Pharmacological management of diabetic dyslipidemia

Introduction: Diabetes mellitus is associated with increased cardiovascular disease (CVD) risk.

Areas covered: Main goal of hypolipidemic treatment in diabetic patients is low-density lipoprotein cholesterol (LDL-C) lowering with the use of statins. Addition of ezetimibe is useful in diabetic patients who cannot achieve their LDL-C target. However, many diabetic patients have increased residual CVD risk, which is mainly attributed to high triglycerides and low high-density lipoprotein (HDL-C) values. The addition of fenofibrate targets these variables and possibly reduces residual CVD risk, but a possible beneficial effect has been shown only in a pre-specified subgroup analysis in patients with high triglycerides and low HDL-C values. The newer proprotein convertase subtilisin/kexin type 9 inhibitors lower substantially LDL-C levels, but data from specifically designed trials in diabetic patients are not currently available. Although the cholesterol ester transfer protein (CETP) inhibitors have shown harmful effects or lack of efficacy in completed clinical trials, the newer CETP inhibitors have promising effects on lipid profile and carbohydrate metabolism, but their effects on CVD risk and safety profile have not been assessed.

Expert commentary: Clinicians have a range of pharmacological options to reduce the CVD risk of diabetic patients.     

依折麦布联合阿托伐他汀对不稳定型心绞痛患者血清甘油三酯的影响

目的 观察依折麦布联合阿托伐他汀对血清甘油三酯(TG)的影响.方法 选择2013年1月至12月在大连医科大学附属第一医院心内科住院,诊断为不稳定型心绞痛且行冠状动脉支架植入术并伴有低密度脂蛋白胆固醇(LDL-C)≥120 mg/dL、TG≥150 mg/dL的患者99例.随机分为两组,对照组52例,给予阿托伐他汀20 mg/d睡前口服;试验组47例,给予阿托伐他汀20 mg/d+依折麦布10 mg/d睡前口服.对两组患者治疗前及治疗4周后TG水平进行对比分析.结果 对照组治疗后TG为(190.25±79.26) mg/dL,与治疗前(228.48±70.10) mg/dL比较,差异有显著性意义(P＜0.01).试验组治疗后TG为(153.34±52.41) mg/dL,与治疗前(255.89±100.03) mg/dL比较,差异有显著性意义(P＜0.01).治疗4周后试验组与对照组比较,TC、rG、HDL和LDL-C差异均有显著性意义(P＜0.05);TC、TG和LDL-C水平均明显下降,且下降幅度显著大于对照组(P＜0.05).两组患者治疗前后肝功能、肾功能、肌酸激酶(CK)无明显变化.结论 对于不稳定型心绞痛患者,阿托伐他汀联合依折麦布能明显降低TG水平,临床应用安全,患者耐受性良好.     

Ezetimibe--a new approach in hypercholesterolemia management

Ezetimibe is the first agent used in hypercholesterolemia treatment known to lower intestinal cholesterol uptake that is able to inhibit NPC1L1 transport proteins in the brush boarder of enterocytes and macrophages. Furthermore, it demonstrates anti-inflammatory and immunomodulatory properties and influences the expression of certain antigens. The drug is rapidly absorbed from the gastrointestinal tract and is then glucuronidated to form the active metabolite. It also undergoes extensive enterohepatic circulation. Various genetic polymorphisms seem to influence the pharmacokinetics of ezetimibe with different effects. The drug also presents a complex impact on cytochrome P450 enzymes, as it is a metabolism-dependent inhibitor of CYP3A4. Ezetimibe does not demonstrate any clinically significant interactions with statins, fibrates, mipomersen sodium, levothyroxine or lopinavir. However, its effect in conjunction with cyclosporine is not neutral. The use of this cholesterol absorption inhibitor has been shown to be safe and effective among patients after cardiac, renal and liver transplants, as well as in HIV patients.     

依泽替米贝联合阿托伐他汀对动脉粥样硬化斑块的影响

目的：本研究选择阿托伐他汀联合依泽替米贝与单一阿托伐他汀药物治疗对比,评估联合用药对血脂和冠状动脉粥样硬化斑块消退的影响。方法：采用前瞻性、随机性的方法,将冠脉造影确诊为冠心病的患者随机分为阿托伐他汀组和阿托伐他汀联合依泽替米贝组。阿托伐他汀组以患者血清中低密度胆固醇浓度（LDL-C）<70 mg·dL^-1为治疗目标。用药9个月后,采用血管内超声定量冠状动脉内斑块,检测血液中相关参数。结果：阿托伐他汀联合依泽替米贝用药组与单独阿托伐他汀用药组相比,前者LDL-C明显降低[（60.5±19.8）mg·dL^-1 vs.（79.8±17.9）mg·dL^-1,P<0.01）]。与单一用药相对比,双联降血脂药物对斑块体积变化具有显著的优越性（-1.3±0.09 vs.-0.3±0.05,P<0.01）。血液中LDL-C浓度的降低幅度和斑块的消退程度具有显著相关性（R=0.207,P<0.05）。结论：阿托伐他汀联合依泽替米贝与阿托伐他汀用药相比,双联降脂药可以显著降低血清中LDL-C浓度,同时加速动脉粥样硬化斑块的消退。     

Statins,fibrates, nicotinic acid,cholesterol absorption inhibitors,anion‐exchange resins,omega‐3 fatty acids: which drugs for which patients?

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potential to decrease vascular risk remains to be proven. In contrast evidence for cardiovascular risk reduction through the mainly triglyceride lowering fibrates as well as for niacin is available. Niacin is the most potent HDL increasing drug currently available and besides increasing HDL cholesterol efficaciously lowers triglycerides and LDL cholesterol. Large ongoing trials address the decisive question whether treatment with fibrates and niacin provides additional cardiovascular risk reduction when given in addition to statin treatment.     

新型选择性胆固醇吸收抑制剂依泽麦布

依泽麦布为一种新型口服调血脂药物，它能选择性抑制肠道对胆固醇和相关植物甾醇的吸收。单独应用或与他汀类药物合用，均能降低具有冠心病风险患者的血清胆固醇水平。本文主要对其作用机制、药代动力学、临床疗效和安全性进行综述。     

HPLC同时测定依折麦布辛伐他汀片中两种成分的含量

目的 建立高效液相色谱法同时测定依折麦布辛伐他汀片中依折麦布和辛伐他汀的含量。方法 色谱柱Phenomenex Luna Phenyl Hexyl(4.6 mm×150 mm,5 μm),以乙腈-0.02 mol·L^-1磷酸二氢钠(pH 4.5)为流动相,梯度洗脱,流速1.0 mL·min^-1,检测波长231 nm,柱温30 ℃。结果 依折麦布在10.0~100.0 μg·mL^-1内线性关系良好(r=0.999 8),辛伐他汀在20.0~200.0 μg·mL^-1内线性关系良好(r=0.999 9)。依折麦布的平均回收率为99.5%,RSD为1.3%(n=9),辛伐他汀的平均回收率为99.8%,RSD为0.9%(n=9)。结论 本方法简便、可靠、准确度高、重复性好,可用于同时测定依折麦布辛伐他汀片中的依折麦布和辛伐他汀的含量。     

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor that significantly lowers low- density lipoprotein cholesterol (LDL-C), and favourably affects triglyceride and high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins. Hepatic and extrahepatic (peripheral) cholesterol synthesis are well-known sources of cholesterol found in LDL-C. However, the emergence of ezetimibe has highlighted intestinal cholesterol absorption as an additional, important source of cholesterol in LDL-C, and has better illuminated how genetic factors, dietary content, pharmaceutical agents, and nuclear receptor activation (such as liver X receptors) all influence the relative contribution of these important cholesterol sources to LDL-C. In fact, investigations into ezetimibe have sometimes challenged existing scientific dogma, has prompted reconsideration of older data, and has helped create ‘new’ paradigms in cholesterol metabolism. Thus, ezetimibe's efficacy, excellent tolerability, and safety has not only expanded potential treatment options for dyslipidaemic patients, but also has promoted exploration of new frontiers of lipid research towards a better understanding of cholesterol metabolism.     

人血浆中依折麦布浓度测定方法的不确定度评定

目的研究高效液相色谱-串联质谱法(HPLC-MS/MS)法测定人血浆中依折麦布浓度的不确定度评定方法。方法对依折麦布浓度测定全过程进行分析,包括测定精密度、称量、标准溶液的配制、固相萃取过程、标准曲线拟合等进行分析评定,根据各分量计算出合成不确定度,由合成不确定度及其分布求得扩展不确定度。结果人血浆中依折麦布浓度为0.20、2.0、16 ng·m L-1,在置信概率为95%时的扩展不确定度分别为(0.213±0.082)、(2.07±0.15)、(16.1±1.11)ng·m L-1。结论测定中的不确定度主要来自标准曲线的拟合过程,评价方法适用于血浆中依折麦布测定的不确定度评定。