HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients

CONTEXT: Recent animal studies have found that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lipid-lowering drugs (statins) substantially increase bone formation, but whether statin use in humans results in clinically meaningful bone formation or a reduction in the risk of osteoporotic fractures is not known. OBJECTIVE: To determine whether the use of statins is associated with reduced hip fracture risk. DESIGN: Case-control study. SETTING AND PATIENTS: A total of 6110 New Jersey residents aged 65 years or older and enrolled in Medicare and either Medicaid or the Pharmacy Assistance for the Aged and Disabled program. Case patients (n=1222) underwent surgical repair of a hip fracture in 1994. Control patients (n=4888) were identified at a ratio of 4:1 and frequency-matched to case patients for age and sex. MAIN OUTCOME MEASURE: Adjusted odds ratio (OR) of hip fracture by statin use in the 180 days and 3 years prior to the index date (the earliest date of admission for surgery), adjusted for demographic and clinical characteristics and health care utilization. RESULTS: Use of statins in either the prior 180 days (adjusted OR, 0.50; 95% confidence interval [CI], 0.33-0.76) or prior 3 years (adjusted OR, 0.57; 95% CI, 0.40-0.82) was associated with a significant reduction in the risk of hip fracture, even after controlling for variables such as race, insurance status, psychoactive medications, estrogen and thiazide use, ischemic heart disease, cancer, and diabetes mellitus. No significant relationship was observed between use of nonstatin lipid-lowering agents and hip fracture risk. Clear relationships were observed between the degree of reduction in hip fracture risk and the extent of statin use; there was no evidence of such relationships with nonstatin lipid-lowering agents. After adjusting for extent of statin use in the prior 3 years, current use (on the index date) was associated with a 71% reduction in risk (adjusted OR, 0.29; 95% CI, 0.10-0.81). The relationship between statin use and hip fracture risk persisted after controlling for variables such as the number of medications, the Charlson comorbidity index score, and hospitalization or nursing home stay in the last 180 days, as well as after excluding patients who were in a nursing home prior to their index date or who died in the year after their index date. Use of nonstatin lipid-lowering agents was not observed to be associated with reduction in hip fracture risk in any of these alternative models or analyses. CONCLUSIONS: These findings support an association between statin use by elderly patients and reduction in the risk of hip fracture. Controlled trials are needed to exclude the possibility of unmeasured confounders. JAMA. 2000;283:3211-3216     

HMG-CoA还原酶抑制剂对腹膜透析患者腹膜纤维化的影响

目的:通过酶联免疫吸附方法(ELISA)检测腹透液中白细胞介素-6(IL-6)、糖类抗原125(CA125)的水平,观察他汀类药物对腹膜透析(PD)患者腹膜纤维化的抑制作用。方法:采用随机对照研究,将50例PD患者随机分为阿托伐他汀(20 mg/d)组和安慰剂组,治疗3个月,停用1个月后,交换处理3个月,留取每次治疗前后腹透液标本及每月留取腹透液标本,观察腹透液中IL-6、CA125的变化情况。结果:阿托伐他汀组治疗后腹透液中IL-6水平较安慰剂组有明显下降,而CA125水平则有明显升高,差异有统计学意义(P<0.05),阿托伐他汀组治疗前后及治疗过程中,CA125呈逐步上升趋势,IL-6水平呈逐步下降趋势,而安慰剂组治疗前后及治疗过程中炎性反应因子变化不明显。结论:阿托伐他汀对腹膜纤维化有一定的拮抗作用。     

吡咯类HMG-CoA还原酶抑制剂的合成及生物活性

目的:设计并合成吡咯类HMG-CoA还原酶抑制剂并测定其对HMG-CoA还原酶的抑制活性。方法:根据他汀类药物的构效关系,设计了一类(3R,5R)-7-[2-(4-氟苯基)-3-芳基-4-芳氨甲酰基-5-环丙基-1-吡咯基]-3,5-二羟基庚酸钠化合物(Ia～Im),通过测定烟酰胺腺嘌呤二核苷酸磷酸(NADPH)的降低速率,得到化合物对HMG-CoA还原酶的抑制活性。结果与结论:设计并合成了未见文献报道的HMG-CoA还原酶抑制剂13个,目标化合物结构经IR、1HNMR和HR-ESIMS确证。对所有化合物进行了HMG-CoA还原酶抑制活性测试,有5个化合物有抑制活性,其中化合物Ie的抑制活性与阳性对照药阿托伐他汀相当。     

Policosanol modulates HMG-CoA reductase activity in cultured fibroblasts

BACKGROUND: Cholesterol biosynthesis is strictly controlled by 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase. METHODS: Transfer of cultured fibroblasts to a lipid-depleted medium (LDM) up-regulates the enzyme levels. This, in turn, is followed by an accelerated biosynthesis of cholesterol. RESULTS: Exposure of Vero fibroblasts to LDM and policosanol (0.5-50 microg/mL), a new cholesterol-lowering drug purified from sugarcane (Saccharum officinarum L.) wax, decreased in a dose-dependent manner cholesterol biosynthesis from [14C]-acetate and 3H-water, but not from [14C]-mevalonate. CONCLUSIONS: This suggests an effect on HMG-CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis. When enzyme activity was measured in the presence of various concentrations of policosanol (0.5-50 microg/mL), reductase was not suppressed. Therefore, there was no evidence for a competitive or noncompetitive inhibition of enzyme activity. However, after treatment of intact cells with policosanol (50 microg/mL) in the presence of LDM, a suppressive effect on enzyme activity was observed, suggesting a modulatory effect of policosanol on reductase activity. The previous inhibition of enzyme up-regulation by policosanol suggests to date a depression of de novo synthesis of HMG-CoA reductase and/or stimulation of its degradation. However, the exact mechanism by which policosanol inhibits the activity of HMG-CoA reductase still remains unclear. Further studies are needed to clarify the precise mechanism of its inhibitory action on cholesterol biosynthesis.     

Cost-effectiveness of HMG-CoA reductase inhibition for primary and secondary prevention of coronary heart disease

To determine the cost-effectiveness of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (such as lovastatin) for the primary and secondary prevention of coronary heart disease, we used the Coronary Heart Disease Policy Model, a computer-stimulated model that estimates the risk factor-specific annual incidence of coronary heart disease and the risk of recurrent coronary events in persons with prevalent coronary heart disease. When used for secondary prevention, 20 mg/d of lovastatin was estimated to save lives and save costs in younger men with cholesterol levels above 250 mg/dL (6.47 mmol/L) and to have a favorable cost-effectiveness ratio regardless of the cholesterol level except in young women with cholesterol levels below 250 mg/dL (6.47 mmol/L). Doses of 40 mg/d of lovastatin had favorable incremental cost-effectiveness ratios in men with cholesterol levels above 250 mg/dL (6.47 mmol/L). By comparison, primary prevention had favorable cost-effectiveness ratios only in selected subgroups based on cholesterol levels and other established risk factors. We conclude that current national recommendations regarding medication for secondary prevention are not as aggressive as our projections would suggest, while recommendations regarding the use of medications for primary prevention should consider the cost of medication as well as the risk factor profile of the individual patient.     

氟伐他汀、辛伐他汀治疗肾病时肝功能损害的比较研究

目的 观察两种他汀类药物治疗肾病综合征高脂血症时肝脏功能损害情况。为临床治疗选择较为合适的他汀类药物提供依据。方法 将118例肾病综合征高脂血症患者随机分为3组，3组均行标准剂量激素和一般对症治疗，A组同时使用氟伐他汀。B组同时使用辛伐他汀，C组不用任何降脂药物。观察使用他汀类药物前后各组患者肝功能的变化。结果 A组患者转氨酶变化与对照组比较差异无统计学意义（P〉0．05）。B组转氨酶在用药后短期内升高。与A组、C组及自身用药之前比较，差异具有统计学意义（P〈0．01）。结论 两种他汀类药物治疗肾病综合征高脂血症时，氟伐他汀肝脏功能损害轻于辛伐他汀。可优先选择。     

Lovastatin对HL-60细胞HMG-CoA还原酶mRNA表达及细胞增殖功能的影响

目的探讨胆固醇合成抑制剂洛伐他汀(10vastatin,LOV)对HL-60细胞HMG-CoA还原酶mRNA表达及细胞增殖功能的影响.方法采用MTT比色法、生长曲线测定、计算细胞生长抑制率、流式细胞仪分析、以及RT-PCR等技术方法,观察LOV对HL-60细胞体外增殖能力、细胞周期分布及HMG-CoA还原酶mRNA表达的影响.结果HL-60细胞经LOV处理后,生长减慢,细胞周期被阻滞在G0/G1期,LOV剂量越大,时间越长,增殖抑制作用越明显;LOV处理HL-60细胞1～3 d,低剂量组(4 lμmol/L)HMG-CoA还原酶mRNA表达上调;而中剂量组(8μnol/L)和高剂量组(16μmol/L)第1天有增加趋势,第2～3天明显降低.结论LOV能显著抑制HL-60细胞增殖,使细胞受阻于G0/G1期,该作用有明显剂量-效应和时间依赖关系;随洛伐他汀处理剂量和时间的不同,HL-60细胞HMG-CoA还原酶mRNA表达表现为上调或下调变化.     

HMG-CoA 还原酶基因单核苷酸多态性与冠心病的关联研究

目的 探讨3-羟基-3-甲基戊二酰辅酶A (3-hydroxy-3-methylglutaryl coenzyme A, HMG-CoA) 还原酶基因的BsuR I和ScrF I等2个限制性内切酶多态位点各等位基因与冠心病（CHD）易感性和冠心病患者血脂水平变化之间的关系。方法 PCR扩增203例CHD患者和100例对照的2个多态位点相应的DNA片段,经限制性内切酶消化并电泳后确定基因型,用SPSS软件进行统计学分析。结果 2个多态位点的等位基因频率和基因型频率在CHD患者组和对照组间无显著差异。ScrF I多态位点AA基因型的CHD患者其TC和LDL-C水平比aa基因型的CHD患者显著增高（P = 0.031;P = 0.028）,TC / HDL-C比值也有显著性差异（P = 0.039）。结论ScrF I多态位点的A等位基因与CHD患者较高的TC和LDL-C水平以及较高的TC / HDL-C比值相关联,这在寻找CHD的危险因素和易感个体的筛查等方面可能有一定的参考意义。