Statin—Fibrate Combination Therapy

Shek, Allen; Ferrill, Mary J.

doi:10.1345/aph.10315

Cited by 250 publications

(137 citation statements)

References 85 publications

(93 reference statements)

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“…Desde a época em que o clofibrato era o único medicamento disponível desse grupo, sabe-se que os fibratos aumentam o conteúdo de colesterol da bile, levando à maior litogenicidade. 8 Tem sido verificado na prática, que a associação das estatinas com os fibratos, aumenta a chance de hepatotoxicidade para 3,2%. 9 …”

Section: Hepatotoxicidade Com Fibratosunclassified

Mecanismos de hepatotoxicidade

Bertolami¹

2005

Arq. Bras. Cardiol.

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Section: Hepatotoxicidade Com Fibratosunclassified

Mecanismos de hepatotoxicidade

Bertolami¹

2005

Arq. Bras. Cardiol.

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“…Synergistic Effect of Fibrates and Statins on the Induction of PDK4 mRNA Since it is known that the risk of rhabdomyolysis increases with combination therapy using fibrate and statin, 5,6) we next examined the effect of bezafibrate together with a statin, pravastatin or simvastatin, on the expression of PDK4 mRNA in the liver and muscles of mice. A higher dose of bezafibrate (2%) gave a result similar to that with a lower dose (0.3%) on the expression levels of PDK4 Table 1) of the drug indicated for 24 h. The drugs used were; Pra, pravastatin; Sim, simvastatin; Ofl, ofloxacin; Bez, bezafibrate from Bezatol; Nor, norfloxacin; Lev, levofloxacin; bez, bezafibrate of reagent grade.…”

Section: Inefficient Induction Of Pdk4 Mrna By Statins and New Quinolmentioning

confidence: 99%

“…Though synergistic clinical benefits of combination therapy with fibrates and statins have been reported, [1][2][3][4] the problem of these drugs especially in combination therapy is the risk of rhabdomyolysis. 5,6) The biochemical basis for the primary fibrate and/or statin-induced rhabdomyosysis is not well understood. 7,8) We previously reported that fibrates rapidly induce pyruvate dehydrogenase kinase 4 (PDK4) mRNA in various tissues of mice.…”

mentioning

confidence: 99%

Fibrates and Statins Rapidly and Synergistically Induce Pyruvate Dehydrogenase Kinase 4 mRNA in the Liver and Muscles of Mice

Motojima

Seto

2003

Biological & Pharmaceutical Bulletin

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Fibrates and statins have been widely used in clinical practice to reduce triglyceride and cholesterol levels, respectively. These drugs are becoming more beneficial in modern society where the patients of high fat diet-associated common diseases are increasing. Though synergistic clinical benefits of combination therapy with fibrates and statins have been reported, [1][2][3][4] the problem of these drugs especially in combination therapy is the risk of rhabdomyolysis. 5,6) The biochemical basis for the primary fibrate and/or statin-induced rhabdomyosysis is not well understood. 7,8) We previously reported that fibrates rapidly induce pyruvate dehydrogenase kinase 4 (PDK4) mRNA in various tissues of mice. 9) Among the tissues examined, the induction of the mRNA in the skeletal muscle was marked. PDK phosphorylates and inactivates pyruvate dehydrogenase complex that catalyzes irreversible decarboxylation of pyruvate to acetyl-CoA. Inactivation of the complex limits oxidation of glucose and three-carbon compounds to maintain blood glucose levels and promotes fatty acid oxidation. Rapid, efficient and general induction of the mRNA by fibrates at the whole body level suggested a metabolic switching hypothesis for the first step in the hypolipidemic effects of fibrates. 9) That is, fibrates rapidly induce transcriptional activation of the PDK4 gene in various tissues, and this is the first step in the action of these agents. Inactivation of pyruvate dehydrogenase by the induced PDK is followed by metabolic switching to limit oxidative fuel to fatty acids apparently similar to the starved condition, although fibrates decrease the serum level of fatty acids in contrast to the state of starvation where the level increases. Enhanced fatty acid utilization is further accelerated by the induction of enzymes involved in fatty acid utilization and repression of apoCIII.10) The model predicts that the muscle will be forced to use amino acids from proteins as an energy source if the metabolic switching and fibrate-induced decreased availability of triglycerides and fatty acids last long. Extensive protein degradation will damage the muscle if the situation is stringent, leading to acute myopathy or rhabdomyolysis. 9)In this study, we tested the hypothesis that induction of PDK4 to limit the oxidation fuel to fatty acid is a potential cause of muscle damage if the availability of fatty acids is limited by hypolipidemic drugs by examining whether the drugs with the risk of rhabdomyolysis, each alone or in combination, further induce PDK4 mRNA in mouse tissues and cultured cells. MATERALS AND METHODS MaterialsWy14,643 (4-chloro-6-(2,3-xylidino)2-pyrimidinyl-thio)acetic acid), clofibrate (2-(p-chlorophenoxy)isobutyric acid ethyl ester), DEHA (di(2-ethylhexyl)adipate), and DEHP (di(2-ethylhexyl)phthalate) were purchased from Tokyo-Kasei (Tokyo, Japan) and bezafibrate was from Sigma (St. Louis, U.S.A.). Troglitazone was from Sankyo (Tokyo, Japan). KOD polymerase and restriction enzymes were obtained from Toyobo (Osaka, Japan). [a-32...

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“…However, concomitant use of a fibrate and a statin has been associated with an increased risk of myopathy. It appears that this risk may differ depending on which statin and fibrate are administered [24,25]. In the present study, we used the combination of bezafibrate (200 mg/day) and rosuvastatin (2.5 mg/day), and showed that administration of the two drugs at these dosages was both effective and safe.…”

Section: Discussionmentioning

confidence: 69%

Combination Lipid Therapy on Lipid Profiles in Patients with Impaired Glucose Tolerance

Kawano¹,

Nagayoshi²,

Ogawa³

et al. 2013

IJCM

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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.

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Statin—Fibrate Combination Therapy

Cited by 250 publications

References 85 publications

Mecanismos de hepatotoxicidade

Mecanismos de hepatotoxicidade

Fibrates and Statins Rapidly and Synergistically Induce Pyruvate Dehydrogenase Kinase 4 mRNA in the Liver and Muscles of Mice

Combination Lipid Therapy on Lipid Profiles in Patients with Impaired Glucose Tolerance

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