Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety

Gavish, Dov; Leibovitz, Eyal; Shapira, I; Rubinstein, Ardon

doi:10.1046/j.1365-2796.2000.00646.x

Cited by 84 publications

(48 citation statements)

References 28 publications

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“…Until now, only two studies addressing this issue have been published. One study (38) combining simvastatin (20 mg/day) and bezafibrate (400 mg/day) had moderate results in terms of TC (Ϫ23%) and LDL cholesterol (Ϫ29%) reduction, although drug combination significantly reduced TG levels by 42% and increased HDL cholesterol by 25%. Of the 148 patients from this study, 2 presented myopathy.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin and Micronized Fenofibrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia

et al. 2002

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FESC 3OBJECTIVE -This study evaluated the effect of a atorvastatin-fenofibrate combination on lipid profile, in comparison to each drug alone, in patients with type 2 diabetes and combined hyperlipidemia (CHL). RESEARCH DESIGN AND METHODS-A total of 120 consecutive patients, who were free of coronary artery disease (CAD) at entry, were studied for a period of 24 weeks. These patients were randomly assigned to atorvastatin (20 mg/day, n ϭ 40), micronized fenofibrate (200 mg/day, n ϭ 40), or a combination of both (atorvastatin 20 mg/day plus fenofibrate 200 mg/day, n ϭ 40). The effect of treatment on LDL cholesterol, triglycerides (TGs), HDL cholesterol, apolipoprotein A-I and B, lipoprotein(a), and plasma fibrinogen (PF) was recorded. Moreover, the percentage of patients that reached the American Diabetes Association treatment goals and the estimated CAD risk status were calculated.RESULTS -No patient was withdrawn from the study because of side effects. The atorvastatin-fenofibrate combination reduced total cholesterol by 37%, LDL cholesterol by 46%, TGs by 50%, and PF by 20%, whereas it increased HDL cholesterol by 22% (P Ͻ 0.0001 for all). These changes were significantly better than those of both monotherapies. Of the patients on drug combination, 97.5% reached the LDL cholesterol treatment goal of Ͻ100 mg/dl, 100% reached the desirable TG levels of Ͻ200 mg/dl, and 60% reached the optimal HDL cholesterol levels of Ͼ45 mg/dl. These rates were significantly higher than those of both monotherapies. Combined treatment reduced the 10-year probability for myocardial infarction from 21.6 to 4.2%.CONCLUSIONS -The atorvastatin-fenofibrate combination has a highly beneficial effect on all lipid parameters and PF in patients with type 2 diabetes and CHL. It improved patients' CAD risk status significantly more than each drug alone. Diabetes Care 25:1198 -1202, 2002C ombined hyperlipidemia (CHL), a highly atherogenic lipid disorder characterized by increased LDL cholesterol, elevated triglycerides (TGs), and low HDL cholesterol, is not rare in patients with type 2 diabetes (1). Moreover, metabolic abnormalities, such as predominance of small dense LDL particles (2) and increased glycation of LDL (3), raise the atherogenic risk in these patients. Glycemic control appears to improve but not normalize these abnormalities (4). Statins or fibrates can be used in this setting. Statins have been shown to reduce atherosclerosis-related morbidity and mortality in patients with diabetes (5,6). On the other hand, fibrates are drugs that can decrease TG concentrations and elevate HDL cholesterol, thus reducing cardiovascular morbidity and mortality (7,8). Recent studies (9,10) showed that statin or fibrate monotherapies can improve the lipid profile in patients with type 2 diabetes and CHL; however, these affect differe n t a s p e c t s o f l i p o p r o t e i n ( L P ) metabolism. Hence, it is difficult to modify the lipid profile of patients with type 2 diabetes and CHL using monotherapy with either a statin or a fibrate, accordi...

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Section: Discussionmentioning

confidence: 99%

Atorvastatin and Micronized Fenofibrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia

et al. 2002

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“…Statins and fibrates. Combination statin and fibrate therapy can significantly benefit dyslipidemia and cardiovascular risk status in T2D patients with combined hyperlipidemia [204][205][206][207]. However, evidence for the effects of combined statin/fibrate therapy on ED in T2D patients is limited.…”

Section: Combination Therapiesmentioning

confidence: 99%

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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■ AbstractType 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

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“…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.…”

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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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Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety

Cited by 84 publications

References 28 publications

Atorvastatin and Micronized Fenofibrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia

Atorvastatin and Micronized Fenofibrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

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

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