Decreased Serum Low-density Lipoprotein Cholesterol Research Articles

Comparison of arterial and interstitial glucose levels in critical state

severe familial hypercholesterolemia (FH) with low-density lipoprotein apheresis (LA), selective inhibition of intestinal cholesterol absorption (ezetimibe) and synthesis (statin). Methods: Patient with resistant hypercholesterolemia (n 11, 5 women, 6 men, age 21-60 y, among them patients with homozygous FH n 3) were treated by diet, statin (simvastatin 40 mg or atorvastatin 40-80 mg daily) and LA. Cell-free plasma has been sampled after centrifugation by Cobe-Spectra. LA was performed using a) cascade filtration (filters Evaflux 4A, Kuraray®, n 4) or b) LDL-immunoadsorption (filters Pockard®, n 7). The effect of combined treatment by ezetimibe (Ezetrol® 10 mg daily) was evaluated after 1, 6 and 12 months. Results: Combined treatment with ezetimibe enabled to reach lower serum LDL-cholesterol after each of LA (1,15 0,89 vs 0,81 0,38 mmol/l). Ezetimibe treatment after 12 months combined by LA and statin significantly decreased serum LDL-cholesterol ( 20,6%). Treatment was effective even in two homozygous FH patiens. Two patients did not respond to ezetimibe therapy. Among them, one FH patient was extra cholesterol synthesizer, and a defective response to ezetimebe is supposed in the other FH individual. Conclusion: A combined treatment with ezetimibe and statin should be used in responding patiens with severe hypercholesterolemia treated by LDL-apheresis. Supported by research projects IGA MH CR NR/8497-3, 1A/8689-4, NR/ 8505-3, NR/9103-4.

Fluvastatin Improves Arterial Stiffness in Patients With Coronary Artery Disease and Hyperlipidemia A 5-Year Follow-up Study

The present study was designed to test the hypothesis that fluvastatin might improve arterial stiffness, as assessed with pulse wave velocity (PWV), in patients with coronary artery disease (CAD) and hyperlipidemia over the long term. Ninety-three patients were randomly assigned to either fluvastatin (group A, n=50) or bezafibrate (group B, n=43) and followed for 5 years. There was no difference in the clinical findings between the 2 groups. In group A, there was a progressive reduction in the brachial-ankle PWV along with a decrease in serum low-density lipoprotein-cholesterol (LDL-C) and C-reactive protein (CRP) by 12 months after fluvastatin, and the improvement was maintained until 5 years after treatment. In group B, despite identical lowering of the serum lipid, PWV was progressively increased. In group A, the percentage change in PWV correlated significantly with that of the serum CRP (r=0.49, p<0.001), but not with that of the serum LDL-C after treatment. The beneficial vascular effects of fluvastatin persisted for a long period in patients with CAD and hyperlipidemia. Its anti-inflammatory action might contribute to the favorable effects on arterial stiffness.

Orlistat for the management of overweight individuals and obesity: a review of potential for the 60-mg, over-the-counter dosage

Orlistat, in the 60-mg over-the-counter dose, was recently approved by the FDA. This lipase inhibitor blocks absorption of ~ 25% of ingested fat and has ~ 85% of the efficacy of the 120-mg dose for weight loss. Over 16 weeks weight loss with diet and orlistat 60 mg averages ~ 5% of initial body weight. The 60-mg dose is better tolerated than the 120-mg dose and the gastrointestinal side effects are minimal when individuals consume < 30% of their energy from fat. In addition to facilitating modest weight loss, orlistat use decreases serum LDL-cholesterol values by ~ 10%. When taken three times daily before meals, orlistat 60 mg modifies lifestyle behavior, encourages lower fat-consumption and sets the stage for other healthy lifestyle changes.

Simultaneous Intake of β-Glucan and Plant Stanol Esters Affects Lipid Metabolism in Slightly Hypercholesterolemic Subjects

Intake of food products rich in water-soluble fiber β-glucan and products enriched with plant stanol esters lower serum cholesterol. Combining 2 functional food ingredients into one food product may achieve additional reductions of serum cholesterol. Our objective was to investigate the effects of a simultaneous intake of β-glucan plus plant stanol esters on lipid metabolism in mildly hypercholesterolemic volunteers. In a randomized, controlled, 3-period crossover study, 40 mildly hypercholesterolemic men and women received muesli in random order twice a day for 4 wk, which provided, in total, 5 g control fiber from wheat (control muesli), 5 g oat β-glucan (β-glucan muesli), or 5 g oat β-glucan plus 1.5 g plant stanols (combination muesli). β-Glucan muesli decreased serum LDL cholesterol by 5.0% compared with control muesli (P = 0.013). Combination muesli reduced LDL cholesterol by 9.6% compared with control muesli (P < 0.001), and by 4.4% compared with β-glucan muesli (P = 0.036). Serum HDL cholesterol and triacylglycerol concentrations did not differ after the 3 treatments. Compared with control muesli, β-glucan muesli increased bile acid synthesis (P = 0.043) and decreased cholesterol absorption (P = 0.011). Addition of plant stanols did not influence bile acid synthesis but decreased cholesterol absorption (P < 0.001) and raised cholesterol synthesis (P = 0.016) compared with control muesli, and the plant stanols decreased cholesterol absorption compared with β-glucan muesli (P = 0.004). The combination muesli decreased serum concentrations of sitostanol compared with control muesli (P = 0.010). Plasma concentrations of lipid-soluble antioxidants did not differ after the 3 treatments. β-Glucan muesli effectively lowered serum LDL cholesterol concentrations. The addition of plant stanol esters to β-glucan-enriched muesli further lowered serum LDL cholesterol, although effects were slightly less than predicted.

Plant sterol or stanol esters retard lesion formation in LDL receptor-deficient mice independent of changes in serum plant sterols

Statins do not always decrease coronary heart disease mortality, which was speculated based on increased serum plant sterols observed during statin treatment. To evaluate plant sterol atherogenicity, we fed low density lipoprotein-receptor deficient (LDLr(+/-)) mice for 35 weeks with Western diets (control) alone or enriched with atorvastatin or atorvastatin plus plant sterols or stanols. Atorvastatin decreased serum cholesterol by 22% and lesion area by 57%. Adding plant sterols or stanols to atorvastatin decreased serum cholesterol by 39% and 41%. Cholesterol-standardized serum plant sterol concentrations increased by 4- to 11-fold during sterol plus atorvastatin treatment versus stanol plus atorvastatin treatment. However, lesion size decreased similarly in the sterol plus atorvastatin (-99% vs. control) and the stanol plus atorvastatin (-98%) groups, with comparable serum cholesterol levels, suggesting that increased plant sterol concentrations are not atherogenic. Our second study confirms this conclusion. Compared with lesions after a 33 week atherogenic period, lesion size further increased in controls (+97%) during 12 more weeks on the diet, whereas 12 weeks with the addition of plant sterols or stanols decreased lesion size (66% and 64%). These findings indicate that in LDLr(+/-) mice 1) increased cholesterol-standardized serum plant sterol concentrations are not atherogenic, 2) adding plant sterols/stanols to atorvastatin further inhibits lesion formation, and 3) plant sterols/stanols inhibit the progression or even induce the regression of existing lesions.

Efficacy and tolerability of ezetimibe 10 mg/day coadministered with statins in patients with primary hypercholesterolemia who do not achieve target LDL-C while on statin monotherapy: A Canadian, multicentre, prospective study – the Ezetrol ® Add-On Study

For patients who have above-target low-density lipoprotein cholesterol (LDL-C) levels while on statin monotherapy, coadministration of a cholesterol absorption inhibitor with the statin may decrease serum LDL-C levels and improve overall lipid profiles. To assess the effectiveness and safety of ezetimibe 10 mg/day coadministered with a statin in patients with primary hypercholesterolemia who have higher than recommended LDL-C levels while on statin monotherapy. A six-week, prospective, multicentre study of eligible patients who had above-target LDL-C levels while on monotherapy with any statin, regardless of dose, for a minimum of four weeks. All patients were treated for six weeks with 10 mg ezetimibe daily coadministered with their current statins. A total of 1141 patients were screened, 953 (83.5%) fulfilled the study inclusion criteria and 837 (87.8%) completed the study. Reasons for withdrawal included: lost to follow-up (50 patients [5.2%]); protocol violations (45 patients [4.7%]); adverse events (19 patients [2.0%]); and withdrawal of consent (two patients [0.2%]). After six weeks of treatment, statistically significant (P = 0.001) mean reductions were observed in LDL-C (30.05%), total cholesterol (20.84%), triglycerides (10.16%), apolipoprotein B (19.84%) and the total cholesterol to high-density lipoprotein cholesterol ratio (19.88%). At six weeks, 674 patients (80.5%) achieved target LDL-C levels. Fifty predominantly mild, nonserious adverse events related to ezetimibe were reported by 32 patients (3.4%). Frequently reported adverse events included constipation (n = 7 [0.7% of patients]), diarrhea (n = 4 [0.4%]) and dizziness (n = 4 [0.4%]). Ezetimibe coadministered with statins is effective in reducing LDL-C in patients who do not attain target LDL-C levels while on statin monotherapy.

Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH). Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH. After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43.7+/-7.8 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period, patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment. The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values. Ambulatory BP decreased after DC (24-hour systolic BP -11.9+/-7.7 mm Hg, P<0.0001; 24-hour diastolic BP -8.5+/-5.0 mm Hg, P<0.0001) but not WC. DC but not WC decreased HOMA-IR (P<0.0001), but it improved QUICKI, ISI, and FMD. DC also decreased serum LDL cholesterol (from 3.4+/-0.5 to 3.0+/-0.6 mmol/L; P<0.05). In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives. These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH.

An ezetimibe–policosanol combination has the potential to be an OTC agent that could dramatically lower LDL cholesterol without side effects

Although many risk factors influence atherogenesis, LDL appears to play a primary role in this process. In prospective epidemiology, coronary risk increases as LDL cholesterol increases, throughout the entire range of concentrations encountered in healthy humans. Coronary risk is minimal in individuals and populations whose serum cholesterol remains quite low throughout life. Thus, practical strategies for achieving large reductions of LDL cholesterol in the general population could have a dramatic impact on coronary mortality rates. Dietary measures have limited potential in this regard; modest restriction of saturated fat has a rather trivial effect on LDL cholesterol, and the very-low-fat quasi-vegan diets that do have a notable effect in this regard currently have little appeal to the majority of the population. With respect to pharmacotherapy, most available hypolipidemic agents with reasonably potent activity entail side effects or compliance difficulties that would render their use too expensive or impractical for population-wide application. However, two agents may have great potential in this regard: policosanol and ezetimibe. The former, a mixture of long-chain alcohols derived from sugar cane wax, has effects on serum lipids comparable to those of statins, and may work by down-regulating expression of HMG-CoA reductase. However, unlike statins, policosanol appears to be devoid of side effects or risks. Ezetimibe is a newly approved drug that is a potent and highly specific inhibitor of an intestinal sterol permease; in daily doses as low as 10 mg, it suppresses intestinal absorption of cholesterol and decreases serum LDL cholesterol by approximately 18%. No side effects have been seen in clinical doses, and the fact that its hypolipidemic activity is additive to that of statins has generated considerable interest. Both policosanol and ezetimibe can be administered once daily. Future studies should determine whether policosanol, like statins, interacts additively with ezetimibe. If so, it may be feasible someday to produce a tablet combining policosanol and ezetimibe that could reduce LDL cholesterol by about 40%, without side effects, and that could be recommended to virtually anyone whose LDL cholesterol levels were not already ideal.

Profiling of hepatic gene expression in rats treated with fibric acid analogs

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal β-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPARα activation, although signaling through other receptors (e.g. PPARγ, RXR) or through non-receptor pathways cannot be excluded.

Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36.

Pitavastatin (NK-104) is a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis. In clinical trials, pitavastatin has been shown to significantly decrease serum LDL cholesterol and triglyceride levels and increase HDL cholesterol. Scavenger receptor-mediated accumulation of oxidized LDL (OxLDL)-derived cholesteryl ester is considered to be a critical step in the development of atherosclerotic foam cell formation. We studied the effect of pitavastatin on CD36 (a class B scavenger receptor) expression by murine macrophages. Treatment of J774 cells and murine peritoneal macrophages with pitavastatin decreased CD36 mRNA expression in a dose-dependent manner. Decreased CD36 mRNA was associated with decreased CD36 cell surface protein expression in human THP-1 cells and human monocyte-derived macrophages. Pitavastatin also reduced the increase in CD36 mRNA, cell surface protein, and binding/uptake of OxLDL induced by peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and/or OxLDL. Pitavastatin did not alter the half-life of CD36 mRNA, which suggests pitavastatin downregulates CD36 expression by reducing CD36 transcription. In addition, pitavastatin significantly decreased PPARgamma mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPARgamma phosphorylation and increased the ratio of phosphorylated PPARgamma to nonphosphorylated PPARgamma. The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPARgamma-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.

Effects of policosanol on borderline to mildly elevated serum total cholesterol levels: a prospective, double-blind, placebo-controlled, parallel-group, comparative study

BackgroundHypercholesterolemia is a major risk factor for coronary heart disease. Clinical studies have shown that lowering elevated serum cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C), is beneficial for patients with borderline to mildly elevated serum total cholesterol (TC) levels (5.0–6.0 mmol/L). Policosanol is a cholesterol-lowering drug made from purified sugar cane wax. The therapeutic range of policosanol is 5 to 20 mg/d. ObjectiveThis study investigated the efficacy and tolerability of policosanol 5 mg/d in patients with borderline to mildly elevated serum TC levels. MethodsThis 14-week, single-center, prospective, double-blind, placebo-controlled, parallel-group, comparative study was conducted in men and women aged 25 to 75 years with a serum TC level ≥4.8 to <6.0 mmol/L. After a 6-week run-in period in which patients were placed on therapeutic lifestyle changes, in particular a cholesterol-lowering diet, patients were randomly assigned to receive policosanol 5-mg tablets or placebo tablets once daily with the evening meal for 8 weeks, and the diet was continued throughout the study. Lipid profile variables, safety indicators, adverse events (AEs), and compliance with study medications were assessed. ResultsOne hundred patients (71 women, 29 men; mean [SD] age, 52 [10] years) entered the study after the dietary run-in period. After 8 weeks of treatment, the mean (SD) serum LDL-C level decreased significantly in the policosanol group (P<0.001 vs baseline and placebo) from 3.57 (0.30) mmol/L to 2.86 (0.41) mmol/L (change, −19.9%). Significantly more patients in the policosanol group (42 patients [84%]) achieved a ≥15% decrease in serum LDL-C than in the placebo group (2 patients [4%]) (P<0.001). Also in the policosanol group, the mean (SD) serum TC level decreased significantly, from 5.20 (0.22) mmol/L to 4.56 (0.44) mmol/L (P<0.001 vs baseline and placebo) (change, −12.3%); the mean (SD) triglyceride (TG) level decreased significantly, from 1.59 (0.57) mmol/L to 1.48 (0.57) mmol/L (P<0.01 vs baseline; P<0.05 vs placebo) (change, −6.9%); and the mean (SD) high-density lipoprotein cholesterol (HDL-C) level increased significantly from 1.05 (0.18) mmol/L to 1.16 (0.21) mmol/L (P<0.001 vs baseline and placebo) (change, +10.5%). The percentage changes were significantly different between the policosanol and placebo groups for serum LDL-C, TC, and HDL-C levels (P<0.001, P<0.001, and P<0.05, respectively), but not for TG. In the placebo group, changes in lipid profile variables from baseline were not significant. Policosanol did not significantly impair any safety indicator and was well tolerated. Three patients (3%) (1 patient [2%] in the policosanol group; 2 patients [4%] in the placebo group) withdrew from the trial, none because of AEs. Two patients (1 patient [2%] each in the policosanol and placebo groups) withdrew from the study because of an unwillingness to return for follow-up; 1 patient (2%) in the placebo group had a change of address and could not be followed up. Overall, 4 patients (4%) (1 patient [2%] in the policosanol group; 3 [6%], placebo) reported AEs; all were mild. Of the patients who received placebo and reported AEs, all 3 (6%) experienced heartburn, and 1 (2%) also experienced dry skin, while the policosanol-treated patient (2%) who reported an AE experienced headache. ConclusionsIn this study of patients with borderline to mildly elevated serum TC levels, based on the criterion that ≥70% of policosanol-treated patients reached the LDL-C goal of a decrease ≥15% from baseline whenever this proportion was different with respect to placebo, 8 weeks of treatment with policosanol 5 mg/d was effective. The decreased LDL-C, TC, and TG levels, increased HDL-C level, and good tolerability found with this treatment support its use in such patients.

Metabolic effects of plant sterols and stanols (Review)

High serum LDL cholesterol concentration is a major risk factor for cardiovascular complications. This risk can be lowered by diet. In this respect foods containing plant sterol or stanol esters can be useful for mildly- and hypercholesteraemic subjects. Plant sterols and stanols, which are structurally related to cholesterol, decrease the incorporation of dietary and biliary cholesterol into micelles. This lowers cholesterol absorption. Furthermore, these components increase ABC-transporter expression, which may also contribute to the decreased cholesterol absorption. Consequently, cholesterol synthesis and LDL receptor activity increase, which ultimately leads to decreased serum LDL cholesterol concentrations. Animal studies have further shown that these dietary components may also lower atherosclerotic lesion development. Plant sterols and stanols also lower plasma lipid-standardized concentrations of the hydrocarbon carotenoids, but not those of the oxygenated cartenoids and tocopherols. Also, vitamin A and D concentrations are not affected. Although absorption of plant sterols and stanols (0.02-3.5%) is low compared to cholesterol (35-70%), small amounts are found in the circulation and may influence other physiological functions. However, there is no consistent evidence that plant sterols or stanols can change the risk of colon or prostate cancer, or immune status. In conclusion, plant sterols and stanols effectively reduce serum LDL cholesterol and atherosclerotic risk. In addition potential effects of plant sterols and stanols on other metabolic processes remain to be elucidated.

Whole grains protect against atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is the most common cause of death in most Western countries. Nutrition factors contribute importantly to this high risk for ASCVD. Favourable alterations in diet can reduce six of the nine major risk factors for ASCVD, i.e. high serum LDL-cholesterol levels, high fasting serum triacylglycerol levels, low HDL-cholesterol levels, hypertension, diabetes and obesity. Wholegrain foods may be one the healthiest choices individuals can make to lower the risk for ASCVD. Epidemiological studies indicate that individuals with higher levels (in the highest quintile) of whole-grain intake have a 29 % lower risk for ASCVD than individuals with lower levels (lowest quintile) of whole-grain intake. It is of interest that neither the highest levels of cereal fibre nor the highest levels of refined cereals provide appreciable protection against ASCVD. Generous intake of whole grains also provides protection from development of diabetes and obesity. Diets rich in wholegrain foods tend to decrease serum LDL-cholesterol and triacylglycerol levels as well as blood pressure while increasing serum HDL-cholesterol levels. Whole-grain intake may also favourably alter antioxidant status, serum homocysteine levels, vascular reactivity and the inflammatory state. Whole-grain components that appear to make major contributions to these protective effects are: dietary fibre; vitamins; minerals; antioxidants; phytosterols; other phytochemicals. Three servings of whole grains daily are recommended to provide these health benefits.

Pharmacological and clinical trial data on a novel phosphate-binding polymer (sevelamer hydrochloride), a medicine for hyperphosphatemia in hemodialysis patients

Hyperphosphatemia is one of the major complications of hemodialysis patients and plays a key role in the pathogenesis of cardiovascular calcification and secondary hyperparathyroidism. Dietary phosphate restriction and removal of phosphate by dialysis are insufficient to control hyperphosphatemia. Therefore, almost all patients undergoing hemodialysis should take oral phosphate binders. Sevelamer hydrochloride (sevelamer) is a novel phosphate-binding polymer that contains neither aluminum nor calcium, and it is not absorbed from the gastrointestinal tract. In rat models with progressive chronic renal insufficiency, in addition to lowering effects on serum levels of phosphorus, calcium x phosphorus product, and parathyroid hormone, dietary treatment of sevelamer can prevent parathyroid hyperplasia, vascular calcification, high turnover bone lesion, and renal functional deterioration. In clinical studies with hemodialysis patients, sevelamer lowers serum phosphorus and calcium x phosphorus product without any incidence of hypercalcemia. Switching calcium-containing phosphate binders to sevelamer can decrease the percentage of hypoparathyroidism and hyperparathyroidism by negative calcium balance and increased dosage of vitamin D, respectively. Sevelamer also decreases serum low-density lipoprotein cholesterol levels by its bile acid-binding capacity. A long-term clinical study has demonstrated that the progression of coronary and aortic calcification in hemodialysis patients is attenuated by sevelamer. Thus, sevelamer offers the promise of impacting cardiac calcification and thereby reducing morbidity and mortality of hemodialysis patients.

Effects of soybean protein and very low dietary cholesterol on serum lipids, biliary lipids, and fecal sterols in humans

Soy-base texturized vegetable protein (TVP; Archer Daniels Midland, Decatur, IL) has been used to decrease serum cholesterol and as a substitute for animal protein to achieve very low levels of dietary cholesterol. The effect of very low dietary cholesterol and of TVP on biliary lipids and fecal sterols is unclear. The study objective was to determine the effects of very low intake of dietary cholesterol, as well as TVP itself, on serum lipids, biliary lipids, and fecal sterols. We studied eight normal subjects living on a metabolic ward during three randomly ordered 6- to 7-week periods: (1) standard cholesterol diet (190 to 550 mg/d), (2) TVP-low-cholesterol diet (17 to 30 mg/d), and (3) TVP-standard cholesterol diet. By analysis of covariance (ANCOVA), reducing dietary cholesterol to these very low levels significantly decreased serum low-density lipoprotein (LDL) cholesterol ( P = .048) but did not affect high-density lipoprotein (HDL) cholesterol or triglyceride. TVP resulted in a borderline significant reduction in LDL cholesterol ( P = .058) with a highly significant reduction in HDL cholesterol ( P = .004) and an increase in serum triglyceride ( P = .010). During TVP ingestion, there was a highly significant increase in the output of fecal neutral sterols ( P = .005) and a tendency for a higher output of fecal acidic sterols ( P = .100). Fecal sterol balance was significantly more negative (indicating increased cholesterol synthesis) during TVP ingestion ( P = .016). Neither TVP nor the very-low-cholesterol diet appreciably affected the gallbladder bile molar percent cholesterol or saturation index. The data are consistent with the hypothesis that to the extent TVP decreases serum LDL cholesterol (an effect of borderline significance in this study), the effect occurs via a reduction in the absorption of cholesterol and perhaps bile acid. However, the potential benefit of decreasing LDL cholesterol in this way seems to be at least partially offset by a concomitant reduction in HDL cholesterol and an increase in serum triglycerides.

Section Review: Cardiovascular &amp; Renal: Squalene epoxidase inhibitors

Squalene epoxidase inhibitors represent an attractive target for the control of sterol biosynthesis. Success in the search for fungal squalene epoxidase inhibitors has led to commercial availability of drugs from this class (e.g., terbinafine from Sandoz). The discovery of NB-598, a potent and selective mammalian squalene epoxidase inhibitor able to decrease serum low density lipoprotein-cholesterol levels in dogs, with a similar potency to simvastatin, has stimulated increased efforts towards the identification of new mammalian squalene epoxidase inhibitors. Such compounds represent an attractive alternative to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors as new therapeutic tools in the control of plasma low density lipoprotein-cholesterol levels, a major risk factor in coronary artery diseases. This article describes the recent development of this class of compounds, reviewing both the primary and patent literature.

Dietary -sitostanol related to absorption, synthesis and serum level of cholesterol in different apolipoprotein E phenotypes

Effects of small amounts of sitosterol, sitostanol and sitostanol esters ( < 1 g/day of free sterols) dissolved in rapeseed oil (RSO) were studied on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and different apolipoprotein E phenotypes on an RSO diet. One of the four groups was an RSO-fed control. Serum total and LDL cholesterol reductions were small in different plant sterol-fed groups, tended to be highest in the sitostanol ester group (−7%), but were significantly reduced by about 5% in the combined plant sterol groups. The reductions were −8% in the subjects with E4 allele and insignificant in those with apo E3/3 phenotype. Cholesterol precursor sterols in serum, markers of cholesterol synthesis, were increased only in the subjects with ϵ4 allele. Cholesterol absorption was reduced by 7%, being 31% in the subjects with ϵ4 allele, and fecal elimination of cholesterol was increased, a finding also indicating increased cholesterol synthesis. The changes in cholesterol absorption were related to those in fecal plant sterols (change in dietary intake) and serum total and LDL cholesterol ( P=0.04, 0.01 and 0.05, respectively). Thus, small amounts of dietary plant sterols ( < 1 g/day), especially sitostanol esters dissolved in dietary fats, decrease serum total and LDL cholesterol by a proportional decrease in cholesterol absorption which, in turn, is associated with a compensatory increase in cholesterol synthesis. The effects are most consistent in subjects with E4 allele, but for effective hypocholesterolemic treatment dietary amount of sitostanol ester should exceed 1 g/day.

Guar gum in insulin-dependent diabetes: effects on glycemic control and serum lipoproteins

We examined the effect of guar gum on glycemic control and serum lipid and lipoprotein profiles in mildly hypercholesterolemic patients with insulin-dependent diabetes. The study was done in a randomized, double-blind fashion with either guar gum or placebo added to the diet four times per day for 6 wk each. Fasting blood glucose and hemoglobin A1c decreased significantly during the guar-gum diet, whereas the diurnal glucose profile was unchanged. In addition, serum low-density-lipoprotein (LDL) cholesterol decreased by 20% and the ratio of LDL cholesterol to high-density-lipoprotein cholesterol by 28% during guar-gum therapy. No changes were seen in the placebo group. In conclusion, guar gum can improve glycemic control and decrease serum LDL-cholesterol concentrations in mildly hypercholesterolemic insulin-dependent diabetic patients and thus reduce risk factors for both micro- and macroangiopathic complications.