Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia

Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.     

Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia.

OBJECTIVE: To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile, including lipoprotein(a) levels, and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia (serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl, respectively, and serum triglyceride level > 200 mg/dl). METHODS: This was a 16-week, open-label, parallel-design study conducted in our lipid clinic. After a 6-week dietary baseline phase, we implemented a treatment phase, during which patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and fibrinogen, as well as muscle and liver enzymes, were measured during screening, and during weeks -4, -2, 0, 8, and 16 of the treatment period. RESULTS: Atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was more effective at lowering levels of triglycerides, and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1. However, micronized fenofibrate could significantly decrease plasma fibrinogen levels, whereas atorvastatin evoked a small increase. CONCLUSION: Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia. However, there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels.     

Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome

Combined hyperlipidemia predisposes subjects to coronary heart disease. Two lipid abnormalities--increased cholesterol and atherogenic dyslipidemia--are potential targets of lipid-lowering therapy. Successful management of both may require combined drug therapy. Statins are effective low-density lipoprotein (LDL) cholesterol-lowering drugs. For atherogenic dyslipidemia (high triglycerides, small LDL, and low high-density lipoprotein [HDL]), fibrates are potentially beneficial. The present study was designed to examine the safety and efficacy of a combination of low-dose simvastatin and fenofibrate in the treatment of combined hyperlipidemia. It was a randomized, placebo-controlled trial with a crossover design. Three randomized phases were employed (double placebo, simvastatin 10 mg/day and placebo, and simvastatin 10 mg/day plus fenofibrate 200 mg/day). Each phase lasted 3 months, and in the last week of each phase, measurements were made of plasma lipids, lipoprotein cholesterol, plasma apolipoproteins B, C-II, and C-III and LDL speciation on 3 consecutive days. Simvastatin therapy decreased total cholesterol by 27%, non-HDL cholesterol by 30%, total apolipoprotein B by 31%, very low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL) cholesterol by 37%, VLDL + IDL apolipoprotein B by 14%, LDL cholesterol by 28%, and LDL apolipoprotein B by 21%. The addition of fenofibrate caused an additional decrease in VLDL + IDL cholesterol and VLDL + IDL apolipoprotein B by 36% and 32%, respectively. Simvastatin alone caused a small increase in the ratio of large-to-small LDL, whereas the addition of fenofibrate to simvastatin therapy caused a marked increase in the ratio of large-to-small LDL species. Simvastatin alone produced a small (6%) and insignificant increase in HDL cholesterol concentrations. When fenofibrate was added to simvastatin therapy, HDL cholesterol increased significantly by 23%. No significant side effects were observed with either simvastatin alone or with combined drug therapy. Therefore, a combination of simvastatin 10 mg/day and fenofibrate 200 mg/day appears to be effective and safe for the treatment of atherogenic dyslipidemia in combined hyperlipidemia.     

Comparison of the effects of atorvastatin or fenofibrate on nonlipid biochemical risk factors and the LDL particle size in subjects with combined hyperlipidemia

Background Combined hyperlipidemia (CH) is an increasingly prevalent risk factor for premature heart disease, and its treatment is troublesome. The aim of this study was to compare the effects of atorvastatin and fenofibrate on nonlipid biochemical risk factors and the low-density lipoprotein (LDL) particle size in subjects with CH. Methods Twenty-nine middle-aged men with CH were randomly assigned to open-label therapy with atorvastatin (10 mg daily) or micronized fenofibrate (200 mg daily); they were sequentially treated with both drugs, with crossover of medication after 10 weeks. Results Atorvastatin was more efficient in the reduction of total cholesterol, whereas fenofibrate was more efficient in the reduction of triglycerides. Only atorvastatin led to a significant reduction of LDL cholesterol and apolipoprotein B. Only fenofibrate increased high-density lipoprotein cholesterol. Neither drug influenced lipoprotein(a). Mean LDL particle size increased both after fenofibrate (3.08%) and atorvastatin (1.77%). Fenofibrate increased serum homocysteine (HCY) by 36.5%. Atorvastatin had no effect on HCY. Only atorvastatin increased fibrinogen by 17.4%. Only fenofibrate reduced C-reactive protein by 51.7%. Neither drug influenced HOMA (homeostasis model assessment) index of insulin resistance. The plasma level of thiobarbituric acid reactive substances, an index of oxidative stress, decreased after both treatments. Conclusions Both atorvastatin and fenofibrate had similar beneficial effects on LDL particle size and on oxidative stress. The effects of both drugs on other parameters such as triglycerides, total and high-density lipoprotein cholesterol, fibrinogen, or HCY differed significantly. These differences, together with the risk profile of a patient, should be considered during selection of a particular lipid-lowering modality. (Am Heart J 2002;144:e6.)     

Comparison of treatment of severe high-density lipoprotein cholesterol deficiency in men with daily atorvastatin (20 mg) versus fenofibrate (200 mg) versus extended-release niacin (2 g)

To determine whether available lipid-modifying medication can increase high-density lipoprotein (HDL) cholesterol in well-defined genetic or familial HDL-deficiency states, we studied 19 men with HDL deficiency (HDL cholesterol <5th percentile for age and gender) 55 +/- 10 years of age. Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had coronary artery disease. Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene. Patients were assigned to sequentially receive atorvastatin 20 mg/day, fenofibrate 200 mg/day, and extended-release niacin 2 g/day for 8 weeks, with a 4-week washout period between each treatment. Patients in whom a statin was required, according to current treatment guidelines, were kept on atorvastatin throughout the study. Baseline HDL cholesterol level was 0.63 +/- 0.12 mmol/L (24 +/- 5 mg/dl), triglycerides 2.01 +/- 0.98 mmol/L (180 +/- 86 mg/dl), and low-density lipoprotein (LDL) cholesterol 2.29 +/- 0.95 mmol/L (94 +/- 39 mg/dl). Mean percent changes in HDL cholesterol on atorvastatin, fenofibrate, and niacin were -6% (p = NS), +6% (p = NS), and +22% (p <0.05), respectively. Furthermore, niacin significantly increased the large alpha-1 apolipoprotein A-I-containing HDL subspecies (12 to 17 nm). In conclusion, niacin was the only effective drug to increase HDL cholesterol. The absolute increase in HDL cholesterol, approximately 0.10 mmol/L (3.9 mg/dl), is of uncertain clinical significance. Biomarkers of HDL-mediated cellular cholesterol efflux were not changed by niacin therapy. Atorvastatin or fenofibrate had little effect on HDL cholesterol; atorvastatin decreased the total cholesterol/HDL cholesterol ratio by 26%. Fenofibrate did not change HDL cholesterol levels and caused an increase in LDL cholesterol. Aggressive LDL cholesterol lowering may be the strategy of choice in such patients.     

Qualitative effect of fenofibrate and quantitative effect of atorvastatin on LDL profile in combined hyperlipidemia with dense LDL.

INTRODUCTION: The association of elevated plasma triglyceride concentrations, decreased HDL-cholesterol, and dense LDL (dLDL) is referred to as the atherogenic lipoprotein phenotype. dLDL particularly plays a role in the metabolic syndrome and type 2 diabetes and may be one of the factors responsible for the increased risk for coronary artery disease in these patients. The effect of fenofibrate and atorvastatin on the LDL subfraction profile in patients with combined hyperlipidemia and a preponderance of dLDL was studied in a sequential design. METHODS: Six male patients with combined hyperlipidemia and dLDL received 160 mg/die supra-bioavailable fenofibrate. After a washout phase of 8 weeks all patients received 10 mg/die atorvastatin for another 8 weeks. At baseline, after fenofibrate, and after atorvastatin treatment LDL subfractions were analyzed by equilibrium density gradient ultracentrifugation. RESULTS: Treatment with atorvastatin and fenofibrate reduced serum cholesterol by 30 % and 21 % (p = 0.046) (p-values for differences between treatment groups), triglycerides by 32 % and 45 %, LDL cholesterol by 28 % and 16 %, and increased HDL cholesterol by 3 % and 6 %, respectively. Atorvastatin and fenofibrate treatment resulted in the following changes of apoB and LDL subfractions: LDL-1 (1.019 - 1.031 kg/L) - 31 % and + 15 % (p = 0.028); LDL-2 (1.031 - 1.034 kg/L) - 14 % and + 57 % (p = 0.028); LDL-3 (1.034 - 1.037 kg/L) - 20 % and + 30 % (p = 0.028); LDL-4 (1.037 - 1.040 kg/L) - 25 % and - 6 %; LDL-5 (1.040 - 1.044 kg/L) - 29 % and - 38 %; and LDL-6 (1.044 - 1.063 kg/L) - 39 % and - 55 % (p = 0.028). As a consequence, fenofibrate reduced LDL density significantly (p = 0.028 versus atorvastatin). CONCLUSIONS: Atorvastatin decreased all LDL-subfractions to a similar extent (quantitative effect) whereas fenofibrate reduced predominantly dLDL and changed the LDL profile towards medium dense LDL-particles (qualitative effect). Since medium dense LDL have a higher affinity to the LDL-receptor fenofibrate may have a higher antiatherogenic potential than assessed by the reduction of total LDL-cholesterol and triglycerides alone.     

The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant-antioxidant system in patients with dyslipidemia

BACKGROUND: Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is used for lipid-lowering therapy, is an effective statin modulating process involved in atherosclerosis. Paraoxonase (PON) associated with high-density lipoprotein (HDL) has been postulated to have a role in protecting low-density lipoprotein (LDL) against oxidative modification. Oxidation of serum LDL is an important early step in the development of atherosclerosis and auto-antibodies against oxidized LDL (AuAb-oxLDL) reflect in-vivo LDL oxidation. DESIGN AND METHODS: To examine the effect of atorvastatin (10 mg/day) therapy on PON activity in serum and HDL, the study group included 40 patients with dyslipidemia (19 women and 21 men), 25 of whom had hypercholesterolemia and of 15 of whom had mixed-type hyperlipidemia. By taking blood samples from the patients, levels of serum lipids, lipid peroxidation product as malondialdehyde (MDA), total antioxidant status (TAS) and AuAb-oxLDL and the activities of PON in serum and isolated HDL were determined. RESULTS: The mean levels of total cholesterol, triglyceride, LDL-cholesterol, MDA and AuAb-oxLDL were decreased while HDL-cholesterol and TAS were increased significantly after lipid-lowering therapy in patients with dyslipidemia. On the other hand, PON activities in serum and HDL were increased significantly. The percentage increase in serum PON activity was associated significantly with the percentage decrease in serum AuAb-oxLDL (r=-0.32, P=0.047) and that of HDL PON activity was associated with the percentage increase in HDL-cholesterol level after atorvastatin therapy (r=0.52, P=0.001). The therapy was more effective in increasing PON activity in patients with HDL levels above 35 mg/dl. CONCLUSION: It was concluded that atorvastatin therapy in dyslipidemic patients decreases the level of oxidative stress and increases PON activity, especially in patients with HDL levels above 35mg/dl.     

Comparison of efficacy and safety of atorvastatin (10mg) with simvastatin (10mg) at six weeks. ASSET Investigators

The 6-week efficacy and safety of atorvastatin versus simvastatin was determined during a 54-week, open-label, multicenter, parallel-arm, treat-to-target study. In all, 1,424 patients with mixed dyslipidemia (triglyceride 200 to 600 mg/dl [2.26 to 6.77 mmol/L]) were stratified to 1 of 2 groups (diabetes or no diabetes). Patients were then randomized to receive either atorvastatin 10 mg/ day (n = 730) or simvastatin 10 mg/day (n = 694). Efficacy was determined by measuring changes from baseline in lipid parameters including low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and apolipoprotein B. Compared with simvastatin, atorvastatin produced significantly greater (p < 0.0001) reductions from baseline in LDL cholesterol (37.2% vs 29.6%), total cholesterol (27.6% vs 21.5%), triglycerides (22.1% vs 16.0%), the ratio of LDL cholesterol to high-density lipoprotein (HDL) cholesterol (41.1% vs 33.7%), and apolipoprotein B (28.3% vs 21.2%), and a comparable increase from baseline in HDL cholesterol (7.4% vs 6.9%). Atorvastatin was also significantly (p < 0.0001) more effective than simvastatin at treating the overall patient population to LDL cholesterol goals (55.6% vs 38.4%). Fewer than 6% of patients in either treatment group experienced drug-attributable adverse events, which were mostly mild to moderate in nature. Diabetic patients treated with either statin had safety characteristics similar to nondiabetics, with atorvastatin exhibiting superior efficacy to simvastatin. In conclusion, atorvastatin, at a dose of 10 mg/day, is more effective than simvastatin 10 mg/day at lowering lipids and reaching LDL cholesterol goals in patients with mixed dyslipidemia. Both statins are well tolerated with safety profiles similar to other members of the statin class.     

Comparison of efficacy and safety of atorvastatin and simvastatin in patients with dyslipidemia with and without coronary heart disease

The efficacy and safety of atorvastatin 10 mg versus simvastatin 20 mg and atorvastatin 80 mg versus simvastatin 80 mg was determined in a 6-week, prospective, randomized, open-label, blinded end-point trial of dyslipidemic patients with and without coronary heart disease. A total of 1,732 patients with hypercholesterolemia and triglycerides < or =600 mg/dl (6.8 mmol/L) were randomized to receive either atorvastatin 10 mg (n = 650), simvastatin 20 mg (n = 650), atorvastatin 80 mg (n = 216), or simvastatin 80 mg (n = 216). The primary efficacy parameter was the change in low-density lipoprotein (LDL) cholesterol from baseline to week 6. Secondary efficacy parameters included the percent change from baseline to week 6 in total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, very-low-density lipoprotein cholesterol, apolipoprotein B, and the percent of patients achieving their National Cholesterol Education Program (NCEP) LDL cholesterol goal at study end. Atorvastatin had significantly greater reductions from baseline in LDL cholesterol than simvastatin in both comparator groups: atorvastatin 10 mg (37.1%) versus simvastatin 20 mg (35.4%) (p = 0.0097), and atorvastatin 80 mg (53.4%) versus simvastatin 80 mg (46.7%) (p <0.0001). Atorvastatin 10 and 80 mg also provided significantly greater reductions in total cholesterol, triglycerides, very-low-density lipoprotein cholesterol, and apolipoprotein B than simvastatin 20 and 80 mg, respectively (all p <0.05). All treatment groups had a significantly decreased LDL cholesterol/HDL cholesterol ratio from baseline (all p <0.0001). In both comparator groups a higher proportion of atorvastatin-treated patients reached their NCEP LDL cholesterol goal compared with simvastatin. All 4 study treatments were well tolerated.     

Effects of atorvastatin on serum lipids, lipoproteins, and hemostasis

Serum levels of lipids and lipoproteins were examined in individuals with hyperlipidemia treated with atorvastatin or colestimide and in healthy volunteers. Modified low-density lipoprotein (LDL) was measured by its faster electrophoretic mobility and expressed as charge modification frequency (CMF). Serum levels of total cholesterol (t-chol), triglyceride (TG), very low-density lipoprotein (VLDL)-chol, low-density lipoprotein (LDL)-chol, and CMF were significantly higher in hyperlipidemia, but there was no significant difference in serum high-density lipoprotein (HDL)-chol levels between hyperlipidemic and healthy subjects. Treatment with atorvastatin resulted in significant decreases of serum t-chol, TG, and LDL-chol levels but not serum HDL-chol and VLDL-chol. Treatment with colestimide significantly reduced serum t-chol, HDL-chol, and LDL-chol levels but not those of TG and VLDL-chol. CMF was significantly reduced by treatment with atorvastatin but not by colestimide. Atorvastatin significantly reduced plasma levels of thrombomodulin, thrombin antithrombin complex (TAT) and tissue type plasminogen activator-plasminogen activator inhibitor-I complex. Colestimide moderately prolonged activated partial thromboplastin time and reduction of TAT. Based on its actions of lowering modified LDL and improving hemostatic abnormalities, we postulate that atorvastatin might inhibit the onset of ischemic diseases.     

Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels

Apolipoprotein B has been shown to be a better predictor of coronary heart disease than low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol may also be a better parameter for coronary heart disease risk assessment and as a target for therapy. Data from the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) were used to assess the correlation between lipid and apolipoprotein B levels before and after lipid-lowering therapy and to examine the effects of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on lipids and apolipoprotein B. The 54-week study randomized 3,916 hypercholesterolemic patients to atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin, initiated at recommended starting doses with titrations as needed at weeks 6, 12, and 18 to achieve National Cholesterol Education Program LDL targets. Compared with LDL cholesterol, non-HDL cholesterol correlated better with apolipoprotein B levels at baseline (r = 0.914, p <0.0001) and at week 54 (r = 0.938, p <0.0001), and the correlation was strong across all baseline triglyceride strata. At starting doses, atorvastatin (10 mg) lowered non-HDL cholesterol by 33.3% compared with 26.6% with simvastatin (10 mg), 24.1% with lovastatin (20 mg), 17.2% with fluvastatin (20 mg), and 17.0% with pravastatin (10 mg). Atorvastatin also provided greater reductions in non-HDL cholesterol after dose titration, and a greater percentage of patients taking atorvastatin achieved non-HDL cholesterol targets. Baseline triglyceride did not affect non-HDL cholesterol reductions with any of the 5 hydroxymethylglutaryl coenzyme A reductase inhibitors. Fewer patients achieved non-HDL cholesterol targets than LDL cholesterol targets, particularly among high-risk patients, implying that if non-HDL cholesterol was used as a target for treatment, more patients would need to be treated more aggressively than National Cholesterol Education Program guidelines require.     

Efficacy of a low dose of pitavastatin compared with atorvastatin in primary hyperlipidemia: results of a 12-week, open label study

BACKGROUND: Pitavastatin has a potent cholesterol-lowering action. The clinical efficacy and safety of a low dose, 1 mg, of pitavastatin were examined. METHODS: The effect of 12 weeks' treatment with pitavastatin 1 mg in an open label, non-randomized trial involving 137 patients with hypercholesterolemia as compared with treatment with atorvastatin 10 mg. RESULTS: Total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride (TG) levels at baseline did not differ between the two groups. At follow-up, there were no significant differences in total cholesterol, LDL cholesterol and HDL cholesterol levels between the groups. The TG levels at follow-up were higher in the pitavastatin group than atorvastatin group (p < 0.01). In patients with hyperlipidemia type IIa, TG levels at follow-up were lower in the atorvastatin subgroup (p < 0.01). However, there was no significant difference in TG levels at follow-up between the two subgroups in patients with hyperlipidemia type IIb. CONCLUSION: Pitavastatin 1 mg daily was safe and efficacious in reducing LDL cholesterol levels as compared with atorvastatin 10 mg daily. Further randomized comparative studies are needed to clarify the effect of a low dose of pitavastatin.     

Effect of statins on LDL particle size in patients with familial combined hyperlipidemia: a comparison between atorvastatin and pravastatin

BACKGROUND AND AIM: Elevation of plasma cholesterol and/or triglycerides, and the prevalence of small dense low density lipoproteins (LDL) particles remarkably increase the risk in patients with familial combined hyperlipidemia (FCHL). There are, at present, inconsistent data on the effects of different treatments on size and density of LDL particles in FCHL patients. METHODS AND RESULTS: A multicenter, randomized, double-blind, double-dummy, parallel group study was designed to evaluate the effect of 3 months' treatment with atorvastatin (10mg/day) or pravastatin (20mg/day) on the lipid/lipoprotein profile and LDL size in a total of 86 FCHL patients. Both statins significantly lowered plasma total and LDL cholesterol, with a significantly higher hypocholesterolemic effect observed with atorvastatin (-26.8+/-11.1% and -35.9+/-11.1%, respectively) compared to pravastatin (-17.6+/-11.1% and -24.5+/-10.2%). The percent decrease in plasma triglycerides was highly variable, but more pronounced with atorvastatin (-19.8+/-29.2%) than with pravastatin (-5.3+/-48.6%). Opposite changes in LDL size were seen with the 2 treatments, with increased mean LDL particle diameter with atorvastatin, and decreased diameter with pravastatin, and significant between treatment difference in terms of percent modification vs baseline (+0.5+/-1.6% with atorvastatin vs -0.3+/-1.8% with pravastatin). CONCLUSIONS: The present results support the evidence indicative of a greater hypocholesterolemic effect of atorvastatin compared to pravastatin, and in addition show a raising effect of atorvastatin on the size of LDL particles in FCHL patients.     

Fibrates in combination with statins in the management of dyslipidemia

While elevated low-density lipoprotein cholesterol is the primary target of hypercholesterolemia treatment, high triglycerides and low high-density lipoprotein cholesterol are also important targets for therapy. Correcting these lipid abnormalities should be an integral part of therapy in hypertensive individuals. Medications such as the fibrates are effective and well tolerated for reducing triglycerides and increasing high-density lipoprotein cholesterol, and their use has resulted in a reduction in cardiovascular events. Fibrates are also recommended as adjunct therapy for patients receiving statins whose low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol is not reduced to goal levels. The combination of a statin and a fibrate may, however, raise the risk of myopathy and rhabdomyolysis. Gemfibrozil, one of the fibrates, but not fenofibrate, interferes with statin glucuronidation, which may increase the risk of myopathy due to elevations in statin serum levels. This may at least partially explain the lower incidence of myopathy with fenofibrate compared with gemfibrozil when combined with statins. Combination therapy with a fibrate and a statin is a potentially useful therapy for patients with atherogenic lipid profiles, for which fenofibrate appears to be a more appropriate choice due to less myopathic potential.     

Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil)

This analysis was conducted to evaluate the effect of baseline triglyceride levels on lipid and lipoprotein changes after treatment with the combination of fluvastatin and fibrates. The analysis involved pooling data from 10 studies that included 1,018 patients with either mixed hyperlipidemia or primary hypercholesterolemia. Patients received a combination of fluvastatin and a fibrate (bezafibrate, fenofibrate, or gemfibrozil) from 16 to 108 weeks. The combination of fluvastatin and a fibrate improved lipid profiles, with reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol that were dependent on baseline triglyceride levels. The greatest triglyceride reductions were observed in patients with high baseline triglyceride levels (> or =400 mg/dl) (41%, p <0.0001). The greatest LDL cholesterol and non-HDL cholesterol reductions occurred in patients with normal baseline triglyceride levels (<150 mg/dl) (35% and 33%, respectively; p <0.0001). The combined fluvastatin-fibrate therapy was well tolerated. Two patients (0.2%) (1 patient on fluvastatin 80 mg + gemfibrozil 1,200 mg and 1 patient on fluvastatin 20 mg + fenofibrate 200 mg) had creatine kinase levels > or =10 times the upper limit of normal, 11 patients (1.1%) had an elevation in alanine transaminase >3 times the upper limit of normal, and 7 patients (0.7%) had elevations in aspartate transaminase >3 times the upper limit of normal. Combined fluvastatin-fibrate therapy takes advantage of the complementary effects of the 2 agents, with the extent of triglyceride, LDL cholesterol, and non-HDL cholesterol lowering dependent on baseline triglyceride levels. The combination of fluvastatin and fibrates was well tolerated with no major safety concerns.     

Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipoprotein (HDL) and its subclasses. Our purpose in this post hoc subanalysis of an open-label study was to compare the effects of daily oral doses of rosuvastatin 40 mg with atorvastatin 80 mg over a 6-week period on direct LDL cholesterol and small dense LDL (sdLDL) cholesterol in 271 hyperlipidemic men and women versus baseline values. Rosuvastatin was significantly (p<0.01) more effective than atorvastatin in decreasing sdLDL cholesterol (-53% vs -46%), direct LDL cholesterol (-52% vs -50%), total cholesterol/HDL cholesterol ratio (-46% vs -39%), and non-HDL cholesterol (-51% vs -48%), The magnitude of these differences was modest, and the 2 statins caused similar decreases in triglyceride levels (-24% and -26%). In conclusion, our data indicate that the 2 statins, given at their maximal doses, significantly and beneficially alter the entire spectrum of lipoprotein particles, but that rosuvastatin is significantly more effective than atorvastatin in lowering direct LDL cholesterol and sdLDL cholesterol.     

Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia

Five multicenter, randomized, double-blind, placebo-controlled studies were conducted in France to compare the efficacy and safety of once-daily simvastatin treatment (10–40 mg/day) with conventional therapy with gemfibrozil 900 mg/day, ciprofibrate 100 mg/day, bezafibrate 400 mg/day, and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia. Simvastatin was associated with statistically significantly greater (p ? 0.01) mean percent reductions in plasma low-density lipoprotein (LDL) cholesterol compared with each of the five fibrate regimens, even when administered at its recommended starting dose of 10 mg/day. Furthermore, approximately 90% of patients treated once daily with simvastatin experienced an at least 20% decrease in plasma LDL cholesterol compared with only 36 to 68% of patients treated with the individual fibrate agents (p ? 0.05). The effectiveness of simvastatin in reducing LDL cholesterol did not differ as a function of the baseline plasma concentrations of total cholesterol or triglycerides. In contrast, the effectiveness of fibrate therapy in lowering plasma LDL cholesterol levels was significantly diminished (p ? 0.05) among patients with triglyceride concentrations > 1.7 mmol/1. Plasma highdensity lipoprotein (HDL) cholesterol levels were increased by approximately 10% after treatment with simvastatin or the fibrates. Although fibrate therapy was more effective overall in lowering plasma triglyceride levels, the effectiveness of simvastatin in reducing plasma triglyceride levels was generally 2- to 4-fold greater in patients with hypercholesterolemia associated with triglyceride levels ? 2.3 mmol/1 than in those with hypercholesterolemia associated with triglyceride levels < 2.3 mmol/1. The results of these studies confirm the superiority of simvastatin to standard fibrate therapy in reducing plasma levels of total and LDL cholesterol. They further indicate that once-daily treatment with simvastatin is effective in patients with isolated hypercholesterolemia or hypercholesterolemia associated with elevated triglyceride levels.     

Combination therapy with fluvastatin and fenofibrate in ischemic heart disease patients with combined hyperlipidemia and type 2 diabetes

AIM: To assess efficacy of combination therapy with fluvastatin and fenofibrate in ischemic heart disease (IHD) patients with combined hyperlipidemia and type 2 diabetes. MATERIAL: Patients with IHD and combined hyperlipidemia with (n=56)) or without type 2 diabetes (n=30). METHODS: After 8-week diet period the patients were randomized to 4 weeks monotherapy with either fluvastatin (40 mg/day) or micronized fenofibrate (200 mg/day). In patients whose low-density lipoprotein cholesterol (LDL CH) remained > 2,6 mmol/1 and triglycerides (TG) > 2.3 mmol/1 combination of fluvastatin 40 mg/day and fenofibrate 200 mg/day was used for the next 12 weeks. RESULTS: Target levels of LDL CH and TG were achieved in 75 and 88%, respectively, of diabetics, and in 73 and 88%, respectively, of non-diabetics. CONCLUSION: The use of combination of fluvastatin and fenofibrate was more effective then monotherapy for correction of lipid abnormalities in combined hyperlipidemia both in diabetics and non-diabetics with IHD.     

Comparison of once-daily,niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE])

This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol <45 mg/dl in men and <50 mg/dl in women) were randomized to atorvastatin, simvastatin, or niacin ER/lovastatin for 16 weeks. The primary efficacy variables were the mean percent change in LDL cholesterol and HDL cholesterol levels from baseline. After 8 weeks, the starting dose niacin ER/lovastatin 1,000/40 mg and the 10-mg starting dose atorvastatin both lowered mean LDL cholesterol by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL cholesterol by 42% versus 34% with the 20-mg starting dose of simvastatin (p <0.001). Niacin ER/lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses (p <0.001). Niacin ER/lovastatin also provided significant improvements in triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B, and HDL subfractions. A total of 6% of study subjects receiving niacin ER/lovastatin withdrew because of flushing. No significant differences were seen among study groups in discontinuance due to elevated liver enzymes. No drug-induced myopathy was observed. Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simvastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either atorvastatin or simvastatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).     

Management of type IIb dyslipidemia

Although the Japan Atherosclerosis Society guideline for the diagnosis and prevention of atherosclerosis cardiovascular diseases for the Japanese population provides targets for low-density lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol to prevent cardiovascular disease in patients with dyslipidemia, there is no guideline specifically targeting the treatment of type IIb dyslipidemia, which is one of the most common types of dyslipidemia, along with type IIa and type IV dyslipidemia. Type IIb dyslipidemia is important because it sometimes accompanies atherogenic lipid profiles, such as small, dense LDL, remnants, low HDL cholesterolemia. It is also associated with type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease (CKD), and most patients with familial combined hyperlipidemia (FCHL) show this phenotype; therefore, it is assumed that patients with type IIb dyslipidemia have a high risk for cardiovascular disease. Thus, the management of type IIb dyslipidemia is very important for the prevention of cardiovascular disease, so we have attempted to provide a guideline for the management of type IIb dyslipidemia.