. 1405-1409.
[23]	K. K. Ray, S. R. Seshasai, S. Erqou, P. Sever, J. W. Jukema, I. Ford and N. Sattar, “Statins and All-Cause Mortality in High-Risk Primary Prevention: A Meta-Analysis of 11 Randomized Controlled Trials Involving 65,229 Participants,” Archives of Internal Medicine, Vol. 170, No. 12, 2010, pp. 1024-1031. doi:10.1001/archinternmed.2010.182
[24]	X. Huang, H. Chen, W. C. Miller, R. B. Mailman, J. L. Woodard, P. C. Chen, D. Xiang, R. W. Murrow, Y. Z. Wang and C. Poole, “Lower Low-Density Lipoprotein Cholesterol Levels Are Associated with Parkinson’s Disease,” Movement Disorders, Vol. 22, No. 3, 2007, pp. 377-381
[25]	C. W. Shults, D. Oakes, K. Kieburtz, M. F. Beal, R. Haas, S. Plumb, J. L. Juncos, J. Nutt, I. Shoulson, J. Carter, K. Kompoliti, J. S. Perlmutter, S. Reich, M. Stern, R. L. Watts, R. Kurlan, E. Molho, M. Harrison, M. Lew and Parkinson Study Group, “Effects of Coenzyme Q10 in Early Parkinson Disease: Evidence of Slowing of the Functional Decline,” Archives of Neurology, Vol. 59, No. 10, 2002, pp. 1541-1550.
[26]	A. Lieberman, K. Lyons, J. Levine and R. Myerburg, “Statins, Cholesterol, Co-Enzyme Q10, and Parkinson’s Disease,” Parkinsonism & Related Disorders, Vol. 11, No. 2, 2005, pp. 81-84.
[27]	L. Mascetelli, F. Pezzetta and M. R. Goldstein, “Why Statin Therapy May Increase the Risk of Posttransplantation Squamous Cell Carcinoma,” Transplant Immunology, Vol. 23, No. 4, 2010, pp. 224-225. doi:10.1016/j.trim.2010.06.001
[28]	J. Kuoppala, A. Lamminpaa and E. Pukkala, “Statins and Cancer: A Systematic Review and Meta-Analysis,” European Journal of Cancer, Vol. 44, No. 15, 2008, pp. 2122-2132. doi:10.1016/j.ejca.2008.06.025
[29]	H. Rosenberg and D. Allard, “Evidence for Caution: Women and Statin Use Women and Health Protection,” Canadian Government White Paper, June 2007.
[30]	P. S. Sever, C. L. Chang, A. K. Gupta, A. Whitehouse, N. R. Poulter and ASCOT Investigators, “The Anglo-Scandinavian Cardiac Outcomes Trial: 11-Year Mortality Follow-Up of the Lipid-Lowering Arm in the UK,” European Heart Journal, Vol. 32, No. 20, 2011, pp. 2525-2532.
[31]	C. M. Machan, P. K. Hrynchak and E. L. Irving, “Age-Related Cataract Is Associated with Type 2 Diabetes and Statin Use,” Optometry & Vision Science, Vol. 89, No. 8, 2012, pp. 1165-1171. doi:10.1097/OPX.0b013e3182644cd1
[32]	R. Nakazato, H. Gransar, D. S. Berman, V. Y. Cheng, F. Y. Lin, S. Achenbach, M. Al-Mallah, M. J. Budoff, F. Cademartiri, T. Q. Callister, H. J. Chang, R. C. Cury, K. Chinnaiyan, B. J. W. Chow, A. Delago, M. Hadamitzky, J. Hausleiter, P. Kaufmann, E. Maffei, G. Raff, L. J. Shaw, T. C. Villines, A. Dunning, G. Feuchtner, Y. J. Kim, J. Leipsic and J. K. Mina, “Statins Use and Coronary Artery Plaque Composition: Results from the International Multicenter Confirm Registry,” Atherosclerosis, Vol. 225, No. 1, 2012, pp. 148-153.
[33]	P. Raggi, M. Davidson, T. Q. Callister, et al., “Aggressive versus Moderate Lipid-Lowering Therapy in Hypercholesterolemic Postmenopausal Women: Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES),” Circulation, Vol. 112, 2005, pp. 563-571. doi:10.1161/CIRCULATIONAHA.104.512681
[34]	A. Schmermund, S. Achenbach, T. Budde, et al., “Effect of Intensive versus Standard Lipid-Lowering Treatment with Atorvastatin on the Progression of Calcified Coronary Atherosclerosis over 12 Months: A Multicenter, Randomized, Double-Blind Trial,” Circulation, Vol. 113, 2006, pp. 427-437. doi:10.1161/CIRCULATIONAHA.105.568147
[35]	R. Saremi, P. D. Reaven and G. Bahn, “For the VADT Investigators. Progression of Vascular Calcification Is Increased with Statin Use in the Veterans Affairs Diabetes Trial (VADT),” Diabetes Care, Vol. 35, No. 11, 2012, pp. 2390-2392. doi:10.2337/dc12-0464
[36]	J. W. McEvoy, M. J. Blaha, A. P. Defilippis, et al., “Coronary Artery Calcium Progression: An Important Clinical Measurement? A Review of Published Reports,” Journal of the American College of Cardiology, Vol. 56, No. 20, 2010, pp. 1613-1622. doi:10.1016/j.jacc.2010.06.038
[37]	J. G. Terry, J. J. Carr, E. O. Kouba, et al., “Effect of Simvastatin (80 mg) on Coronary and Abdominal Aortic Arterial Calcium (From the Coronary Artery Calcification Treatment with Zocor [CATZ] Study),” American Journal of Cardiology, Vol. 99, No. 12, 2007, pp. 1714-1717. doi:10.1016/j.amjcard.2007.01.060
[38]	D. Lee and A. Goldberg, “Atrogin1/MAFbx: What Atrophy, Hypertrophy, and Cardiac Failure Have in Common,” Circulation Research, Vol. 109, No. 2, 2011, pp. 123-126.
[39]	P. J. Barter, M. Caulfield, M. Eriksson, S. M. Grundy, J. J. P. Kastelein, M. Komajda, J. Lopez-Sendon, L. Mosca, J. C. Tardif, D. D. Waters, C. L. Shear, J. H. Revkin, K. A. Buhr, M. R. Fisher, A. R. Tall and B. Brewer, “For the Illuminate Investigators. Effects of Torcetrapib in Patients at High Risk for Coronary Events,” The New England Journal of Medicine, Vol. 357, 2007, No. 21, pp. 2109-2122.