Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome

Background: Raised triglycerides (TG), decreased high‐density lipoprotein cholesterol (HDL‐C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). Objective: To compare the effect of high‐dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω‐3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. Methods: We previously randomised patients with low‐density lipoprotein cholesterol (LDL‐C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω‐3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. Results: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL‐C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. Conclusions: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.     

Contribution of apo CIII reduction to the greater effect of 12-week micronized fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients

BACKGROUND: Apolipoprotein (apo) CIII plays an important role in the catabolism of triglyceride-rich lipoproteins as it is a potent inhibitor of lipoprotein lipase (LPL). A low LPL activity has been simultaneously associated with hypertriglyceridemia, low HDL cholesterol and with small LDL particles. AIM: To compare the effects of a 12-week treatment with micronized fenofibrate (200 mg) versus atorvastatin (10 mg) on apo CIII and lipoprotein-lipid levels including LDL size. METHOD: After a 4-week washout period, dyslipidemic patients were randomized to either micronized fenofibrate (n = 64) or atorvastatin (n = 72). RESULTS: Both fenofibrate and atorvastatin significantly decreased apo CIII levels by -0.03 +/- 0.03 versus -0.01 +/- 0.03 g/l respectively, and increased LDL size by 4.9 +/- 3.3 versus 1.8 +/- 2.9 A. Improvements in these parameters were significantly greater with fenofibrate (P < 0.0001). Significant relationships were found between changes in triglycerides and changes in apo CIII (r = 0.81 and r = 0.59, P < 0.0001) as well as between changes in LDL size and changes in apo CIII (r = -0.41 and r = -0.45, P < 0.001), in both fenofibrate and atorvastatin groups. respectively. CONCLUSION: The substantial reduction in apo CIII induced by micronized fenofibrate plays an important role in the greater effect of micronized fenofibrate than atorvastatin on plasma triglycerides and LDL size.     

Cholesterol guidelines, lipoprotein cholesterol levels, and triglyceride levels: potential for misclassification of coronary heart disease risk

By using National Cholesterol Education Program guidelines for serum cholesterol (less than 200 mg/dl is designated "desirable," and 200 to 239 mg/dl is designated "borderline-high," and greater than or equal to 240 mg/dl is designated "high"), low-density and high-density lipoprotein (LDL, HDL) cholesterol levels and triglyceride levels were quantitated in 897 self-referred fasting subjects to assess the potential for coronary risk misclassification. With cholesterol less than 200 mg/dl, misclassification was arbitrarily identified by an LDL level greater than or equal to the 75th percentile, a triglyceride level greater than or equal to the 90th percentile, or an HDL level less than or equal to the 10th percentile. With the cholesterol level in the 200 to 239 mg/dl range, misclassification was identified by an LDL level greater than or equal to the 75th percentile, a triglyceride level greater than or equal to the 90th percentile, and an HDL level less than or equal to the 10th percentile or greater than or equal to the 90th percentile (or both). With a cholesterol level greater than or equal to 240 mg/dl, misclassification was identified by an HDL level less than or equal to the 10th percentile, or greater than or equal to the 90th percentile. With the cholesterol level less than 200 mg/dl, misclassification is rare, occurring in 14.5% of the subjects. With the cholesterol level in the 200 to 239 mg/dl range, and greater than or equal to 240 mg/dl, misclassification occurred in 46.7% and 17.6% of the subjects, respectively. The importance of routine lipoprotein analysis when the cholesterol level is greater than or equal to 240 mg/dl is emphasized by the finding that 65% of the subjects in this category had top quartile LDL levels, 8% had bottom decile HDL levels, and 30% had top decile triglyceride levels. To avoid misclassification, fasting HDL, LDL, and triglyceride levels should probably be measured in all subjects with screening cholesterol levels greater than or equal to 200. There is remarkably little misclassification with top quartile LDL or bottom decile HDL levels (or both) when the cholesterol level is less than 200 mg/dl.     

High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia

Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin- fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin- fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side- effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.      

Atorvastatin, a New HMG-CoA Reductase Inhibitor as Monotherapy and Combined With Colestipol

BACKGROUND: Atorvastatin, a new HMG-CoA reductase inhibitor in clinical development has demonstrated an acceptable safety profile and marked cholesterol and triglyceride reduction at doses ranging from 10-80 mg/day. Since bile acid sequestering resins are often used in combination with HMGRIs to enhance cholesterol reduction, this trial was conducted to explore the use of atorvastatin alone and combined with colestipol in patients with primary hyperlipidemia. METHODS AND RESULTS: One hundred six patients with low-density lipoprotein (LDL) cholesterol >4.1 mM/L (160 mg/dL) and plasma triglycerides <3.9 mM/L (350 mg/dL) were randomized to treatment consisting of 20 g/day colestipol, 10 mg/day atorvastatin, or 10 mg/day atorvastatin plus 20 g/day colestipol for 12 weeks. Percent change from baseline in lipid variables were measured. The atorvastatin group showed a significant reduction in LDL cholesterol of 35% after 12 weeks. Combination therapy provided an additional 10% reduction in LDL cholesterol over that observed for atorvastatin alone. Twenty-one percent of all patients in the atorvastatin monotherapy group experienced associated adverse events compared with 60% in the combination therapy group. Ninety percent of atorvastatin monotherapy patients were compliant at every visit compared with 75% receiving combination therapy. CONCLUSIONS: Although the combination of atorvastatin plus colestipol was more effective in lowering LDL cholesterol than atorvastatin alone, atorvastatin 10 mg/day monotherapy provided a better safety profile and improved patient compliance, which may result in improved long-term cholesterol control.     

Effects of atorvastatin 10 mg and fenofibrate 200 mg on the low-density lipoprotein profile in dyslipidemic patients: A 12-week, multicenter, randomized, open-label, parallel-group study

Background: Elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations are highly atherogenic, especially the small, dense LDL (sdLDL) species. Fenofibrate has been reported to shift the LDL profile by decreasing the sdLDL subfraction and increasing larger LDL subclasses. Atorvastatin, anantihyperlipidemic agent, has been reported to reduce plasma total cholesterol (TC) and triglyceride (TG) concentrations and thus could modify the LDL profile.Objective: The aim of this study was to compare the effects of fenofi brate and atorvastatin on standard lipid concentrations and the LDL profile.Methods: In this randomized, open-label, parallel-group study, men and women aged 18 to 79 years with type II primary dyslipidemia, defined as LDL-C ≥160 and TG 150 to 400 mg/dL, after a 4- to 6-week washout period while eating an appropriate diet, were randomized to receive either atorvastatin 10 mg once daily or fenofi-brate 200 mg once daily. Plasma lipid concentrations and cholesterol and apolipoprotein (apo) B (reflecting the LDL particle number) in each LDL subfraction prepared by ultracentrifiigation were determined at baseline and after 12 weeks of treatment. Tolerability was assessed using adverse events (AEs) obtained on laboratory analysis and vital sign measurement. Adherence was assessed by counting unused drug supplies.Results: A total of 165 patients (117 men, 48 women; mean [SD] age, 50.1 [10.7] years; mean TC concentration, 289 mg/dL) were randomized to receive atorvastatin (n = 81) or fenofibrate (n = 84). Compared with fenofibrate, atorvastatin was associated with a significantly greater mean (SD) percentage decrease in TC (27.0% [12.3%] vs 16.5% [12.9%]; P < 0.001), calculated LDL-C (35.4% [15.8%] vs 17.3% [17.2%]; P < 0.001), TC/high-density lipoprotein cholesterol (HDL-C) ratio (29.1% [16.3%] vs 22.9% [15.9%]; P = 0.001), and apoB (30.3% [12.7%] vs 19.6% [15.5%]; P < 0.001). Compared with atorvastatin, fenofibrate was associated with a significantly greater decrease in TG (37.2% [25.9%] vs 20.2% [27.3%]; P < 0.001) and a significantly greater increase in HDL-C concentration (10.4% [15.7%] vs 4.6% [12.1%]; P = 0.017). Fibrinogen concentration was significantly different between the 2 groups (P = 0.002); it was decreased with fenofibrate use (4.6% [23.7%]) and was increased with atorvastatin use (5.7% [23.5%]). Atorvastatin did not markedly affect the LDL distribution; it was associated with a homogeneous decrease in cholesterol and apoB concentrations in all subfractions, whereas fenofibrate was associated with a marked movement toward a normalized LDL profile, shifting the sdLDL subfractions toward larger and less atherogenic particles, particularly in those patients with baseline TG ≥200 mg/dL. No serious AEs related to the study treatments were reported. A total of 5 AEs were observed in 8 patients, including: abdominal pain, 3 patients (2 in the atorvastatin group and 1 in the fenofibrate group); abnormal liver function test results, 1 (fenofibrate); increased creatine Phosphokinase activity, 2 (atorvastatin); gastrointestinal disorders, 1 (fenofibrate); and vertigo, 1 (fenofibrate).Conclusion: In these dyslipidemic patients, fenofibrate treatment was associated with an improved LDL subfraction profile beyond reduction in LDL-C, particularly in patients with elevated TG concentration, whereas atorvastatin was associated with equally reduced concentrations of cholesterol and apoB in all LDL subfractions independent of TG concentrations.     

Contribution of apo CIII reduction to the greater effect of 12-week micronized fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients

BACKGROUND. Apolipoprotein (apo) CIII plays an important role in the catabolism of triglyceride-rich lipoproteins as it is a potent inhibitor of lipoprotein lipase (LPL). A low LPL activity has been simultaneously associated with hypertriglyceridemia, low HDL cholesterol and with small LDL particles.

AIM. To compare the effects of a 12-week treatment with micronized fenofibrate (200 mg) versus atorvastatin (10 mg) on apo CIII and lipoprotein-lipid levels including LDL size.

METHOD. After a 4-week washout period, dyslipidemic patients were randomized to either micronized fenofibrate (n = 64) or atorvastatin (n = 72).

RESULTS. Both fenofibrate and atorvastatin significantly decreased apo CIII levels by -0.03 ± 0.03 versus -0.01 ± 0.03 g/l respectively, and increased LDL size by 4.9 ± 3.3 versus 1.8 ± 2.9 Å. Improvements in these parameters were significantly greater with fenofibrate (P < 0.0001). Significant relationships were found between changes in triglycerides and changes in apo CIII (r = 0.81 and r = 0.59, P < 0.0001) as well as between changes in LDL size and changes in apo CIII (r = -0.41 and r = -0.45, P < 0.001), in both fenofibrate and atorvastatin groups. respectively.

CONCLUSION. The substantial reduction in apo CIII induced by micronized fenofibrate plays an important role in the greater effect of micronized fenofibrate than atorvastatin on plasma triglycerides and LDL size.     

国产阿托伐他汀治疗高危冠心病患者的疗效和安全性

目的:观察国产阿托伐他汀强化降脂治疗对冠心病高危患者的疗效和其安全性。方法:选择临床确诊为冠心病高危患者104例,随机分为两组:阿托伐他汀10mg.d-1组(n=50);阿托伐他汀40mg.d-1组(n=54)。分别于用药前、用药1个月、3个月、6个月时测定血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C),高密度脂蛋白胆固醇(HDL-C)、三酰甘油(TG)、血糖(GLU)、肝肾功能和肌酸激酶(CK),共治疗6个月。结果:(1)治疗6个月后,与治疗前相比,阿托伐他汀10mg.d-1组LDL-C、TC、TG水平分别降低38.04%、29.37%、20.74%,HDL水平升高了5.98%。40mg.d-1组LDL-C、TC、TG水平分别降低49.14%、37.69%、26.98%,HDL水平升高3.48%。10mg.d-1组LDL-C的达标率为54.00%,40mg.d-1组LDL-C的达标率为79.24%。两组间LDL-C的达标率有显著差异(P<0.01)。(2)两组间治疗前后肝肾功能和肌酸激酶等未见明显差异。结论:口服阿托伐他汀40mg.d-1较10mg.d-1治疗能更有效的降低LDL-C、TC和TG水平,使LDL-C水平达标率高,且两者的安全性一致。     

Clinical Efficacy and Tolerability of Ezetimibe in Combination With Atorvastatin in Japanese Patients With Hypercholesterolemia—Ezetimibe Phase IV Randomized Controlled Trial in Patients With Hypercholesterolemia

ObjectiveThe purpose of this study was to compare the efficacy and tolerability of combination therapy of ezetimibe and atorvastatin in patients with high LDL cholesterol that had not reached the lipid management target value with 10 mg atorvastatin monotherapy, against increasing the dose to 20 mg atorvastatin or switching to 2.5 mg rosuvastatin.Design, setting, and participantsThis was an open-label, randomized, multicenter, 3-parallel-group comparison trial at 23 community hospitals and clinics in Japan (enrollment period March 2009 to May 2010) in 125 patients with high LDL cholesterol.InterventionsA total of 125 Japanese patients with high LDL cholesterol level were randomized to 1 of the following 3 treatment groups: the ezetimibe (10 mg/d) and atorvastatin (10 mg/d) group, the atorvastatin (20 mg/d) group, or the rosuvastatin (2.5 mg/d) group for 12 weeks after treatment with 10 mg atorvastatin alone for 4 weeks.Main outcome measurePercent change in LDL cholesterol level from baseline (4 weeks after treatment with 10 mg atorvastatin alone) until study completion.ResultsThe percent change in LDL cholesterol level from baseline until study completion was statistically greater for the combination of 10 mg ezetimibe + 10 mg atorvastatin compared with increasing atorvastatin to 20 mg (?25.8% vs ?15.1%; P < 0.0001). A similar result was observed for ezetimibe + atorvastatin compared with switching to 2.5 mgt rosuvastatin (?25.8% vs 0.8%; P < 0.0001). The proportion of patients who reached the target LDL cholesterol value with the combination of ezetimibe + atorvastatin was significantly higher than increasing atorvastatin and switching to rosuvastatin (78.7%, 41.3%, and 3.1%, respectively). Although 5 serious adverse experiences bearing no relation to the study medications were reported, there were no adverse reactions.ConclusionsThe combination of 10 mg ezetimibe +10 mg atorvastatin was more effective than increasing atorvastatin to 20 mg or switching to 2.5 mg rosuvastatin in patients with hypercholesterolemia whose LDL cholesterol levels had not reached the recommended target value with 10 mg atorvastatin monotherapy for 4 weeks. Ezetimibe coadministration with atorvastatin was well tolerated. ClinicalTrials.gov identifier: NCT00871351.     

Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment. METHODS: We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment. RESULTS: We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048). CONCLUSIONS: We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol-lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.     

Efficacy and tolerability of lovastatin in elderly hypercholesterolemic patients.

In a previously published multicenter study (Kannel and associates, 1990), the effects of six months' treatment with lovastatin were evaluated in patients with hypercholesterolemia. In the present report the results from the 144 elderly patients (aged 65 to 83 years) are presented and compared with those from the 343 patients aged less than 65 years. The initial dose of lovastatin was 20 mg daily and could be increased to a maximum of 80 mg/day. After one month of treatment, in both the elderly and younger patients, levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein cholesterol, and triglycerides, and the total cholesterol: high-density lipoprotein (HDL) cholesterol and LDL:HDL [corrected] cholesterol ratios were significantly lower and high-density lipoprotein cholesterol levels were significantly higher. These improvements in the lipid profile were maintained for six months in both patient groups. LDL cholesterol goals of less than 130 mg/dl in patients with coronary heart disease (CHD) or two CHD risk factors and less than 160 mg/dl among the other patients were achieved by 53% of the elderly patients and 40% of the younger patients at one month (P less than 0.01) and by 62% and 47% at six months (P less than 0.01). By the end of the study, the mean daily dose of lovastatin was 35.4 mg for the elderly and 38.4 mg for the younger patients. The drug was generally well tolerated by all patients. The results indicate that both elderly and younger hypercholesterolemic patients respond well to treatment with lovastatin.     

Beneficial effects of atorvastatin in the treatment of hyperlipidemia after renal transplantation

Despite the availability of various lipid lowering drugs, the treatment of hyperlipidemia, one of the most important risk factors for morbidity and mortality after organ transplantation, remains a therapeutic challenge. We investigated the safety and efficacy of a new HMG-CoA reductase inhibitor, atorvastatin, in renal transplant patients whose serum lipids were insufficiently controlled by diet and treatment with other lipid lowering drugs. Twenty-four patients (14 males/10 females; mean age 51.2 +/- 2.3 years) were converted to low dose atorvastatin (10 mg/day) at a mean of 67.7 +/- 8.6 months after renal transplantation and prospectively followed for 3 months after initiation of the study drug. HDL, LDL, and total cholesterol, triglycerides, serum creatinine and CPK levels were evaluated pre (-3, -1, 0 months) and post conversion (+1, +3 months). In the eighteen patients who completed the study, low dose atorvastatin therapy led to a significant reduction in total cholesterol (304.6 +/- 13.2 vs. 247.6 +/- 12.0 mg/dl; p = 0.007) and LDL cholesterol (191.9 +/- 9.0 vs. 141.8 +/- 14.7 mg/dl; p < 0.0001) and a modest reduction in serum triglyceride levels at three months after conversion. We conclude that low dose atorvastatin (10 mg/day) can be successfully used and appears to be safe in the treatment of posttransplant hyperlipidemia. Its long-term effects on patient morbidity and mortality as well as graft survival should be investigated in larger and more prolonged prospective trials.     

Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence

The objective of this study was to determine vitamin D supplementation effects on concentrations of atorvastatin and cholesterol in patients. Sixteen patients (8 men, 8 women; 10 Caucasians, 4 African Americans, 1 Hispanic, 1 Asian), aged 63 +/- 11 years (mean +/- SD, weight 92 +/- 31 kg) on atorvastatin (45 +/- 33 mg/day) were studied with and without supplemental vitamin D (800 IU/day for 6 weeks). Levels of vitamin D (1,25-dihydroxy(OH) and 25 OH-metabolites), atorvastatin (parent, OH-acid metabolites, lactone, and lactone metabolites), and cholesterol (total, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol) were determined at 0.5, 3, and 10 h after dosing. Vitamin D supplementation increased vitamin D-25-OH metabolites (P < 0.0001) without increased 1,25-dihydroxy vitamin D. Atorvastatin and active metabolite concentrations (P < 0.001) as well as LDL-cholesterol and total-cholesterol levels (97 +/- 28 mg/dl vs. 83 +/- 30 and 169 +/- 35 mg/dl vs. 157 +/- 37, P < 0.005) were lower during vitamin D supplementation. The conclusion of the study is that vitamin D supplementation lowers atorvastatin and active metabolite concentrations yet has synergistic effects on cholesterol concentrations.     

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study

OBJECTIVE: The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS: A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS: End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58-0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48-0.98], P = 0.037) and any cardiovascular event (0.85 [0.73-1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS: Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.     

Lipid and blood pressure treatment goals for type 1 diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study

OBJECTIVE--Subjects with type 1 diabetes are at high risk for many long-term complications, including early mortality and coronary artery disease (CAD). Few data are available on which to base goal levels for two major risk factors, namely blood pressure and lipid/lipoproteins. The objective of this study was to determine at which levels of LDL and HDL cholesterol, triglycerides, and blood pressure the relative risks of type 1 diabetic complications increase significantly. RESEARCH DESIGN AND METHODS--Observational prospective study of 589 patients with childhood-onset type 1 diabetes (<17 years) aged > or =18 years at baseline; 10-year incidence of mortality, CAD, lower-extremity arterial disease, proliferative retinopathy, distal symmetric polyneuropathy, and overt nephropathy. Relative risks were determined using traditional groupings of blood pressure and lipid/lipoproteins, measured at baseline, using the lowest groupings (<100 mg/dl [2.6 mmol/l] LDL cholesterol, <45 mg/dl [1.1 mmol/l] HDL cholesterol, <100 mg/dl [1.1 mmol/l] triglycerides, <110 mmHg systolic blood pressure, and <80 mmHg diastolic blood pressure) as reference. Adjustments for age, sex, and glycemic control were examined. RESULTS--Driven mainly by strong relationships (RR range 1.8-12.1) with mortality, CAD, and overt nephropathy, suggested goal levels are as follows: LDL cholesterol <100 mg/dl (2.6 mmol/l), HDL cholesterol >45 mg/dl (1.1 mmol/l), triglycerides <150 mg/dl (1.7 mmol/l), systolic blood pressure <120 mmHg, and diastolic blood pressure <80 mmHG: Age, sex, and glycemic control had little influence on these goals. CONCLUSIONS--Although observational in nature, these data strongly support the case for vigorous control of lipid levels and blood pressure in patients with type 1 diabetes.     

An assessment of the efficacy of atorvastatin in achieving LDL cholesterol target levels in patients with coronary heart disease: a general practice study

Adherence to evidence-based guidelines for the secondary prevention of coronary heart disease (CHD) has been shown to be poor in a number of surveys. In this open-label, non-comparative 17-week trial, 399 patients with existing CHD and LDL cholesterol concentration > 3.4 mmol/l (130 mg/dl) were treated with atorvastatin 10 mg daily. After 5 weeks, the dose of atorvastatin was adjusted according to a patient's LDL cholesterol level. Of the 379 patients remaining in the study after five weeks of treatment, dose titration was not required for 355 patients (94%) who had reached the target LDL cholesterol of < or = 3.4 mmol/l. Of the 23 patients titrated to higher doses, 11 achieved the target LDL cholesterol after treatment for 17 weeks. Atorvastatin was well tolerated during the course of the study. Achieving LDL cholesterol targets without the need for dose titration simplifies clinical management and should encourage better adherence to evidence-based recommendations for secondary prevention of CHD.     

Clinical experience and future directions for low-density lipoprotein apheresis in the United States.

The United States Liposorber Study was a 22 week randomized controlled study of low-density lipoprotein (LDL) apheresis with an optional follow-up phase. The procedure was found to acutely lower LDL cholesterol by up to 81%, have good tolerability, and produce a reduction in the frequency of cardiovascular events. Studies outside the United States have found therapy with LDL apheresis to be associated with a favorable clinical outcome including improved myocardial perfusion, but variable regression of coronary artery disease (CAD). Improvement in blood viscosity and endothelial function may help explain the symptomatic benefits observed with relatively small changes in angiography. Based upon favorable clinical experience, LDL apheresis using dextran sulfate cellulose columns has recently received approval for commercialization in the United States in patients with inadequate responses to diet and drug therapy and LDL levels > or = 200 mg with CAD present or LDL levels > or = 300 mg/dl without CAD.     

Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X

BACKGROUND: This study investigated the effects of comicronised fenofibrate in patients with dyslipidemia and polymetabolic syndrome X. DESIGN: After a 6-week dietary run-in phase, 37 male patients eligible on lipid criteria entered a 12-week treatment phase consisting of diet plus one capsule daily containing 200 mg of comicronised fenofibrate (Lipanthyl(R)). RESULTS: A significant reduction in plasma concentrations of total cholesterol, LDL cholesterol and triglyceride was observed after 4, 8 and 12 weeks of treatment with fenofibrate. The improvement in the atherogenic index LDL/HDL cholesterol from a pretreatment 3.8 to 3.0 after treatment was highly statistically significant and may be judged as satisfactory. Significant changes were also observed in haemostatic factors (fibrinogen reduced by 19%, factor VII activity reduced by 18%). Fasting serum insulin levels and insulin response (area under the curve) after oral glucose load were significantly reduced by 26.8% and 18.7%, respectively, indicating an improvement of insulin sensitivity. Systolic and diastolic blood pressure were significantly reduced. Uric acid was significantly reduced by 21.6%. CONCLUSION: These favourable effects of comicronised fenofibrate both on lipid and non lipid parameters, including insulin sensitivity, may confer to this product a particular interest in the treatment of patients with polymetabolic syndrome X.     

Efficacy of atorvastatin therapy in ischaemic heart disease - effects on oxidized low-density lipoprotein and adiponectin

The lipid-lowering and anti-atherosclerotic effects of atorvastatin (10 mg/day) were investigated by measuring changes in the levels of oxidized low-density lipoprotein (LDL), serum lipids (total cholesterol [TC], LDL-cholesterol [LDL-C] and triglycerides [TG]), and in the protein adiponectin. This was undertaken in 22 patients with ischaemic heart disease and serum LDL-C levels > 100 mg/dl. After 3 months of therapy, atorvastatin significantly decreased serum lipids, oxidized LDL was reduced from 457.0 +/- 148.6 to 286.9 +/- 88.5 nmol/l, and adiponectin increased from 9.7 +/- 7.4 to 13.9 +/- 9.98 microg/ml. No significant correlation was observed between adiponectin and LDL-C, TG and high-density lipoprotein cholesterol. Atorvastatin therapy was not associated with side-effects, such as myalgia and gastrointestinal disorders, and did not give abnormal laboratory test results. It is concluded that atorvastatin decreases serum lipid and oxidized LDL levels, and increases adiponectin levels in patients with ischaemic heart disease.     

Efficacy and tolerability of atorvastatin/fenofibrate fixed-dose combination tablet compared with atorvastatin and fenofibrate monotherapies in patients with dyslipidemia: A 12-week,multicenter, double-blind,randomized, parallel-group study

Background: Coadministration of statin and fenofibrate monotherapies is frequently used to treat patients with dyslipidemia; however, a fixed-dose combination (FDC) tablet is not currently marketed.Objective: This study evaluates a new FDC tablet of atorvastatin 40 mg and fenofibrate 100 mg.Methods: This was a 12-week, multicenter, doubleblind, randomized, parallel-group Phase IIb study. Adults with dyslipidemia (non?HDL-C >130 mg/dL and triglycerides [TG] ≥150 but ≤500 mg/dL) were randomly assigned in a 1:1:1 ratio to receive the FDC, atorvastatin 40 mg, or fenofibrate 145 mg for 12 weeks. Study medication was taken once daily in the evening, without regard to meals. Patients attended follow-up visits after 4, 8, and 12 weeks of the double-blind treatment. The primary efficacy end points were the mean percentage changes from baseline to the final visit (week 12) in non?HDL-C, HDL-C, and TG. Secondary variables were LDL-C, VLDL-C particle concentration, total cholesterol, apolipoprotein B, lipoprotein (a), high-sensitivity C-reactive protein, fibrinogen, homocysteine, creatinine, myeloperoxidase, and lipoproteinassociated phospholipase A2. Tolerability was assessed by adverse events, laboratory parameters, vital signs, physical examinations, and ECGs.Results: Patients (n = 220) were aged 26 to 87 years; 115 (52.3%) were men and 105 (47.7%) were women; 189 (85.9%) were white, 17 (7.7%) were black, and 15 (6.8%) were Hispanic or Latino; and mean (SD) weight was 200.5 (40.85) lb (range, 103.5–367.4 lb). Previous treatments were statins (25.9% [57/220]), fibrates (1.8% [4/220]), and dietary supplements (25.5% [56/220]); 57.7% (127/220) of patients were treatment naive. Use of the FDC was associated with an improvement in non?HDL-C (?44.8%) that was significantly greater than with fenofibrate monotherapy (?16.1%; P < 0.001) but was not significantly different from that with atorvastatin monotherapy (?40.2%; P = NS). HDL-C increased significantly more in the FDC group (19.7%) than with atorvastatin (6.5%; P < 0.001) but was not significantly different from fenofibrate (18.2%; P = NS). TG lowering in the FDC group (?49.1%) was significantly greater than with both atorvastatin (?28.9%; P < 0.001) and fenofibrate (?27.8%; P = 0.001). LDL-C lowering in the FDC group (?42.3%) was significantly greater than with fenofibrate (?13.9%; P < 0.001) but not significantly different from atorvastatin (?43.1%; P = NS). The FDC had either comparable or significantly greater improvements in other lipid variables and multiple secondary variables. The FDC was generally well tolerated; the tolerability profile was consistent with those of atorvastatin and fenofibrate monotherapies. Treatment-emergent adverse events (ie, those occurring after the first dose of study medication) were recorded in 43 of 73 patients (58.9%) for the FDC, 49 of 74 (66.2%) for atorvastatin, and 48 of 73 (65.8%) for fenofibrate.Conclusions: In this 12-week study, patients with dyslipidemia treated with the 40/100-mg atorvastatin/ fenofibrate FDC had a significantly greater reduction in TG than those treated with atorvastatin 40 mg or higher-dose fenofibrate 145 mg. Treatment with the FDC was also associated with a significantly greater reduction in non?HDL-C compared with fenofibrate alone and a greater increase in HDL-C compared with atorvastatin alone. All treatments were generally well tolerated.