Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenofibrate and other fibrate derivatives are commonly used to treat hyperlipidemia. It is not yet clear how they exert their modulatory effects on plasma lipoproteins. To investigate whether these drugs act on the liver to primarily inhibit very low density lipoprotein production, we utilized the highly differentiated human hepatoma cell line, Hep G2. At concentrations greater than 15 micrograms/mL, fenofibrate caused a 30% decrease in secreted apolipoprotein B (apo B) after 4 days of treatment. Pulse-chase studies demonstrated that this was not due to inhibition of apo B synthesis. Triglyceride synthesis by fenofibrate-treated Hep G2 cells was decreased by 30%, and the amount secreted into the medium was reduced by 50%. At a low concentration of drug (5 micrograms/mL), triglyceride secretion was reduced markedly while apo B secretion remained unchanged. Thus, apo B secretion is less sensitive to fenofibrate than the synthesis and secretion of triglyceride, and may be secondary to changes in the latter. Fenofibrate has also been shown to raise plasma high density lipoprotein concentrations. We found that low concentrations of fenofibrate caused a 20-101% increase in secreted apolipoprotein AI (apo AI), and pulse-chase immunoprecipitation studies showed that this was due to an increase in apo AI synthesis. Fenofibrate was compared to clofibrate to investigate whether their relative effects on lipoprotein production in Hep G2 cells were comparable to their relative effects on plasma lipoproteins. Both fibrates decreased the secretion of apo B to the same extent, but only fenofibrate increased apo AI secretion. Fenofibrate was more effective than clofibrate in inhibiting the secretion of lipids by these cells. Thus, the known effects of fenofibrate on plasma lipoproteins can be attributed to its direct modulation of lipoprotein synthesis in the liver cell. Hep G2 cells may thus be useful in testing the relative efficacy of fibric acid derivatives in vitro.
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PMID:Modulation of lipoprotein production in Hep G2 cells by fenofibrate and clofibrate. 131 85

This report describes the response of patients with severe coronary artery disease to a dynamic fat load test and monitors the change induced by fenofibrate therapy. The presence of disease was associated with prolonged and exaggerated hypertriglyceridemia following the meal and with lower basal HDL cholesterol and HDL subfraction masses. A further indicator of risk was the persistence of increased amounts of retinyl palmitate in the plasma of severely affected individuals 24 h after its ingestion with the meal. These observations are consistent with the proposal that the clearance of chylomicrons and their remnants is impaired in coronary atherosclerosis. Fenofibrate reduced alimentary lipemia following the fat load in both normo- and hypercholesterolemic subjects. This was associated with a 10% rise in plasma HDL cholesterol levels. The improvement in chylomicron catabolism probably derived from a 37% increase (P less than 0.001) in lipoprotein lipase activity induced by fenofibrate. Hepatic lipase on the other had was only slightly affected by treatment.
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PMID:Postprandial lipemia, fenofibrate and coronary artery disease. 210 83

The first well-controlled studies of fenofibrate in the United States indicate that the drug is safe and effective for the treatment of type IIa and type IIb hyperlipidemia. Fenofibrate produced a marked reduction in triglyceride (TG) levels (p less than 0.01) as well as a uniform decrease in very-low-density lipoprotein (VLDL) cholesterol levels (p less than 0.01) and a rise in high-density lipoprotein (HDL) cholesterol levels (p less than 0.01) in 227 subjects with both type IIa and IIb hyperlipidemias. Low-density lipoprotein (LDL) cholesterol levels also fell: 20.3% in type IIa and 6% in type IIb subjects. Fenofibrate also affected the structure and composition of some of the major classes of lipoproteins: increases in apolipoproteins (apo) AI and AII and decreases in apo B and apo E were consistent with reductions in TG, VLDL, and LDL and increases in HDL. Tolerance of fenofibrate was excellent, with most side effects being transitory or reversible. Thus, based on the lipid hypothesis of atherosclerosis, therapy with fenofibrate can potentially lead to significant reductions in cardiovascular disease in type IIa and type IIb hyperlipoproteinemia.
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PMID:Review of the effects of fenofibrate on lipoproteins, apoproteins, and bile saturation: US studies. 265 21

Approximately 15% of myocardial infarction survivors less than 60 years of age have a plasma lipid abnormality defined as combined hyperlipidaemia. Patients with this condition are at substantial risk for future cardiovascular events. Combined hyperlipidaemia involves elevations in both plasma triglycerides and low-density lipoprotein (LDL) cholesterol and may share similarities with hyperapolipoproteinaemia, LDL-pattern B and the small LDL-pattern. Treatment is directed at reduction of LDL-cholesterol and plasma triglyceride values. Nicotinic acid and the fibric acid derivatives are useful therapeutic agents. Fenofibrate is a fibric acid derivative that lowers both triglycerides and LDL-cholesterol in combined hyperlipidaemia. In combined hyperlipidaemia, fenofibrate has been shown to reduce significantly plasma triglycerides by approximately 40%, LDL-cholesterol by 6%, and to increase high-density lipoprotein cholesterol by 15%. Apoproteins are favourably altered with increases in apoprotein-A, decreases in apoprotein-E and inconsistent decreases in apoprotein-B. Fenofibrate is well tolerated with primarily dermatological side-effects.
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PMID:A review of combined hyperlipidaemia and its treatment with fenofibrate. 265 34

To investigate the lipoprotein effect of fenofibrate in hypercholesterolemia or combined hyperlipidemia (types II A and II B hyperlipidemias, respectively), 240 patients were recruited and 227 randomized to a double-blind randomized trial lasting 24 weeks and 192 patients continued to participate in an open-label phase for another 24 weeks. A 100-mg dose of fenofibrate or a matching placebo was given three times daily. Fenofibrate side effects in excess of placebo affected 6 percent of fenofibrate users and were confined almost entirely to skin rashes. In 180 hypercholesterolemic patients randomly assigned to receive fenofibrate versus placebo, triglyceride and very low-density lipoprotein cholesterol levels decreased 38 percent, total cholesterol levels decreased 17.5 percent, and low-density lipoprotein cholesterol levels decreased 20.3 percent with fenofibrate treatment. High-density lipoprotein cholesterol levels increased 11.1 percent with a decrease in the low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio of 27 percent. All differences were statistically significant (p less than 0.01). In combined hyperlipidemic (type II B) patients, triglyceride levels decreased by 45 percent, very low-density lipoprotein cholesterol levels decreased 52.7 percent, total cholesterol levels decreased 16 percent, low-density lipoprotein cholesterol levels decreased 6 percent, and high-density lipoprotein levels increased 15.3 percent for a low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio decrease of 13 percent. All differences were again statistically significant (p less than 0.01). In both groups of patients, the onset of the drug effect was generally rapid, with maximal total and low-density lipoprotein cholesterol level lowering achieved within four weeks in hypercholesterolemic patients and maximal triglyceride and cholesterol level lowering in hypertriglyceridemic patients achieved in two weeks. Maximum high-density lipoprotein increases occurred after four weeks in type II A patients and 12 to 16 weeks in type II B patients. Fenofibrate is a well-tolerated drug in the fibric acid series and has putatively beneficial effects on triglyceride, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations in both type II A and type II B hyperlipidemic patients. If the lipid hypothesis of atherosclerosis applies to the lipoprotein changes induced by fenofibrate, reductions in cardiovascular disease risk in both type II A and II B hyperlipidemic patients should result from fenofibrate treatment.
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PMID:Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. 331 54

The study involved 18 patients aged from 17 to 71 years with idiopathic type IIa hypercholesterolaemia and 10 patients aged from 34 to 67 years with type IIb mixed hyperlipidaemia (HLP). During a first period of at least 3 months, the patients were established on a diet adapted to each type of HLP. Fenofibrate in daily doses of 5 mg/kg bodyweight was then added to the dietetic regimen. The effectiveness of the drug was assessed after 6 months and 1 year. In type IIa HLP patients LDL-cholesterol decreased by 29-30%. In type IIb HLP patients there was a decrease of 45-70% in VLDL-cholesterol of 12-15% in LDL-cholesterol and of 38-61% in VLDL-triglycerides. HDL levels measured before treatment were slightly higher than those reported in the literature and were not significantly modified by fenofibrate, except for HDL-triglycerides in type IIa patients after 12 months' treatment. As in all previous studies on lipoprotein fractions, the decrease in VL-DL-cholesterol was not accompanied by an increase in LDL-cholesterol. Fenofibrate was well tolerated, both clinically and biologically. There were no changes in serum bilirubin levels. Alkaline phosphatase levels were significantly reduced but remained within physiological values. A slight increase in mean transaminase levels due to a transient rise in 4 patients was observed after 3 and 65 months' treatment. Routine measurements of these parameters are advised during long-term fenofibrate treatment.
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PMID:[One year fenofibrate treatment of type II primary hyperlipidaemia. Effects on lipoproteins and biological tolerance (author's transl)]. 720 42

The effect of fenofibrate on plasma cholesteryl ester transfer protein (CETP) activity in relation to the quantitative and qualitative features of apoB- and apoA-I-containing lipoprotein subspecies was investigated in nine patients presenting with combined hyperlipidemia. Fenofibrate (200 mg/d for 8 weeks) induced significant reductions in plasma cholesterol (-16%; P < .01), triglyceride (-44%; P < .007), VLDL cholesterol (-52%; P = .01), LDL cholesterol (-14%; P < .001), and apoB (-15%; P < .009) levels and increased HDL cholesterol (19%; P = .0001) and apoA-I (12%; P = .003) levels. An exogenous cholesteryl ester transfer (CET) assay revealed a marked decrease (-26%; P < .002) in total plasma CETP-dependent CET activity after fenofibrate treatment. Concomitant with the pronounced reduction in VLDL levels (37%; P < .005), the rate of CET from HDL to VLDL was significantly reduced by 38% (P = .0001), whereas no modification in the rate of cholesteryl ester exchange between HDL and LDL occurred after fenofibrate therapy. Combined hyperlipidemia is characterized by an asymmetrical LDL profile in which small, dense LDL subspecies (LDL-4 and LDL-5, d = 1.039 to 1.063 g/mL) predominate. Fenofibrate quantitatively normalized the atherogenic LDL profile by reducing levels of dense LDL subspecies (-21%) and by inducing an elevation (26%; P < .05) in LDL subspecies of intermediate density (LDL-3, d = 1.029 to 1.039 g/mL), which possess optimal binding affinity for the cellular LDL receptor. However, no marked qualitative modifications in the chemical composition or size of LDL particles were observed after drug treatment. Interestingly, the HDL cholesterol concentration was increased by fenofibrate therapy, whereas no significant change was detected in total plasma HDL mass. In contrast, the HDL subspecies pattern was modified as the result of an increase in the total mass (11.7%) of HDL2a, HDL3a, and HDL3b (d = 1.091 to 1.156 g/mL) at the expense of reductions in the total mass (-23%) of HDL2b (d = 1.063 to 1.091 g/mL) and HDL3c (d = 1.156 to 1.179 g/mL). Such changes are consistent with a drug-induced reduction in CETP activity. In conclusion, the overall mechanism involved in the fenofibrate-induced modulation of the atherogenic dense LDL profile in combined hyperlipidemia primarily involves reduction in CET from HDL to VLDL together with normalization of the intravascular transformation of VLDL precursors to receptor-active LDLs of intermediate density.
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PMID:Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. 864 Apr 4

In order to investigate the effect of fenofibrate on microcirculation, 16 patients (5 female, 11 male, age 58 +/- 8 years) were studied with the aid of nailfold capillaroscopy before and after treatment with 200 mg fenofibrate per day over six weeks. Fenofibrate resulted in a significant decrease in triglycerides, total and LDL-cholesterol and apolipoprotein B and an increase in apolipoprotein A. As a parameter of an improved microcirculation the time to peak capillary blood cell velocity during postreactive hyperemia (occlusion of the lower arm for 2 minutes, 200 mmHg) decreased markedly from 45 +/- 5 to 16 +/- 3 s, p < 0.0001). Fibrinogen levels were significantly decreased (p < 0.04) in contrast to other parameters with a possible impact on microvascular perfusion (hemoglobin, hematocrit, mean platelet volume, total protein) and to blood pressure and heart rate. These findings suggest that fenofibrate treatment improves microcirculation in patients with hyperlipidemia. This beneficial effect of fenofibrate may arise from two leading mechanisms. One of these might be the decrease in fibrinogen levels reducing plasma viscosity, the other mechanism might be an indirect effect on functional abnormalities of the vascular endothelium arising from hyperlipdidemia. By lowering plasma lipids fenofibrate is likely to restore the impaired formation or efficacy of the endothelium derived relaxing factor (nitric oxide, NO).
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PMID:Fenofibrate improves microcirculation in patients with hyperlipidemia. 951 68

Fenofibrate, a fibric acid derivative, is used as adjunctive therapy with diet for treatment of hyperlipidemia. Side effects include gastrointestinal complaints and, rarely, elevations in liver function tests. According to the drug's package insert, elevations in serum creatinine may occur; although, no postmarketing case reports of fenofibrate-induced elevations in serum creatinine are on file with the manufacturer. Fenofibrate was the probable cause of elevations in serum creatinine concentrations in six patients at our clinic. As the implications of these elevations may be serious, routine serum creatinine monitoring is recommended at baseline and 1-2 months after starting fenofibrate.
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PMID:Fenofibrate-Induced elevation in serum creatinine. 1156 Feb 5

Fenofibrate is a member of the fibrate class of hypolipidemic agents used clinically to treat hypertriglyceridemia and mixed hyperlipidemia. The fibrates were developed primarily on the basis of their cholesterol and triglyceride lowering in rodents. Fibrates have historically been ineffective at lowering triglycerides in experimentally-induced dyslipidemia in nonhuman primate models. The spontaneously obese rhesus monkey is a well-recognized animal model for the study of human obesity and type 2 diabetes, and many of these monkeys exhibit naturally occurring lipid abnormalities, including elevated triglycerides and low HDL cholesterol (HDL-C), similar to patients with type 2 diabetes. To explore whether the obese rhesus model was predictive of the lipid lowering effects of fibrates, we evaluated fenofibrate in six hypertriglyceridemic, hyperinsulinemic, nondiabetic animals in a 20-week, dose-escalating study. The study consisted of a 4-week baseline period, two treatment periods of 10 mg/kg twice daily (b.i.d) for 4 weeks and 30 mg/kg b.i.d. for 8 weeks, and a 4-week washout period. Fenofibrate (30 mg/kg b.i.d) decreased serum triglycerides 55% and LDL-C 27%, whereas HDL-C increased 35%. Apolipoproteins B-100 and C-III levels were also reduced 70% and 29%, respectively. Food intake, body weight, and plasma glucose were not affected throughout the study. Interestingly, plasma insulin levels decreased 40% during the 30 mg/kg treatment period, suggesting improvement in insulin sensitivity. These results support the use of obese rhesus monkey as an excellent animal model for studying the effects of novel hypolipidemic agents, particularly agents that impact serum triglycerides and HDL-C.
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PMID:Effects of fenofibrate on lipid parameters in obese rhesus monkeys. 1159 Feb 9


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