Combination statin–fibrate therapy: safety aspects

Patients with type 2 diabetes or metabolic syndrome remain at high residual risk of cardiovascular events even after intensive statin therapy. While treatment guidelines recommend the addition of a fibrate to statin therapy in this setting, concerns about the potential for myopathy may limit the use of this combination in clinical practice. These concerns are certainly justified for gemfibrozil, which interferes with statin glucuronidation, leading to elevation in statin plasma concentrations and an increased risk of myotoxicity in combination with a range of commonly prescribed statins. However, the available evidence refutes suggestions that this is a class effect for fibrates. Fenofibrate does not adversely influence the metabolism or pharmacokinetics of any of the commonly prescribed statins. This in turn translates to a reduced potential for myotoxicity in combination with a statin. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the efficacy and safety of fenofibrate plus simvastatin combination therapy in type 2 diabetes patients.     

Prediction of cardiovascular risk in people with diabetes.

People with diabetes are at high risk of cardiovascular morbidity and mortality, especially if they have already developed vascular problems. For patients who are apparently free of vascular complications, risk tables are often used to assess the risk of cardiovascular events in the following years, and to decide on treatment with statins or anti-platelet therapy. These risk prediction tables include estimates of traditional cardiovascular risk factors and are based on populations, some of which only contained a very small number of people with diabetes. Multiple problems can be identified with these tables, and many seriously underestimate cardiovascular risk in people with diabetes. Possible ways of addressing this include using risk estimation tools based solely on diabetic populations, adding in additional traditional variables such as triglycerides or left ventricular hypertrophy, including novel cardiovascular risk factors, or intervening at a lower level of estimated risk in people with diabetes compared with non-diabetic subjects. Alternatively, estimates of individual risk could be abandoned and all people with diabetes could be treated with statins and other effective agents.     

Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio

1 Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction.
2 This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio.
3 Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels >6.0  mmol l⁻¹) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects.
4 Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls ( P <0.05 and P <0.001). The difference was not significant between fibrate-treated patients and untreated patients.
5 Ubiquinone serum levels were lower in statin-treated patients (0.75  mg l⁻¹±0.04) than in untreated hypercholesterolaemic patients (0.95  mg l⁻¹±0.09; P <0.05).
6 We conclude that statin therapy can be associated with high blood lactate/pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.     

Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine levels

Elevated plasma concentrations of homocysteine, a sulfur-containing amino acid, are a risk factor for coronary, cerebral and peripheral artery disease. Next to other factors, drugs used for the prevention or treatment of cardiovascular disease may modulate plasma homocysteine levels. Thus, a drug induced homocysteine increase may counteract the desired cardioprotective effect. The aim is to summarize the current knowledge on the effect of two important classes of drugs, lipid-lowering drugs and anti-hypertensive drugs, on homocysteine metabolism. Among the lipid-lowering drugs, especially the fibric acid derivatives, which are used for treatment of hypertriglyceridemia and low HDL-cholesterol, are associated with an increase of homocysteine by 20%-50%. This increase can be reduced, but not totally avoided by the addition of folic acid, vitamin B12 and B6 to fibrates. HMG-CoA reductase inhibitors (statins) do not influence homocysteine concentrations substantially. The effects of nicotinic acid and n3-fatty acids on the homocysteine concentrations are less clear, more studies are necessary to clarify their influence on homocysteine. Antihypertensive drugs have also been studied with respect to homocysteine metabolism. A homocysteine increase has been shown after treatment with hydrochlorothiazide, a lowering was observed after treatment with beta-blockers, but no effect with ACE-inhibitors. The clinical significance of the homocysteine elevation by fibrates and thiazides is not clear. However, individual patients use these drugs for long time, indicating that even moderate increases may be important.     

贝特类调脂药物可减少2型糖尿病患者心血管事件——循证医学的新证据

积极有效的调脂治疗对减少2型糖尿病心血管并发症具有重要意义,为了将最新、最可靠的调脂治疗进展提供给临床医生,本文对贝特类药物在糖尿病性血脂异常中应用的系统评价(Systematic Review,SR)、Meta-分析和大样本随机对照试验(Randomized Controlled Trial,RCT)进行了检索和评价,发现早期系统评价具有相当大的局限性,应及时进行数据更新和重新评价。而几项最新的大规模临床随机对照试验对贝特类药物在减少糖尿病人心血管并发症中可能具有独特的治疗作用进行了重要研究,发现贝特类药物可明显降低糖尿病人和／或具有典型糖尿病性血脂异常的超重病人的心血管事件的发生率。临床医生应根据2型糖尿病脂代谢异常的特点及病人的具体实际进行科学的选择。     

Role of Fibrates and HMG-CoA Reductase Inhibitors in Gallstone Formation

Fibrate derivatives and HMG-CoA reductase inhibitors modify homeostasis of cholesterol. The aim of this study was to assess in an unselected population whether these hypolipidemic drugs are risk factors for cholelithiasis or, conversely, are protective agents. Both sexes, all socioeconomic categories, pregnant women, and cholecystectomized subjects were included. Clinical data collection and gallbladder ultrasonography were both carried out in a double-blind fashion. Fibrate derivatives were predominantly fenofibrate, HMG-CoA reductase inhibitors were simvastatin and pravastatin. On univariate analysis, age (>50 years), sex, and use of fibrates were found to be significantly related to the presence of cholelithiasis. Age, sex, and fibrate treatment remained independently correlated with the presence of gallstones on multivariate analysis. With fibrates, the relative risk for lithiasis was 1.7 (P = 0.04). The HMG-CoA reductase inhibitors were not associated with a protective effect on univariate analysis. Of the lipid-lowering drugs, only fibrate derivatives were found to increase the risk of gallstone formation.     

Visualization and quantitation of peroxisomes using fluorescent nanocrystals: treatment of rats and monkeys with fibrates and detection in the liver.

Peroxisome proliferation in the liver is a well-documented response that occurs in some species upon treatment with hypolipidemic drugs, such as fibrates. Typically, liver peroxisome proliferation has been estimated by direct counting via electron microscopy, as well as by gene expression, enzyme activity, and immunolabeling. We have developed a novel method for the immunofluorescent labeling of peroxisomes, using an antibody to the 70-kDa peroxisomal membrane protein (PMP70) coupled with fluorescent nanocrystals, Quantum Dots. This method is applicable to standard formalin-fixed, paraffin-embedded tissues. Using this technique, a dose-dependent increase in PMP70 labeling was evident in formalin-fixed liver sections from fenofibrate-treated rats. In formalin-fixed liver sections from cynomolgus monkeys given ciprofibrate, quantitative image analysis showed a statistically significant increase in PMP70 labeling compared to control; the increase in hepatic PMP70 protein levels was corroborated by immunoblotting using total liver protein. An increase in hepatic peroxisome number in ciprofibrate-treated monkeys was confirmed by electron microscopy. An advantage of the Quantum Dot/PMP70 method is that a single common protocol can be used to label peroxisomes from several different species, and many of the common problems that arise with immunolabeling, such as fading and low signal strength, are eliminated.