Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk.

AIMS: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome. METHODS: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent. RESULTS: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo. CONCLUSIONS: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal-OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality.

Maintenance of lower proportions of (n - 6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n - 3) fatty acids.

Competition between the (n - 3) and (n - 6) types of highly unsaturated fatty acids can diminish the abundance of (n - 6) eicosanoid precursors in a tissue, which in turn can diminish the intensity of tissue responses that are mediated by (n - 6) eicosanoids. The mixture of 20- and 22-carbon highly unsaturated fatty acids maintained in the phospholipids of human plasma is related to the dietary intake of 18:2 (n - 6) and 18:3 (n - 3) by empirical hyperbolic equations in a manner very similar to the relationship reported for laboratory rats (Lands, W.E.M., Morris, A. and Libelt, B. (1990) Lipids 25, 505-516). Analytical results from volunteers ingesting self-selected diets showed an inter-individual variance for the proportion of (n - 6) eicosanoid precursors in the fatty acids of plasma phospholipids of about 5%, but the variance among multiple samples taken from the same individual throughout the day was less (about 3%), closer to the experimental variance of the analytical procedure (about 1%). The reproducibility of the results makes it likely that analysis of fatty-acid composition of plasma lipids from individuals will prove useful in estimating the diet-related tendency for severe thrombotic, arthritic or other disorders that are mediated by (n - 6) eicosanoids. Additional constants and terms were included in the equations to account for the effects of 20- and 22-carbon highly unsaturated (n - 3) fatty acids in the diet. A lower constant for the 20- and 22-carbon (n - 3) fatty acids compared to that for the 18-carbon (n - 3) fatty acid in decreasing the ability of dietary 18:2 (n - 6) to maintain 20:4 (n - 6) in tissue lipids confirmed the greater competitive effectiveness of the more highly unsaturated n - 3 fatty acids in the elongation/desaturation process. Also, a lower constant for direct incorporation of 20-carbon fatty acids of the n - 6 vs. the n - 3 type indicated a greater competitive effectiveness of 20:4 (n - 6) relative to 20:5 (n - 3) in reesterification after release from tissue lipids. The equations may be used in reverse to estimate the dietary intakes of the (n - 3) and (n - 6) fatty acids by using the composition of the fatty acids that had been maintained in plasma lipids.

Marine oil capsule therapy for the treatment of hyperlipidemia.

Because marine oil capsules may vary widely in their content of omega-3 fatty acids, saturated fat, and cholesterol composition and, therefore, their biologic potency, we compared the lipid-lowering effects of three representative preparations in patients with different forms of hyperlipidemia. The ester and triglyceride forms of marine oil both effectively lowered triglyceride, but the response of low-density lipoprotein cholesterol was variable; it declined modestly in patients with hypercholesterolemia and was either unchanged or increased in those with hypertriglyceridemia. The saturated fat and cholesterol content of the marine oil preparation appeared to influence the low-density lipoprotein cholesterol response. Therefore, marine oil capsules are useful for lowering levels of very-low-density lipoprotein cholesterol, but the large dose required to achieve and sustain this effect (4.5 g of omega-3 fatty acids, or nine to 18 capsules daily) may limit long-term compliance.

Efficacy of the National Cholesterol Education Program Step I diet. A randomized trial incorporating quick-service foods.

OBJECTIVE: To determine the effect of incorporating quick-service meals into a Step I diet on the achievement of the National Cholesterol Education Program (NCEP) guidelines and on the blood lipid response of hyperlipidemic subjects (as possibly, the achievement of, and adherence to, dietary goals may be assisted by the inclusion of familiar foods, instead of their exclusion). METHODS: This was a randomized, parallel design study in free-living subjects. Hypercholesterolemic men and women (low-density lipoprotein cholesterol [LDL-C] level, 3.36 to 5.69 mmol/L [130 to 220 mg/dL]) who were consuming a high-fat diet (> 33% of total calories from fat) were randomly assigned to either a traditional NCEP Step I diet (n = 44) or an NCEP Step I diet with the incorporation of frequent quick-service meals (NCEP-QS, n = 45). RESULTS: After 8 weeks of treatment, both groups similarly reduced their reported dietary intakes of energy (approximately 30%), total percent fat (approximately 8%), percent saturated fat (approximately 3%), and cholesterol (approximately 38% to 28%). Both groups also experienced a decrease in the levels of total serum cholesterol (NCEP Step I diet, 8%; NCEP-QS Step I diet, 3%) and LDL-C (NCEP Step I diet, 10%; NCEP-QS Step I diet, 4%). However, compared with the group receiving the NCEP-QS Step I diet, the subjects who were consuming the NCEP Step I diet showed a significantly greater reduction in their total serum cholesterol and LDL-C levels over time (P < .05). Weight loss was significantly correlated (P < .001) with the decrease in the total serum cholesterol and LDL-C levels for all subjects combined. CONCLUSIONS: Hyperlipidemic subjects who were consuming an NCEP Step I diet, with or without the incorporation of quick-service meals, experienced a significant decrease in their total serum cholesterol and LDL-C levels, body weight, and reported fat intake. The beneficial responses in lipid levels were modestly mitigated in the quick-service diet group.

A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women.

OBJECTIVES: To evaluate and compare the lipid-altering effects of conjugated estrogens and pravastatin, alone and in combination, in postmenopausal women with hypercholesterolemia. METHODS: This was a double-blind, randomized, placebo-controlled clinical trial with 4 parallel groups. Participants (N = 76) were randomly assigned to receive conjugated estrogens, 0.625 mg/d; pravastatin sodium, 20 mg/d; conjugated estrogens plus pravastatin; or a placebo for 16 weeks. RESULTS: Primary end points were changes in serum lipid parameters. Among participants treated with conjugated estrogens, levels of non-high density lipoprotein cholesterol (non-HDL-C) (13.0%) and calculated low density lipoprotein cholesterol (LDL-C) (13.5%) decreased, while levels of HDL-C (22.5%) and triglycerides (4.2%) increased. Participants in the pravastatin group achieved reductions of 23.7% and 25.4% in non-HDL-C and calculated LDL-C levels, respectively. Levels of HDL-C increased slightly (3.7%) and triglycerides decreased by 12.1%. Among participants treated with a combination of conjugated estrogens plus pravastatin, the non-HDL-C (-25.2%) and calculated LDL-C (-28.7%) responses were similar to those of the pravastatin group, and the HDL-C response (21.2%) was similar to that observed in the conjugated estrogens group. Triglyceride levels remained similar to baseline (-0.9%) in the combined treatment group. CONCLUSIONS: Administration of conjugated estrogens resulted in potentially antiatherogenic changes in levels of non-HDL-C, HDL-C, and calculated LDL-C. The HDL-C response to combined treatment was similar to that observed in women taking conjugated estrogens alone, while the non-HDL-C and LDL-C responses to combined treatment were similar to those produced by pravastatin therapy alone. These findings support the position of the National Cholesterol Education Program that estrogen replacement, with a progestin where indicated, should be given consideration as a therapeutic option for the management of hypercholesterolemia in postmenopausal women.

Comparison of the effects of lean red meat vs lean white meat on serum lipid levels among free-living persons with hypercholesterolemia: a long-term, randomized clinical trial.

BACKGROUND: Patients with hypercholesterolemia are often counseled to limit or eliminate intake of red meats, despite evidence that lean red meats (LRMs) are not hypercholesterolemic in comparison with lean white meats (LWMs). The objective of this study was to evaluate the long-term effects on serum lipids of incorporating LRM (beef, veal, and pork) vs LWM (poultry and fish) into a National Cholesterol Education Program (NCEP) Step I diet in free-living individuals with hypercholesterolemia. METHODS: Subjects included 191 men and women with a serum low-density lipoprotein cholesterol level of 3.37 to 4.92 mmol/L (130-190 mg/dL) and triglyceride level less than 3.96 mmol/L (350 mg/dL). After a 4-week baseline phase, subjects were counseled to follow an NCEP Step I diet including 170 g (6 oz) of lean meat per day, 5 to 7 days per week. Based on random assignment, subjects were instructed to consume at least 80% of their meat in the form of LRM or LWM. Fasting serum lipid levels were assessed 4, 12, 20, 28, and 36 weeks after randomization. RESULTS: After randomization, mean concentrations of total cholesterol (6.09 mmol/L [235.7 mg/dL] vs 6.08 mmol/L [235.2 mg/dL]) and low-density lipoprotein cholesterol (3.99 mmol/L [154.1 mg/dL] vs4.01 mmol/L [154.7 mg/dL]) were nearly identical in the LRM and LWM groups (1%-3% below baseline) during treatment. Mean triglyceride levels remained similar to baseline values and high-density lipoprotein cholesterol concentrations increased by approximately 2% in both groups. CONCLUSIONS: The NCEP Step I diets containing primarily LRM or LWM produced similar reductions in low-density lipoprotein cholesterol and elevations in high-density lipoprotein cholesterol levels, which were maintained throughout 36 weeks of treatment.

Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women.

OBJECTIVE: To evaluate the influence of 2 continuous combined estrogen-progestin replacement products, compared with unopposed estrogen and placebo, on cardiovascular risk markers in postmenopausal women in a randomized, double-blind, placebo-controlled trial. METHODS: Two hundred seventy healthy postmenopausal women were randomly assigned to 1 of 4 treatment groups: placebo, unopposed 17-beta estradiol (1 mg), 1 mg of 17-beta estradiol with 0.25 mg of norethindrone acetate, or 1 mg of 17-beta estradiol with 0.5 mg of norethindrone acetate. The primary outcome variable was change from baseline in low-density lipoprotein cholesterol concentration. Additional outcome variables included changes in other serum lipid levels, hemostatic variables, and indicators of carbohydrate metabolism. RESULTS: The low-density lipoprotein cholesterol level was reduced to a similar degree in all groups receiving active treatment (10%-14% from baseline; P =.001 for 17-beta estradiol with 0.5 mg of norethindrone acetate, P =.004 for 17-beta estradiol with 0.25 mg of norethindrone acetate, and P =. 001 for 1 mg of 17-beta estradiol vs placebo). Compared with unopposed 17-beta estradiol, 17-beta estradiol with 0.5 mg of norethindrone acetate enhanced the reductions in total cholesterol and apolipoprotein B levels (P<.01 vs 17-beta estradiol). 17-beta Estradiol plus norethindrone blunted or reversed the increases in levels of high-density lipoprotein cholesterol, apolipoprotein A-I, and triglycerides produced by 17-beta estradiol alone. Effects of 17-beta estradiol plus norethindrone on hemostatic variables were similar to those of 17-beta estradiol except for factor VII activity, which was significantly reduced with 17-beta estradiol combined with 0.25 mg (P<.01) and 0.5 mg (P<.05) of norethindrone acetate. 17-beta Estradiol plus norethindrone appeared to blunt reductions in C-peptide and insulin levels produced by unopposed 17-beta estradiol but did not elevate these values compared with placebo. CONCLUSIONS: 17-beta Estradiol plus norethindrone produced favorable changes in most cardiovascular risk markers evaluated and has a profile distinct from that of unopposed 17-beta estradiol. The impact of these differences on cardiovascular events warrants investigation. Arch Intern Med. 2000;160:3315-3325.

Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.

OBJECTIVES: To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. METHODS: Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. RESULTS: Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. CONCLUSIONS: Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.

Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in humans.

Cyclooxygenase (COX) exists as constitutive (COX-1) and inducible (COX-2) isoforms. Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and diclofenac inhibit both COX-1 and COX-2. The role of COX-2 in the genesis of fever in monkeys and humans was examined with use of the specific COX-2 inhibitor rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 microg/kg intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing). A single-dose, parallel-group, double-blind randomized trial was conducted in 94 patients with fever caused by a viral-type illness. Mean baseline temperature was similar for all groups (-38.5 degrees C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo and the mean +/- SE change in oral temperature at 4 hours after dosing was -0.97 degrees C +/- 0.11 degrees C, -1.19 degrees C +/- 0.09 degrees C, -1.20 degrees C +/- 0.11 degrees C, and 0.01 C +/- 0.17 C, respectively (P < .001 for active treatments versus placebo). Specific inhibition of COX-2 by rofecoxib results in antipyretic activity in monkeys and humans comparable to dual COX-1/COX-2 inhibitors such as diclofenac or ibuprofen. The data support the hypothesis that it is the COX-2 isoform that is primarily involved in the genesis of fever in humans.

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.

Long-term cholesterol-lowering effects of psyllium as an adjunct to diet therapy in the treatment of hypercholesterolemia.

BACKGROUND: Hypercholesterolemia is a major risk factor for coronary heart disease and nutrition management is the initial therapeutic approach. OBJECTIVE: This multicenter study evaluated the long-term effectiveness of psyllium husk fiber as an adjunct to diet in the treatment of persons with primary hypercholesterolemia. DESIGN: Men and women with hypercholesterolemia were recruited. After following an American Heart Association Step I diet for 8 wk (dietary adaptation phase), eligible subjects with serum LDL-cholesterol concentrations between 3.36 and 4.91 mmol/L were randomly assigned to receive either 5.1 g psyllium or a cellulose placebo twice daily for 26 wk while continuing diet therapy. RESULTS: Serum total and LDL-cholesterol concentrations were 4.7% and 6.7% lower in the psyllium group than in the placebo group after 24-26 wk (P < 0.001). Other outcome measures did not differ significantly between groups. CONCLUSIONS: Treatment with 5.1 g psyllium twice daily produces significant net reductions in serum total and LDL-cholesterol concentrations in men and women with primary hypercholesterolemia. Psyllium therapy is an effective adjunct to diet therapy and may provide an alternative to drug therapy for some patients.

Long-term effects of consuming foods containing psyllium seed husk on serum lipids in subjects with hypercholesterolemia.

The effects of consuming foods containing 0 (control), 3.4, 6.8, or 10.2 g psyllium seed husk (PSH)/d for 24 wk on the serum lipid profile were assessed in this randomized, double-blind controlled study. Men and women (n = 286) with LDL-cholesterol concentrations between 3.36 and 5.68 mmol/L (130 and 220 mg/dL) were randomly assigned to one of four treatment groups after following a low-fat diet for > or = 8 wk. At week 24, LDL cholesterol was 3% above baseline in the control group. In the group consuming 10.2 g PSH/d, LDL cholesterol remained below baseline during treatment, with a value 5.3% below that of the control group at week 24 (P < 0.05 compared with the control group). No significant differences were observed in HDL cholesterol or triacylglycerol. Although modest, the effect of 10.2 g PSH/d on LDL cholesterol (relative to the control) persisted throughout the 24-wk treatment period, indicating potential for long-term benefit.

Lipid responses to plant-sterol-enriched reduced-fat spreads incorporated into a National Cholesterol Education Program Step I diet.

BACKGROUND: Plant sterol esters reduce cholesterol absorption and lower circulating blood cholesterol concentrations when incorporated into the habitual diet. OBJECTIVE: This randomized, double-blind, 3-group parallel, controlled study evaluated the influence of esterified plant sterols on serum lipid concentrations in adults with mild-to-moderate primary hypercholesterolemia. DESIGN: Subjects incorporated a conventional 50%-fat spread into a National Cholesterol Education Program Step I diet for a 4-wk lead-in period, followed by a 5-wk intervention period of the diet plus either a control reduced-fat spread (40% fat; n = 92) or a reduced-fat spread enriched with plant sterol esters to achieve intakes of 1.1 g/d (n = 92; low-sterol group) or 2.2 g/d (n = 40; high-sterol group). RESULTS: Subjects in the low- and high-sterol groups who consumed > or = 80% of the scheduled servings (per-protocol analyses) had total cholesterol values that were 5.2% and 6.6% lower, LDL-cholesterol values that were 7.6% and 8.1% lower, apolipoprotein B values that were 6.2% and 8.4% lower, and ratios of total to HDL cholesterol that were 5.9% and 8.1% lower, respectively, than values for the control group (P < 0.001 for all). Additionally, triacylglycerol concentrations decreased by 10.4% in the high-sterol group. Serum concentrations of fat-soluble vitamins and carotenoids were generally within reference ranges at baseline and postintervention. Serum plant sterol concentrations increased from baseline (0.48% of total sterol by wt) to 0.64% and 0.71% by wt for the low- and high-sterol groups, respectively (P < 0.05 compared with control). CONCLUSION: A reduced-fat spread containing plant sterol esters incorporated into a low-fat diet is a beneficial adjunct in the dietary management of hypercholesterolemia.

Effects of dietary supplementation with marine lipid concentrate on the plasma lipoprotein composition of hypercholesterolemic patients.

Although the triglyceride-lowering actions of n-3 fatty acids of marine lipids are now well-recognized, their effects on plasma lipoproteins have not been studied systematically in patients with hypercholesterolemia. To address this question, we supplemented the Phase 1 American Heart Association diets of 14 hypercholesterolemic ambulatory outpatients with a commercially available preparation of marine lipid concentrate (SuperEPA) containing 7.5 g n-3 fatty acids per day and studied their plasma lipids and lipoproteins before and after 30 days of treatment. Both plasma triglyceride and cholesterol levels fell uniformly in all patients while the mean VLDL- and LDL-cholesterol decreased by 58% (P less than 0.005) and 13% (P less than 0.025) respectively. The decrease in whole plasma cholesterol was significantly correlated with the fall in LDL-cholesterol (r = 0.85, P less than 0.01), and not VLDL-cholesterol (r = 0.39, NS). Among the other potentially beneficial actions observed was an increase in HDL2 in all patients (mean increment 41%, P less than 0.005), and an increase in the HDL2/HDL3 ratio (+46%, P less than 0.001) and decreases in the LDL/HDL ratio (-14%, P less than 0.005) and in the unesterified cholesterol/lecithin ratio (-17%; P less than 0.001) in plasma. The increase in the unesterified cholesterol/esterified cholesterol ratio in VLDL and HDL3 suggested that marine lipid therapy resulted in a reduction in the size of lipoprotein particles in these fractions. Since these changes may reduce cardiovascular risk, these findings suggest that marine lipids may prove useful in the treatment of certain patients with hypercholesterolemia.

The effects of colestipol tablets compared with colestipol granules on plasma cholesterol and other lipids in moderately hypercholesterolemic patients.

The purpose of this study was to investigate and compare the efficacy, safety, and patient acceptability of a new formulation of colestipol, colestipol tablets (T), with those of colestipol granules (G), in a randomized, double-blind, placebo-controlled, multicenter study. Three hundred and seventeen patients with primary hypercholesterolemia who were following a low-fat, low-cholesterol diet (NCEP Step I diet), and had low-density lipoprotein cholesterol (LDL-C) levels > or = 4.14 mmol/l (160 mg/dl) and < or = 6.46 mmol/l (250 mg/dl) were studied. Study medication was taken twice a day, with breakfast and supper, for 8 weeks. The six parallel treatment groups consisted of colestipol tablets 2 g b.i.d. and 8 g b.i.d., matching placebo tablets b.i.d., colestipol granules 2 g b.i.d. and 8 g b.i.d., and matching placebo granules b.i.d.. Study endpoints included absolute change and percentage change from baseline in selected lipid, lipoprotein, and apolipoprotein measurements; LDL-C lowering was the primary efficacy endpoint. Treatment with colestipol tablets and colestipol granules resulted in virtually identical, statistically significant (P < or = 0.05) reductions of LDL-C, total cholesterol (TC), TC/HDL-C, and apolipoprotein B (apo B). Compared with placebo, all active treatments (tablets 4 g/day, tablets 16 g/day, granules 4 g/day, granules 16 g/day) significantly reduced LDL-C (12%, 24%, 12%, 25%, respectively), TC (7%, 15%, 8%, 15%, respectively), TC/HDL-C (8%, 14%, 9%, 15%, respectively) and apo B (12%, 20%, 13%, 22%, respectively). All active treatments significantly increased lipoprotein particle AI (LpAI) (5%, 23%, 14%, 18%, respectively). VLDL-C and triglycerides increased significantly in the high-dose groups. The proportions of patients reporting adverse events, largely gastrointestinal-related, were not different among the active treatment groups. The treatments were well-tolerated, and no drug-related serious adverse events were reported. Patients experienced with granule medication prior to this study preferred tablets over granules. This study demonstrates that colestipol tablets are an effective treatment to reduce LDL-C in patients with primary hypercholesterolemia, are equivalent to colestipol granules, are well-tolerated, and are preferred over granules by patients.

Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia.

Although acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce lipid levels in several animal models, the safety and lipid modifying activity of any single agent in this class has not been demonstrated in humans. The safety and efficacy of avasimibe (CI-1011), a new, unique, wholly synthetic ACAT inhibitor, was evaluated in the treatment of 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia (low levels of high-density lipoprotein cholesterol [HDL-C]). Following an 8-week placebo and dietary-controlled baseline period, patients were randomly assigned to double-blind treatment with placebo, 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks. At all evaluated doses, avasimibe treatment resulted in prompt and significant reductions (P<0.05) in plasma levels of total triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) with mean reductions of up to 23% and 30% respectively, apparently independent of dose. No statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C or apolipoprotein (apo) B were detected. ApoAI levels were also unchanged on all doses of avasimibe apart from the 500 mg dosage, which was associated with a significant decrease in plasma apoAI. The relevance of this latter finding in only one dosage group is not known. All doses of avasimibe were well tolerated with no resulting significant abnormalities of biochemical, hematological, or clinical parameters.

Fluvastatin Long-Term Extension Trial (FLUENT): summary of efficacy and safety.

The Fluvastatin Long-Term Extension Trial (FLUENT) evaluated the safety and efficacy of fluvastatin over a period of 48 weeks. All 918 enrolled patients had severe primary hypercholesterolemia (mean baseline low-density lipoprotein [LDL] cholesterol, 227 mg/dL) and had completed one of three previous short-term studies of fluvastatin. This open-label extension study used a starting dose of 20 mg of fluvastatin at bedtime. The dose was titrated to 40 mg to achieve LDL levels of < 3.36 mmol/L (130 mg/dL). If necessary, cholestyramine was added to the fluvastatin treatment to achieve this level. After 48 weeks of treatment, the mean percent change from baseline was statistically significant for LDL (-30.7%; p < 0.001), total (-21.9%; p < 0.001), and HDL (+3.5%; p < 0.001) cholesterol. Of the 836 patients who completed the study, only four (0.5%) withdrew because of drug-related adverse events, which were mainly gastrointestinal. There was one purported case of myopathy in a patient who had a recent history of strenuous physical activity. Newly occurring or worsening lens abnormalities were generally mild and did not require discontinuation of treatment. In conclusion, these results indicate that fluvastatin is safe, effective, and well tolerated in the long-term treatment of primary hypercholesterolemia.

Fluvastatin administration at bedtime versus with the evening meal: a multicenter comparison of bioavailability, safety, and efficacy.

Fluvastatin is a totally synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that is effective in reducing cholesterol when given in a single evening dose. Absorption and rate of bioavailability may be affected when administered with food, but the effect of mealtime dosing on efficacy and safety has not been evaluated. This multicenter, double-blind, placebo-controlled crossover study was performed in 44 patients with primary hypercholesterolemia. Patients received 20 mg of fluvastatin with the evening meal and placebo at bedtime for 6 weeks, followed by 12 weeks of placebo at mealtime and fluvastatin at bedtime (group 1). Group 2 received the opposite treatment schedule, and group 3 received placebo at mealtime and at bedtime for 12 weeks before receiving 20 mg of fluvastatin at bedtime instead of placebo for the final 6 weeks. Fluvastatin with the evening meal resulted in a marginally lower peak serum concentration (p < 0.1) and a significantly delayed time to peak concentration compared with bedtime dosing, but there were no statistically significant differences in the extent of bioavailability. At the end of the first 6 weeks of treatment, similar reductions in low-density lipoprotein (LDL) cholesterol were obtained whether fluvastatin was given at mealtime (-21.8%; p < 0.001) or at bedtime (-23.9%; p < 0.001). After crossover of groups 1 and 2, the results remained constant. With fluvastatin, there were comparable reductions in total cholesterol (p < 0.001) and in LDL:high-density lipoprotein (HDL) ratio (p < 0.001) irrespective of the time of dosing. In conclusion, fluvastatin had a similar tolerability, safety, and efficacy, whether given with the evening meal or at bedtime. There were no serious adverse events nor changes in physical examination findings or laboratory values attributable to treatment.

Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia.

PURPOSE: To examine the efficacy and safety of colesevelam hydrochloride, a novel, nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin in a multicenter, randomized, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL] cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose, n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34), colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with simvastatin 20 mg (n = 37), for 6 weeks. RESULTS: Mean LDL cholesterol levels decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61 mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone (P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride levels were similar to those for simvastatin alone. Side effects were similar among treatment groups, and there were no clinically important changes in laboratory parameters. CONCLUSION: Coadministration of colesevelam and simvastatin was effective and well tolerated, providing additive reductions in LDL cholesterol levels compared with either agent alone.

Antioxidants and lipid metabolism. Implications for the present and direction for the future.

Numerous angiographic trials have demonstrated that the atherosclerotic process can be modified through reductions in levels of low-density lipoprotein (LDL) cholesterol. Recent research has focused on other potential modalities by which atheroroma development might be inhibited. These newer strategies include reduction of the oxidative potential of LDL particles through modification of dietary fat intake; prevention of LDL oxidation through the use of antioxidants; and inhibition of monocyte and macrophage function by omega-3 fatty acids and leukotriene-1 antagonists. Inhibition of acyl-coenzyme A:cholesterol acyltransferase (ACAT) may block intestinal cholesterol absorption and reduce synthesis of very-low-density lipoprotein (VLDL), while simultaneously enriching high-density lipoprotein (HDL) cholesterol. Modification of cholesterol ester transfer protein may be associated with improved reverse cholesterol transport or enlarged HDL particles. In the future, a wide variety of therapeutic modalities may be available for use alone or in combination to reverse atherosclerosis or prevent its progression.