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.     

A Multicenter, Placebo-Controlled, Dose-Ranging Study of Atorvastatin

BACKGROUND: Coronary heart disease (CHD) is the number one cause of death in Western societies. Elevated levels of plasma low-density lipoprotein (LDL) cholesterol and triglycerides (TG) increase the risk for CHD. 3-Hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase inhibitors effectively reduce plasma cholesterol levels in patients with hypercholesterolemia. This study assesses the safety and dose-related effects of atorvastatin calcium on lipoprotein fractions in patients with LDL cholesterol levels between 160 mg/dL (4.1 mM) and 250 mg/dL (6.5 mM) or less and TG levels of 400 mg/dL (4.5 mM) or less. METHODS AND RESULTS: Sixty-five patients were enrolled in a 6-week, randomized, placebo-controlled, parallel-group study. Patients received placebo or atorvastatin 10, 20, 40, 60, or 80 mg once daily. Adjusted mean decreases in LDL cholesterol for patients receiving atorvastatin 10, 20, 40, 60, and 80 mg were 37%, 42%, 50%, 52%, and 59%, respectively, compared with a mean increase of 0.3% for patients receiving placebo; the differences between each of the atorvastatin dose groups and placebo were statistically significant (P =.0001). Total cholesterol, triglycerides, and apolipoprotein B were significantly reduced in atorvastatin groups (P =.0001). Adverse events were similar in the placebo and atorvastatin treatment groups. No patient had a serious adverse event or withdrew because of an adverse event during this study. CONCLUSIONS: Atorvastatin effectively lowered plasma LDL cholesterol, triglycerides, and apoB levels in a dose-related manner. Atorvastatin was well tolerated in hyperlipidemic patients over a 6-week period.     

Atorvastatin, a New HMG-CoA Reductase Inhibitor, Does Not Affect Glucocorticoid Hormones in Patients With Hypercholesterolemia

BACKGROUND: Atorvastatin calcium (Lipitor) is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The present study was conducted to examine the effect of pronounced cholesterol lowering on adrenal function in patients with severe hypercholesterolemia. METHODS AND RESULTS: Adrenal function was examined under basal conditions and following adrenal corticotropin hormone stimulation in 40 patients (36 with heterogeneous familial and 4 with polygenic hypercholesterolemia). The study was part of a larger study comparing the efficacy and safety of atorvastatin, colestipol, atorvastatin + colestipol, and simvastatin + colestipol treatment over a 1-year period. Maximum doses of all agents were studied: 80 mg atorvastatin once daily, 40 mg simvastatin once daily, and 20 g/day colestipol. At the end of the 1-year treatment period, reductions in low-density lipoprotein cholesterol were 57%, 54%, and 49% for the atorvastatin, colestipol + atorvastatin, and colestipol + simvastatin groups, respectively. No clinically significant changes in basal serum cortisol levels were seen in any treatment group during the 1-year treatment period. Mean serum cortisol concentrations and area under the curve for cortisol concentration versus time data following adrenal corticotropin hormone stimulation were not clinically different during treatment compared with values obtained at baseline for any of the treatment groups. CONCLUSIONS: Treatment with maximum doses of atorvastatin for 1-year did not have any adverse effects on adrenal function under basal conditions or during maximum stimulation. Similarly, colestipol therapy alone and in combination with either atorvastatin or simvastatin did not appear to affect adrenal function.     

Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia

OBJECTIVE: This study evaluated the effect of a atorvastatin-fenofibrate combination on lipid profile, in comparison to each drug alone, in patients with type 2 diabetes and combined hyperlipidemia (CHL). RESEARCH DESIGN AND METHODS: A total of 120 consecutive patients, who were free of coronary artery disease (CAD) at entry, were studied for a period of 24 weeks. These patients were randomly assigned to atorvastatin (20 mg/day, n = 40), micronized fenofibrate (200 mg/day, n = 40), or a combination of both (atorvastatin 20 mg/day plus fenofibrate 200 mg/day, n = 40). The effect of treatment on LDL cholesterol, triglycerides (TGs), HDL cholesterol, apolipoprotein A-I and B, lipoprotein(a), and plasma fibrinogen (PF) was recorded. Moreover, the percentage of patients that reached the American Diabetes Association treatment goals and the estimated CAD risk status were calculated. RESULTS: No patient was withdrawn from the study because of side effects. The atorvastatin-fenofibrate combination reduced total cholesterol by 37%, LDL cholesterol by 46%, TGs by 50%, and PF by 20%, whereas it increased HDL cholesterol by 22% (P < 0.0001 for all). These changes were significantly better than those of both monotherapies. Of the patients on drug combination, 97.5% reached the LDL cholesterol treatment goal of <100 mg/dl, 100% reached the desirable TG levels of <200 mg/dl, and 60% reached the optimal HDL cholesterol levels of >45 mg/dl. These rates were significantly higher than those of both monotherapies. Combined treatment reduced the 10-year probability for myocardial infarction from 21.6 to 4.2%. CONCLUSIONS: The atorvastatin-fenofibrate combination has a highly beneficial effect on all lipid parameters and PF in patients with type 2 diabetes and CHL. It improved patients' CAD risk status significantly more than each drug alone.     

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.     

The familial hypercholesterolemia regression study: a randomized comparison of therapeutic reduction of both low-density lipoprotein and lipoprotein(a) versus low-density lipoprotein alone.

Lipoprotein (a) [Lp (a)] is a risk factor for coronary heart disease (CHD), especially in the presence of a raised low-density lipoprotein (LDL)-cholesterol (LDL-C). To ascertain whether reduction of both LDL and Lp(a) is more advantageous than reduction of LDL alone, patients with heterozygous FH and CHD were selected randomly to receive either LDL apheresis fortnightly plus simvastatin 40 mg/day or colestipol 20 g plus simvastatin 40 mg/day. Quantitative coronary angiography was undertaken before and after 2.1 years. Changes in serum lipids were similar in both groups except for the greater reduction of LDL-C and Lp(a) by apheresis. There were no significant differences in primary angiographic endpoints, and none of the angiographic changes correlated with Lp(a). Although LDL apheresis plus simvastatin was more effective than colestipol plus simvastatin in reducing LDL-C and Lp(a), it was not more beneficial in influencing coronary atherosclerosis. Decreasing Lp(a) seems unnecessary if LDL-C is reduced below 130 mg/dl.     

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.     

Efficacy and Tolerability of Pitavastatin Versus Pitavastatin/Fenofibrate in High-risk Korean Patients with Mixed Dyslipidemia: A Multicenter,Randomized, Double-blinded,Parallel, Therapeutic Confirmatory Clinical Trial

PurposeDyslipidemia is an important risk factor for cardiovascular disease (CVD). Statins are known to effectively reduce not only low-density lipoprotein cholesterol (LDL-C) level but also death and nonfatal myocardial infarction due to coronary heart disease. The risk for CVD from atherogenic dyslipidemia persists when elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels are not controlled with statin therapy. Therefore, statin/fenofibrate combination therapy is more effective in reducing CVD risk. Here, we assessed the efficacy and tolerability of pitavastatin/fenofibrate combination therapy in patients with mixed dyslipidemia and a high risk for CVD.MethodsThis multicenter, randomized, double-blind, parallel-group, therapeutic-confirmatory clinical trial evaluated the efficacy and tolerability of fixed-dose combination therapy with pitavastatin/fenofibrate 2/160 mg in Korean patients with a high risk for CVD and a controlled LDL-C level (<100 mg/dL) and a TG level of 150–500 mg/dL after a run-in period with pitavastatin 2 mg alone. In the 8-week main study, 347 eligible patients were randomly assigned to receive pitavastatin 2 mg with or without fenofibrate 160 mg after a run-in period. In the extension study, patients with controlled LDL-C and non–HDL-C (<130 mg/dL) levels were included after the completion of the main study. All participants in the extension study received the pitavastatin/fenofibrate combination therapy for 16 weeks for the assessment of the tolerability of long-term treatment.FindingsThe difference in the mean percentage change in non–HDL-C from baseline to week 8 between the combination therapy and monotherapy groups was −12.45% (95% CI, −17.18 to −7.72), and the combination therapy was associated with a greater reduction in non-HDL-C. The changes in lipid profile, including apolipoproteins, fibrinogen, and high-sensitivity C-reactive protein from baseline to weeks 4 and 8 were statistically significant with combination therapy compared to monotherapy at all time points. Furthermore, the rates of achievement of non–HDL-C and apolipoprotein B targets at week 8 in the combination therapy and monotherapy groups were 88.30% versus 77.98% (P = 0.0110) and 78.94% versus 68.45% (P = 0.0021), respectively. The combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy.ImplicationsIn these Korean patients with mixed dyslipidemia and a high risk for CVD, combination therapy with pitavastatin/fenofibrate was associated with a greater reduction in non–HDL-C compared with that with pitavastatin monotherapy, and a significantly improvement in other lipid levels. Moreover, the combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. Therefore, pitavastatin/fenofibrate combination therapy could be effective and well tolerated in patients with mixed dyslipidemia. ClinicalTrials.gov identifier: NCT03618797.     

A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study After a 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. RESULTS: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of -44.8% to -602%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels > or =3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels > or =10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS). CONCLUSION: The EZE/SIMVA tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia.     

An assessment of the efficacy of atorvastatin in treating patients with dyslipidaemia to target LDL-cholesterol goals: the atorvastatin matrix study

A total of 531 patients from 57 hospital centres across the UK, who had previously been treated with lipid-lowering agents in combination or alone, in whom the degree of cholesterol reduction was insufficient to achieve European Atherosclerosis Society target levels, were treated with atorvastatin over a 12-week period. The dose of atorvastatin (10, 20 or 80 mg/day) was determined by assignment of risk based on entry level cholesterol levels and the presence of other established CHD risk factors. Atorvastatin was successful in achieving target LDL-cholesterol levels in 86% of mild risk patients, 88% of moderate risk patients and 52% of high risk patients. Compliance with atorvastatin was 96% and treatment was well tolerated. This study demonstrates that atorvastatin is effective in achieving target lipid levels in a large proportion of patients and that the dose required can be predicted by an assessment of the patient's risk profile.     

Effects of Fixed-dose Combination of Low-intensity Rosuvastatin and Ezetimibe Versus Moderate-intensity Rosuvastatin Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia: A Randomized,Double-blind,Multicenter, Phase III Study

PurposeWe investigated whether the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy in patients requiring cholesterol-lowering therapy.MethodsThis was a multicenter randomized, double‐blind study to investigate the safety and efficacy of a fixed-dose combination of rosuvastatin 2.5 mg and ezetimibe 10 mg (R2.5+E10) compared to those of ezetimibe 10 mg monotherapy (E10), rosuvastatin 2.5 mg (R2.5), and rosuvastatin 5 mg monotherapy (R5) in patients with hypercholesterolemia. A total of 348 patients at 15 centers in Korea were screened, and 279 patients were randomized to different groups in the study. Clinical and laboratory examinations were performed at baseline and 4 and 8 weeks after intervention. The primary endpoint was the percentage change of low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up.FindingsBaseline characteristics were similar among the four groups. There were significant changes in lipid profiles at the 8-week follow-up. A greater decrease in the LDL cholesterol levels (primary endpoint) were found in the R2.5+E10 group (−45.7±18.6%) than in the E10 group (−16.7±14.7%, p<0.0001), R2.5 group (−32.6±15.1%, p<0.0001), and R5 group (−38.9±13.9%, p=0.0003). Similar outcomes were observed regarding the decrease in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B protein. In addition, changes in the triglyceride and HDL levels in the R2.5+E10 group were significantly different compared with those in the E10 group; however, the changes were similar to those in the other treatment groups. In patients with low and moderate risk, all patients achieved the target LDL cholesterol levels in the R2.5+E10 group (100%) compared to 13.0% in the E10 group, 47.6% in the R2.5 group, and 65.2% in the R5 group. Adverse effects were rare and similar in the four groups.ImplicationsFixed-dose combination of low-intensity rosuvastatin and ezetimibe was more effective in lowering LDL cholesterol and achieving LDL cholesterol goals than moderate-intensity rosuvastatin monotherapy. These findings suggest that the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy for cholesterol management, particularly in patients with low and moderate risk. ClinicalTrials.gov identifier: NCT04652349.     

The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results

The Cholesterol Lowering Atherosclerosis Study (CLAS) is a prospective, placebo-controlled, angiographic trial designed to test the hypothesis that aggressive lowering of LDL cholesterol with concomitant increase in HDL cholesterol will reverse or retard the atherosclerotic process. Specifically, CLAS was designed to determine whether combined therapy with colestipol plus niacin will produce clinically significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions. To this purpose, 188 subjects were randomized to diet plus drug or diet plus placebo. We report on methodological aspects of planning and evaluating this study, including the choice of the study population, procedures for recruitment, the experimental design including sample size considerations, methods for evaluating outcome, and methods for evaluating compliance to treatment. Comparison of baseline data indicated no significant differences between groups at the time of randomization. Subjects were predominantly male, Caucasian, 54 years of age, 20% above ideal weight, with normal blood pressure. The average age at bypass was 50 years. The average lipids were cholesterol (243 mg/dL), HDL (45 mg/dL), and LDL (168 mg/dL). Finally, the distribution of baseline coronary stenosis was equivalent between the two groups (average number of lesions per subject = 10.6).     

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.     

Anti-proteinuric effects of combination therapy with enalapril and losartan in patients with nephropathy due to type 2 diabetes

The benefits of angiotensin-converting enzyme inhibitors and angiotensin II (ATII) receptor antagonist therapy of diabetic nephropathy (DNP) are thought to be largely the result of attenuation of ATII effects on proteinuria. The aim of the study was to ascertain whether there is the additive anti-proteinuric effect of enalapril plus losartan in DNP. Twenty-two patients with DNP were studied. Patients were randomly assigned to enalapril 10 mg/day (11 patients) or losartan 50 mg/day (11 patients) administered in a single oral dose in the morning for 12 weeks. and then, in 10 patients (five patients from enalapril group and five patients from losartan group), combination therapy (10 mg/day enalapril and 50 mg/day losartan) was started and continued for 12 weeks. In 12 patients, initial drugs dosages were doubled (six patients 20 mg/day enalapril and six patients 100 mg/day losartan), and monotherapy was continued for 12 weeks. Blood pressure and proteinuria were measured before and after therapy. Adverse effects were recorded at every visit. Proteinuria decreased by 33% with enalapril and losartan administered alone (p < 0.05). Co-administration of enalapril and losartan decreased proteinuria by a greater extent compared with enalapril and losartan administered alone (51%, p<0.05). This proteinuria level was significantly lower than the proteinuria level of 12 weeks therapy with enalapril and losartan alone. The decrease of proteinuria was 37% in double-dose monotherapy group (p < 0.05). Reduction of mean arterial blood pressure (MAP) in co-administration of enalapril and losartan was higher than enalapril and losartan administered alone (p < 0.05). Combination of enalapril and losartan decreased proteinuria and MAP by a greater extent compared with enalapril and losartan administered alone. We have found that proteinuria reduction induced by combined therapy is maintained throughout short-term follow-up; a greater anti-proteinuric response was observed in the patients with DNP.     

A crossover comparison of the efficacy and safety of lovastatin and gemfibrozil in the treatment of hyperlipidemic organ transplant recipients.

Hypercholesterolemia is associated with accelerated atherosclerosis in transplant recipients. It has been notoriously difficult to treat pharmacologically due to the complex interactions that occur with lipid-lowering drugs and immunosuppressive therapies. The purpose of the current study was to compare the efficacy and safety of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (lovastatin, 20 mg/d) with a fibric acid derivative (gemfibrozil, 600 mg twice a day). We used a randomized, crossover design in 18 solid organ transplant recipients who followed the National Cholesterol Education Program Adult Treatment Guidelines diet for 8 weeks and had persistent elevations of total cholesterol (>240 mg/dL). Each patient received each therapy for a minimum of 8 weeks (mean 14.2 +/- 2.4, range 8-20 weeks). The participants had stable allograft function and were treated with a standard immunosuppressive regimen containing cyclosporine, prednisone, and azathioprine. Lovastatin therapy reduced the mean total cholesterol by 15.5% (271.9 mg/dL to 229.9 mg/dL; p = 0.02) and the mean low-density lipoprotein (LDL) cholesterol by 22.7% (178.2 mg/dL to 137.8 mg/dL; p = 0.07). There were no significant changes in high-density lipoprotein (HDL) cholesterol or triglycerides. Conversely, when these same patients were treated with gemfibrozil, the mean total cholesterol decreased by 7.9% (271.9 mg/dL to 250.5 mg/dL; p = NS) and the LDL cholesterol decreased by 5.1% (178.2 mg/dL to 169.1 mg/dL; p = NS). In addition, the mean triglyceride concentration decreased significantly by 46.1% (234.0 mg/dL to 126.3 mg/dL; p = 0.002) and the mean HDL cholesterol increased 15.4% (48.8 mg/dL to 56.3 mg/dL; p = 0.09). In all patients, the serum creatinine, hepatocellular enzymes, and creatinine phosphokinase remained stable. Lovastatin was discontinued in three patients for myalgias, one patient with unexplained anemia, and one patient with parasthesias. These results suggest that lovastatin and gemfibrozil are both safe and efficacious in transplant patients. However, neither therapy alone completely corrects abnormalities of high LDL cholesterol and low HDL cholesterol in transplant recipients.     

不同调脂治疗方案对冠心病患者血脂和IL-6、TNF-α水平的影响

目的比较冠心病患者单用阿托伐他汀（40 mg/d）及阿托伐他汀（10 mg/d）和依折麦布（10 mg/d）联合治疗的调脂作用及安全性,并探讨其对白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）的影响。方法选取冠状动脉狭窄50%～70%的冠心病患者42例,均不植入支架,分为阿托伐他汀组（19例）和阿托伐他汀＋依折麦布组（23例）。在服药前、用药4周、用药12周时分别测定总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、肝功能、肾功能、肌酸激酶（CK）、IL-6和TNF-α水平。结果 2组均在用药后4周就可以明显降低患者的TC和LDL-C。12周时阿托伐他汀组的LDL-C为（1.94±0.49）mmol/L,较用药前下降37.82%,阿托伐他汀＋依折麦布组的LDL-C为（1.92±0.54）mmol/L,下降38.26%,2组之间比较无差异。2组患者的肝功能、肾功能、CK在用药后无明显异常。40 mg/d阿托伐他汀治疗12周时IL-6和TNF-α明显降低,而阿托伐他汀＋依折麦布组治疗前、后的差异无统计学意义。结论 2种治疗方案的降脂疗效无差异,且均没有引起患者肝、肾功能及CK异常。较大剂量阿托伐他汀（40 mg/d）治疗可引起血清IL-6和TNF-α降低,对冠状动脉狭窄的冠心病患者可能有稳定斑块的作用。     

Colesevelam hydrochloride: a novel bile acid-binding resin

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. METHODS: MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. CONCLUSIONS: Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.     

Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group

OBJECTIVE: To evaluate the efficacy and safety of four doses of pioglitazone monotherapy in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 408 patients randomized in this multicenter double-blind placebo-controlled clinical trial. Patients who had HbA1c > or = 7.0%, fasting plasma glucose (FPG) > or = 140 mg/dl, and C-peptide > 1 ng/ml were randomized to receive placebo or 7.5, 15, 30, or 45 mg pioglitazone administered once a day for 26 weeks. RESULTS: Patients treated with 15, 30, or 45 mg pioglitazone had significant mean decreases in HbA1c (range -1.00 to -1.60% difference from placebo) and FPG (-39.1 to -65.3 mg/dl difference from placebo). The decreases in FPG were observed as early as the second week of therapy; maximal decreases occurred after 10-14 weeks and were maintained until the end of therapy (week 26). In the 15-, 30-, or 45-mg pioglitazone groups, there were significant mean percent decreases in triglycerides, significant mean percent increases in HDL cholesterol, and only small percent changes in total cholesterol and LDL. The subset of patients naive to therapy had greater improvements in HbA1c and FPG (difference from placebo of -2.55% and -79.9 mg/dl for the 45-mg group) compared with previously treated patients. The overall adverse event profile of pioglitazone was similar to that of placebo. There was no evidence of drug-induced hepatotoxicity or drug-induced elevations of alanine aminotransferase levels in this study CONCLUSIONS: Pioglitazone monotherapy significantly improves HbA1c and FPG while producing beneficial effects on serum lipids in patients with type 2 diabetes with no evidence of drug-induced hepatotoxicity.     

Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low‐density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m²) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic‐pump inhibitor. In the absence of specific lipid‐lowering therapy, plasma lipid levels at first visit were: total‐cholesterol = 522 mg/dL, LDL‐cholesterol = 434 mg/dL, HDL‐cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24‐week treatment, the LDL‐cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL‐apheresis (H.E.L.P.system) was started as add‐on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL‐cholesterol was reduced by 49.4%, thus reaching an inter‐apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein‐apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.