Effective use of combination lipid therapy

Despite the benefits of statin therapy, low-density lipoprotein (LDL) cholesterol management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL cholesterol goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL cholesterol, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL cholesterol, and reduce non-HDL cholesterol to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.     

Effective use of combination lipid therapy

Despite the benefits of statin therapy, low-density lipoprotein cholesterol (LDL-C) management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL-C and non-high-density lipoprotein cholesterol (HDL-C) goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL-C goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL-C, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL-C, and reduce non-HDL-C to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable, if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.     

联合应用阿托伐他汀和烟酸缓释片治疗混合性高脂血症的疗效及安全性观察

目的:探讨联合应用阿托伐他汀和烟酸缓释片治疗混合性高脂血症的临床疗效及安全性。方法:入选混合性高脂血症患者121例,随机分入阿托伐他汀组(10 mg／d,n=64)、联合治疗组(阿托伐他汀10 mg／d+烟酸缓释片500 mg／d,n=57),疗程3个月。观察治疗前后主要血脂参数的变化率、达标率以及不良反应。结果:①2组血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)水平均有不同程度的改善,但联合治疗组血脂参数的变化幅度更大,明显优于阿托伐他汀组(P均<0．01～0．05)。②联合治疗组TC、LDL-C和TG的达标率分别为75．44％、64．91％和61．40％,三项全部达标者占45．61％,明显高于阿托伐他汀组(P均<0．01)。③联合治疗组不良反应的发生率和阿托伐他汀组相比差异无统计学意义(P均>0．05)。结论:研究结果提示,烟酸缓释片(500 mg/d)与阿托伐他汀(10 mg／d)联合治疗可以更全面地改善混合性高脂血症患者的血脂异常,具有良好的安全性和耐受性。     

Comparison of combined statin-fibrate treatment to monotherapy in patients with mixed hyperlipidemia

BACKGROUND: Statins are the preferred drugs for the treatment of hypercholesterolemia, and fibrates for hypertriglyceridemia. In patients with mixed hyperlipidemia, monotherapy with one of these agents may not be effective and combined treatment may be preferable. AIM: To compare retrospectively the efficacy and safety of combined statin-fibrate treatment in patients with mixed hyperlipidemia in whom previous monotherapy with one of these agents occurred ineffective. METHODS AND RESULTS: The initial study group consisted of 327 patients who received micronised fenofibrate and 93 patients who received simvastatin for 12 months. Both agents caused significant changes in lipid profile. Following fibrate therapy, total cholesterol (TC), LDL-cholesterol (LDL-C) and triglyceride (TG) levels decreased by 27.9%, 28.2% and 58%, respectively, and following simvastatin therapy by 33.6%, 42.8% and 37.5%, respectively. The HDL-cholesterol (HDL-C) level increased after fenofibrate by 14.8% and remained unchanged following simvastatin therapy. The TC/HDL-C ratio decreased following fenofibrate by 35.6%, and following simvastatin by 35.3%. In some patients the required reduction in lipid parameters was not achieved fenofibrate or simvastatin. Subsequently, 93 patients underwent combined therapy by adding a second agent (simvastatin in a dose of 20 mg/day or fenofibrate in a dose of 200 mg per day) which was continued for another 12 months. The addition of simvastatin to fenofibrate decreased TC, LDL-C and TG levels by 35.5%, 42.1% and 59.6%, respectively in comparison to before treatment volumes. HDL-C level was increased by 11.1%, and TC/HDL-C ratio decreased by 45.3%. The addition of fenofibrate to simvastatin decreased TC, LDL-C and TG levels by 39.3%, 48.9% and 51,6%, respectively. HDL-C level was increased by 13.4%, and TC/HDL-C ratio decreased by 49.3%. No clinical side effects nor an increase in the transaminase levels, requiring termination of the treatment, were observed. CONCLUSIONS: Combined therapy with 20 mg of simvastatin and 200 mg of micronised fenofibrate is highly effective and safe in patients with mixed hyperlipidemia.     

Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial)

Patients with combined hyperlipidemia (elevated triglyceride [TG] levels, elevated low-density lipoprotein [LDL] cholesterol, and multiple lipoprotein abnormalities) are at increased risk for coronary heart disease. We conducted a multicenter (in the United States), randomized, double-blind, active-controlled, 18-week study to determine if combination therapy with simvastatin plus fenofibrate is more effective in reducing elevated TG levels, thus improving the lipoprotein pattern in patients with combined hyperlipidemia compared with simvastatin monotherapy, and to evaluate safety and tolerability. Patients (aged 21 to 68 years) with a diagnosis of combined hyperlipidemia (fasting TG levels >/=150 and 130 mg/dl) received simvastatin monotherapy (20 mg/day, n = 207) or simvastatin 20 mg plus fenofibrate (160 mg/day) combination therapy (n = 411) for 12 weeks following a 6-week diet and placebo run-in period. From baseline to week 12, median TG levels decreased 43.0% (combination therapy) and 20.1% (simvastatin monotherapy [treatment difference -23.6%, p <0.001]). Mean LDL cholesterol levels decreased 31.2% and 25.8% (treatment difference -5.4%, p <0.001), and high-density lipoprotein cholesterol levels increased 18.6% and 9.7% (treatment difference 8.8%, p <0.001) in the combination therapy versus monotherapy groups, respectively. No drug-related serious adverse experiences were observed. No patient experienced clinical myopathy or severe abnormalities in liver function. Combination therapy with simvastatin 20 mg and fenofibrate 160 mg in patients with combined hyperlipidemia resulted in additional improvement in all lipoprotein parameters measured compared with simvastatin 20 mg monotherapy and was well tolerated. Thus, this combination therapy is a beneficial therapeutic option for managing combined hyperlipidemia.     

Effectiveness of ezetimibe alone or in combination with twice a week Atorvastatin (10 mg) for statin intolerant high-risk patients

This study was undertaken to investigate the effect of ezetimibe (10 mg/day) alone or in combination with atorvastatin (10 mg twice a week) on hypercholesterolemia in 56 high-risk patients intolerant to daily statin use. Ezetimibe monotherapy was well tolerated (2 withdrawals) and induced a mean reduction in low-density lipoprotein (LDL) cholesterol of 20% (p <0.05) at the third month. However, of the 54 patients still taking ezetimibe, only 5 (9%) were at their LDL cholesterol targets. Atorvastatin 10 mg twice a week was then added to ezetimibe and was well tolerated (3 withdrawals). This combination reduced LDL cholesterol (in a treatment-based analysis) by 37% compared with baseline (p <0.001), with 43 (84%) patients reaching their LDL cholesterol goals. When patients (n = 34, 25 men) with baseline serum creatinine values in the upper 2 tertiles were analyzed separately, there was a significant (p = 0.041) decrease in serum creatinine levels after 6 months of treatment. In conclusion, the combination of ezetimibe plus atorvastatin 10 mg twice a week might be a therapeutic option for high-risk patients intolerant to daily statin monotherapy.     

Effect of levothyroxine on total lipid profiles as assessed by analytical capillary isotachophoresis in a patient with hypothyroidism

The patient was a 51-year-old Japanese female who had been diagnosed with hyperlipidemia. At the first medical examination, her serum levels of total cholesterol (TC) and triglyceride (TG) were 482 and 205 mg/dl, respectively. Since hyperlipidemia was not improved by pravastatin, atorvastatin or niceritrol, and since the levels of thyroid-stimulating hormone (TSH) and free T4 were 730 IU/ml and 0.3 ng/dl, respectively, the patient was diagnosed as secondary hyperlipidemia with hypothyroidism. A method for the charge isolation of lipoproteins using capillary isotachophoresis (cITP) is proposed as a clinical application because it allows us to quantitatively measure electronegative low-density lipoprotein cholesterol (LDL-C), a potent marker of coronary heart disease. After 5 months of treatment with levothyroxine, Serum TC and LDL-C levels drastically decreased without statin treatment and high-density lipoprotein cholesterol (HDL-C) increased. In the lipoprotein profiles as assessed by cITP after treatment with levothyroxin, all HDL-C subfractions were increased and fast-migrating LDL/electronegative LDL appeared to be greatly reduced after treatment, while the area under the non-modified LDL peak was increased. The cITP analysis was able to obtain more information about coronary risk factors and may be clinically useful for evaluating the effect of treatment with levothyroxine in patients with hypothyroidism and secondary hyperlipidemia.     

Cross-over trial of intensive monotherapy with atorvastatin and combined therapy with atorvastatin and colestimide for Japanese familial hypercholesterolemia.

BACKGROUND: In familial hypercholesterolemia (FH), low-density lipoprotein-cholesterol (LDL-C)-lowering therapy is important to avoid predisposition to coronary artery disease. This study investigated the advantages of combined therapy with atorvastatin and colestimide vs intensive monotherapy with atorvastatin. METHODS AND RESULTS: The trial used a randomized cross-over design consisting of 2 16-week periods of open-label drug therapy. Among the 24 initial patients, 17 heterozygous FH patients (age: 54.1 years; 5 males) were enrolled after 20 mg/day atorvastatin failed to achieve their target level. The patients received 20 mg/day atorvastatin and 3 g/day colestimide or 40 mg/day atorvastatin. Fifteen patients completed the trial and their LDL-C reduced from 5.07 +/- 1.10 mmol/L to 3.76 +/- 0.90 mmol/L with the combined therapy and to 3.81 +/- 0.50 mmol/L with the intensive monotherapy. Although the 2 therapies showed comparable mean effects for decreasing LDL-C, similar adverse reaction and cost, each therapy was predominantly more effective in some patients than in others. The triglyceride and high-density lipoprotein cholesterol levels were similar in both therapies. CONCLUSIONS: To achieve the therapeutic target of LDL-C level for refractory FH, the LDL-C-lowering therapy selected can be either intensive monotherapy or combined therapy as the next to standard statin therapy.     

Is it necessary to add fibrate to statin therapy in the management of dyslipidemia of metabolic syndrome?

The available data have suggested a significant association between hypertriglyceridemia and cardiovascular disease. Although atherogenic dyslipidemia in patients with metabolic syndrome is characterized by high triglyceride, low HDL cholesterol and near normal LDL cholesterol levels, lowering LDL cholesterol is the first priority in treating dyslipidemia in patients with metabolic syndrome. The use of statins as monotherapy is still leaving some of these patients with mixed atherogenic dyslipidemia at high risk for coronary events. So, it seems beneficial to add a fibrate to statin therapy in the management of dyslipidemia of metabolic syndrome, especially in patients with inadequately corrected triglyceride levels with statin monotherapy.     

Ezetimibe: A First‐in‐Class,Novel Cholesterol Absorption Inhibitor

Significant numbers of patients at risk for coronary heart disease (CHD) fail to reach National Cholesterol Education Program (NCEP)‐designated low density lipoprotein cholesterol (LDL‐C) goals in spite of the wide range of currently available treatments, including combination therapies. Ezetimibe, the first in a class of novel cholesterol absorption inhibitors, demonstrated lipid‐lowering and antiatherosclerotic activity in experimental and clinical hypercholesterolemia. Studies in hypercholesterolemic dogs showed that ezetimibe coadministered with statins caused greater lipid‐lowering effects compared to either drug alone. These effects were confirmed in clinical studies of patients with primary hypercholesterolemia where initiation of treatment with ezetimibe plus a statin, or addition of ezetimibe to ongoing statin therapy, produced significant incremental reductions in LDL‐C, as well as incremental increases in high‐density lipoprotein cholesterol (HDL‐C) and reductions in triglyceride levels. Combination therapy also significantly increased the number of patients attaining LDL‐C goal at the end of treatment, compared to statin monotherapy. In studies using simvastatin, atorvastatin, pravastatin, and lovastatin, addition of ezetimibe to low dose statin was as effective as a 2‐ to 3‐fold upward titration of the corresponding statin dose. Ezetimibe‐statin combination therapy provided similar improvements in patients with primary hypercholesterolemia, as well as with heterozygous and homozygous familial hypercholesterolemia. Ezetimibe monotherapy effectively reduced plasma campesterol and sitosterol in patients with homozygous sitosterolemia. Clinical studies showed that ezetimibe was well tolerated, with a safety profile comparable to placebo when administered as monotherapy and comparable to statin alone when coadministered with a statin. These data provide strong evidence that, through their complementary lipid‐lowering mechanisms, ezetimibe coadministered with a statin offers an effective combination treatment option for patients with hypercholesterolemia, including those with genetically inherited disease.     

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

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

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

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

Comparison of atorvastatin versus fenofibrate in reaching lipid targets and influencing biomarkers of endothelial damage in patients with familial combined hyperlipidemia

Statins and fibrates have different effects on lipid abnormalities of familial combined hyperlipidemia (FCHL); thus, the selection of the first-line drug is troublesome. We evaluated to what extent monotherapy with a potent statin is more effective than fibrate in reaching the recommended lipid targets in FCHL. Fifty-six patients were randomized to receive optimal dosage of atorvastatin (n = 27) or 200 mg/d micronized fenofibrate (n = 29) for 24 weeks. To reach the optimal dosage, atorvastatin was up-titrated at each follow-up visit if low-density lipoprotein (LDL) cholesterol >130 mg/dL (>100 mg/dL in patients with coronary or cerebrovascular disease). The effects of fenofibrate and atorvastatin on lipoprotein fractions as well as on plasma levels of endothelin-1 (ET-1) and adrenomedullin (AM) were also evaluated. At end of trial, a greater proportion of patients on atorvastatin (average dosage, 20.8 mg/d) reached lipid targets in comparison with those on fenofibrate (64% vs 32.1%, P = .02). Atorvastatin was significantly more effective in reducing total cholesterol, LDL cholesterol, apolipoprotein B, and non-high-density lipoprotein (HDL) cholesterol. Conversely, triglycerides decreased and HDL increased more during fenofibrate. Nevertheless, atorvastatin produced a marked reduction in very low-density lipoprotein and very low-density lipoprotein remnants. Atorvastatin lowered all LDL subtypes, although fenofibrate appeared to be more effective on denser LDL. Compared with 43 normolipemic controls, FCHL patients presented increased baseline plasma levels of ET-1 (P = .007) but not of AM. Fenofibrate, but not atorvastatin, significantly lowered ET-1 levels by 16.7% (P < .05). Neither drug significantly affected plasma concentrations of AM. In summary, although fenofibrate showed superiority in raising HDL and reducing ET-1, atorvastatin was more effective in reaching lipid targets in FCHL so that it can be proposed as the first-line option in the management of this atherogenic hyperlipidemia.     

Effects of increasing doses of atorvastatin on the atherogenic lipid subclasses commonly associated with hypertriglyceridemia

The increased cardiovascular risk associated with hypertriglyceridemia is thought to be due in part to high levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL). In this post hoc analysis, effects of increasing doses of atorvastatin (10, 20, 40, and 80 mg) on atherogenic lipid subclasses commonly associated with hypertriglyceridemia were evaluated in 191 men and women who were candidates for lipid-lowering therapy and had baseline TG levels >200 mg/dl (2.3 mmol/L). After 8 weeks of treatment, in addition to significantly decreasing LDL cholesterol and TG levels, atorvastatin significantly increased LDL peak particle diameter (p <0.01) and significantly decreased the concentration of small LDL subclasses IIIa and IIIb (p <0.0001) from baseline at all doses. These effects were more pronounced with higher compared with lower doses of atorvastatin. Each dose of atorvastatin also significantly lowered levels of very LDL, intermediate-density lipoprotein (p <0.0001), and small very LDL subclass 3 (p <0.0001). Greater decreases were achieved by those patients receiving higher doses of atorvastatin (20, 40, and 80 mg). The increase in LDL size correlated with the decrease in TG levels, but not with the decrease in LDL cholesterol levels. However, the decrease in small dense LDL cholesterol concentrations correlated significantly with TG and LDL cholesterol decreases. In conclusion, atorvastatin significantly lowered levels of TG-rich remnant lipoproteins and favorably changed LDL particle size in patients with hypertriglyceridemia. These effects may explain the benefits of statin therapy in high-risk patients with hypertriglyceridemia even when levels of LDL cholesterol are at goal.     

不同调脂方案对冠心病患者C反应蛋白和CD40配体的影响

目的 观察在冠状动脉狭窄50%～70%的冠心病患者中应用阿托伐他汀和依折麦布联合治疗调脂作用和安全性,及其对C-反应蛋白(CRP)、CD40配体(CD40L)的影响. 方法选取冠状动脉狭窄50%～70%的冠心病患者42例,均未植入支架,分为他汀组19例(40 mg阿托伐他汀)和联合治疗组(10 mg阿托伐他汀+10 mg依折麦布)23例.在服药前、用药4周、用药12周测定总胆固醇(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、CRP和CD40L. 结果 (1)他汀组和联合治疗组均在4周时患者的TC、LDL-C降低,12周时他汀组的LDL-C为(1.94±0.49)mmol/L,联合治疗组为(1.92±0.54)mmol/L,两组差异无统计学意义;(2)他汀组和联合治疗组患者肝功能、肾功能、肌酸激酶用药后无明显升高;(3)两组CRP在12周时较基线均有降低,他汀组CD40L降低. 结论单用他汀治疗和联合治疗降脂疗效无差异.两种治疗均未引起患者肝、肾功能和肌酸激酶异常.40 mg阿托伐他汀治疗可降低患者CRP、CD40L.     

Atorvastatin versus four statin-fibrate combinations in patients with familial combined hyperlipidaemia

BACKGROUND: Statin-fibrate combinations are very effective in the treatment of familial combined hyperlipidaemia (FCHL). Nonetheless, they have not been extensively used because of the fear of side effects. Thus, a therapeutic alternative is required for this lipid disorder. OBJECTIVE: To compare the long-term (one-year) efficacy of atorvastatin monotherapy with those of four statin-fibrate combinations in 675 FCHL patients. METHODS: Patients were randomly assigned to atorvastatin monotherapy (A 20 mg/day) n = 134, or pravastatin (P 20 mg/day)+gemfibrozil (G 1200 mg/day) n = 135, simvastatin (S 20 mg/day)+G (1200 mg/day) n = 137, P (20 mg/day)+ciprofibrate (C 100 mg/day) n = 135, and S (20 mg/day)+C (100 mg/day) n = 134. RESULTS: Twelve patients on statin-fibrate combinations were withdrawn from the study because of side effects: three because of CK elevation, two because of myalgia and seven due to increase in serum transaminase levels. One patient on A was withdrawn because of persistent epigastric discomfort. Atorvastatin reduced low density lipoprotein cholesterol and apoprotein B more than all four combinations (-45% vs. maximum -40% of S+C, and -39% vs. maximum -32% of the same combination, respectively, P < 0.001 for both), but had a lesser effect on triglycerides (-38% vs. maximum -53% of S+C, P = 0.0002) and high density lipoprotein cholesterol (6% vs. maximum 21% of S+G, P = 0.0003). The effect of A on plasma fibrinogen was analogous to that of G combinations (-8% vs. -9% of P+G and -11% of S+G, P = NS vs. baseline and among each other) and inferior to that of the ciprofibrate combinations (-8% vs. -24% of P+C, P = 0.0002 and -26% S+C, P = 0.0001). A had a lower treatment cost and better patient compliance, P = 0.04 vs. C combinations and P = 0.02 vs. G combinations. CONCLUSIONS: The data suggest that statin-fibrate combinations have a beneficial effect on all lipid parameters. Atorvastatin monotherapy has a better effect on LDL-C and apoprotein B than statin-fibrate combinations, but a lesser effect on HDL-C, TG and in the case of ciprofibrate combinations, fibrinogen. The clinical significance of these findings should be tested in a large, long-term survival study.     

Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?

OBJECTIVES: We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose. BACKGROUND: Reducing the level of low-density lipoprotein cholesterol (LDL-C) with statins induces important pleiotropic effects such as platelet inhibition. An insufficient LDL-C reduction often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with a low statin dose. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy. METHODS: Fifty-six patients with coronary artery disease were assigned randomly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks. The levels of LDL-C, platelet activation markers after stimulation, platelet aggregation, and plasma chemokine levels (i.e., regulated on activation normally T-cell expressed and secreted [RANTES]) were measured before and after changing lipid-lowering medication. RESULTS: Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (-5.2 +/- 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 +/- 1.8 arbitrary units; p < 0.005) despite a similar reduction of LDL-C (atorvastatin -1.01 +/- 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 +/- 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin. CONCLUSIONS: Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects.     

Hochdosierte Statintherapie für kardiovaskuläre Risikopatienten

Lowering LDL cholesterol (LDL-C) with statins decreases cardiovascular risk; therefore LDL-C is the primary target in lipid therapy. The amount of risk reduction is the greater, the lower the LDL-C values achieved by statin therapy are. Current guidelines therefore require an LDL-C as low as < 70 mg/dl in patients who are at a very high risk of cardiovascular events. This stringent treatment goal depending on the baseline LDL-C values typically can only be obtained with higher doses of potent statins. Randomised trials demonstrate the efficacy of high-dose therapy with atorvastatin 80 mg/day with regard to the prevention of cardiovascular events in patients after acute coronary syndromes (PROVE-IT TIMI 22 trial), in patients with stable coronary artery disease (TNT trial), and in patients after stroke or TIA (SPARCL trial). Moreover, potent statin treatment reduces the progression of coronary atherosclerosis (REVERSAL and ASTEROID trials). Furthermore, large meta-analyses of the efficacy of high-dose statin therapy confirm its safety; in particular, muscle-related adverse events are not more frequent than with standard statin doses. It is recommended that evidence-based statin doses be used in clinical practice; the dosages used in clinical trials should be given rather than titrating patients to LDL-C targets by increasing statin doses in a stepwise manner. Whether the strong LDL-C lowering combination of simvastatin plus ezetimibe will reduce cardiovascular events over and above simvastatin monotherapy is currently being tested in the ongoing IMPROVE-IT trial. Importantly, despite the large body of evidence in favour of high-dose statin therapy for patients at high cardiovascular risk, high-dose statin therapy is still underused and LDL-C goals are still not met in the majority of these patients.     

Atorvastatin and the plasma activities of lipoprotein lipase,hepatic lipase and lecithin:cholesterol acyltransferase in patients with mixed hyperlipidemia

Background: Atorvastatin provokes a strong reduction in plasma total cholesterol (TC) and LDL-cholesterol (LDL-C), an effect attributed to the increase in the receptor-mediated catabolism of LDL and well-demonstrated for statins. In addition, atorvastatin induces a reduction in plasma triglycerides (TG), an effect that must be ascribed to another mechanism. Methods: Ten patients with mixed hyperlipidemia (TC and TG greater than 250 and 200 mg/dl, respectively) were treated with atorvastatin, 10 mg/day for 1 month and 20 mg/day for another month. The plasma activities of lecithin:cholesterol acyltransferase (LCAT), of lipoprotein lipase (LPL), and of hepatic lipase (HL) were measured before and at the end of treatment. The changes were analyzed in relation to changes in plasma lipids and in components of lipoproteins. Results: A marked increase (65%) in the plasma LCAT was observed, together with a slight (18.1%) decrease in the plasma HL activity. Plasma activity of LPL remained unchanged. Conclusions: In this uncontrolled study, atorvastatin provoked a marked increase in the turnover of cholesteryl esters in accordance with the well-known stimulating effect of statins on the receptor-mediated catabolism of LDL. The marked decrease in TG is explained not by an increased activity of LPL but probably by a reduced synthesis of VLDL by the liver. The results must be confirmed in a placebo-controlled study.     

Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates

Subjects with moderate combined hyperlipidemia (n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL(1)) apoB (4.52+/-3.06 pools per day on atorvastatin; 5.48+/-4.76 pools per day on simvastatin versus 2.26+/-1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL(1) concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL(1) to VLDL(2) and of VLDL(2) to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54+/-0.30 pools per day at baseline to 1.17+/-0.87 pools per day on atorvastatin and to 0.95+/-0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58-84% by statin treatment (P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22+/-0.04 pools per day) increased to 0.44+/-0.11 pools per day on atorvastatin and 0.38+/-0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.