Opening a new lipid "apo-thecary": incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) represent the cornerstone of drug therapy to reduce low-density lipoprotein (LDL) cholesterol and cardiovascular risk. However, even optimal statin management of LDL cholesterol leaves many patients with residual cardiovascular risk, in part because statins are more effective in reducing LDL cholesterol than apolipoprotein B (Apo B). Apo B may be a better marker of atherogenic risk than LDL cholesterol because Apo B measures the total number of all atherogenic particles (total atherosclerotic burden), including LDL, very low-density lipoprotein, intermediate-density lipoprotein, remnant lipoproteins, and lipoprotein(a). To determine whether Apo B is a better indicator of baseline cardiovascular risk and residual risk after lipid therapy compared with LDL cholesterol, a MEDLINE search of the literature published in English from January 1, 1975, through December 1, 2010, was conducted. On the basis of data from most population studies, elevated Apo B was more strongly associated with incident coronary heart disease than similarly elevated LDL cholesterol. Apo B was also a superior benchmark (vs LDL cholesterol) of statins' cardioprotective efficacy in both primary-prevention and secondary-prevention trials. To minimize cardiovascular risk among persons with hypercholesterolemia or dyslipidemia, the best available evidence suggests that intensive therapy with statins should be initiated to achieve the lowest possible Apo B level (with adequate drug toleration) and then other therapies (eg, niacin, bile acid resins, ezetimibe) added to potentiate these Apo B-lowering effects. In future consensus lipid-lowering treatment guidelines, Apo B should be considered as an index of residual risk, a potential parameter of treatment efficacy, and a treatment target to minimize risk of coronary heart disease.     

Novel HDL-based therapeutic agents

Reduction in low-density lipoprotein cholesterol (LDL-C) levels has been associated with a 25-30% reduction in cardiovascular disease risk. However, there still remains a significant and quantifiable risk. Since epidemiologic data have demonstrated that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease, novel therapeutic agents are currently being developed to either raise HDL-C levels or enhance HDL functionality. This review will highlight some of these therapeutic agents including cholesteryl ester transfer protein inhibitors, apolipoprotein A-I mimetics, RVX-208, and apolipoprotein A-I based infusion therapies. For each therapeutic class, an overview of the mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be provided.     

A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance

BACKGROUND: Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared. OBJECTIVES: This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared. METHODS: This was a multicenter, open-label, parallel-group trial. Patients with LDL-C levels>or=140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable. RESULTS: Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack of >or=6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P=0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P=0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (-40.1 vs -33.0, respectively; P=0.002), as were the percent changes in non-HDL-C (-37.4 vs -31.1; P=0.004), Apo B (-35.1 vs -28.2; P<0.001), and Apo E (-28.1 vs -17.8; P<0.001). The significant results for these parameters were unchanged when all 189 subjects who received>or=1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group (P=NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value>3 times the upper limit of normal (P=NS). CONCLUSIONS: In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.     

Familial hypercholesterolaemia: optimum treatment strategies

Familial hypercholesterolaemia (FH) is a hereditary metabolic disorder characterised by defects in the low-density lipoprotein (LDL) receptor, elevated LDL cholesterol (LDL-C) levels and an extremely high risk for premature cardiovascular disease. Heterozygous FH occurs in about one of every 500 individuals in the United States and Europe. The high prevalence of FH and associated morbidity and mortality strongly support aggressive screening and treatment. There are two major barriers to effective management of FH: 1) the failure to screen for this disease in people who may be at increased risk for it; and 2) the inability of most available therapies to enable achievement of LDL-C goals. More aggressive screening, coupled with new genetic screening techniques, and more powerful 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have the potential to overcome these limitations. Automated genetic assays are now available for detection of common LDL receptor mutations in individuals at risk for FH, and they have been used effectively to identify patients with this condition. Recent clinical trial results with the new synthetic statin rosuvastatin (Crestor; AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK; licensed from Shionogi & Co, Ltd, Osaka, Japan) in patients with heterozygous FH have shown that it decreased LDL-C by 58% and increased high-density lipoprotein cholesterol (HDL-C) by 12%. Rosuvastatin was significantly superior to high-dose atorvastatin in improving these lipid parameters as well as total cholesterol, apolipoprotein (apo) B, apo A-I, and the LDL-C/HDL-C ratio. Thus, new screening tools and medical therapies have the potential to significantly improve management and reduce cardiovascular disease risk for patients with FH.     

Torcetrapib/atorvastatin combination therapy

Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy lipid-altering drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in lipid levels, and complementary actions upon important lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin alone.     

Torcetrapib/atorvastatin combination therapy

Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy lipid-altering drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in lipid levels, and complementary actions upon important lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin 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.     

风湿性心脏病和扩张型心肌病患者血脂与载脂蛋白测定结果分析

目的通过测定风湿性心脏病(RHD)和扩张型心肌病(DCM)患者血脂与载脂蛋白水平,探讨RHD和DCM患者血脂与载脂蛋白异常的意义.方法 86例RHD患者、50例DCM患者和106例健康体检者,采用酶法测定血脂.免疫比浊法测定载脂蛋白.结果 RHD和DCM患者血脂代谢异常主要表现为血脂和载脂蛋白的普遍降低,尤其是总胆固醇(TC)、低密度脂蛋白胆固醇( LDL-C)、载脂蛋白B(Apo B)在DCM组降低明显,异常率分别达40.0%、40.0%、70.0%;与对照组相比,RHD和DCM患者TC、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、载脂蛋白A-I(Apo AI)均降低(P<0.05),而DCM组同时伴LDL-C和Apo B明显降低(P<0.05);与RHD组比较,DCM组LDL-C和Apo B明显降低(P<0.05,0.001).结论 RHD和DCM患者的血脂和载脂蛋白普遍降低,DCM患者降低更明显,对RHD和DCM患者不应盲目采取降血脂治疗.     

Quantification of human serum apolipoprotein A-I by zone immunoelectrophoresis assay and a procedure for the preparation of an A-I standard

A zone immunoelectrophoresis assay (ZIA) for human serum apolipoprotein A-I (Apo A-I) is described. In this immunologic technique, glass capillaries filled with agarose gel containing anti-Apo A-I are used. Apo A-I produces zones of immunoprecipitates with migration distances directly proportional to the apolipoprotein concentration. Two plasmas and their isolated high density lipoprotein (HDL) fractions, having different particle size distribution patterns have been analyzed for Apo A-I using rocket electroimmunoassay in parallel with ZIA. A good agreement between the two methods was obtained. With ZIA, Apo A-I complexed with lipids in HDL yielded concentration values that were unaffected by lipoprotein particle size and by delipidation. A standard curve, linear between 0.5 and 3.5 mg Apo A-I/1, was obtained with ZIA. A protocol for the preparation of an Apo A-I standard without prior purification of the apolipoprotein is presented. Using ZIA, 75 serum samples representing a heterogeneous study population were analyzed for Apo A-I. A mean value of 1.23 g/l with a relative standard deviation of 28% was obtained. The corresponding mean for total HDL cholesterol was 1.64 mmol/l (RSD = 61%).     

Review of efficacy of rosuvastatin 5 mg

The prevalence of coronary heart disease (CHD) has been increasing in the past few decades in Japan, as it has in industrialised countries worldwide. CHD risk can be substantially reduced by lowering low-density lipoprotein cholesterol (LDL-C) in patients with dyslipidaemia. Statins are highly effective for this indication, but many patients treated with these drugs still do not meet their treatment goals, often because clinicians fail to titrate these patients to a higher, potentially more effective, dose. Thus, there is a need for more effective agents that can help patients reach their goals at starting doses. This paper reviews key clinical results for a new agent, rosuvastatin. The data show that rosuvastatin 5 mg is highly effective in lowering LDL-C to recommended levels for most patients (mean reductions ranging from 42 to 52%). In addition, rosuvastatin 5 mg effectively lowers triglycerides (-16%), total cholesterol (-30%), non-high-density lipoprotein cholesterol (non-HDL-C; -38%) and apolipoprotein (apo) B levels (-33%) and increases HDL-C (+8.2-13%) in a wide range of patients with hypercholesterolaemia, including the elderly, obese patients, postmenopausal women and patients with hypertension, CHD, diabetes and metabolic syndrome. The 5-mg dose of rosuvastatin dose also produces greater reductions in LDL-C and larger increases in HDL-C than recommended initial doses of atorvastatin, simvastatin or pravastatin (for LDL-C reductions, p <0.001 vs. atorvastatin 10 mg, simvastatin 20 mg and pravastatin 20 mg; for HDL-C elevations, p <0.01 vs. atorvastatin 10 mg). These results demonstrate that rosuvastatin 5 mg produces favourable effects on the lipid profile and helps more patients achieve LDL-C goals than comparator statins.     

非高密度脂蛋白胆固醇与心脑血管病风险研究进展

大量的流行病学及临床数据显示低密度脂蛋白胆固醇水平与动脉粥样硬化性心血管病的发病风险相关。许多一级预防和二级预防的试验显示降低低密度脂蛋白胆固醇能够显著减少心血管病的发病风险。但是,即使经过强化的降脂治疗,很多患者仍有显著的复发风险,这说明除低密度脂蛋白胆固醇外还存在其他的残留风险。学者们用载脂蛋白B,非高密度脂蛋白胆固醇来估算这种残留风险。本文讨论了非高密度脂蛋白胆固醇和冠心病及卒中的关系。     

'Trig-onometry': non-high-density lipoprotein cholesterol as a therapeutic target in dyslipidaemia

Targeting elevations in low-density lipoprotein cholesterol (LDL-C) remains the cornerstone of cardiovascular prevention. However, this fraction does not adequately capture elevated triglyceride-rich lipoproteins (TRLs; e.g. intermediate-density lipoprotein, very low density lipoprotein) in certain patients with metabolic syndrome or diabetic dyslipidaemia. Many such individuals have residual cardiovascular risk that might be lipid/lipoprotein related despite therapy with first-line agents (statins). Epidemiological evidence encompassing > 100,000 persons supports the contention that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior risk factor vs. LDL-C for incident coronary heart disease (CHD) in certain patient populations. In studies with clinical end-points evaluated in the current article, a 1:1 to 1:3 relationship was observed between reductions in non-HDL-C and in the relative risk of CHD after long-term treatment with statins, niacin (nicotinic acid) and fibric-acid derivatives (fibrates); this relationship increased to 1:5 to 1:10 in smaller subgroups of patients with elevated triglycerides and low HDL-C levels. Treatment with statin-, niacin-, fibrate-, ezetimibe-, and omega 3 fatty acid-containing regimens reduced non-HDL-C by approximately 9-65%. In a range of clinical trials, long-term treatment with these agents also significantly decreased the incidence of clinical/angiographic/imaging efficacy outcome variables. For patients with dyslipidaemia, consensus guidelines have established non-HDL-C treatment targets 30 mg/dl higher than LDL-C goals. Ongoing prospective randomised controlled trials should help to resolve controversies concerning (i) the clinical utility of targeting non-HDL-C in patients with dyslipidaemia; (ii) the most efficacious and well-tolerated therapies to reduce non-HDL-C (e.g. combination regimens); and (iii) associations between such reductions and clinical, angiographic, and/or imaging end-points.     

Achievement of English National Service Framework lipid-lowering goals: pooled data from recent comparative treatment trials of statins at starting doses

Despite the importance of reducing cardiovascular disease (CVD) risk, detailed in guidelines in many countries, repeated surveys show poor physician performance in attaining guideline lipid targets, which is associated with reluctance by physicians to up-titrate statins from starting doses. Data from randomised, double-blind trials comparing common starting doses of atorvastatin, pravastatin, rosuvastatin and simvastatin for 12 weeks in hypercholesterolaemic patients were therefore analysed for achievement of lipid-lowering goals recommended by the England National Service Framework (NSF) for coronary heart disease (CHD). In three pooled trials, rosuvastatin 10 mg (n = 389) reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol more significantly than atorvastatin 10 mg (n = 393) (p < 0.001). NSF goals were achieved by 83% of rosuvastatin patients vs. 55% of atorvastatin patients (p < 0.001) at relevant starting doses. In two pooled trials, rosuvastatin 10 mg (n = 226) reduced LDL-C and total cholesterol more significantly than simvastatin 20 mg (n = 249) and pravastatin 20 mg (n = 252) (p < 0.001). NSF goals were achieved at starting doses by 83% of rosuvastatin patients vs. 51% of simvastatin patients and 19% of pravastatin patients (p < 0.001 vs. each comparator). This improved achievement of NSF lipid target, at starting doses, was also seen in high-risk patients (those eligible for secondary prevention or primary prevention because of a 10-year CVD risk of >30%) with 84% patients on rosuvastatin vs. 58% on atorvastatin and 75% of patients on rosuvastatin vs. 49% on simvaststin and 24% on pravastatin. In summary, there are considerable and clinically significant variations in the achievement of lipid goals between common starting doses of statins in hypercholesterolaemic patients.     

Apolipoprotein and lipid abnormalities in uremic children on hemodialysis

Plasma lipids and six plasma apolipoproteins were studied in uremic children on hemodialysis. Significant increases in plasma triglyceride, apolipoproteins (Apo) C-II and C-III and decreases in total cholesterol, HDL-cholesterol, Apo A-I, Apo A-II and Apo B were found in uremic children. The levels of Apo C-I did not differ between uremic children and normal controls. The ratio of (Apo A-I + Apo A-II)/HDL-cholesterol was significantly increased. These results indicate that uremic children on hemodialysis have similar lipid and apolipoprotein abnormalities to those found in adults who may have a risk of cardiovascular disease.     

The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: An updated meta-analysis

Background: In 2005, the Cholesterol Treatment Trialists' Collaboration (CTTC) quantified the relationship between reduction in low-density lipoprotein cholesterol (LDL-C) achieved by statin treatment and reduction in cardiovascular risk. Since this publication, several large statin trials have been reported.Objective: The objective of our analysis was to extend the CTTC results by including active-controlled trials and other trials published since 2005.Methods: A literature search in English (1966–December 2008) was undertaken of MEDLINE, EMBASE, Derwent drug file databases, and the Cochrane library using standard MESH terms (cardiovascular disease, death, fatal outcome, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, lovastatin, and hydroxymethylglutaryl coenzyme A reductase inhibitors) to identify randomized trials of statins (placebo controlled, active controlled, or usual care) that reported clinical outcomes, enrolled >1000 subjects, and followed them up for ≥1 year. Random effects meta-regression was used to analyze the relationship between absolute changes in LDL-C and risk for cardiovascular events.Results: Twenty-five trials were included in a primary analysis involving 155,613 subjects, 6321 vascular deaths, 23,791 major vascular events, 11,357 major coronary events, and 4717 strokes. For every 25-mg/dL (0.65-mmol/L) reduction in LDL-C, the relative risk (95% CI) for various cardiovascular outcomes was as follows: vascular mortality, 0.89 (0.87–0.92); major vascular events, 0.86 (0.84–0.88); major coronary events, 0.84 (0.82–0.86); and stroke, 0.90 (0.86–0.94).Conclusions: Based on meta-regression analysis of these trials, there was a significant positive relationship between reduction in LDL-C and reduction in the risk for major cardiovascular events. These results support and extend the findings of the CTTC.     

Cost-effectiveness analysis of rosuvastatin versus atorvastatin, simvastatin, and pravastatin from a Canadian health system perspective

OBJECTIVE: The primary objective of this study was to assess the cost-effectiveness of the most commonly prescribed doses of rosuvastatin, atorvastatin, simvastatin, and pravastatin for managing various lipid parameters in patients with hypercholesterolemia over a 1-year time horizon from a Canadian health care perspective. METHODS: Incremental cost-effectiveness ratios (ICERs) were estimated for branded rosuvastatin compared with branded atorvastatin, generic simvastatin, and generic pravastatin in patients with hypercholesterolemia in terms of percent reduction in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio, as well as in TC, HDL-C, triglycerides (TG), apolipoprotein (Apo) B, the ApoB/ApoA-I ratio, and attainment of the Canadian LDL-C goal. The pharmacoeconomic model was constructed for a 1-year time horizon using efficacy data from a randomized, open-label trial including 2268 adults and the wholesale acquisition costs of branded rosuvastatin and atorvastatin and generic simvastatin and pravastatin in British Columbia. RESULTS: The most commonly prescribed doses of each of the 4 statins in British Columbia were as follows: rosuvastatin 10 mg (75.8% of all rosuvastatin doses); atorvastatin 10 and 20 mg (46.4% and 35.3%, respectively, of all atorvastatin doses); simvastatin 20 and 40 mg (42.5% and 31.8%, respectively, of all simvastatin doses); and pravastatin 20 and 40 mg (55.0% and 34.1%, respectively, of all pravastatin doses). Rosuvastatin 10 mg was dominant (ie, was more effective at a lower cost) relative to atorvastatin 10 and 20 mg, simvastatin 20 and 40 mg, and pravastatin 40 mg in terms of reductions in LDL-C, TC/ HDL-C ratio, TC, ApoB, and ApoB/ApoA-I ratio, increases in HDL-C, and attainment of the LDL-C goal. Compared with pravastatin 20 mg, the ICER per percent reduction in LDL-C, TC/HDL-C ratio, TC, TG, ApoB, or ApoB/ApoA-I or increase in HDL-C ranged from $3.89 to $26.07; the value for 1 additional patient achieving the LDL-C goal was $419.75. When the statin doses were aggregated based on the Canadian statin-utilization pattern, rosuvastatin was dominant relative to atorvastatin on all effectiveness measures evaluated. When rosuvastatin was compared with generic simvastatin and pravastatin, the annual costs for 1 additional patient achieving the LDL-C goal were $144.51 and $373.91, respectively. Based on the sensitivity analysis, rosuvastatin was associated with the highest probability of cost-effectiveness compared with the other statins over a broad range of monetary values per unit of clinical effect. CONCLUSION: When percent changes in lipid parameters and rates of LDL-C goal attainment were considered in patients with hypercholesterolemia in British Columbia, rosuvastatin 10 mg was more cost-effective than the most frequently used doses of atorvastatin (10 and 20 mg), generic simvastatin (20 and 40 mg), and generic pravastatin (20 and 40 mg).     

Cardiovascular risk reduction: What do recent trials with rosuvastatin tell us?

Abundant evidence from large-scale clinical trials supports the importance of lowering low-density lipoprotein cholesterol (LDL-C) to decrease the risk of cardiovascular disease (CVD) events. The LDL-C targets in various guidelines remain important treatment goals but, even in trials where statin therapy achieves substantial reduction of LDL-C, a significant number of CVD events still occur and the residual risk remains high. These findings suggest that lipid parameters other than LDL-C, such as high-density lipoprotein cholesterol (HDL-C), triglycerides, and LDL particle size, can influence the risk of CVD. On this basis, other strategies that can alter the lipid profile, in particular raising HDL.C, may provide additional benefits. Other factors such as HDL-C functionality and susceptibility to oxidation and inflammatory factors can also influence cardiovascular risk. In addition to the modifications of the lipid profile, statins have cholesterolindependent beneficial pleiotropic effects. The contribution of these effects to event reduction is not yet fully understood. Recently, the body of evidence has expanded to support the use of intensive statin therapy in broader patient populations. The JUPITER trial has shown the benefit of intensive statin treatment in low-risk subjects with high levels of high-sensitivity C-reactive protein and average levels of LDL-C. Unlike the setting of primary and secondary prevention, the results of statin trials in patients with heart failure have shown no clear benefit in terms of survival. The recently published AURORA trial was carried out to investigate the effect of rosuvastatin in patients with end-stage renal disease undergoing chronic hemodialysis. In this trial no benefit on cardiovascular events was shown with statin therapy. In conclusion, large outcomes trials have clearly shown that statin treatments have a favorable benefit/risk profile in a large range of patients at different levels of risk, with the exception of patients with heart failure and those with renal disease undergoing dialysis. Further evidence is needed on the role of therapeutic strategies on the so-called residual risk.     

Statins for treatment of dyslipidemia in chronic kidney disease.

Dyslipidemia is a potent cardiovascular (CV) risk factor in the general population. Elevated low-density lipoprotein cholesterol (LDL-C) and/or low high-density lipoprotein (HDL-C) are well-established CV risk factors, but more precise determinants of risk include increased apoprotein B (ApoB), lipoprotein(a) [Lp(a)], intermediate and very low-density lipoprotein (IDL-C, VLDL-C; "remnant particles"), and small dense LDL particles. Lipoprotein metabolism is altered in association with declining glomerular filtration rate such that patients with non dialysis-dependent chronic kidney disease (CKD) have lower levels of HDL-C, higher triglyceride, ApoB, remnant IDL-C, remnant VLDL-C, and Lp(a), and a greater proportion of oxidized LDL-C. Similar abnormalities are prevalent in hemodialysis (HD) patients, who often manifest proatherogenic changes in LDL-C in the absence of increased levels. Patients treated with peritoneal dialysis (PD) have a similar but more severe dyslipidemia compared to HD patients due to stimulation of hepatic lipoprotein synthesis by glucose absorption from dialysate, increased insulin levels, and selective protein loss in the dialysate analogous to the nephrotic syndrome. In the dialysis-dependent CKD population, total cholesterol is directly associated with increased mortality after controlling for the presence of malnutrition-inflammation. Treatment with statins reduces CV mortality in the general population by approximately one third, irrespective of baseline LDL-C or prior CV events. Statins have similar, if not greater, efficacy in altering the lipid profile in patients with dialysis-dependent CKD (HD and PD) compared to those with normal renal function, and are well tolerated in CKD patients at moderate doses (相似文献   

阻塞性睡眠呼吸暂停低通气综合征对心血管危险因素的影响

目的探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)在心血管疾病发病中的作用。方法将2007年1月~2008年12月在呼吸睡眠监测中心就诊的成年患者,进行多导睡眠图(PSG)检测,根据睡眠呼吸暂停低通气指数(AHI)将所有对象分为轻度组(AHI为5~20次/h)、中度组(AHI为21~40次/h)、重度组(AHI大于40次/h)和健康对照组(AHI小于5次/h);全自动生化仪检测血清胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、载脂蛋白A-I、载脂蛋白B、脂蛋白a;ELISA法检测患者外周血清C反应蛋白。结果所有入选对象M型超声心动图检测结果均在正常范围内。血脂检测显示:①HDL-C、载脂蛋白A-I在OSAHS组和对照组间比较无统计学意义;②脂蛋白a、载脂蛋白B水平在OSASH各组间比较无统计学意义,但均高于对照组(P均小于0.05);③与对照组相比,OSAHS患者的甘油三酯和LDL-C水平明显升高(P<0.05),重度组明显高于轻中度组(P<0.05),轻中度组间差异无统计学意义(P>0.05);④与健康对照组相比,OSAHS患者的外周血总胆固醇水平显著升高,并随着OSAHS病情加重呈升高趋势,差异均有统计学意义(P<0.05)。OSAHS患者外周血清C反应蛋白水平明显高于健康对照组,并且随着病情加重逐渐上升,差异均有统计学意义(P<0.05)。结论OSAHS可引起患者血清C反应蛋白和血脂升高,导致OSAHS患者心血管疾病的发病率和死亡率上升,这将为临床上心血管疾病的早期诊断和OSAHS的治疗提供新思路。     

Combination treatment with atorvastatin plus niacin provides effective control of complex dyslipidemias: a literature review

Patients with dyslipidemia receive a cardiovascular benefit from lowering low-density lipoprotein cholesterol (LDL-C). Atorvastatin is currently one of the most effective approved medications for lowering LDL-C, and has been shown to significantly reduce cardiovascular risk in many patient groups. However, even with substantial lowering of LDL-C with atorvastatin, patients still have a residual risk for coronary heart disease. Elevated triglyceride levels and low high-density lipoprotein cholesterol (HDL-C) levels may contribute to this risk. Approved medications targeting these secondary lipid parameters include fibrates, omega-3 fatty acids, and niacin. Among these medications, niacin provides the optimal increase in HDL-C levels and has efficacy similar to the other medications in lowering triglyceride levels. However, there are challenges to adherence with niacin treatment. The most common challenge during niacin treatment is flushing, although it typically decreases with ongoing use and can be ameliorated by pretreatment with aspirin and counseling by the prescriber. A combination of atorvastatin and niacin may provide more complete normalization of the lipid profile and increased cardiovascular benefits. A literature review of the PubMed and Embase databases was conducted for clinical studies that reported on the lipid-modifying efficacy of the atorvastatin plus niacin combination. Identified studies involved patients at risk for coronary heart disease and patients with established coronary heart disease. Overall, the studies were small but indicated that atorvastatin in combination with niacin was efficacious in normalizing lipid parameters. Larger lipid studies as well as studies evaluating cardiovascular outcomes during atorvastatin plus niacin treatment are warranted.