Gemfibrozil increases both apo A-I and apo E concentrations. Comparison to other lipid regulators in cholesterol-fed rats

HDL cholesterol (HDL-C) was increased by gemfibrozil (+3.6-fold), fenofibrate (+1.3-fold) and ciprofibrate (+1.2-fold) but not clofibrate or bezafibrate when dosed PO at 50 mg/kg for 2 weeks in cholesterol-fed rats. Cholesterol in apo B-containing lipoproteins decreased with gemfibrozil (-76%), clofibrate (-12%) and ciprofibrate (-12%). Plasma apo B decreased to the greatest extent with gemfibrozil (-86%) followed by ciprofibrate (-47%), fenofibrate (-40%), clofibrate (-24%) and bezafibrate (-20%). Only gemfibrozil increased plasma apo E levels which are characteristically low in this rat model. Gemfibrozil, fenofibrate and ciprofibrate increased apo A-I concentrations. It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI (fenofibrate, ciprofibrate) or both apo E and A-I (gemfibrozil). It is hypothesized that drugs which alter the metabolism of both HDL peptides result in the greatest HDL-C elevation in the rat.     

Effects of fenfluramine in hypertriglyceridemic obese subjects

Forty-four hyperlipidemic obese subjects, selected because of their refractoriness towards diet-therapy, participated voluntarily in a 12-week double-blind study comparing the effects of a long-acting fenfluramine (Ponderal Pacaps) to those of a placebo. In spite of no dietetic intervention, a significant 3-kg weight loss (P less than 0.001) was observed in the fenfluramine-treated group, accompanied by a significant improvement of most atherogenic parameters of plasma lipoproteins. Fenfluramine-induced weight loss produced decrease in total cholesterol (P less than 0.05), total triglycerides (P less than 0.05), LDL cholesterol (P less than 0.05), total apoprotein B (P less than 0.005) and LDL apoprotein B (P less than 0.001). An apoprotein B LDL depletion seemed to occur, as suggested by the reduction of LDL cholesterol/apoprotein B ratio (P less than 0.001). Total plasma apoprotein A did not change but the total apoprotein B/total apoprotein A ratio decreased significantly (P less than 0.005). Moreover, fenfluramine increased both HDL phospholipid (P less than 0.005) and HDL cholesterol (P less than 0.05) resulting in a fall of the atherogenic LDL-cholesterol/HDL cholesterol ratio (P less than 0.001) as well as an elevation of the anti-atherogenic HDL cholesterol/LDL + VLDL cholesterol ratio (P less than 0.001). The placebo group demonstrated some improvement in lipid blood parameters without weight loss, indicating a possible qualitative amelioration of nutritional habits. Thus, fenfluramine reduces the risk for cardiovascular disease in hyperlipidemic obese individuals not responding to behavioral intervention.     

Effects of ciprofibrate and fenofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats

The plasma lipoprotein and liver lipid composition, and the lipid, cholesterol and apolipoprotein synthesis have been studied in normal and diet-induced hyperlipidemic rats, receiving ciprofibrate (2.5 mg/kg body weight) or fenofibrate (50 mg/kg b.w.) for 8 days. Ciprofibrate is about 25-fold more active than fenofibrate in reducing plasma triglyceride and cholesterol concentrations both in normolipemic and in hyperlipemic rats. In normolipemic rats ciprofibrate reduced the concentration and the lipid content of all lipoprotein classes. The incorporation of [14C]palmitate and [3H]leucine into the lipoproteins was reduced by ciprofibrate and fenofibrate. The reduction in lipoprotein production was confirmed by prevention of Triton-induced hyperlipemia. Liver and plasma cholesterol synthesis estimated by 3H2O and [14C]mevalonate incorporation indicated an inhibitory effect on HMG-CoA reductase. Administration of ciprofibrate or fenofibrate to rats fed a fat and cholesterol-rich diet partially prevented liver steatosis and hyperlipemia. Both drugs reduced the overproduction of lower density lipoproteins. The ratio of (VLDL + LDL)-cholesterol/HDL-cholesterol which was increased by the diet alone from 0.4 (normal) to 11 remained close to the normal value in the animals receiving ciprofibrate. In the hyperlipemic animals, ciprofibrate reduced the incorporation of [3H]oleate into the liver and plasma glycerolipid and increased cholesterol esterification. Ciprofibrate efficiently reduces plasma levels of cholesterol, triglyceride and phospholipid. Cholesterol and glycerolipid synthesis in the liver were significantly reduced leading to a lower lipoprotein secretion rate in both normolipidemic and diet-induced hyperlipidemic rats.     

The effects of conjugated equine estrogens plus cyclical dydrogesterone on serum lipoproteins and apoproteins in postmenopausal women

Serum lipoprotein and apoprotein concentrations were monitored for 24 weeks in 26 postmenopausal women treated with conjugated equine estrogens (0.625 mg/day) with the addition of dydrogesterone (10 mg/day) for the last 12 days of each 28 day cycle. The women had had no previous hormone replacement therapy. The estrogen plus dydrogesterone regimen caused significant (P less than 0.05) increases in triacylglycerol and HDL cholesterol concentrations. Both HDL2 and HDL3 cholesterol were increased. There were no other significant changes in lipoprotein concentrations. Both apoprotein AI and apoprotein AII concentrations increased significantly (P less than 0.05) over the study period. The ratios of apoprotein AI to apoprotein AII, apoprotein AI to HDL cholesterol and apoprotein AII to HDL cholesterol did not change. At the doses employed in this study, the use of dydrogesterone as a progestogen alters the effects of conjugated equine estrogens on lipoproteins and reinforces the view that the effects of a combined HRT regimen cannot be predicted from a consideration of the effects of the individual components.     

High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus: measurement of HDL turnover using tritiated HDL

High density lipoprotein (HDL) kinetics were studied by injecting [3H]apoprotein A-I (apoA-I)/HDL into 12 subjects with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM). The results indicate that the mean fractional catabolic rate (FCR) of apoA-I/HDL was significantly faster [0.63 +/- 0.07 (+/- SEM) vs. 0.39 +/- 0.02 1/day; P less than 0.001] and the apoA-I/HDL synthetic rate greater (29.4 +/- 2.9 vs. 22.9 +/- 1.3 mg/kg X day; P less than 0.02) in patients with NIDDM than in normal subjects. Furthermore, there were statistically significant inverse relationships between apoA-I/HDL FCR and plasma levels of both HDL cholesterol (r = -0.71; P less than 0.001) and apoA-I (r = -0.63; P less than 0.001). In addition, the increase in apoA-I/HDL FCR was directly related to fasting plasma glucose (r = 0.78; P less than 0.001) and insulin (r = 0.76; P less than 0.001) concentrations. These data support the view that the decrease in plasma HDL cholesterol and apoA-I levels commonly found in patients with noninsulin-dependent diabetes is due to an increase in the catabolic rate of apoA-I/HDL secondary to the defects in carbohydrate metabolism present in these patients.     

Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia

The aim of this study was to evaluate the effects of rosuvastatin and fenofibrate alone and in combination in type 2 diabetes associated with combined hyperlipidaemia. A total of 216 patients with total cholesterol >/=200 mg/dl (>/=5.17 mmol/l) and triglycerides >/=200 and <800 mg/dl (>/=2.26 and <9.03 mmol/l) were randomised to one of two placebo groups, rosuvastatin 5 mg or rosuvastatin 10 mg for 6 weeks (fixed-dose phase). During the subsequent 18-week dose-titration phase, one placebo group received titrated rosuvastatin 10, 20 and 40 mg (placebo/rosuvastatin); one placebo group received titrated fenofibrate 67 mg once, twice and three times daily (placebo/fenofibrate); and patients receiving 5 or 10 mg rosuvastatin received titrated fenofibrate as above (rosuvastatin 5mg/fenofibrate and rosuvastatin 10 mg/fenofibrate groups). Doses were increased at 6-week intervals if low-density lipoprotein (LDL) cholesterol remained >50 mg/dl (>1.3 mmol/l). At 24 weeks, the placebo/rosuvastatin group and placebo per fenofibrate group had triglyceride reductions of 30.3% versus 33.6%, respectively (P = NS), and LDL cholesterol was reduced by 46.7% in the rosuvastatin group and increased by 0.7% in the fenofibrate group (P < 0.001). The triglyceride reduction in the rosuvastatin 10 mg/fenofibrate group (47.1%) was significantly greater than in the placebo/rosuvastatin group (P = 0.001), with no significant differences in other lipid measures found between these two groups. No significant differences in effect on high-density lipoprotein (HDL) were observed among treatment groups. In the fixed-dose phase, rosuvastatin 5 and 10 mg reduced triglycerides by 24.5 and 29.5%, respectively, and decreased LDL cholesterol by 40.7 and 45.8%, respectively. All treatments were well tolerated. These results indicated that rosuvastatin produces marked reductions in triglycerides and LDL cholesterol when used alone or in combination with fenofibrate in type 2 diabetes patients with elevated cholesterol and triglyceride levels and may constitute a valuable treatment option in the diabetic population.     

Plasma high density lipoprotein particle size alteration by simvastatin treatment in patients with hypercholesterolaemia.

Twenty-two patients with pronounced hypercholesterolaemia were treated with simvastatin in increasing doses, i.e. 10, 20 and 40 mg O.D. Each treatment regimen had a duration of 6 weeks. In addition to the expected low density lipoprotein (LDL)-lowering effect, simvastatin altered the plasma HDL particle size spectrum by selective elevation of the plasma HDL2b and HDL3a levels, as defined by polyacrylamide gradient gel electrophoresis (gge). While the reduction in LDL cholesterol by simvastatin was dose dependent, the effect on HDL was maximal already at 10 mg daily. On treatment with simvastatin 10 mg O.D., the plasma HDL2b and HDL3a concentrations increased by 30% (P less than 0.001) and 12% (P less than 0.01) respectively. On the corresponding treatment with simvastatin LDL cholesterol decreased by 31% (P less than 0.001). The very low density lipoprotein (VLDL) cholesterol to triglyceride ratio was significantly lowered by treatment with 10 mg simvastatin O.D. suggesting a compositional change in VLDL. Positive univariate correlations between treatment-induced decreases in plasma HDL3b/3c levels and VLDL triglyceride concentration were seen. It is suggested that inhibition of cholesterol synthesis in hypercholesterolaemic subjects by simvastatin treatment alters the composition of VLDL, which may affect the close relation between HDL and VLDL, in turn producing selective elevations of the plasma HDL2b and HDL3a levels.     

The effect of statins and fibrates on interferon-gamma and interleukin-2 release in patients with primary type II dyslipidemia

The aim of the study was to assess the effect of two major groups of hypolipemic drugs, HMG-CoA reductase inhibitors (statins) and PPARalpha activators (fibrates), on the secretory function of T-lymphocytes in patients with primary type II dyslipidemia. Sixty-three patients with type IIa dyslipidemia were randomized to fluvastatin (40 mg daily; n = 33) or simvastatin (20mg daily; n = 30), while 68 type IIb dyslipidemic patients were treated with micronized ciprofibrate (100mg daily; n = 34) or micronized fenofibrate (200mg daily; n = 34). Lipid profile and cytokine (interferon-gamma and interleukin-2) release by phytohemagglutinin-stimulated lymphocytes were determined at the beginning of the study and after 30 and 90 days of treatment. Compared to healthy subjects (n = 59), both type IIa and IIb dyslipidemic patients exhibited higher baseline release of interferon-gamma and interleukin-2. Fluvastatin, simvastatin and, to a less extent, ciprofibrate and fenofibrate inhibited the release of both cytokines, but this effect did not correlate with their lipid-lowering potential. Hypolipemic agents also slightly reduced plasma interleukin-2 levels. Our study suggests that the beneficial effect of hypolipemic drugs involves their inhibitory action on the secretory function of T-lymphocytes. This lipid-independent action is stronger for statins than for fibrates and probably results from their "class" effect. The treatment-induced reduction in the release of both cytokines may contribute to the clinical effectiveness of statins and fibrates in the therapy of atherosclerosis and in the management of organ transplant recipients.     

Prevalence of serum lipid abnormalities in chronic hemodialysis.

Fasting levels of serum triglyceride, cholesterol, high-density lipoprotein (HDL), apoprotein A-I, HDL cholesterol, and HDL triglyceride were measured in 94 uremic males receiving maintenance hemodialysis and 6 uremic males receiving chronic peritoneal dialysis. These patients had higher serum triglyceride levels (p less than 0.001) and lower cholesterol levels (p less than 0.001) than normal controls. The dialysis patients treated with androgen or propranolol and those who were hypothyroid or diabetic had significantly higher triglyceride levels than the other dialysis subjects. The dialysis patients who had no additional secondary causes of hypertriglyceridemia had abnormalities in HDL; in comparison to normals and triglyceride-matched controls, these patients had elevated HDL triglyceride levels and low HDL cholesterol levels, despite similar HDL apoprotein A-I levels. The HDL cholesterol levels appeared to be lower in those patients than could be accounted for by their degree of hypertriglyceridemia.     

Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia

Nicotinic acid was given in a 4-g daily dose for 6 weeks to 41 weight-stable patients of mean age (+/- SD) 52 +/- 9 years, with type IIa, type IIb or type IV hyperlipoproteinaemia (HLP), in order to study its effects on serum cholesterol concentrations of high density lipoprotein (HDL) subfractions HDL2 and HDL3. The triglyceride and cholesterol levels of serum very low density (VLDL) and low density (LDL) lipoproteins decreased during treatment (P less than 0.001). Serum HDL and HDL2 cholesterol levels increased by 37% and 135%, respectively. These changes were positively correlated (r = 0.93; P less than 0.001). There was no significant change in mean serum HDL3 cholesterol concentration. A negative correlation existed between changes in HDL3 and HDL2 cholesterol levels (r = -0.54; P less than 0.001). Multiple stepwise linear regression analyses revealed that the initial HDL3 cholesterol predicted more than 30% of the increase in HDL2 cholesterol. Changes in the concentrations of HDL2 and HDL3 cholesterol after 6 weeks of drug treatment were not related to the type of HLP, neither were these effects of nicotinic acid correlated with changes in VLDL or LDL lipid levels. The concept has previously been proposed, on the basis of in vitro data, that HDL2 is formed from HDL3 particles in the blood. Our results suggest that, in man, this reaction is stimulated in vivo by prolonged nicotinic acid therapy.     

Comparison about the efficacy and tolerability between simvastatin and bezafibrate in the treatment of hypercholesterolemia]

Simvastatin and bezafibrate actions on blood lipids and their side effects were compared in a double-blind trial involving 24 adults with severe type IIa or IIb primary hypercholesterolemia (mean plasma cholesterol = 4.35 g/l). During a 12-week period, the patients received either bezafibrate, 600 mg 3 times a day, or simvastatin, 10 or 20 mg once a day, with a doubling of the dosage at week 6 if the LDL-cholesterol level remained above 1.40 g/l. Simvastatin significantly reduced LDL-cholesterol by -39.5% (p less than 0.001), total cholesterol by 33.9% (p less than 0.005) and apoprotein B by -28% (p less than 0.001). Bezafibrate significantly reduced LDL-cholesterol (-19.8%, p less than 0.001) and total cholesterol (-17.5%, p less than 0.002), but not apoprotein B. Bezafibrate also reduced triglycerides by -26.6% and raised HDL-cholesterol by +27.6%. Simvastatin was more effective than bezafibrate in lowering LDL-cholesterol (p less than 0.002), total cholesterol (p less than 0.005) and apoprotein B (p less than 0.05). Tolerance of both drugs was considered excellent.     

High density lipoprotein metabolism in endurance athletes and sedentary men

BACKGROUND. Endurance athletes have higher high density lipoprotein (HDL) concentrations than sedentary controls. To examine the mechanism for this effect, we compared HDL apoprotein metabolism in 10 endurance athletes aged 34 +/- 6 years (mean +/- SD) and 10 sedentary men aged 36 +/- 8 years. METHODS AND RESULTS. Subjects were maintained on controlled diets for 4 weeks, and metabolic studies using autologously labeled 125I HDL were performed during the final 2 weeks. Lipids and lipoproteins were measured daily during these 2 weeks, and the average of 14 values was used in the analysis. HDL cholesterol (58 +/- 14 versus 41 +/- 10 mg/dl), HDL2 cholesterol (26 +/- 10 versus 12 +/- 8 mg/dl), and apolipoprotein A-I (apo A-I) (144 +/- 18 versus 115 +/- 22 mg/dl) were higher in the athletes, whereas triglyceride concentrations (60 +/- 18 versus 110 +/- 48 mg/dl) were lower (p less than 0.01 for all). Postheparin lipoprotein lipase activity was not different, but hepatic triglyceride lipase activity was 27% lower (p less than 0.06) in the athletes. The athletes' mean clearance rate of triglycerides after an infusion of Travamulsion (1 ml/kg) was nearly twofold that of the inactive men (5.8 +/- 1.5 versus 3.2 +/- 0.9%/min, p less than 0.001). There was no differences in HDL apoprotein synthetic rates, whereas the catabolic rates of both apo A-I (0.15 +/- 0.02 versus 0.22 +/- 0.05 pools per day, p less than 0.01) and apolipoprotein A-II (apo A-II) (0.15 +/- 0.02 versus 0.20 +/- 0.04 pools per day, p less than 0.05) were reduced in the trained men. Apo A-I and apo A-II half-lives correlated with HDL cholesterol in each group (r greater than 0.76, p less than 0.05 for all) but not consistently with lipase activities or fat clearance rates. This relation between apoprotein catabolism and HDL cholesterol was strongest at HDL cholesterol concentrations of less than 60 mg/dl. CONCLUSIONS. We conclude that higher HDL levels in active men are associated with increased HDL protein survival. The mechanisms mediating this effect require better definition, and other factors appear to contribute to HDL cholesterol and protein concentrations among individual subjects.     

A comparative study of the effects of acipimox and clofibrate in type III and type IV hyperlipoproteinemia

Acipimox, an analogue of nicotinic acid, is a hypolipidemic drug with antilipolytic activity. Ten patients with type III and 10 with type IV hyperlipoproteinemia participated in a comparative open cross-over study of the effect of acipimox (750 mg/day) and clofibrate (2 g/day) on lipoproteins, apoliproproteins and postheparin lipase activities during 6 weeks. During acipimox treatment 2 type III patients complained of flushing, resulting in one drop-out. In the type III patients serum cholesterol decreased 30% (P less than 0.01) during treatment with acipimox and 24% (P less than 0.01) with clofibrate, and serum triglycerides 48% (P less than 0.01) and 34% (P less than 0.01), respectively. In the type IV patients serum cholesterol remained unchanged and serum triglycerides decreased 34% (P less than 0.05) and 35% (P less than 0.01), respectively. HDL cholesterol increased during treatment with both drugs in both groups between 6 and 15% (P less than 0.05) mainly due to a rise in HDL3 cholesterol (d greater than 1.100 g/ml). LDL cholesterol increased significantly during treatment with clofibrate, but not with acipimox. There were no or slight changes in the apoproteins A and B. Postheparin lipoprotein lipase increased during clofibrate treatment and hepatic lipase decreased during acipimox treatment. We concluded that acipimox in a dose of 750 mg/day has a similar hypolipidemic effect as 2 g clofibrate daily in type III and IV hyperlipoproteinemia.     

A dose-response relationship between sex hormone-induced change in hepatic triglyceride lipase and high-density lipoprotein cholesterol in postmenopausal women

In previous studies, we have demonstrated a temporal relationship between the postheparin hepatic triglyceride lipase (HTGL) response to sex steroids and the high-density lipoprotein (HDL) cholesterol response. To determine if this relationship is dose-dependent, we compared the effect of three graduated doses of orally administered estradiol and norgestrel in two groups of six postmenopausal women. With estradiol administration, postheparin HTGL activity decreased from 91 +/- 46 to 50 +/- 29 nmol/min/mL, baseline to high dose (P less than .05); HDL cholesterol increased from 54 +/- 6 to 64 +/- 10 mg/dL (P less than .05); HDL2 cholesterol increased from 16 +/- 4 to 23 +/- 7 mg/dL (P less than .05); and HDL3 cholesterol concentration did not change. With norgestrel administration, HTGL activity increased from 79 +/- 19 to 109 +/- 24 nmol/min/mL (P less than .05); HDL cholesterol decreased from 64 +/- 17 to 43 +/- 7 mg/dL (P less than .05); HDL2 cholesterol decreased from 21 +/- 17 to 6 +/- 5 mg/dL (P less than .05); and HDL3 cholesterol concentration decreased from 43 +/- 8 to 38 +/- 8 mg/dL (P less than .05). The HTGL activity response was inversely correlated with estrogen dose (rs = -.733, P = .0001) and directly correlated with progestin dose (rs = .895, P = .0001). The HDL cholesterol response was directly correlated with estrogen dose (HDL: rs = .741, P = .001; HDL2: rs = .586, P = 0.003) and inversely correlated with progestin dose (HDL: rs = -.933, P = .0001; HDL2: rs = -.866, P = .0001; HDL3: rs = -.576, P = .003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-dependent effect on serum cholesterol and apoprotein B concentrations by consumption of boiled, non-filtered coffee

The effects of boiled coffee (BC) and filtered coffee (FC) on serum lipoproteins were compared in 41 healthy subjects whose serum cholesterol concentration was less than 7 mmol/l. The subjects consumed in random order BC and FC for 4-week periods in a crossover design. The individual daily consumption ranged from 2 to 14 cups (mean 5.7 cups per day) and was similar during both study periods. The serum total and LDL-cholesterol and apoprotein B concentrations were higher (P less than 0.001) and HDL-cholesterol lower (P less than 0.05) after BC than after FC. Bodyweight, apoprotein A-I and triglycerides remained unchanged. In the 16 subjects who consumed coffee less than 5 cups per day the difference in serum total cholesterol between the BC and FC periods was non-significant (P = 0.16). The differences in serum total cholesterol and LDL-cholesterol between the periods showed significant linear correlations with the amount of coffee consumed daily (r = 0.52, P less than 0.001 and r = 0.33, P less than 0.05, respectively) but no association was found between the difference in HDL-cholesterol and the amount of coffee (r = 0.14, P = 0.39). The results indicate a dose-dependent increasing effect on serum total and LDL-cholesterol and apoprotein B concentrations of boiled coffee.     

Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen

Serum proteins and lipoproteins were determined in 23 menopausal females after surgery for early forms of breast cancer and the results compared with data from a matched group of randomly selected healthy females. The patients were randomly divided into 2 groups, one serving as a control group, the other receiving 40 mg tamoxifen daily for 2 months. Breast cancer patients were found to have significantly higher concentrations of serum cholesterol than controls (7.90 +/- 1.15 vs. 6.87 +/- 1.18 mmol/l, P less than 0.001), which was the result of a 16% higher concentration in LDL cholesterol (P less than 0.05) and a 13% higher concentration in HDL cholesterol (P less than 0.05). During tamoxifen therapy total TG tended to increase, whereas total cholesterol fell. Significant lipoprotein changes were found in the LDL fraction where LDL-TG increased from 0.46 to 0.56 (P less than 0.01) and LDL cholesterol fell from 5.11 to 4.10 mmol/l (P less than 0.001). During tamoxifen therapy haptoglobin and orosomucoid concentrations fell significantly (P less than 0.01), whereas those of alpha-antitrypsin and ceruloplasmin increased (P less than 0.001). Factors such as diet and weight may explain the differences between breast cancer patients and controls. The tamoxifen-induced changes indicate that this anti-oestrogen exerted a mild oestrogen-like effect with regard to protein and lipoprotein metabolism.     

Statin + fibrate combination therapy--fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease

We evaluated the use of combination therapy (ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n = 13 in the ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P< or =0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with ciprofibrate (32 and 36%, respectively; P< or =0.001) than with bezafibrate (21 and 26%, respectively; P< or =0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option. Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed.     

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. I. A dose-response study

This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P less than or equal to 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P less than or equal to 0.001). Triglycerides decreased by as 15.4% (P less than or equal to 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P less than or equal to 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.     

Comparative effects of statin and fibrate on nitric oxide bioactivity and matrix metalloproteinase in hyperlipidemia

OBJECTIVE: Because the lipoprotein effects of statin and fibric acid derivatives therapies differ, we studied the effects of these therapies in patients with hyperlipidemia on lipoproteins, vasomotor function, and plaque stability. METHODS: We administered simvastatin, 20 mg daily, to 27 patients with hypercholesterolemia and coronary artery disease, or fenofibrate, 200 mg daily, to 27 patients with pure hypertriglyceridemia during 8 weeks. RESULTS: As expected, simvastatin significantly lowered total cholesterol and low-density lipoprotein cholesterol (LDL-C) more, and fenofibrate decreased triglyceride and increased high-density lipoprotein cholesterol (HDL-C) more than either therapy. Simvastatin and fenofibrate significantly improved the percent flow-mediated dilator response to hyperemia by 183+/-41% and by 30+/-7%, respectively (each P<0.001); however, simvastatin significantly improved more (P<0.001). Simvastatin and fenofibrate significantly lowered plasma levels of tumor necrosis factor alpha (TNF-alpha) by 13+/-4% and by 10+/-4%, respectively (P=0.009 and P=0.006, respectively) with a similar degree (P=0.614). Simvastatin significantly reduced plasma levels of total MMP-9 and TIMP-1 more (P=0.005 and P=0.036, respectively), compared with fenofibrate showing no reduction. There were significant correlations between the degree of changes in TNF-alpha and the degree of changes in MMP-9 activity (r=0.376, P=0.053). CONCLUSIONS: Simvastatin and fenofibrate demonstrated antiatherosclerotic effects via different mechanisms.     

Influence of beta 2 agonism and beta 1 and beta 2 antagonism on adverse effects and plasma lipoproteins: results of a multicenter comparison of dilevalol and metoprolol

Dilevalol combines vasodilation due to selective beta 2 agonism and nonselective beta antagonism. We studied 311 patients randomized to dilevalol and 138 to metoprolol in a multicenter trial. After a 4-week placebo washout, dilevalol was titrated from 200 to 1,600 mg once daily and metoprolol from 100 to 400 mg to a goal supine diastolic blood pressure less than 90 and greater than or equal to 10 mm Hg decrease from baseline. Responders were followed for 1 year. The average age of patients was 51 years; 72% were men and 54% were white. Both drugs reduced blood pressure effectively to a similar level. Fewer patients discontinued dilevalol than did those taking metoprolol (9 vs 16%; p less than 0.03). More metoprolol-treated patients withdrew because of depression (6 vs less than 1%; p = 0.03) and impotence (5 vs less than 1%; p = 0.03). Lipoprotein levels before and after treatment were measured in 99 patients treated for 53.5 weeks with dilevalol (mean dose 438 mg). Dilevalol increased high-density lipoprotein (HDL) cholesterol by 2.5 mg/dl to 47.2 (p = 0.05), reduced low-density lipoprotein (LDL) cholesterol by 2.5 mg/dl, increased HDL/LDL by 0.03, and decreased total cholesterol/HDL cholesterol by 0.18. Triglycerides increased by 21 mg/dl (p = 0.06). In patients with an initial HDL cholesterol less than 35 mg/dl, dilevalol increased it by 9 mg/dl. In patients treated with metoprolol, the only significant change (p = 0.02) was a 41.9-mg/dl increase in triglyceride levels.(ABSTRACT TRUNCATED AT 250 WORDS)