The Effect of Atorvastatin on Liver Function among Patients with Coronary Heart Disease in Gaza Strip
Affiliation(s)
Department of Pharmacology, Al-Azhar University, Gaza, Palestine. Department of Pharmaceutical Chemistry, Al-Azhar University, Gaza, Palestine. Faculty of Pharmacy, Al-Azhar University, Gaza, Palestine. Faculty of Intermediate Studies, University of Palestine, Gaza, Palestine.
Department of Pharmacology, Al-Azhar University, Gaza, Palestine. Department of Pharmaceutical Chemistry, Al-Azhar University, Gaza, Palestine. Faculty of Pharmacy, Al-Azhar University, Gaza, Palestine. Faculty of Intermediate Studies, University of Palestine, Gaza, Palestine.
ABSTRACT
Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are considered as one of the most important drugs and the drug of choice for reducing an abnormal cholesterol level. Statins are normally used to decrease the risk of coronary heart disease (CHD), but they tend to be associated with liver adverse effects. The objective of this prospective study was to investigate the effect of atorvastatin therapy on the liver function in patients with CHD. Study comprised of 66 newly diagnosed CHD patients who were selected from UNRWA clinics in the Gaza Strip. The patients were clinically examined and treated with atorvastatin (10 - 40 mg/day). A questionnaire was used to collect the data concerning patient’s characteristics. Total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), liver enzymes tests such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and total and direct blood bilirubin were measured before starting treatment and after 3 and 6 months of treatment. The results showed a significant increase in the mean values of ALT, AST, total bilirubin and direct bilirubin levels after 3 months then decreased after the next 3 months, but they were higher than the baseline with insignificant association.
Cite this paper
Taleb, M. , Almasri, I. , Siam, N. , Najim, A. and Ahmed, A. (2014) The Effect of Atorvastatin on Liver Function among Patients with Coronary Heart Disease in Gaza Strip. Pharmacology & Pharmacy, 5, 781-788. doi: 10.4236/pp.2014.58088.
Taleb, M. , Almasri, I. , Siam, N. , Najim, A. and Ahmed, A. (2014) The Effect of Atorvastatin on Liver Function among Patients with Coronary Heart Disease in Gaza Strip. Pharmacology & Pharmacy, 5, 781-788. doi: 10.4236/pp.2014.58088.
References
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http://dx.doi.org/10.1016/j.pharmthera.2009.01.002 [2] Hurst, M. (2008) Hurst Reviews, Pathophysiology Review. 1st Edition, McGraw-Hill, New York, 194-199. [3] Torpy, J., Burke, A. and Glass, R. (2009) Coronary Heart Disease Risk Factors. JAMA, 302, 2388.
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http://dx.doi.org/10.1016/j.cld.2007.06.010 [7] Golomb, B. and Evans, M. (2008) Statin Adverse Effects A Review of the Literature and Evidence for a Mitochondrial Mechanism. American Journal of Cardiovascular Drugs, 8, 373-418.
http://dx.doi.org/10.2165/0129784-200808060-00004 [8] Mckenney, J. (2003) Pharmacologic Characteristics of Statins. Clinical Cardiology, 26, 32-38.
http://dx.doi.org/10.1002/clc.4960261507 [9] Thadani1, U. (2009) Treatment with Statins in High-Risk Patients: Relevance of Time to Titration of Dose and Adverse Outcomes. American Journal of Cardiovascular Drugs, 3, 211-212. [10] Chalasani, N. (2005). Statins and Hepatotoxicity: Focus on Patients with Fatty Liver. Hepatology, 41, 690-695.
http://dx.doi.org/10.1002/hep.20671 [11] Armitage, J. (2007) The Safety of Statins in Clinical Practice. Lancet, 370, 1781-1790.
http://dx.doi.org/10.1016/S0140-6736(07)60716-8 [12] Cohen, D., Anania, F. and Chalasani, N. (2006) An Assessment of Statin Safety by Hepatologists. American Journal of Cardiology, 97, S77-S81.
http://dx.doi.org/10.1016/j.amjcard.2005.12.014 [13] Deeg, R. and Ziegenhorn, J. (1983) Kinetic Enzymatic Method for Automated Determination of Total Cholesterol in Serum. Clinical Chemistry, 29, 1798-1802. [14] Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, without Use of the Preparative Ultracentrifuge. Clinical Chemistry, 18, 499-502. [15] Lopes-Virella, M., Stone, P., Ellis, S. and Colwell, J. (1977) High Density Lipoprotein and Low Density Lipoproteins. Clinical Chemistry, 23, 882. [16] National Cholesterol Education Program (NCEP), Third Report (2002) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation, 106, 3143-3421. [17] Calderon, R.M., Cubeddu, L.X., Goldberg, R.B. and Schiff, E.R. (2010) Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Mayo Clinic Proceedings, 85, 349-356.
http://dx.doi.org/10.4065/mcp.2009.0365 [18] Fraser, A. (2002) Interpretation of Liver Enzyme Tests—A Rapid Guide. Zealand Family Physician Journal, 29, 117-120. [19] Chang, C.Y. and Schiano, T.D. (2007) Review Article: Drug Hepatotoxicity. Alimentary Pharmacology & Therapeutics, 25, 1135-1151.
http://dx.doi.org/10.1111/j.1365-2036.2007.03307.x [20] Al-Jubori, Z. and Mahmood, I. (2007) Comparative Effects of Lovastatin and Simvastatin on Liver Function Tests in Hyperlipdaemic Patients. The Medical Journal of Basrah University, 25, 19-24. [21] Tolman, K. (2002) The Liver and Lovastatin. American Journal of Cardiology, 89, 1374-1380.
http://dx.doi.org/10.1016/S0002-9149(02)02355-X [22] Buse, J. (2003) Statin Treatment in Diabetes Mellitus. Clinical Diabetes, 21, 168-172.
http://dx.doi.org/10.2337/diaclin.21.4.168 [23] Gotto, A.M. (2003) Safety and Statin Therapy: Reconsidering the Risk and Benefits. JAMA Internal Medicine, 163, 657-659.
http://dx.doi.org/10.1001/archinte.163.6.657 [24] Pelli, N., Setti, M., Cella, P., Toncini, C. and Indiveri, F. (2003) Autoimmune Hepatitis Revealed by Atorvastatin. European Journal of Gastroenterology & Hepatology, 15, 921-924. [25] Castro, M., Hermo, J., Baz, A., Luaces, C., Perez, R. and Clofent, J. (2006) Acute Cholestatic Hepatitis after Atorvastatin Reintroduction. Gastroenterología y Hepatología, 29, 21-24. [26] Angulo, P. (2002) Nonalcoholic Fatty Liver Disease. New England Journal of Medicine, 346, 1221-1231.
http://dx.doi.org/10.1056/NEJMra011775 [27] Bernini, F., Poli, A. and Paoletti, R. (2001) Safety of HMG-CoA Reductase Inhibitors: Focus on Atorvastatin. Cardiovascular Drugs and Therapy, 15, 211-218.
http://dx.doi.org/10.1023/A:1011908004965 [28] Wierzbicki, A., Lumb, P., Semra, Y. and Crook, M. (1998) Effect of Atorvastatin on Plasma Fibrinogen. Lancet, 351, 569-570.
http://dx.doi.org/10.1016/S0140-6736(05)78556-1 [29] Wierzbicki, A., Lumb, P. and Chik, G. (2001) Comparison of Therapy with Simvastatin 80 mg and 120 mg in Patients with Familial Hypercholesterolaemia. International Journal of Clinical Practice, 55, 673-675. [30] Wierzbicki, A., Poston, R. and Ferro, A. (2003) The Lipid and Non-Lipid Effects of Statins. Pharmacology & Therapeutics, 99, 95-112.
http://dx.doi.org/10.1016/S0163-7258(03)00055-X [31] Macdonald, J. and Halleck, M. (2004) The Toxicology of HMG-CoA Reductase Inhibitors: Prediction of Human Risk. Toxicologic Pathology, 32, 26-41.
http://dx.doi.org/10.1080/01926230490462057 [32] Minha, S., Golzman, G., Adar, I. and Rapoport, M. (2009) Cholestatic Jaundice Induced by Atorvastatin: A Possible Association with Antimitochondrial Antibodies. Israel Medical Association Journal, 11, 440-441. [33] CDER-PH RMA, AASLD Conference (2000) Clinical White Paper on Drug-Induced Hepatotoxicity. [34] Ahmed, A. and Cudmore, M. (2009) Can the Biology of VEGF and Haem Oxygenases Help Solve Pre-Eclampsia? Molecular and Cellular Mechanisms of Angiogenesis. Biochemical Society Transactions, 37, 1237-1242.
http://dx.doi.org/10.1042/BST0371237 [35] Wassmann, S., Laufs, U., Baumer, A., Muller, K., Ahlbory, K., Linz, W., et al. (2001) HMG-CoA Reductase Inhibitors Improve Endothelial Dysfunction in Normocholesterolemic Hypertension via Reduced Production of Reactive Oxygen Species. Hypertension, 37, 1450-1457.
http://dx.doi.org/10.1161/01.HYP.37.6.1450 [36] Wassmann, S., Laufs, U., Muller, K., Konkol, C., Ahlbory, K., Baumer, A., et al. (2002) Cellular Antioxidant Effects of Atorvastatin in Vitro and in Vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 300-305.
http://dx.doi.org/10.1161/hq0202.104081 [37] Perez-Guerrero, C., De Sotomayor, M., Jimenez, L., Herrera, M. and Marhuenda, E. (2003) Effects of Simvuastatin on Endothelial Function after Chronic Inhibition of Nitric Oxide Synthase by L-NAME. Journal of Cardiovascular Pharmacology, 42, 204-210.
http://dx.doi.org/10.1097/00005344-200308000-00008 [38] Larrey, D. (2002) Epidemiology and Individual Susceptibility to Adverse Drug Reactions Affecting the Liver. Seminars in Liver Disease, 22, 145-155.
http://dx.doi.org/10.1055/s-2002-30101 [39] Sheth, S., Gordon, F. and Chopra, S. (1997) Nonalcoholic Steatohepatitis. Annals of Internal Medicine, 126, 137-145.
http://dx.doi.org/10.7326/0003-4819-126-2-199701150-00008 [40] Kiortsis, D., Nikas, S., Hatzidimou, K., Tsianos, E. and Elisaf, M.S. (2003) Lipid-Lowering Drugs and Serum Liver Enzymes: The Effects of Body Weight and Baseline Enzyme Levels. Fundamental & Clinical Pharmacology, 17, 491-494.
http://dx.doi.org/10.1046/j.1472-8206.2003.00176.x [41] Shepherd, J., Cobb, S., Ford, I., et al. (1995) Fibrates and Statins in the Treatment of Hyperlipidemia: An Appraisal of Their Efficacy and Safety. European Journal of Cardiology, 16, 5-13. [42] Ballantyne, C., Blazing, M., Hunninghake, D., Davidson, M.H., Yuan, Z., DeLucca, P., Ramsey, K.E., Hustad, C.M. and Palmisano, J. (2003) Effect on High-Density Lipoprotein Cholesterol of Maximum Dose Simvastatin and Atorvastatin in Patients with Hypercholesterolemia: Results of the Comparative HDL Efficacy and Safety Study (CHESS). American Heart Journal, 146, 862-869.
http://dx.doi.org/10.1016/S0002-8703(03)00440-X [43] Illingworth, D., Crouse, J., Hunninghake, D., Davidson, M.H., Escobar, I.D., Stalenhoef, A.F., et al. (2001) A Comparison of Simvastatin and Atorvastatin up to Maximal Recommended Doses in a Large Multicenter Randomized Clinical Trial. Current Medical Research and Opinion, 17, 43-50. [44] Shepherd, J., Blauw, G., Murphy, M., Bollen, E.L.E.M., Buckley, B.M., Cobbe, S.M., et al. (2002) Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER): A Randomized Controlled Trial. Lancet, 360, 1623-1630.
http://dx.doi.org/10.1016/S0140-6736(02)11600-X [45] Law, M. and Rudnicka, A. (2006) Statin Safety: A Systematic Review. American Journal of Cardiology, 97, S52-S60.
http://dx.doi.org/10.1016/j.amjcard.2005.12.010 [46] Gladding, P., Pilmore, H. and Edwards, C. (2004) Potentially Fatal Interaction between Diltiazem and Statins. Annals of Internal Medicine, 140, W31. [47] Onusko, E. (2008) Statins and Elevated Liver Tests: What’s the Fuss? Even When Liver Function Tests Are Moderately Elevated, Statins Are Safe for Most Patients. Journal of Family Practice, 57, 449-452.
[1] Ludman, A., Venugopal, V., Yellon, D., et al. (2009) Statins and Cardioprotection—More than Just Lipid Lowering? Pharmacology & Therapeutics, 122, 30-43.
http://dx.doi.org/10.1016/j.pharmthera.2009.01.002 [2] Hurst, M. (2008) Hurst Reviews, Pathophysiology Review. 1st Edition, McGraw-Hill, New York, 194-199. [3] Torpy, J., Burke, A. and Glass, R. (2009) Coronary Heart Disease Risk Factors. JAMA, 302, 2388.
http://dx.doi.org/10.1001/jama.302.21.2388 [4] White, F. and Wang, L. (2006) Statins and Coronary Artery Disease. The Internet Journal of Cardiovascular Research, 3. [5] Kapur, N. and Musunuru, K. (2008) Clinical Efficacy and Safety of Statins in Managing Cardiovascular Risk. Journal of Vascular Health and Risk Management, 2, 341-353. [6] Bhardwaj, S. and Chalasani, N. (2007) Lipid Lowering Agents That Cause Drug-Induced Hepatotoxicity. Clinics in Liver Disease, 11, 597-613.
http://dx.doi.org/10.1016/j.cld.2007.06.010 [7] Golomb, B. and Evans, M. (2008) Statin Adverse Effects A Review of the Literature and Evidence for a Mitochondrial Mechanism. American Journal of Cardiovascular Drugs, 8, 373-418.
http://dx.doi.org/10.2165/0129784-200808060-00004 [8] Mckenney, J. (2003) Pharmacologic Characteristics of Statins. Clinical Cardiology, 26, 32-38.
http://dx.doi.org/10.1002/clc.4960261507 [9] Thadani1, U. (2009) Treatment with Statins in High-Risk Patients: Relevance of Time to Titration of Dose and Adverse Outcomes. American Journal of Cardiovascular Drugs, 3, 211-212. [10] Chalasani, N. (2005). Statins and Hepatotoxicity: Focus on Patients with Fatty Liver. Hepatology, 41, 690-695.
http://dx.doi.org/10.1002/hep.20671 [11] Armitage, J. (2007) The Safety of Statins in Clinical Practice. Lancet, 370, 1781-1790.
http://dx.doi.org/10.1016/S0140-6736(07)60716-8 [12] Cohen, D., Anania, F. and Chalasani, N. (2006) An Assessment of Statin Safety by Hepatologists. American Journal of Cardiology, 97, S77-S81.
http://dx.doi.org/10.1016/j.amjcard.2005.12.014 [13] Deeg, R. and Ziegenhorn, J. (1983) Kinetic Enzymatic Method for Automated Determination of Total Cholesterol in Serum. Clinical Chemistry, 29, 1798-1802. [14] Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, without Use of the Preparative Ultracentrifuge. Clinical Chemistry, 18, 499-502. [15] Lopes-Virella, M., Stone, P., Ellis, S. and Colwell, J. (1977) High Density Lipoprotein and Low Density Lipoproteins. Clinical Chemistry, 23, 882. [16] National Cholesterol Education Program (NCEP), Third Report (2002) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation, 106, 3143-3421. [17] Calderon, R.M., Cubeddu, L.X., Goldberg, R.B. and Schiff, E.R. (2010) Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Mayo Clinic Proceedings, 85, 349-356.
http://dx.doi.org/10.4065/mcp.2009.0365 [18] Fraser, A. (2002) Interpretation of Liver Enzyme Tests—A Rapid Guide. Zealand Family Physician Journal, 29, 117-120. [19] Chang, C.Y. and Schiano, T.D. (2007) Review Article: Drug Hepatotoxicity. Alimentary Pharmacology & Therapeutics, 25, 1135-1151.
http://dx.doi.org/10.1111/j.1365-2036.2007.03307.x [20] Al-Jubori, Z. and Mahmood, I. (2007) Comparative Effects of Lovastatin and Simvastatin on Liver Function Tests in Hyperlipdaemic Patients. The Medical Journal of Basrah University, 25, 19-24. [21] Tolman, K. (2002) The Liver and Lovastatin. American Journal of Cardiology, 89, 1374-1380.
http://dx.doi.org/10.1016/S0002-9149(02)02355-X [22] Buse, J. (2003) Statin Treatment in Diabetes Mellitus. Clinical Diabetes, 21, 168-172.
http://dx.doi.org/10.2337/diaclin.21.4.168 [23] Gotto, A.M. (2003) Safety and Statin Therapy: Reconsidering the Risk and Benefits. JAMA Internal Medicine, 163, 657-659.
http://dx.doi.org/10.1001/archinte.163.6.657 [24] Pelli, N., Setti, M., Cella, P., Toncini, C. and Indiveri, F. (2003) Autoimmune Hepatitis Revealed by Atorvastatin. European Journal of Gastroenterology & Hepatology, 15, 921-924. [25] Castro, M., Hermo, J., Baz, A., Luaces, C., Perez, R. and Clofent, J. (2006) Acute Cholestatic Hepatitis after Atorvastatin Reintroduction. Gastroenterología y Hepatología, 29, 21-24. [26] Angulo, P. (2002) Nonalcoholic Fatty Liver Disease. New England Journal of Medicine, 346, 1221-1231.
http://dx.doi.org/10.1056/NEJMra011775 [27] Bernini, F., Poli, A. and Paoletti, R. (2001) Safety of HMG-CoA Reductase Inhibitors: Focus on Atorvastatin. Cardiovascular Drugs and Therapy, 15, 211-218.
http://dx.doi.org/10.1023/A:1011908004965 [28] Wierzbicki, A., Lumb, P., Semra, Y. and Crook, M. (1998) Effect of Atorvastatin on Plasma Fibrinogen. Lancet, 351, 569-570.
http://dx.doi.org/10.1016/S0140-6736(05)78556-1 [29] Wierzbicki, A., Lumb, P. and Chik, G. (2001) Comparison of Therapy with Simvastatin 80 mg and 120 mg in Patients with Familial Hypercholesterolaemia. International Journal of Clinical Practice, 55, 673-675. [30] Wierzbicki, A., Poston, R. and Ferro, A. (2003) The Lipid and Non-Lipid Effects of Statins. Pharmacology & Therapeutics, 99, 95-112.
http://dx.doi.org/10.1016/S0163-7258(03)00055-X [31] Macdonald, J. and Halleck, M. (2004) The Toxicology of HMG-CoA Reductase Inhibitors: Prediction of Human Risk. Toxicologic Pathology, 32, 26-41.
http://dx.doi.org/10.1080/01926230490462057 [32] Minha, S., Golzman, G., Adar, I. and Rapoport, M. (2009) Cholestatic Jaundice Induced by Atorvastatin: A Possible Association with Antimitochondrial Antibodies. Israel Medical Association Journal, 11, 440-441. [33] CDER-PH RMA, AASLD Conference (2000) Clinical White Paper on Drug-Induced Hepatotoxicity. [34] Ahmed, A. and Cudmore, M. (2009) Can the Biology of VEGF and Haem Oxygenases Help Solve Pre-Eclampsia? Molecular and Cellular Mechanisms of Angiogenesis. Biochemical Society Transactions, 37, 1237-1242.
http://dx.doi.org/10.1042/BST0371237 [35] Wassmann, S., Laufs, U., Baumer, A., Muller, K., Ahlbory, K., Linz, W., et al. (2001) HMG-CoA Reductase Inhibitors Improve Endothelial Dysfunction in Normocholesterolemic Hypertension via Reduced Production of Reactive Oxygen Species. Hypertension, 37, 1450-1457.
http://dx.doi.org/10.1161/01.HYP.37.6.1450 [36] Wassmann, S., Laufs, U., Muller, K., Konkol, C., Ahlbory, K., Baumer, A., et al. (2002) Cellular Antioxidant Effects of Atorvastatin in Vitro and in Vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 300-305.
http://dx.doi.org/10.1161/hq0202.104081 [37] Perez-Guerrero, C., De Sotomayor, M., Jimenez, L., Herrera, M. and Marhuenda, E. (2003) Effects of Simvuastatin on Endothelial Function after Chronic Inhibition of Nitric Oxide Synthase by L-NAME. Journal of Cardiovascular Pharmacology, 42, 204-210.
http://dx.doi.org/10.1097/00005344-200308000-00008 [38] Larrey, D. (2002) Epidemiology and Individual Susceptibility to Adverse Drug Reactions Affecting the Liver. Seminars in Liver Disease, 22, 145-155.
http://dx.doi.org/10.1055/s-2002-30101 [39] Sheth, S., Gordon, F. and Chopra, S. (1997) Nonalcoholic Steatohepatitis. Annals of Internal Medicine, 126, 137-145.
http://dx.doi.org/10.7326/0003-4819-126-2-199701150-00008 [40] Kiortsis, D., Nikas, S., Hatzidimou, K., Tsianos, E. and Elisaf, M.S. (2003) Lipid-Lowering Drugs and Serum Liver Enzymes: The Effects of Body Weight and Baseline Enzyme Levels. Fundamental & Clinical Pharmacology, 17, 491-494.
http://dx.doi.org/10.1046/j.1472-8206.2003.00176.x [41] Shepherd, J., Cobb, S., Ford, I., et al. (1995) Fibrates and Statins in the Treatment of Hyperlipidemia: An Appraisal of Their Efficacy and Safety. European Journal of Cardiology, 16, 5-13. [42] Ballantyne, C., Blazing, M., Hunninghake, D., Davidson, M.H., Yuan, Z., DeLucca, P., Ramsey, K.E., Hustad, C.M. and Palmisano, J. (2003) Effect on High-Density Lipoprotein Cholesterol of Maximum Dose Simvastatin and Atorvastatin in Patients with Hypercholesterolemia: Results of the Comparative HDL Efficacy and Safety Study (CHESS). American Heart Journal, 146, 862-869.
http://dx.doi.org/10.1016/S0002-8703(03)00440-X [43] Illingworth, D., Crouse, J., Hunninghake, D., Davidson, M.H., Escobar, I.D., Stalenhoef, A.F., et al. (2001) A Comparison of Simvastatin and Atorvastatin up to Maximal Recommended Doses in a Large Multicenter Randomized Clinical Trial. Current Medical Research and Opinion, 17, 43-50. [44] Shepherd, J., Blauw, G., Murphy, M., Bollen, E.L.E.M., Buckley, B.M., Cobbe, S.M., et al. (2002) Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER): A Randomized Controlled Trial. Lancet, 360, 1623-1630.
http://dx.doi.org/10.1016/S0140-6736(02)11600-X [45] Law, M. and Rudnicka, A. (2006) Statin Safety: A Systematic Review. American Journal of Cardiology, 97, S52-S60.
http://dx.doi.org/10.1016/j.amjcard.2005.12.010 [46] Gladding, P., Pilmore, H. and Edwards, C. (2004) Potentially Fatal Interaction between Diltiazem and Statins. Annals of Internal Medicine, 140, W31. [47] Onusko, E. (2008) Statins and Elevated Liver Tests: What’s the Fuss? Even When Liver Function Tests Are Moderately Elevated, Statins Are Safe for Most Patients. Journal of Family Practice, 57, 449-452.