William S. Harris

Safety and efficacy of Omacor in severe hypertriglyceridemia

Background Severe hypertriglyceridemia is a risk factor for acute pancreatitis, therefore decreasing serum triglyceride concentrations is an important component of risk management. Omega-3 fatty acids are well known hypotriglyceridemic agents, but their efficacy in severe forms of the disorder is not well documented. Our objective was to examine the effects of Omacor, a drug composed of 85% omega-3 fatty acid ethyl esters. Methods Forty-two patients with triglyceride concentrations between 5.65 and 22.60 mmol/l (500 and 2000 mg/dl) were studied in a prospective, double-blind, placebo-controlled trial of Omacor (4 g/day for 4 months). Results Compared with baseline values, Omacor significantly reduced mean triglyceride concentrations by 45% (P< 0.00001), cholesterol by 15% (P< 0.001), very-low-density lipoprotein cholesterol by 32% (P< 0.0001) and cholesterol: High density lipoprotein (HDL) cholesterol ratio by 20% (P = 0.0013), and increased HDL cholesterol by 13% (P = 0.014) and low-density lipoprotein cholesterol by 31% (P = 0.0014). The placebo had no effect on these parameters. Omacor was well tolerated and no patient discontinued medication because of side effects. Conclusions Four capsules of Omacor per day markedly decreased triglyceride concentrations in patients with severe hypertriglyceridemia. The availability of a potent and safe omega-3 fatty acid preparation for this patient population should diminish the risk for acute pancreatitis, and may also reduce the long-term risk for cardiovascular disease.

n-3 fatty acids and lipoproteins: Comparison of results from human and animal studies

The impact of n-3 fatty acids (FA) on blood lipoprotein levels has been examined in many studies over the last 15 yr in both animals and humans. Studies in humans first demonstrated the potent triglyceride-lowering effect of n-3 FA, and these were followed up with animal studies to unravel the mechanism of action. This paper reviews the reported effects of n-3 FA on blood lipoproteins in 72 placebo-controlled human trials, at least 2 wk in length and providing 7 or less g of n-3 FA/day. Trials in normolipidemic subjects (triglycerides <2.0 mM; 177 mg/dL) were compared to those in hypertriglyceridemic patients (triglycerides ≥2.0 mM). In the healthy subjects, mean triglyceride levels decreased by 25% (P<0.0001), and total cholesterol (C) levels increased by 2% (P<0.009) due to the combined increases in low density lipoprotein (LDL)-C (4%,P<0.02) and high density lipoprotein (HDL)-C (3%,P<0.008). In the patients, triglyceride levels decreased by 28% (P<0.0001), LDL-C rose by 7% (P<0.0001), but neither total C nor HDL-C changed significantly. Although the effect on triglyceride levels is also observed in rats and swine, it is rarely seen in mice, rabbits, monkeys, dogs, and hamsters. Whereas n-3 FA have only a minor impact on lipoprotein C levels in humans, they often markedly lower both total C and HDL-C levels in animals, especially monkeys. These differences are not widely appreciated and must be taken into account when studying the effects of n-3 FA on lipoprotein metabolism.

The Efficacy of Intensive Dietary Therapy Alone or Combined with Lovastatin in Outpatients with Hypercholesterolemia

BACKGROUNDnA diet low in saturated fat and cholesterol is the standard initial treatment for hypercholesterolemia. However, little quantitative information is available about the efficacy of dietary therapy in clinical practice or about the combined effects of diet and drug therapy.nnnMETHODSnOne hundred eleven outpatients with moderate hypercholesterolemia were treated at five lipid clinics with the National Cholesterol Education Program Step 2 diet (which is low in fat and cholesterol) and lovastatin (20 mg once daily), both alone and together. A diet high in fat and cholesterol and a placebo identical in appearance to the lovastatin were used as the respective controls. Each of the 97 patients completing the study (58 men and 39 women) underwent four consecutive nine-week periods of treatment according to a randomized, balanced design: a high-fat diet-placebo period, a low-fat diet-placebo period, a high-fat diet-lovastatin period, and a low-fat diet-lovastatin period.nnnRESULTSnThe level of low-density lipoprotein (LDL) cholesterol was a mean of 5 percent (95 percent confidence interval, 3 to 7 percent) lower during the low-fat diet than during the high-fat diet (P < 0.001). With lovastatin therapy as compared with placebo, the reduction was 27 percent. Together, the low-fat diet and lovastatin led to a mean reduction of 32 percent in the level of LDL cholesterol. The level of high-density lipoprotein (HDL) cholesterol fell by 6 percent (95 percent confidence interval, 4 to 8 percent) during the low-fat diet (P < 0.001) and rose by 4 percent during treatment with lovastatin (P < 0.001). The ratio of LDL to HDL cholesterol and the level of total triglycerides were reduced by lovastatin (P < 0.001), but not by the low-fat diet.nnnCONCLUSIONSnThe effects of the low-fat-low-cholesterol diet and lovastatin on lipoprotein levels were independent and additive. However, the reduction in LDL cholesterol produced by the diet was small, and its benefit was possibly offset by the accompanying reduction in the level of HDL cholesterol.

Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans

The aim of this study was to determine whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or both, were responsible for the triglyceride (TG)-lowering effects of fish oil. EPA (91% pure) and DHA (83% pure), a fish oil concentrate (FOC; 41% EPA and 23% DHA) and an olive oil (OO) placebo (all ethyl esters) were tested. A total of 49 normolipidemic subjects participated. Each subject was given placebo for 2–3 wk and one of the n-3 supplements for 3 wk in randomized, blinded trials. The target n-3 fatty acid (FA) intake was 3 g/day in all studies. Blood samples were drawn twice at the end of each supplementation phase and analyzed for lipids, lipoproteins, and phospholipid FA composition. In all groups, the phospholipid FA composition changed to reflect the n-3 FA given. On DHA supplementation, EPA levels increased to a small but significant extent, suggesting that some retroconversion may have occurred. EPA supplementation did not raise DHA levels, however, FOC and EPA produced significant decreases in both TG and very low density lipoprotein (VLDL) cholesterol (C) levels (P<0.01) and increases in low density lipoprotein (LDL) cholesterol levels (P<0.05). DHA supplementation did not affect cholesterol, triglyceride, VLDL, LDL, or high density lipoprotein (HDL) levels, but it did cause a significant increase in the HDL2/HDL3 cholesterol ratio. We conclude that EPA appears to be primarily responsible for TG-lowering (and LDL-C raising) effects of fish oil.

Garlic supplementation and lipoprotein oxidation susceptibility

Interventions which make serum lipoproteins less susceptible to oxidation may be antiatherogenic. The antioxidant properties of garlic which have been demonstratedin vitro led us to investigate the effects of garlic supplements on lipoprotein oxidation susceptibility in humans. Ten healthy volunteers were given 600 mg/d of garlic powder (6 tablets of Kwai®) for two weeks in a placebo-controlled, randomized, double-blind crossover trial. We found that although serum lipid and lipoprotein levels were not lowered in this short time period, theex vivo susceptibility of apolipoprotein B-containing lipoproteins to oxidation was significantly decreased (−34%). Because garlic has been reported to beneficially affect serum lipid levels, platelet function, fibrinolysis and blood pressure, this additional effect of retarding lipoprotein oxidation may contribute to the potential antiatherosclerotic effect of garlic.

Effects of a Low Saturated Fat, Low Cholesterol Fish Oil Supplement in Hypertriglyceridemic Patients: A Placebo-Controlled Trial

STUDY OBJECTIVEnTo determine the effects of fish oil supplements low in saturated fat and cholesterol on plasma lipid and lipoprotein levels in hypertriglyceridemic patients.nnnDESIGNnSingle-blind, placebo-controlled (safflower oil), crossover trial with 6-week treatment periods.nnnSETTINGnOutpatient lipid clinic in a university medical center.nnnPATIENTSnEleven adult patients had isolated hypertriglyceridemia (type IV) and seven had concomitant hypercholesterolemia (Type IIb).nnnINTERVENTIONnTwelve 1-g capsules of either fish oil or placebo (safflower oil) were taken daily during each treatment period.nnnMEASUREMENTS AND MAIN RESULTSnBlood was drawn at the fifth and sixth week of each period and analyzed for total lipids; cholesterol in very low, low (LDL), and high density (HDL) lipoproteins (mmol/L); and apoprotein B (mg/dL). Compared with the placebo, fish oil lowered plasma triglyceride levels (4.0 +/- 1.8 to 2.5 +/- 1.0), and raised LDL cholesterol levels (3.7 +/- 1.75 to 4.25 +/- 0.85), apolipoprotein B levels (122 +/- 29 to 140 +/- 34), and the ratio of LDL cholesterol to HDL cholesterol (4.0 +/- 0.9 to 4.7 +/- 1.4) (P less than 0.05; mean +/- SD). No significant changes were seen in levels of HDL or HDL cholesterol subfractions. Similar responses were seen in patients with both type IIb and IV lipoprotein phenotypes.nnnCONCLUSIONSnBecause the fish oil supplement contributed negligible amounts of cholesterol and saturated fat to the diet, the n-3 fatty acids most likely caused the observed effects. These findings indicate that relatively small amounts of fish oil can have beneficial effects on plasma triglyceride levels in hypertriglyceridemic patients, but the increase in LDL cholesterol and apoprotein B levels, and in the LDL cholesterol to HDL cholesterol ratio suggests the need for careful monitoring of plasma lipoprotein changes during fish oil supplementation, and for a careful evaluation of their long-term benefits.

Effect of Atorvastatin on Hemorheologic- Hemostatic Parameters and Serum Fibrinogen Levels in Hyperlipidemic Patients

Plasma fibrinogen and hemorheologic-hemostatic factors contribute to dyslipidemia-induced morbidity. Some of these parameters can be favorably affected when abnormal serum lipoprotein levels are corrected. Thus, we investigated whether treatment with atorvastatin would result in changes in plasma viscosity and other hemorheologic and hemostatic parameters. Twenty-two hyperlipidemic men at a university lipid clinic were treated single-blinded with atorvastatin 80 mg/day for 12 weeks to determine hemostatic-hemorheologic parameters including blood viscosity, fibrinogen levels, whole blood platelet aggregation, tissue plasminogen activator antigen, hematocrit, plasminogen activator inhibitor activity, factor VII activity, red blood cell (RBC) deformity and lipid ratio, sedimentation rate, and fasting serum lipoprotein levels. Atorvastatin treatment provided significant lowering of serum lipoprotein levels: low-density lipoprotein -53% (p = 0.0001), very low density lipoprotein -43% (p = 0.0001), and triglycerides -35% (p < 0.0001). These effects were accompanied by changes in plasma viscosity -10% (p = 0.0007), arachidonic acid-induced whole blood platelet aggregation -11% (p = 0.006), factor VII -8% (p = 0.001), RBC lipid composition +5% (p = 0.0003), and RBC sedimentation -33% (p = 0.0002). Plasma fibrinogen levels were not affected. Thus, atorvastatin 80 mg/day produced marked reductions in serum low-density lipoprotein cholesterol (-53%), very low density lipoprotein cholesterol (-43%), and triglycerides levels (-35%), and significant changes in plasma viscosity as well as other hemorheologic-hemostatic parameters, but no changes in plasma fibrinogen levels.

Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans

A common pharmacologic approach to lowering elevated serum cholesterol levels has been to interfere with intestinal sterol absorption. Inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) should produce this effect. In this study, we examined the effects of CL 277,082, N‐(2,4‐difluorophenyl)‐N‐(4‐neopentylbenzyl)‐N‐(n‐heptyl)urea, an ACAT inhibitor, on cholesterol metabolism in humans. Eight healthy male volunteers were given a placebo for 14 days, followed by 750 mg/day CL 277,082 for 20 days in a single‐blind, crossover design. Subjects were studied in a hospital research unit and were fed strictly controlled diets. Cholesterol absorption was measured by the dual isotope method during the final week of both the placebo and the drug phases. Sterol balance was also assessed during these two periods by measuring cholesterol intake, and fecal neutral and acidic sterol excretion rates. Plasma lipids and lipoproteins were measured at the end of each period. The drug was well tolerated and produced no detectable clinical or laboratory side effects. Cholesterol absorption, sterol excretion rates, and plasma lipoprotein levels were all unaffected by treatment. We conclude that CL 277,082 may not interfere with ACAT activity or cholesterol absorption in humans at the doses given under the conditions tested in this study.

Effects of pravastatin with niacin or magnesium on lipid levels and postprandial lipemia

This study was designed to evaluate the therapeutic effectiveness of 3 different pharmacologic lipid-lowering regimens in the treatment of patients with clustered lipid risk factors. Sixty-five patients with low high-density lipoprotein (HDL) levels and hypertriglyceridemia were randomized to 1 of 3 treatment arms: pravastatin/niacin, pravastatin/magnesium, or pravastatin/placebo. After 18 weeks, patients in the pravastatin/niacin group had a -41% change in the total cholesterol/HDL ratio compared with -13% in the pravastatin/magnesium arm and -16% in the pravastatin/placebo group. The HDL2 and HDL3 subfractions, as well as the apolipoprotein A-I levels, were increased significantly only in the pravastatin/niacin arm. The levels of small dense low-density lipoprotein (LDL) cholesterol (LDL3) were decreased to a greater extent in the pravastatin/niacin arm (-43%) than in either the pravastatin/magnesium (-13%) or the pravastatin/placebo (-20%) arm. Only the pravastatin/niacin regimen significantly diminished postprandial lipemia (-32% change in the remnant particle triglyceride concentration and decreased very-low-density lipoprotein remnant levels). Thus, in this group of patients with clustered risk factors, the combination of pravastatin and niacin resulted in significant improvements in HDL and triglyceride levels, total cholesterol to HDL ratio, small dense LDL levels, and postprandial lipemia. Pravastatin alone or in combination with magnesium resulted in less significant changes that were largely limited to LDL cholesterol reduction.

Effects of dietary fish oil on platelet function and plasma lipids in hyperlipoproteinemic and normal subjects

We studied the effects of dietary supplementation with an encapsulated fish oil concentrate (Maxepa) on platelet function, fibrinolysis, and plasma lipids and lipoproteins in 9 normal subjects, 10 patients with type IV hyperlipoproteinemia, and 6 with type IIB hyperlipoproteinemia. After a baseline period, the subjects crossed over randomly between treatment periods with Maxepa (providing 3.24 g eicosapentaenoic acid and 2.16 g docosahexaenoic acid per day) and safflower oil (used as a control), given for 6 weeks each. Administration of Maxepa led to a slight prolongation of the bleeding time in all groups and to modest inhibition of platelet aggregation in the type IV hyperlipoproteinemics and normal subjects, with partial (41%) inhibition of thromboxane synthesis from baseline levels noted in the normal group. Plasma total fibrinolytic actively did not change significantly in any group. Maxepa treatment resulted in a marked decrease in triglyceride and VLDL-cholesterol and a slight increase in HDL-cholesterol was noted after Maxepa in the type IV hyperlipoproteinemics (4.11 +/- 0.13 mmol/l vs. 3.10 +/- 0.16 mmol/l, Maxepa vs. safflower oil). We conclude that dietary supplementation with fish oil results in a relatively minor degree of inhibition of platelet function in normal and hyperlipoproteinemic subjects, and a potentially adverse increase in LDL-cholesterol in type IV hyperlipoproteinemics.