Reduction In LDL-cholesterol Concentrations Research Articles

New Clinical Perspectives of Hypolipidemic Drug Therapy in Severe Hypercholesterolemia

Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated Low-Density Lipoprotein Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or even non responsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA-reductase) inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (The National Cholesterol Education Program (NCEP) ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL - prior Coronary Heart Disease (CHD) or CHD equivalent - or ≥ 250 mg/dL (no prior CHD or CHD risk-equivalent). The only current therapy option for these patients is Low Density Lipoprotein-apheresis (LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the Low-Density Lipoprotein receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B (ApoB) synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HoFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C and triglycerides (TG). Lomitapide is currently being developed for patients with HoFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe, genetically determined dyslipidemias, are reviewed.

Pharmacological strategies for lowering LDL cholesterol: statins and beyond

A continuous, graded relationship exists between LDL cholesterol (LDL-C) levels and risk of cardiovascular disease (CVD). This finding has been confirmed at progressively lower levels of LDL-C by results from clinical trials of therapies, particularly high-potency statins, which provide increasingly greater reductions in LDL-C levels. On the basis of this clinical trial evidence, progressively lower LDL-C goals for increasing numbers of patients, stratified by absolute CVD risk, have been recommended in guidelines for cholesterol management and CVD prevention. Some notable exceptions have been made, however, such as patients with end-stage renal disease or heart failure. To achieve low LDL-C goals, statins are first-line pharmacological therapy and can be combined with other agents to provide additional reductions in LDL-C levels as well as improvements in other lipoprotein fractions. Investigational agents that reduce LDL-C levels by other mechanisms are under development and could provide additional therapeutic strategies to achieve optimal LDL-C levels. These agents could be particularly appropriate for patients with severely elevated LDL-C levels, such as those with genetic dyslipidemia, for whom maximal drug therapy is insufficient to reduce LDL-C concentrations to recommended levels.

β-glucan from barley and its lipid-lowering capacity: a meta-analysis of randomized, controlled trials

To more precisely quantify the effect of barley β-glucan on blood lipid concentrations in humans and to examine the factors that could affect its efficacy. Eleven eligible randomized clinical trials published from 1989 to 2008 were identified from nine databases. Weighted mean effect sizes were calculated for net differences in lipid profile using a random effect model (RevMan 4.2). Overall, barley and β-glucan isolated from barley lowered total and low-density lipoprotein (LDL) cholesterol concentrations by 0.30 mmol/l (95% confidence interval (CI): -0.39 to -0.21, P<0.00001) and 0.27 mmol/l (95% CI: -0.34 to -0.20, P<0.00001), respectively, compared with control. The pattern of cholesterol-lowering action of barley in this analysis could not be viewed as a dose-dependent response. There were no significant subgroup differences by type of intervention and food matrix. Increased consumption of barely products should be considered as a dietary approach to reduce LDL cholesterol concentrations.

Scientific Opinion on the substantiation of a health claim related to soy protein and reduction of blood cholesterol concentrations pursuant to Article 14 of the Regulation (EC) No 1924/2006

Following an application from HarlandHall Ltd. on behalf of the Soya Protein Association (SPA), the European Vegetable Protein Federation (EUVEPRO), and the European Natural Soyfood Manufacturers Association (ENSA) submitted pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of United Kingdom, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver a scientific opinion on soy protein and reduction of blood cholesterol concentrations. The scope of the application was proposed to fall under a health claim referring to reduction of a disease risk. The food constituent that is the subject of the health claim is soy protein, i.e. the protein component of the soybean Glycine max. The Panel considers that soy protein is sufficiently characterised. The claimed effect is “reduces blood cholesterol and may therefore reduce the risk of (coronary) heart disease”. The target population is healthy adults. The Panel considers that lowering LDL-cholesterol is a beneficial physiological effect by reducing the risk of coronary heart disease. In weighing the evidence, the Panel took into account that the results from the four human intervention studies identified by the applicant as being controlled for the macronutrient composition of the test products do not support an effect of the protein component of soy on LDL-cholesterol concentrations, and that the proposed mechanism by which the protein component of soy would exert the claimed effect is not supported by available scientific evidence. The Panel concludes that a cause and effect relationship has not been established between the consumption of soy protein and the reduction of LDL-cholesterol concentrations. © European Food Safety Authority, 2010

Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial

Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs >/=50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11.4 mmol/L (SD 3.6) in the mipomersen group and 10.4 mmol/L (3.7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24.7%, 95% CI -31.6 to -17.7) than with placebo (-3.3%, -12.1 to 5.5; p=0.0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. ISIS Pharmaceuticals and Genzyme Corporation.

Plasma PCSK9 Is Associated with Age, Sex, and Multiple Metabolic Markers in a Population-Based Sample of Children and Adolescents

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein convertase that posttranslationally promotes the degradation of the low-density lipoprotein receptor (LDLR) in hepatocytes and increases plasma LDL cholesterol (LDL-C). Heterozygote gain-of-function mutations of PCSK9 are associated with the familial hypercholesterolemia phenotype, whereas loss-of-function variants are associated with reduced LDL-C concentrations and lower coronary risk. Plasma PCSK9 correlates with body mass index, triglyceridemia, total cholesterol, and LDL-C in adults, but no data are available in youth. We studied 1739 French Canadian youth ages 9, 13, and 16 years who participated in the Quebec Child and Adolescent Health and Social Survey, a province-wide school-based survey conducted in 1999. An ELISA assay was used to measure plasma PSCK9. The mean (SD) plasma PCSK9 concentration was 84.7 (24.7) microg/L in the sample. In boys, plasma PCSK9 decreased with age, whereas the inverse was true for girls. There were statistically significant positive associations between PCSK9 and fasting glucose, insulin, and HOMA-IR (homeostasis model assessment of insulin resistance). In multivariable analysis, a 10% higher fasting insulin was associated with a 1%-2% higher PCSK9 in both sexes. There were also positive associations between PCSK9 and total cholesterol, LDL-C, and triglycerides, as well as with HDL-C and apolipoproteins A1 and B. PCSK9 is associated with age, sex, and multiple metabolic markers in youth. A novel finding is that PCSK9 is associated with fasting insulinemia, which suggests that PCSK9 could play a role in the development of dyslipidemia associated with the metabolic syndrome. .

Pleiotropic effects of statins

Results of numerous epidemiologic studies indicate that elevated serum cholesterol, especially the LDL fraction, is a major cause of coronary heart disease (CHD). Epidemiologic and angiographic evidence from primary and secondary prevention studies involving several HMG-CoA reductase inhibitors (statins) indicate that decreasing elevated serum cholesterol concentration (specifically LDL-cholesterol) can reduce the incidence of CHD and/or progression of atherosclerosis and results in a decrease in associated morbidity and mortality. It has been estimated that each 1% reduction in LDL-cholesterol concentration may result in a 1% decrease in the incidence of CHD. Furthermore, an analysis of pooled data from primary and secondary prevention studies found that treatment with a statin for a median duration of 5.4 years was associated with a 31% and 21% reduction in the risk of major coronary events and total mortality, respectively. This paper deals with the pharmacology of statins, specially with the pleiotropic effects of these drugs.

Efectos pleiotrópicos de las estatinas

Results of numerous epidemiologic studies indicate that elevated serum cholesterol, especially the LDL fraction, is a major cause of coronary heart disease (CHD). Epidemiologic and angiographic evidence from primary and secondary prevention studies involving several HMG-CoA reductase inhibitors (statins) indicate that decreasing elevated serum cholesterol concentration (specifically LDL-cholesterol) can reduce the incidence of CHD and/or progression of atherosclerosis and results in a decrease in associated morbidity and mortality. It has been estimated that each 1% reduction in LDL-cholesterol concentration may result in a 1% decrease in the incidence of CHD. Furthermore, an analysis of pooled data from primary and secondary prevention studies found that treatment with a statin for a median duration of 5.4 years was associated with a 31% and 21% reduction in the risk of major coronary events and total mortality, respectively. This paper deals with the pharmacology of statins, specially with the pleiotropic effects of these drugs.

Dose-response effects of different plant sterol sources in fat spreads on serum lipids and C-reactive protein and on the kinetic behavior of serum plant sterols

To test the dose-response effect on low-density lipoprotein cholesterol (LDL-c) of plant sterols (PS) from different sources in a low-fat spread. Dose responses of soybean oil (BO), tall oil (TO) and a mix of tall oil and rapeseed oil (TO/RP) as fatty acid esters were tested in a parallel design in free-living subjects recruited from the general community who had elevated cholesterol concentrations. Subjects received either control for 6 weeks or 1.6 g PS per day for 3 weeks, then 3.0 g/day for 3 weeks. LDL-c was lowered significantly by consumption of 1.6 g/day of PS (-10.4%, range -7.3 to -11.4%). Increasing the dose to 3.0 g/day modestly reduced LDL-c concentrations further to -14.7%. TO, containing 78% sitosterol, produced an increase in serum sitosterol of 6.5 nmol/ml, while BO, containing only 27% campesterol, produced an increase in serum campesterol of 9.5 nmol/ml in 6 weeks. After PS withdrawal, serum sterols declined by 50% within 2 weeks. Different PS sources were equally effective in lowering serum LDL-c concentrations. The decrease in absolute concentrations of LDL-c was dependent on the baseline concentrations.

Soy Protein, Isoflavones, and Cardiovascular Health

This editorial summarizes the recent American Heart Association (AHA) Science Advisory on soy protein and isoflavones (phytoestrogens) published in the February 21, 2006, issue of Circulation .1 Soy protein and isoflavones have gained considerable attention for their potential role in improving risk factors for cardiovascular disease. This scientific advisory report assesses the more recent work published on soy protein and its component isoflavones. In 22 randomized trials, isolated soy protein with isoflavones compared with milk or other proteins decreased LDL cholesterol concentrations in most studies; the average effect was approximately 3%. This reduction is very small compared with the large amount of soy protein tested in these studies, averaging 50 g, approximately half the usual total daily protein intake. No significant effects were evident on HDL cholesterol, triglycerides, lipoprotein(a), or blood pressure. Among 19 studies of soy isoflavones, the average effect on LDL cholesterol and other lipid risk factors was nil. Soy protein or isoflavones have not been shown to lessen vasomotor symptoms of menopause, and results are mixed regarding slowing of postmenopausal bone loss. The efficacy and safety of soy isoflavones for preventing or treating cancer of the breast, endometrium, and prostate are not established; evidence from clinical trials is meager and cautionary as regards a possible adverse effect. For this reason, use of isoflavone supplements in food or pills is not recommended. Thus, earlier research indicating that soy protein compared with other proteins has clinically important favorable effects has not enjoyed confirmation. In contrast, many soy products should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat. In October 1999, the US Food and Drug Administration (FDA) approved labeling for foods containing soy protein as protective against coronary heart disease.2 …

Fish Consumption Shifts Lipoprotein Subfractions to a Less Atherogenic Pattern in Humans

The effect of fish consumption on plasma lipoprotein subfraction concentrations was studied in 22 men and women (age > 40 y). Subjects were provided an average American diet (AAD, 35% of energy as fat, 14% as saturated fat, and 35 mg cholesterol/MJ) for 6 wk before being assigned to a National Cholesterol Education Program (NCEP) Step 2 high-fish diet (n = 11, 26% of energy as fat, 4.5% as saturated fat, and 15 mg cholesterol/MJ) or a NCEP Step 2 low-fish diet (n = 11, 26% of energy as fat, 4.0% as saturated fat, and 11 mg cholesterol/MJ) for 24 wk. All food and drink were provided to study participants. Consumption of the high-fish NCEP Step 2 diet was associated with a significant reduction in medium and small VLDL, compared with the AAD diet, whereas the low-fish diet did not affect VLDL subfractions. Both diets significantly reduced LDL cholesterol concentrations, without modifying LDL subfractions. Both diets also lowered HDL cholesterol concentrations. However, the high-fish diet significantly lowered only the HDL fraction containing both apolipoprotein (apo) AI and AII (LpAI:AII) and did not change HDL subfractions assessed by NMR, whereas the low-fish diet significantly lowered the HDL fraction containing only apo AI (LpAI) and the large NMR HDL fractions, resulting in a significant reduction in HDL particle size. Neither diet affected VLDL and LDL particle size. Our data indicate that within the context of a diet restricted in fat and cholesterol, a higher fish content favorably affects VLDL and HDL subspecies.

Plant sterol ester–enriched spread lowers plasma total and LDL cholesterol in children with familial hypercholesterolemia

Naturally occurring plant sterol esters (SEs) favorably affect serum cholesterol concentrations in humans and could aid in the treatment of children with familial hypercholesterolemia (FH). We studied the effect of SE-enriched spread on serum lipids, lipoproteins, carotenoids, fat-soluble vitamins, and physiologic variables in children with FH aged 7-12 y. In a randomized, double-blind crossover study comprising two 8-wk interventions, 38 children with FH consumed 18.2 +/- 1.5 g SE spread/d, corresponding to 1.60 +/- 0.13 g SEs, or a control spread. Blood samples were analyzed at the start and end of each diet period. Plasma LDL-cholesterol concentrations decreased by 10.2% (P = 0.003) during the SE period compared with the control period. Total cholesterol and apolipoprotein B concentrations were reduced by 7.4% (P = 0.007 and P = 0.020, respectively) during the SE period. No changes were observed in HDL cholesterol, triacylglycerol, or apolipoprotein A-I. Serum concentration of lipid-adjusted lycopene decreased by 8.1% (P = 0.015) in the SE period, with no changes in the other carotenoids. Lipid-adjusted retinol and alpha-tocopherol concentrations increased by 15.6% (P < 0.001) and 7.1% (P = 0.027), respectively. There was an increase (16.8%, P = 0.04) in alanine transaminase in the SE period, but this was explained by a significantly lower starting concentration in the SE period than in the control period. The children consumed a recommended American Heart Association Step I diet during both intervention periods. A daily intake of 1.6 g SEs induces an additional reduction in LDL-cholesterol concentrations in children with FH consuming a recommended diet.

A comparison of the effects of 2 doses of soy protein or casein on serum lipids, serum lipoproteins, and plasma total homocysteine in hypercholesterolemic subjects , , ,

Studies have shown that soy protein reduces some atherogenic lipid and lipoprotein concentrations, although lipoprotein(a) concentrations may be increased. The dose response of soy protein has not been established; neither has its effect on plasma total homocysteine. Our objective was to evaluate the effect of 2 doses of soy protein on lipid, lipoprotein, and homocysteine concentrations. Four to 24 wk after being instructed to consume a lipid-lowering diet, 130 men and women with LDL-cholesterol concentrations > or = 4 mmol/L were studied during a parallel group trial in which 4 interventions were assigned randomly. Thirty grams isolated soy protein (ISP) and 10 g cotyledon fiber or 50 g ISP and 16.6 g cotyledon fiber or equivalent doses of casein and cellulose were consumed daily as a beverage for 16 wk. When the 2 groups who consumed ISP were compared with the 2 groups who consumed casein, the differences in the net changes from baseline to week 16 in the concentrations of LDL cholesterol and plasma total homocysteine were -0.26 mmol/L (95% CI: -0.43, -0.09 mmol/L; P = 0.01) and -0.8 micromol/L (-1.4, -0.2 micromol/L; P = 0.005), respectively. The effect of the ISP dose was not significant. There were no significant differences between the 2 ISP and the 2 casein groups in changes in lipoprotein(a), HDL-cholesterol, or triacylglycerol concentrations. Adding 30-50 g soy protein/d to a lipid-lowering diet significantly reduced LDL-cholesterol concentrations without increasing lipoprotein(a) concentrations. Plasma total homocysteine concentrations also decreased, suggesting a novel, possibly antiatherosclerotic effect.

The impact of dietary mono- and poly-unsaturated fatty acids on risk factors for atherosclerosis in humans

The fatty acid composition of the diet has various effects on atherosclerosis risk factors. Dietary saturated fatty acids (SFA) and trans-unsaturated fatty acids increase the low-density lipoprotein (LDL)-/high-density lipoprotein (HDL)-cholesterol ratio in serum, while these fats do not have a significant bearing on serum triglyceride levels. By contrast, dietary monounsaturated fatty acids (MUFA), n-6 polyunsaturated fatty acids (PUFA), and α-linolenic acid (C18:3n-3) similarly reduce LDL cholesterol concentrations, while their influence on serum HDL cholesterol and triglycerides is not appreciable. Dietary long-chain n-3 PUFA slightly increase serum LDL cholesterol concentrations, but are nevertheless considered salubrious with regard to serum lipids due to the distinct triglyceride-lowering effects. MUFA-rich compared to n-6 PUFA-rich diets strongly reduce the in vitro oxidizability of LDL. The available studies on this subject also suggest that n-3 PUFA in the small amounts usually present in the diet are not unduly harmful. These findings are consistent with reports from observational studies: the amount of SFA is positively and the amount of MUFA and n-6 PUFA in the diet is inversely associated with the risk of cardiovascular disease in most epidemiological studies. The available studies have had an impact on current dietary guidelines, which unanimously recommend that most of the dietary fat should be in the form of MUFA, while the amount of SFA and trans fatty acids in the diet should be as low as possible.

A double-blind trial on the effects of atorvastatin on glycemic control in Japanese diabetic patients with hypercholesterolemia

A double-blind, placebo-controlled, parallel-group study was performed to determine whether atorvastatin, a new HMG-CoA reductase inhibitor, could effectively and safely reduce plasma LDL-cholesterol concentrations in Japanese patients with type-2 diabetes without influencing glycemic control. The subjects were patients with hypercholesterolemia (serum cholesterol concentration ≥5.7 mmol/l (220 mg/dl)) and stable glycemic control. The fasting concentrations of hemoglobin A 1C (HbA 1C), fructosamine, and 1,5-anhydroglucitol (1,5-AG) were measured as indices of glycemic control. Plasma lipid concentrations and the safety of the drug were also examined. Forty eligible patients in two groups of 20 each were administered atorvastatin (10 mg/day) or placebo. Neither atorvastatin nor placebo caused a significant change in HbA 1C, fructosamine, or 1,5-AG concentrations. Atorvastatin significantly reduced total cholesterol and LDL-cholesterol concentrations from baseline by 29.7% ( p<0.0001) and 41.6% ( p<0.0001), respectively. The incidence of clinical adverse events and that of abnormal changes in laboratory test values did not differ between the two groups. In this trial, atorvastatin effectively and safely reduced LDL-cholesterol concentrations in diabetic patients with hypercholesterolemia without influencing glycemic control. These findings are clinically important because there are many diabetic patients with hypercholesterolemia and such patients have a high risk of developing arteriosclerotic disease.

Hyperlipidemia: impact of therapy

PERSISTENT hyperlipidemia is a common complication in solid organ transplant recipients. It has been reported in 37% to 45% of renal transplant recipients, 60% to 80% of heart transplant recipients, and 45% of liver transplant recipients. The lipoprotein abnormalities include elevations in total cholesterol, LDL-cholesterol, apolipoprotein B, and triglyceride concentrations. There are also qualitative alterations in the lipoprotein fractions such as increased oxidative LDL and IDL particles and reduced HDL2 fraction. Hyperlipidemia is an established risk factor for cardiovascular events. In renal transplant recipients, up to 50% of deaths were cardiovascular related. Hyperlipidemia has also been implicated as a risk factor for transplant coronary vasculopathy in cardiac transplant recipients, chronic allograft dysfunction in renal transplant recipients, and the vanishing bile duct syndrome in liver transplant recipients. There are multiple lines of evidence on the role of hyperlipidemia in graft vasculopathy. In rabbit and rat cardiac transplant models, lipogenic diets accelerate coronary vasculopathy, and treatment with a HMG-CoA reductase inhibitor reduced cardiac allograft vasculopathy. Pravastatin has been shown to improve rat survival and decrease the incidence of chronic rejection in a rat orthotopic liver transplant model. Vascular lesions from renal allografts with chronic rejection contain apolipoproteins A-I, A-II, B and oxidized LDL in the vascular intima. Finally, in observational studies Isoniemi et al found that elevated total cholesterol, LDL-cholesterol, and triglyceride levels correlated with renal allograft dysfunction. Dimeny et al found that pretransplant cholesterol levels predicted late graft failure. Although there is no direct evidence confirming the benefits of treating hyperlipidemia in transplant patients, compelling evidence from studies involving the general population suggests that hyperlipidemia in transplant patients should be managed similarly. Effective lipid-lowering treatment may also promote allograft survival. Mild hyperlipidemia may be corrected with dietary treatment alone such as the American Heart Association Step I diet. HMGCoA reductase inhibitors arc highly effective in lowering LDL-cholesterol levels. The use of lovastatin, pravastatin, simvastatin, and fluvastatin have reduced LDL-cholesterol concentrations by 20% to 40% in heart and kidney transplant recipients. It is now generally accepted that low doses of HMG-CoA reductase inhibitors are safe in patients treated with cyclosporine A. Other lipid-lowering agents have been less well studied. Gemfibrozil has been used for treatment of hypertriglyceridemia in heart transplant patients. Bile acid sequestrants are not well tolerated because of their gastrointestinal side effects. Theoretically, they could interfere with the intestinal absorption of cyclosporine A. Nicotinic acid has been shown to lower the LDL cholesterol and triglyceride concentrations and increase the HDL cholesterol concentration in renal transplant recipients. However, flushing and gastrointestinal side effects are commonly encountered. Finally, omega-3-polyunsaturated fatty acids in fish oil has been shown to lower serum triglyceride concentrations. Experimental models have shown that HMG-CoA reductase inhibitors have effects on different cell lines. They decrease the proliferation of mitogen-stimulated T-lymphocytes and cytotoxic T-lymphocytes. Other effects include diminished B-lymphocyte activation and decreased vascular smooth muscle cell migration and proliferation. The effects of HMG-CoA reductase inhibitors on monocyte chemotaxis, expression of adhesion molecules, and natural killer cell cytotoxicity were reversed by mevalonate. In clinical trials the use of pravastatin in heart transplant recipients significantly increased the 1-year patient survival and decreased the incidence of clinically severe acute rejection episodes. Pravastatin-treated patients also showed less progression of transplant coronary vasculopathy compared to controls. Similar findings were also shown by Wenke et al. The use of simvastatin in heart transplant patients was associated with significantly better long-term survival and a lower incidence of transplant coronary vasculopathy based on intracoronary ultrasound findings. In summary, hyperlipidemia is an important complication in solid organ transplant recipients. Correction of hyperlipidemia may prevent atherosclerotic vasculopathy and may retard the progressing of graft vasculopathy. HMG-CoA reductase inhibitors may also function as immunomodulators and have effects on the effector immunoreactive cells.

The effect of growth hormone replacement therapy for up to 12 months on lipoprotein composition and lipoprotein(a) in growth hormone-deficient adults

The effect of growth hormone replacement therapy in near physiological doses on lipoprotein composition and serum lipoprotein(a) concentrations was investigated in growth hormone-deficient subjects. A randomised, double-blind, placebo-controlled trial of recombinant growth hormone was undertaken for 6 months followed by an open extension for a further 6 months (0.125 IU/kg per week for the first 4 weeks of each 6 month period and thereafter 0.25 IU/kg per week). A total of 18 patients with isolated growth hormone deficiency or hypopituitarism were studied. Lipid concentrations were estimated in lipoprotein fractions and protein concentrations were measured in low density lipoprotein (LDL). Glucose and glycated haemoglobin in blood and insulin, cholesterol, triglyceride, apolipoproteins A-I and B and lipoprotein(a) concentrations were measured in serum. In the placebo-controlled phase fasting blood glucose concentrations increased with growth hormone treatment from 5.0±0.2 to 5.8±0.2 mmol/l ( P=0.02) (mean±S.E.M.), although no significant changes were seen in lipids or lipoproteins. In the group receiving active treatment total serum cholesterol decreased from 6.0±0.4 to 5.2±0.3 mmol/l ( P=0.002) after 6 months, due to reduced LDL cholesterol concentrations. Low density lipoprotein protein concentrations fell (0.8±0.1 versus 0.7±0.1 g/l) ( P=0.005), and LDL phospholipid levels decreased from 0.9±0.1 to 0.7±0.1 mmol/l ( P=0.007). Serum cholesterol and LDL composition reverted to pre-treatment values by 12 months. Fasting blood glucose remained above pre-treatment values ( P=0.036) and fasting insulin was significantly increased ( P=0.044). There was no effect of growth hormone therapy on serum triglyceride, apolipoprotein or lipoprotein(a) concentrations. In conclusion, growth hormone therapy with near physiological doses has no long term effects on serum lipoprotein(a) concentrations or lipoprotein composition.

Treatment of hyperlipidemia in renal transplant recipients.

Treatment of hyperlipidemia in renal transplant recipients.

A psyllium-enriched cereal for the treatment of hypercholesterolemia in children: a controlled, double-blind, crossover study

Psyllium, a water-soluble fiber, has been shown to lower total serum and low-density-lipoprotein (LDL)-cholesterol concentrations in adult hypercholesterolemic subjects and may be effective in the treatment of hypercholesterolemia in children. The effects of a psyllium-enriched cereal were compared with a matched control cereal in a double-blind, crossover fashion in 25 children, 6-18 y old, with hypercholesterolemia. After an 8-wk diet-stabilization period, the subjects were randomly assigned to receive the active or control cereals for 6 wk, followed by a 6-wk washout period and a 6-wk crossover treatment period. Whereas no changes were noted in total and LDL-cholesterol concentrations during consumption of the control cereal, significant changes were seen during the psyllium-cereal periods [0.31 mmol/L (12.1 mg/dL) and 0.28 mmol/L (10.9 mg/dL); P = 0.03 and 0.01, respectively]. The psyllium-enriched cereal was well tolerated throughout the trial. Consumption of the psyllium-enriched cereal resulted in a modest 7% reduction in LDL-cholesterol concentrations compared with the control cereal when used in this pediatric hypercholesterolemic sample. Psyllium offers a potential adjunct to a low-fat diet for the treatment of hypercholesterolemia in the pediatric population because of its ease of incorporation into various foods.

Low density lipoprotein binding to monolayer cultures of hepatocytes isolated from hamsters fed different dietary fatty acids

(i) The aim of these studies was to investigate the effect of dietary cholesterol and dietary fat on the expression of the hepatic low density lipoprotein (LDL) receptor. (ii) Low density lipoprotein (LDL) binding to monolayer cultures of hepatocytes isolated from hamsters fed different amounts of cholesterol and fats was measured. (iii) Hepatocytes isolated from hamsters fed a low cholesterol diet (< 0.008% w/w) specifically bound LDL and this binding increased with time in culture. By comparison, LDL binding to hepatocytes isolated from hamsters fed 0.12% (w/w) cholesterol was lower and there was no time dependent increase. Intermediate levels of binding were seen for hepatocytes from hamsters fed 0.06% (w/w) cholesterol. (iv) In hamsters fed 10% (w/w) fat in the presence of 0.06% (w/w) cholesterol, significantly more LDL receptors were expressed by hepatocytes from animals fed safflower oil compared to those isolated from lard or olive oil fed animals. (v) The reduced LDL cholesterol concentrations frequently observed for hamsters fed polyunsaturated fatty acids thus reflects an increase in the number of LDL receptors expressed in the liver. However, other explanations are needed for the effects of monounsaturated fatty acids.