Objective: This study compared the effects of combination statin and fibrate therapy with either statin or fibrate monotherapy on lipid profiles in patients with impaired glucose tolerance (IGT) and a high risk for cardiovascular disease. Methods & Patients: Forty-five patients with IGT and dyslipidemia (men 25, women 20, mean age 61.7 ± 2.4 yrs) were assigned randomly to the 3 treatment groups for a 6-month period. Results: After 6 months of treatment, low density lipoprotein levels decreased in every group, especially the statin and statin + fibrate groups. Triglyceride levels also decreased in all three groups, especially the fibrate and statin + fibrate groups. High density lipoprotein cholesterol and fasting blood glucose levels did not change in any group. The levels of remnant like cholesterol particles decreased in the fibrate and statin + fibrate groups. There was no change during the study in the levels of creatine phosphokinase, lactate dehydrogenase, or creatinine. Conclusion: Combination statin and fibrate therapy results in greater improvement in lipid profiles than monotherapy with either drug. No marked adverse effects were observed with combination therapy during the study .
KeywordsStatinsFibratesDyslipidemia
T. Almdal, H. Scharling, J. S. Jensen and H. Vestergaad, “The Independent Effect of Type 2 Diabetes Mellitus on Ischemic Heart Disease, Stroke, and Death. A Population-Based Study of 13000 Men and Women with 20 Years of Follow-Up,” Archives of Internal Medicine, Vol. 164, No. 13, 2004, pp. 1422-1426. doi:10.1001/archinte.164.13.1422
R. Collins, J. Armitage, S. Parish, P. Sleigh and R. Peto, “MRC/BHF Heart Protection Study of Cholesterol-Lowering with Simvastatin in 5963 People with Diabetes: A Randomized Placebo-Controlled Trial,” Lancet, Vol. 361, No. 9374, 2003, pp. 2005-2016. doi:10.1016/S0140-6736(03)13636-7
H. B. Rubins, S. J. Robins, D. Collins, et al., “Diabetes, Plasma Insulin, and Cardiovascular Disease: Subgroup Analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT),” Archives of Internal Medicine, Vol. 162, No. 22, 2002, pp. 2597-2604. doi:10.1001/archinte.162.22.2597
World Health Organization, “Report of a WHO Study Group. Prevention of Diabetes Mellitus: World Health Org.,” Tech. Rep. Ser., No. 844, Geneva, 1994.
A. Noma, H. Okabe, K. Netsu-Nakayama, Y. Ueno and H. Shinohara, “Improved Method for Simultaneous Determination of Cholesterol in High- and Low-Density Lipoproteins,” Clinical Chemistry, Vol. 25, No. 8, 1979, pp. 1480-1481.
H. Kawano, T. Motoyama, N. Hirai, K. Kugiyama, H. Yasue and H. Ogawa, “Endothelial Dysfunction in Hypercholesterolemia Is Improved by L-Arginine Administration: Possible Role of Oxidative Stress,” Atherosclerosis, Vol. 161, No. 2, 2002, pp. 375-380. doi:10.1016/S0021-9150(01)00671-2
H. Fukushima, K. Kugiyama, S. Sugiyama, O. Honda, S. Koide, S. Nakamura, H. Kawano, H. Soejima, S. Miyamoto, K. Kugiyama, M. Yoshimura, T. Sakamoto and H. Ogawa, “Comparison of Remnant-Like Lipoprotein Particles in Postmenopausal Women with and without Coronary Artery Disease and with Men with Coronary Artery Disease,” American Journal of Cardiology, Vol. 88, No. 12, 2001, pp. 1370-1373. doi:10.1016/S0002-9149(01)02115-4
M. H. Criqui, G. Heiss, R. Cohn, L. D. Cowan, C. M. Suchindran, S. Bangdiwala, et al., “Plasma Triglyceride Level and Mortality from Coronary Heart Disease,” New England Journal of Medicine, Vol. 328, 1993, pp. 1220- 1225. doi:10.1056/NEJM199304293281702
P. Cullen, “Evidence That Triglycerides Are an Independent Coronary Heart Disease Risk Factor,” American Journal of Cardiology, Vol. 86, No. 9, 2000, pp. 943-949. doi:10.1016/S0002-9149(00)01127-9
H. B. Rubins, S. J. Robins, D. Collins, C. L. Fye, J. W. Anderson, M. B. Elam, et al., “Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol,” New England Journal of Medicine, Vol. 341, 1999, pp. 410-418. doi:10.1056/NEJM199908053410604
The BIP Study Group, “Secondary Prevention by Raising HDL Cholesterol and Reducing Triglycerides in Patients with Coronary Artery Disease: The Bezafibrate Infarction Prevention (BIP) Study,” Circulation, Vol. 102, 2000, pp. 21-27. doi:10.1161/01.CIR.102.1.21
K. L. Goa, L. B. Barradell and G. L. Plosker, “Bezafibrate. An Update of Its Pharmacology and Use in the Management of Dyslipidaemia,” Drugs, Vol. 52, No. 5, 1996, pp. 725-753. doi:10.2165/00003495-199652050-00008
K. Sano, T. Nakamura, M. Hirano, Y. Kitta, T. Kobayashi, D. Fujioka, Y. Saito, T. Yano, K. Watanabe, Y. Watanabe, H. Mishina, J. Obata, K. Kawabata and K. Kugiyama, “Comparative Study of Bezafibrate and Pravastatin in Patients with Coronary Artery Disease and High Levels of Remnant Lipoprotein,” Circulation Journal, Vol. 74, No. 8, 2010, pp. 1644-1650.
J. Shepherd, S. M. Cobbe and I. Ford (For the West of Scotland Coronary Prevention Study Group), “Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia,” New England Journal of Medicine, Vol. 333, 1995, pp. 1301-1307. doi:10.1056/NEJM199511163332001
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,” New England Journal of Medicine, Vol. 339, No. 19, 1998, pp. 1349-1357. doi:10.1056/NEJM199811053391902
F. M. Sacks, M. A. Pfeffer and L. A. Moye (For the Cholesterol and Recurrent Events Trial Investigators), “The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels,” New England Journal of Medicine, Vol. 335, 1996, pp. 1001-1009. doi:10.1056/NEJM199610033351401
Scandinavian Simvastatin Survival Study Group, “Randomized Trial of Cholesterol Lowering in 4444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S),” Lancet, Vol. 344, No. 8934, 1994, pp. 1383-1389.
J. R. Downs, M. Clearfield, S. Weis, 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,” Journal of the American Medical Association, Vol. 279, No. 20, 1998, pp. 1615-1622. doi:10.1001/jama.279.20.1615
O. Eliav, D. Schurr, P. Pfister, Y. Friedlander and E. Leitersdorf, “High-Dose Fluvastatin and Bezafibrate Combination Treatment for Heterozygous Familial Hypercholesterolemia,” American Journal of Cardiology, Vol. 76, No. 1, 1995, pp. 76A-79A. doi:10.1016/S0002-9149(05)80023-2
M. Farnier and S. Dejager (The French Fluvastatin Study Group), “Effect of Combined Fluvastatin-Fenofibrate Therapy Compared with Fenofibrate Monotherapy in Severe Primary Hypercholesterolemia,” American Journal of Cardiology, Vol. 85, No. 1, 2000, pp. 53-57. doi:10.1016/S0002-9149(99)00606-2
L. E. Spieker, G. Noll, M. Hannak and T. F. Luscher, “Efficacy and Tolerability of Fluvastatin and Bezafibrate in Patients with Hyperlipidemia and Persistently High Triglyceride Levels,” Journal of Cardiovascular Pharmacology, Vol. 35, No. 3, 2000, pp. 361-365. doi:10.1097/00005344-200003000-00003
E. Leitersdorf, E. N. Muratti, O. Eliav, V. Meiner, S. Eisenberg, E. J. Dann, E. Sehayek, T. K. Peters and Y. Stein, “Efficacy and Safety of a Combination Fluvastatin- Bezafibrate Treatment for Familial Hypercholesterolemia: Comparative Analysis with a Fluvastatin-Cholestyramine Combination,” American Journal of Medicine, Vol. 96, No. 5, 1994, pp. 401-407. doi:10.1016/0002-9343(94)90165-1
P. Pauciullo, C. Borgnino, R. Paoletti, M. Mariani and M. Mancini, “Efficacy and Safety of a Combination of Fluvastatin and Bezafibrate in Patients with Mixed Hyperlipidaemia (FACT Study),” Atherosclerosis, Vol. 150, No. 2, 2000, pp. 429-436. doi:10.1016/S0021-9150(00)00379-8
A. Shek and M. J. Ferrill, “Statin-Fibrate Combination Therapy,” Annals of Pharmacotherapy, Vol. 35, No. 7-8, 2001, pp. 908-917. doi:10.1345/aph.10315
T. Prueksaritanont, C. Tang, Y. Qui, L. Mu, R. Subramanian and J. H. Lin, “Effects of Fibrates on Metabolism of Statins in Human Hepatocytes,” Drug Metabolism and Disposition, Vol. 30, No. 11, 2002, pp. 1280-1287. doi:10.1124/dmd.30.11.1280
N. R. Phillips, D. Waters and R. J. Havel, “Plasma Lipoproteins and Progression of Coronary Artery Disease Evaluated by Angiography and Clinical Events,” Circulation, Vol. 88, 1993, pp. 2762-2770. doi:10.1161/01.CIR.88.6.2762
H. N. Hodis, W. J. Mack, S. P. Azen, P. Alaupovic, J. M. Pogoda, L. LaBree, et al., “Triglyceride- and Cholesterol- Rich Lipoproteins Have a Differential Effect on Mid/ Moderate and Severe Lesion Progression as Assessed by Quantitative Coronary Angiography in a Controlled Trial of Lovastatin,” Circulation, Vol. 90, 1994, pp. 42-49. doi:10.1161/01.CIR.90.1.42
J. R. McNamara, P. K. Shah, K. Nakajima, L. A. Cupples, P. W. Wilson, J. M. Ordovas, et al., “Remnant-Like Particle (RLP) Cholesterol Is an Independent Cardiovascular Disease Risk Factor in Women: Results from the Framingham Heart Study,” Atherosclerosis, Vol. 154, No. 1, 2001, pp. 229-236. doi:10.1016/S0021-9150(00)00484-6
K. Kugiyama, H. Doi, T. Motoyama, H. Soejima, K. Misumi, H. Kawano, et al., “Association of Remnant Lipoprotein Levels with Impairment of Endothelium- Dependent Vasomotor Function in Human Coronary Arteries,” Circulation, Vol. 97, 1998, pp. 2519-2526. doi:10.1161/01.CIR.97.25.2519
K. Kugiyama, H. Doi, K. Takazoe, H. Kawano, H. Soejima, Y. Mizuno, et al., “Remnant Lipoprotein Levels in Fasting Serum Predict Coronary Events in Patients with Coronary Artery Disease,” Circulation, Vol. 99, 1999, pp. 2858-2860. doi:10.1161/01.CIR.99.22.2858
S. M. Grundy, “Hypertriglyceridemia, Atherogenic Dyslipidemia, and the Metabolic Syndrome,” American Journal of Cardiology, Vol. 81, No. 4, 1998, pp. 18B-25B. doi:10.1016/S0002-9149(98)00033-2
T. Nakamura, H. Takano, K. Umetani, K. Kawabata, J. E. Obata, Y. Kitta, et al., “Remnant Lipoproteinemia Is a Risk Factor for Endothelial Vasomotor Dysfunction and Coronary Artery Disease in Metabolic Syndrome,” Atherosclerosis, Vol. 181, No. 2, 2005, pp. 321-327. doi:10.1016/j.atherosclerosis.2005.01.012