The benefit of fibrates in the treatment of 'bad HDL-C responders to statins'

BACKGROUND: Lowering high levels of low-density lipoprotein cholesterol (LDL-C) is the primary aim in the prevention of cardiac events. However, low levels of high-density lipoprotein cholesterol (HDL-C) are also associated with an increased risk of ischemic heart disease. Some patients have lower HDL-C during statin treatment than before the treatment. These patients were first described in 2002 as 'bad HDL-C responders to statins'. The aim of this study was to describe the benefit of fibrates in monotherapy for these patients. METHODS: A cross-sectional survey of lipid levels, cardiovascular disease and risk factors in outpatients treated for dyslipidemia. For this study we analyzed the lipid levels, drug treatment and medical history for 14 patients with low HDL-C (<40 mg/dl) during statin treatment and ever treated with fibrates. RESULTS: Total cholesterol (TC) and LDL-C were respectively 8% and 6% higher with fibrates compared to statins. Mean HDL-C was 49% higher during fibrate treatment and TC to HDL-C and LDL-C to HDL-C were respectively 26% and 27% lower with fibrates. CONCLUSIONS: Patients with low levels of HDL-C during statin treatment had far better levels for HDL-C, TC to HDL-C and LDL-C to HDL-C with fibrates in monotherapy. For bad HDL-C responders to statins with low or normal LDL-C treatment with fibrates instead of statins should be considered. For those with high LDL-C fibrates should be added to statins. A randomized double-blind crossover trial with simvastatin and fenofibrate has been initiated to corroborate these findings.     

Serum lipid comparison in patients treated by statins or fibrates: existence of bad HDL-C responders to statins

INTRODUCTION: Major cardiac events are strongly associated with high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C). The HDL-C target level (40 mg/dl) is often not achieved with statins. The aim of this study was to compare the proportions of patients achieving the HDL-C target levels after one year of treatment with statins or fibrates. Furthermore, a subgroup with low HDL-C levels during statin treatment was investigated and suggestions are made for a better management of these patients. METHODS: A survey of lipid levels, cardiovascular disease and risk factors in 120 outpatients treated with a statin or a fibrate for hyperlipidaemia (total cholesterol (TC) > 250 mg/dl or triglycerides (TG) > 200 mg/dl after diet). After one year of treatment the proportions of patients achieving the target levels for TC, LDL-C, HDL-C,TG,TC/HDL-C and LDL-C/HDL-C are compared for statins and fibrates. RESULTS: The proportions of patients achieving the target lipid levels with statins or fibrates are comparable except for HDL-C. Compared to the baseline, the proportion of patients achieving the HDL-C target level of 40 mg/dl increases only by 8.3% for statins and by 42.9% for fibrates. In total, 38.5% of the statin group had low HDL-C-levels after one year of treatment. Among these patients, eight were treated with a fibrate before the statin and six were treated with a fibrate afterwards. In those 14 patients, mean HDL-C increased during fibrate treatment by 48.5% and TC/HDL-C and LDL-C/HDL-C decreased by 25.7 and 26.5%, respectively as compared with statins. CONCLUSIONS: Patients with low levels of HDL-C during statin treatment had far better levels of HDL-C, TC/HDL-C and LDL-C/HDL-C with fibrates. A randomised double-blind crossover trial with simvastatin and fenofibrate has been initiated to corroborate these findings.     

Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia

OBJECTIVES: The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia. BACKGROUND: Despite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals. METHODS: After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =145 mg/dl to < or =250 mg/dl and triglycerides (TG) < or =350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups. RESULTS: Ezetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo. CONCLUSIONS: When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.     

Effects of simvastatin,an HMG-CoA reductase inhibitor,in patients with hypertriglyceridemia

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.     

Dose-response effects of atorvastatin and simvastatin on high-density lipoprotein cholesterol in hypercholesterolaemic patients: a review of five comparative studies

Epidemiological evidence and clinical trials with fibrate therapy show a clear relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), the hydroxy-methylglutaryl-coenzyme A reductase inhibitors (statins), also raise the levels of HDL-C. This review summarizes the results of five randomized, multicenter studies in hypercholesterolaemic patients in which multiple doses of atorvastatin and simvastatin were compared for their effects on lipids and lipoproteins including HDL-C. Both statins reduced LDL cholesterol and achieved parallel decreases in TG, with atorvastatin showing a slight overall superiority in these studies. Both HDL-C and apolipoprotein (Apo) A-I, its associated apoprotein, were significantly and consistently increased by all doses of simvastatin. However, atorvastatin had a different dose-response effect from simvastatin on both lipid parameters. Whereas HDL-C and Apo A-I were elevated by low doses of atorvastatin, the effect diminished markedly with increasing dose suggesting a possible negative dose-response effect. At higher doses, simvastatin increased HDL-C and Apo A-I significantly more than atorvastatin. These data indicate that statins may not be identical in all their clinical properties relevant to reducing the risks of atherosclerosis.     

Effect of combining psyllium fiber with simvastatin in lowering cholesterol

BACKGROUND: Soluble fiber supplements are recommended to reduce levels of low-density lipoprotein cholesterol (LDL-C). We evaluated the LDL-C-lowering effect of psyllium husk added to low-dose simvastatin therapy. METHODS: In a 12-week blinded placebo-controlled study, patients were randomized to receive 20 mg of simvastatin plus placebo, 10 mg of simvastatin plus placebo, or 10 mg of simvastatin plus 15 g of psyllium (Metamucil) daily. Levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were determined after 4 and 8 weeks of treatment. RESULTS: The study group comprised 68 patients. All treatments were well tolerated, and after 8 weeks the mean LDL-C levels in the group receiving 10 mg of simvastatin plus placebo fell by 55 mg/dL (1.42 mmol/L) from baseline, compared with 63 mg/dL (1.63 mmol/L) in the group receiving 10 mg of simvastatin plus psyllium (P = .03). The mean lowering of LDL-C in the group receiving 20 mg of simvastatin plus placebo was the same as that in the group receiving 10 mg of simvastatin plus psyllium. Similar results were seen for apolipoprotein B and total cholesterol. No significant changes from baseline triglyceride or high-density lipoprotein cholesterol levels occurred. CONCLUSIONS: Dietary psyllium supplementation in patients taking 10 mg of simvastatin is as effective in lowering cholesterol as 20 mg of simvastatin alone. Psyllium soluble fiber should be considered as a safe and well-tolerated dietary supplement option to enhance LDL-C and apolipoprotein B lowering.     

Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography.

OBJECTIVES: We investigated whether simvastatin attenuates plaque inflammation by using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) co-registered with computerized tomography. BACKGROUND: Inflammation plays a key role in progression and destabilization of atherosclerotic plaque. 18F-fluorodeoxyglucose PET is a promising tool for visualizing inflammation of atherosclerotic plaque. Antiinflammatory action is one of the pleiotropic effects of statins. METHODS: Forty-three consecutive subjects, who underwent 18FDG-PET for cancer screening and had 18FDG uptakes in the thoracic aorta and/or the carotid arteries, were randomized to either statin group receiving simvastatin (n = 21) or diet group receiving dietary management only (n = 22). The maximum standardized uptake values (SUVs) were measured in individual plaques, and were averaged for analysis of the subjectwise results. The responses were assessed after 3-month treatments. RESULTS: Positron emission tomography revealed 117 and 123 18FDG-positive plaques in the statin and diet groups, respectively. Simvastatin, but not diet alone, attenuated plaque (18)FDG uptakes and decreased the SUVs (p < 0.01). Simvastatin reduced low-density lipoprotein cholesterol (LDL-C) by 30% (p < 0.01) and increased high-density lipoprotein cholesterol (HDL-C) by 15% (p < 0.01), whereas LDL-C and HDL-C levels were not changed in the diet group. In the statin group, the decrease in the SUV was well correlated with the HDL-C elevation (p < 0.01) but not with the LDL-C reduction. CONCLUSIONS: 18F-fluorodeoxyglucose PET visualized plaque inflammation and simvastatin attenuated it. The LDL-C-independent effects of simvastatin may participate in the beneficial effect. 18F-fluorodeoxyglucose PET has a potential for visually monitoring plaque inflammation and the therapeutic effectiveness of statins.     

三磷酸腺苷结合盒转运体A1基因多态性与辛伐他汀调脂的关系

目的：研究三磷酸腺苷结合盒转运体A1（ABCA1）基因R219K多态性对血脂水平及辛伐他汀调脂治疗的影响。方法：原发性高脂血症患者80例,给予辛伐他汀20mg／d,治疗8周,治疗前后测定患者血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）及高密度脂蛋白胆固醇（HDL-C）浓度,治疗期间进行不良反应的监测。使用TaqMan荧光探针技术测定患者ABCA1基因R219K多态性。根据不同的基因型分组,比较不同基因型之间血脂水平变化的差异。进而判定不同基因型对血脂水平及辛伐他汀疗效的影响。结果：ABCA1 R219K基因存在三种基因型,即RR、RK和KK基因型。辛伐他汀治疗前RR基因型和RK基因型HDL—C水平明显低于KK基因型（P〈0．05）。辛伐他汀治疗8周后,三种基因型TC、TG、LDL-C水平均较前降低,HDL—C水平均较前升高;治疗后RR及RK基因型HDL—C水平仍低于KK型（P〈O．05）;但TC、TG、LDL—C和HDL—C水平的变化在不同基因型组之间无显著差异（P〉0．05）。结论：ABCA1基因R219K单核苷酸多态性可影响HDL—C水平,K等位基因与高HDL-C水平相关,但与辛伐他汀治疗的个体差异性无关。     

Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients

We compared the effects of five different statins (atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin) on the lipid, lipoprotein, and apolipoprotein (apo) A-I-containing high-density lipoprotein (HDL) subpopulation profiles of 86 coronary heart disease (CHD) patients. Patients with established CHD, and low density lipoprotein (LDL) cholesterol (C)>130 mg/dl, and triglyceride (TG)<400 mg/dl, were treated with atorvastatin 20, 40, and 80 mg/day and one of the other four statins at 20, 40, and when available 80 mg/day in increasing doses (4 weeks of each dose) in a randomized crossover fashion. There was an 8-week placebo controlled washout period between different drug treatments. All five statins on each dose resulted in significant reductions in total- and LDL-C compared to placebo treatment. There were also decreases in plasma TG and increases in HDL-C and apoA-I concentrations, but not all treatments changed these parameters significantly. Each statin except fluvastatin improved the HDL subpopulation profile by increasing the concentrations of the large, cholesterol-rich, LpA-I alpha-1 and prealpha-1 HDL subpopulations. CHD patients have significantly lower concentration of the large, LpA-I alpha-1 HDL particles compared to controls. Our data indicate that statins which are the most effective in lowering LDL-C and TG are also the most effective agents in modifying the HDL subpopulation profile in CHD patients towards the patterns found in healthy individuals. The order of efficacy of statins in increasing alpha-1 HDL subpopulation was: atorvastatin, simvastatin, pravastatin, lovastatin and fluvastatin.     

Comparison of rosuvastatin with atorvastatin, simvastatin and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholesterolaemic patients with or without the metabolic syndrome in the MERCURY I trial

AIM: The metabolic syndrome (MS) increases the risk of coronary heart disease, yet few data are available on the effects of statin treatment in improving lipid measures in patients with the syndrome. This analysis compares the effects of statin therapy on plasma low-density lipoprotein cholesterol (LDL-C) goal achievement and lipid levels in hypercholesterolaemic patients with or without the MS. METHODS: The Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY I (MERCURY I) trial compared rosuvastatin 10 mg with atorvastatin 10 mg and 20 mg, simvastatin 20 mg and pravastatin 40 mg over 8 weeks in patients with coronary or other atherosclerotic diseases or diabetes who had fasting levels of LDL-C of >or=2.99 mmol/l and triglycerides of <4.52 mmol/l. Modified National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria for the MS were met by 1342 (43%) of 3140 patients. RESULTS: LDL-C goal achievement rates and reductions in LDL-C, total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) were similar in patients with and without the MS within statin treatment groups; triglycerides were reduced more and HDL-C tended to be increased more in patients with the MS, as expected. Treatment with rosuvastatin 10 mg was more effective in allowing patients with and without the MS to reach European and ATP III LDL-C goals, compared to atorvastatin 10 mg, simvastatin 20 mg and pravastatin 40 mg (p < 0.0001 for all comparisons); consistently produced greater reductions in LDL-C, total cholesterol and non-HDL-C, compared to these treatments; and produced similar or greater reductions in triglycerides and increases in HDL-C, compared to the other treatments. CONCLUSIONS: Statin therapy is effective in allowing LDL-C goal achievement and improving the lipid profile in hypercholesterolaemic high-risk patients with the MS. Rosuvastatin 10 mg presents significant advantages in goal achievement and lipid lowering over other statins at commonly used doses in patients both with and without the MS.     

Efficacy and safety of statins in hypercholesterolemia with emphasis on lipoproteins

Information of the effect of statin on lipoproteins such as apolipoprotein (apo) A-I, lipoprotein (a) [Lp (a)], or apolipoprotein B levels is limited. This investigation was a crossover study designed to evaluate the efficacy and safety of atorvastatin and simvastatin in patients with hyperlipidemia. Sixty-six patients were involved in the study. Group I consisted of 32 patients, who were first treated with atorvastatin (10 mg) then switched to simvastatin (10 mg). Group II consisted of 34 patients, who were first treated with simvastatin then switched to atorvastatin. Each regimen was used for 3 months (phase I), stopped for 2 months, and then restarted for another 3 months (phase II). Both statins effectively reduced total cholesterol, low-density lipoprotein cholesterol (LDL-C), apo B, and Lp (a) (P < 0.001 in all comparisons). A significant increase in the high-density lipoprotein cholesterol (HDL-C) was noted after both statin treatments (P < 0.05 in all comparisons). Both statins caused an increase in the apo A-I levels, and the extent of changes in apo A-I revealed no difference between the two drugs. Compared to the simvastatin group, there were more patients in the atorvastatin group achieving the National Cholesterol Education Program ATP-III LDL-C goal (P < 0.05) and European LDL-C goal (P < 0.001). Both treatments were well tolerated; no patient was withdrawn from the study. This study demonstrates that both statins can effectively improve lipid profiles in patients with hyperlipidemia. Atorvastatin is more effective in helping patients reach the ATP-III and European LDL-C goals than simvastatin at the same dosage.     

Prevalence of mixed dyslipidemia among Australian patients undergoing lipid-modifying therapy

BACKGROUND:

Few studies have assessed the prevalence of mixed dyslipidemia (MD) and the effectiveness of lipid-modifying therapy (LMT) for the treatment of abnormal levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) in Australian clinical practice.

OBJECTIVE:

To estimate the prevalence of MD in Australian patients undergoing LMT.

METHODS:

Patients 35 years of age and older undergoing LMT for ≥1 year were enrolled from nine general practice and cardiologist/endocrinologist outpatient clinics in Australia between April 2007 and May 2008. Lipid levels, including LDL-C, HDL-C and TG levels, were prospectively collected at the enrollment date and from patient records one year before LMT was initiated. Normal lipid levels were assessed according to Australian guidelines. Multivariate logistic regression was used to evaluate predictors of normal lipid level attainment.

RESULTS:

Of 297 patients (mean age 60.1 years; 43% male), the prevalence of MD before LMT was 61%; 93% of patients had elevated LDL-C levels, 17% had low HDL-C levels and 62% had elevated TG levels. Following LMT (98.3% statins), 31% of patients had MD. The prevalence of elevated LDL-C levels, low HDL-C levels and elevated TG levels were 44%, 21% and 42%, respectively. Baseline lipid levels were significant predictors of attainment of normal LDL-C levels (OR 0.42 [95% CI 0.27 to 0.63]) and TG levels (OR 0.26 [95% CI 0.16 to 0.45]).

CONCLUSION:

Among Australian patients primarily treated with statins, nearly one-third had MD despite LMT. LMT considerably improved LDL-C goal attainment; however, a large proportion of patients did not achieve normal HDL-C and TG levels. Patients may benefit from a more comprehensive approach to lipid management that treats all three lipid risk factors, as suggested in clinical guidelines.     

依泽替米贝联合辛伐他汀改善冠心病患者血脂水平的疗效

目的：评价依泽替米贝/辛伐他汀联合用药改善冠心病患者血脂水平的疗效.方法：稳定使用辛伐他汀20mg的182例冠心病患者按数字法被随机分为：联合用药组（90例,依泽替米贝10mg＋辛伐他汀20mg）,辛伐他汀组（92例,辛伐他汀40mg）.分别在治疗前,治疗后6周评估病人的低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、总胆固醇/高密度脂蛋白胆固醇比率（TC/HDL-C）、LDL-C＜2.6mmol/L的病人比例等指标.结果：与辛伐他汀组比较,联合用药组LDL-C（-15.9％比-27.6％）、TC（-10.46％比-18.7％）和TC/HDL-C（-9.7％比-19.4％）等指标下降幅度更显著,LDL-C＜2.6 mmol/L的比例（40.2％比74.4％）显著升高,P＜0.05～0.01.两组间不良反应事件发生率差别无显著性.结论：对于单独使用辛伐他汀治疗未能达到推荐低密度脂蛋白胆固醇治疗目标的患者来说,联合依泽替米贝是一种有效的治疗方案.     

Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes mellitus patients with combined hyperlipidemia

Recent studies have shown that statins are effective in reducing fasting low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels. However, it remains unknown if treatment with statins also lowers daily postprandial triglyceride concentrations, which may promote atherogenesis in type 2 diabetes subjects. Forty-one subjects with type 2 diabetes and combined hyperlipidemia who had stable glycemic control were randomly assigned to take simvastatin 20 mg (n = 27) or a placebo (n = 14) once daily for 12 weeks. The medication dosage was doubled after 4 weeks if a subject's LDL-C was not less than 130 mg/dL. Among these participants, 24 subjects (15 on simvastatin and 9 on placebo) agreed to take a meal tolerance test with isocaloric mixed meals (carbohydrate, 52%; fat, 33%, and protein, 15% of the daily caloric intake) and daytime hourly blood sampling from 8 AM to 4 PM. Simvastatin treatment reduced the fasting total cholesterol level from 237 +/- 5 to 178 +/- 6 mg/dL (-25%), the LDL cholesterol level from 150 +/- 6 to 87 +/- 5 mg/dL (-40%), and raised high-density lipoprotein-cholesterol (HDL-C) level from 36 +/- 2 to 40 +/- 2 mg/dL (+11%) (all P <.001). Fasting and daily ambient triglyceride concentrations from 8 AM to 4 PM decreased significantly in response to simvastatin administration (P <.001), but not to the placebo (P =.305). Simvastatin treatment not only decreased total cholesterol and LDL-C levels and increased HDL-C levels effectively, it also decreased fasting, as well as daily postprandial triglyceride concentrations, but had no effect on glycemic control in type 2 diabetes subjects with combined hyperlipidemia.     

Baseline lipid values partly determine the response to high-dose simvastatin in patients with familial hypercholesterolemia. The examination of probands and relatives in Statin studies with familial hypercholesterolemia (ExPRESS FH)

Statins decrease low-density lipoprotein cholesterol (LDL-C), and additionally, reduce triglycerides (TG) and raise high-density lipoprotein cholesterol (HDL-C) levels. This study evaluated the frequency of abnormal TG and HDL-C levels in patients with classical familial hypercholesterolemia (FH) and assessed therapeutic response at different baseline levels of these lipoproteins after 1 year of statin therapy. A total of 508 FH patients were included and mean LDL-C levels (8.37+/-2.12 mmol l(-1)) were severely elevated. After a washout period of 6 weeks, all patients started monotherapy with 80 mg simvastatin. Remarkably, LDL-C reduction was dependent on baseline LDL-C levels ranging from 51.1 to 45.5% in the top versus the bottom third of the LDL-C distribution. Unexpected in FH, elevated baseline TG levels were seen in 30% and low HDL-C levels in 15% of all patients. Also, changes in these lipoproteins were dependent on baseline levels; TG reduction was 40.7 versus 22.2% in patients with elevated versus normal levels, while HDL-C increase was 29.1 versus 11.4% in patients with low versus normal HDL-C levels. In conclusion, FH patients with the worst lipoprotein profile showed the greatest benefit from high-dose simvastatin treatment, since changes in these parameters were partly determined by baseline lipid levels.     

Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients

AIM: In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low-density lipoprotein cholesterol (LDL-C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose-lowering properties and their modest beneficial effects on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid-modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD-treated T2DM patients. METHODS: This was a randomized, double-blind, parallel group, multicentre study in T2DM patients, 30-75 years of age, who had been on a stable dose of a TZD for at least 3 months and had LDL-C > 2.6 mmol/l (100 mg/dl) prior to study entry. Other antidiabetic medications were also allowed. Following 6 weeks of open-label simvastatin 20 mg/day, patients were randomized to the addition of either blinded ezetimibe 10 mg/day (n = 104) or an additional blinded simvastatin 20 mg/day (total simvastatin 40 mg/day; n = 110) for 24 weeks. Patients were stratified according to TZD type and dose (pioglitazone 15-30 vs. 45 mg/day; rosiglitazone 2-4 vs. 8 mg/day). RESULTS: LDL-C was reduced more (p < 0.001) by adding ezetimibe 10 mg to simvastatin 20 mg (-20.8%) than by doubling the dose of simvastatin to 40 mg (-0.3%). Ezetimibe plus simvastatin 20 mg also produced significant incremental reductions in non-HDL-C (p < 0.001), very low-density lipoprotein cholesterol (p < 0.05) and apolipoprotein B (p < 0.001) relative to simvastatin 40 mg. There were no differences between the groups with respect to changes in TG and HDL-C levels, and both treatments were well tolerated. CONCLUSIONS: Co-administration of ezetimibe with simvastatin, a dual inhibition treatment strategy targeting both cholesterol synthesis and absorption, is well tolerated and provides greater LDL-C-lowering efficacy than increasing the dose of simvastatin in T2DM patients taking TZDs.     

The effects of simvastatin combined with different antioxidant vitamin regimens on serum lipid profile in patients with low HDL cholesterol levels]

OBJECTIVE: This study was designed to compare the effects of simvastatin versus a combination of simvastatin with vitamin C or E on serum lipid profile, particularly, high-density lipoprotein (HDL)-cholesterol (C) level, in patients with a low HDL-C level. METHODS: Fifty-nine women and 49 men, who had a baseline HDL-C level equal to or lower than 40 mg/dl were randomized to one of the following study treatment groups: Group S (n=39) simvastatin 20 mg/day, Group S+C (n=33) simvastatin 20 mg/day + vitamin C 500 mg/day, and Group S+E (n=36) simvastatin 20 mg/day + vitamin E 400 IU/day. The groups' lipid profiles were obtained at baseline, 3rd and 6th months. RESULTS: Comparing with baseline values, total-C and low-density cholesterol (LDL-C) values significantly reduced (p<0.001) and HDL-C values significantly increased (Group S--33.9+/-3.9 mg/dl vs. 39.8+/-6.9 mg/dl, Group S+C--34.2+/-3.5 mg/dl vs. 38.1+/-6.1 mg/dl, Group S+E--33.1+/-3.6 mg/dl vs. 34.8+/-5.9 mg/dl, p<0.001) on therapy within the groups; however, there were no significant differences among the groups with regards to these parameters. The HDL-C levels increased from baseline by 14.0%, 11.7% and 10.2% in Group S, S+C, and S+E, respectively (p>0.05). CONCLUSION: A combination of simvastatin with antioxidant vitamins does not offer any beneficial effect over simvastatin alone. Particularly vitamin E seems to blunt the simvastatin induced HDL-C increase.     

停用辛伐他汀对冠心病及冠心病危险因素患者血管内皮功能的影响

目的 观察在冠心病及冠心病危险因素患者中,停用辛伐他汀治疗对血管内皮功能的影响,并探讨相应作用机制。方法 入选33例血清胆固醇（Tc）水平未达标的冠心病及冠心病危险因素患者,分别于基线水平、停药前（即辛伐他汀20mg治疗4周后）及停用辛伐他汀1周时,采用高分辨超声技术检测肱动脉血流介导性扩张（FMD）评估血管内皮依赖性舒张功能,并测定一氧化氮（NO）、血浆内皮素（ET）、6-酮-前列腺素F1α（6-keto-PGF1α）和血栓素B2（TXB2）的水平及主要血脂参数的变化。结果 辛伐他汀治疗4周后可有效降低冠心病及冠心病危险因素患者TC、低密度脂蛋白胆固醇（LDL-C）水平,并明显改善患者肱动脉内皮依赖性舒张功能（FMD）。然而,停用辛伐他汀治疗1周后,所有患者肱动脉内皮依赖性舒张功能均较停药前明显下降（4．82士0．71）％与11．51±0．87％,P〈0．01）,甚至低于未服用辛伐他汀时的基线水平（4．82±0．71％与5．89±0．65％,P〈0．01）,其中冠心病患者停药后FMD下降幅度较仅有冠心病危险因素患者更显著（65．6％与56．3％,P〈0．01）。停药1周后,患者血清NO水平较停药前及基础值均明显降低,而血浆ET水平升高。血浆TXB,水平在停药前后无明显变化。此外,停药后患者血清LDL-C水平虽较治疗4周时有所升高,但仍未恢复至基线水平。停药后肱动脉FMD的变化仅与血清NO降低幅度呈正相关关系（r=0．674。P=0．004）,而与血清LDL-C水平变化无明显相关性（r=-0．414,P=0．083）。结论 在TC水平未达标的冠心病及冠心病危险因素患者中突然终止辛伐他汀治疗可在1周内完全逆转该药对血管内皮功能的改善作用,甚至还可能导致血管内皮功能进一步恶化。并且这种撤药反应随基础疾病的严重性增加。停药所致血管内皮功能损害可能与血管内皮源性的NO减少有关,是非胆固醇依赖性作用。     

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort

Background

Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity.

Objective

To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment.

Methods

Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs.

Results

Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017).

Conclusions

Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.     

Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia

Besides hyperglycemia and hypertension, a recently recognized risk factor for diabetic retinopathy (DR) appears to be hyperlipidemia. While studies using earlier generation lipid lowering agents in DR were disappointing, a randomized trial using HMG-CoA Reductase Inhibitors has strong rationale, though hitherto not attempted. The aim of the present study was to compare the HMG-CoA Reductase Inhibitor, simvastatin, with placebo in patients having DR in a double-blind randomized placebo-controlled trial. Fifty patients with diabetes mellitus (Type 1 and 2) with good glycemic control and hypercholesterolemia and having DR (non-clinically significant macular edema and visual acuity 6/24 or better) in either or both eyes were randomized to simvastatin 20-mg per day or placebo, and were followed up for 180 days. On simvastatin therapy, total cholesterol and low-density lipoprotein cholesterol (LDL-C) decreased (P < 0.001, respectively), and the level of high-density lipoprotein cholesterol (HDL-C) increased (P < 0.001). VA improved in four patients using simvastatin, (not statistically different from placebo group) and worsening of VA occurred in seven patients in the placebo group and none in the simvastatin group (P = 0.009). Fundus fluorescein angiography and color fundus photograph showed improvement in one patient in the simvastatin group, while seven patients showed worsening in the placebo group (P = 0.009). The observations of the current study suggest that the HMG-CoA Reductase Inhibitor simvastatin significantly retards the progression of retinopathy in diabetic patients with hypercholesterolemia. The potential of this class of drugs for the primary prevention of DR and other microvascular complications needs to be explored further.