Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia

Objective

Controversial findings exist regarding potential influence of statin therapy on diabetic incidence. Aim of this study was to investigate the role of long duration statin treatment on diabetes mellitus (DM) incidence of Heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) patients.

Methods

Study population consisted of 212 hFH and 147 FCH patients that visited Lipid Outpatient Department (mean follow up of 11 and 10 years respectively). Several clinical data such as history of DM, cardiovascular disease, thyroid function, metabolic syndrome, glucose levels, lipid profile and lifestyle data were obtained. In order to compare the effects of different doses of different types of statins, a “statin treatment intensity product” was used.

Results

14% of FCH and only 1% of hFH patients developed DM during follow up. Although univariate analysis showed a statistical trend (p = 0.06) in the association between new onset DM and statin treatment intensity (STI) in the FCH subgroup of patients with normal baseline glucose levels, this was no longer significant after adjusting for several confounders. Furthermore, the type of statins used did not seem to play a role in the development of DM either in hFH or FCH patients.

Conclusion

Long duration of high STI does not seem to be associated with diabetic risk in hFH patients. High STI used in the FCH population is not associated with increased risk of new onset DM compared to low STI. Further studies are required in order to clarify the potential diabetogenic effects of statins in these high risk populations.     

Insulin resistance and oxidative stress in familial combined hyperlipidemia

Oxidative stress is associated with atherosclerosis. Familial combined hyperlipidemia (FCH) is considered as a human model of primary dyslipidemia and atherosclerosis frequently associated with insulin resistance (IR), but there are few data on its possible relation to oxidative stress. The objective of this study was to evaluate oxidative stress status using different markers in subjects with FCH assessing its possible correlation with anthropometric parameters and IR. This was a cross-sectional study. A cohort of 40 FCH patients (20 with IR (HOMA ≥ 3.2) and 20 without IR (HOMA < 3.2)), and 20 healthy volunteers were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose and insulin levels in plasma, HOMA, and representative indicators of oxidative stress such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), reduced glutathione (GSH), oxidized glutathione (GSSG) and GSSG/GSH ratio in mononuclear cells. All parameters were determined at basal conditions with standard methodology in the three groups. All FCH subjects showed an increased status of oxidative stress compared to the control group. When the impact of IR was investigated, significant differences between groups were observed in terms of increased levels of 8-oxo-dG, GSSG and GSSG/GSH ratio in FCH subjects with IR indicating higher levels of oxidative stress in these patients. Correlation studies showed that 8-oxo-dG and GSSG/GSH ratio are independently related to IR with odds ratio of 3.5 and 7.4, respectively. We conclude that FCH is related to oxidative stress, especially in the presence of IR.     

A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia

We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49–50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77 ± 0.15 mmol/l vs. 1.15 ± 0.20 mmol/l, P < 0.005; 71.4 ± 9.1 mg/dl vs. 134.0 ± 14.7 mg/dl, P < 0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C.     

Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia

Background and aimsCardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins.Methods and resultsAmong primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included.LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (<15% or <30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects.ConclusionAccording to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.     

Pulse wave velocity in familial combined hyperlipidemia

BACKGROUND: In the present cross-sectional study we investigated whether familial combined hyperlipidemia (FCH) is associated with an increased arterial wall stiffness, and whether measures of arterial wall stiffness in FCH family members could contribute to cardiovascular risk stratification. METHODS: Ninety-eight subjects with FCH and 230 unaffected relatives filled out a questionnaire about their smoking habits, medical history, and medication use. Fasting venous blood was drawn after discontinuation of any lipid-lowering medication. Pulse wave velocity (PWV) and augmentation index (AIx) were determined by applanation tonometry as surrogate markers of arterial stiffness. RESULTS: Patients with FCH had a significantly increased PWV compared to their unaffected relatives (9.07 +/- 2.75 v 8.28 +/- 2.62 m/sec, P = .005), whereas AIx was not increased (21.6 +/- 12.7 v 15.6 +/- 14.1, P = .96). Age- and gender-adjusted PWV was an equally good predictor of the presence of cardiovascular disease (CVD) in FCH family members as the most predictive combination of age- and gender-adjusted clinical and biochemical risk factors, including total cholesterol, HDL-cholesterol, and systolic blood pressure (area under the receiver operating curve (ROC) [AUC] 0.83 [0.76-0.90] v AUC 0.84 [0.78-0.91], P = .83). Addition of PWV to the multivariable prognostic model, including these age- and gender-adjusted traditional risk factors, did not increase the predictive ability for CVD (AUC 0.84 [0.79-0.89]). CONCLUSIONS: Patients with FCH are characterized by an increased arterial stiffness. The PWV predicts the presence of CVD equally well as any combination of clinical and traditional biochemical risk factors, but PWV has no additional value in addition to traditional risk factor screening in FCH families.     

阿托伐他汀联合非诺贝特治疗老年混合型高脂血症临床疗效观察

目的 探讨中等剂量阿托伐他汀片剂和非诺贝特胶囊联合应用治疗混合性高脂血症的临床疗效及安全性.方法 混合性高脂血症患者226例,随机分为：阿托伐他汀组112例,阿托伐他汀（20 mg/d）治疗;联合治疗组114例,阿托伐他汀（20 mg/d）和非诺贝特胶囊（200 mg/d）共治疗3个月.观察治疗前、后各项血脂参数的变化、达标率及不良反应.结果 除阿托伐他汀组高密度脂蛋白胆固醇（HDL-C）水平与治疗前相比无明显改善[（0.99±0.27）mmol/L比（0.95±0.24）mmol/L,P＞0.05]外,两组患者各项血脂参数如血清总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和甘油三酯（TG）水平与治疗前相比均有不同程度的改善[阿托伐他汀组：（4.22±0.46）mmol/L比（7.18±0.52）mmol/L,（2.76±0.34）mmol/L比（4.46±0.43）mmol/L,（3.05±0.44）mmol/L比（3.81±0.48）mmol/L;联合治疗组：（3.43±0.42）mmol/L比（7.15±0.50）mmol/L,（2.18±0.31）mmol/L比（4.44±0.42）mmol/L,（1.62±0.31）mmol/L比（3.85±0.51）mmol/L;P均＜0.05],但联合治疗组TG、TC、LDL-C降低的幅度和HDL-C升高幅度较大[（3.05±0.44）mmol/L比（1.62±0.31）mmol/L,（4.22±0.46）mmol/L比（3.43±0.42）mmol/L,（2.76±0.34）mmol/L比（2.18±0.31）mmol/L,（1.23±0.30）mmol/L比（0.99±0.27）mmol/L,P均＜0.05],达标率更高（69.6%比13.4%,83.3%比71.4%,80.7%比67.9%,49.1%比9.8%,P均＜0.05）,明显优于阿托伐他汀组,两组患者不良反应的发生率相比差异无统计学意义（P＞0.05）.结论 中等剂量阿托伐他汀（20 mg/d）和非诺贝特胶囊（200 mg/d）联合应用对混合性高脂血症患者具有良好的安全性和有效性,值得临床推广应用.     

血脂康对高脂血症患者低密度脂蛋白颗粒和氧化型低密度脂蛋白的影响

目的探讨血脂康对高脂血症患者低密度脂蛋白(LDL)颗粒和氧化型低密度脂蛋白(ox-LDL)的影响。方法连续入选未服用降脂药物治疗的受试人群40例(其中高脂血症患者20例,健康受试者20例),分为血脂康组(n=20例)和对照组(n=20例)。Lipoprint脂蛋白分类检测仪对LDL颗粒进行分类。治疗8周后比较两组治疗前后LDL颗粒和ox-LDL的变化。结果与治疗前相比,治疗后血脂康组的血清低密度脂蛋白胆固醇(LDLC)、总胆固醇(TC)、甘油三酯(TG)和载脂蛋白B的浓度显著降低(P0. 05),小颗粒LDLC的浓度和小颗粒LDL的百分比均降低(P0. 05)。经血脂康治疗后,ox-LDL的浓度显著降低(P0. 05)。结论血脂康治疗8周可显著改善高脂血症患者的血脂谱,并降低致动脉粥样硬化性小颗粒LDLC浓度和百分比,同时减少氧化应激反应。     

小剂量氟伐他汀联合非诺贝特治疗老年混合型高脂血症的临床研究

目的观察小剂量氟伐他汀联合非诺贝特治疗老年混合型高脂血症的疗效及安全性。方法将入选的70例老年混合型高脂血症患者，随机分为氟伐他汀单药治疗组（12=35，20mg／d），氟伐他汀（20mg／d）、非诺贝特（200mg，隔日1次）联合治疗组（12=35），疗程均为12周。结果联合治疗组血脂参数变化最显著，降低低密度脂蛋白胆固醇、三酰甘油和升高高密度脂蛋白胆固醇的能力明显优于单药组（P〈0．01或P〈0．05），且未发现明显不良反应。结论小荆量氟伐他汀与非诺贝特联合治疗可以更有效地改善老年混合型高脂血症患者的血脂异常，具有良好的安全性和耐受性。     

Association of heterozygous familial hypercholesterolemia with smaller HDL particle size

Small, dense HDL particles have been associated with factors known to increase the risk of cardiovascular disease, such as obesity, hypertriglyceridemia, small dense LDL particles, decreased HDL-cholesterol levels and increased apoA-I fractional catabolic rate from plasma. In order to assess the potential contribution of HDL particle size to atherosclerosis in heterozygous familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of HDL particles in a large cohort of well defined FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. All subjects were apoE3 homozygotes. HDL particles were characterized by non-denaturing polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. The integrated HDL size was significantly smaller in the FH group compared to controls (FH = 87.3 ± 5.2 Å versus controls = 91.6 ± 4.9 Å, P < 0.0001). In each groups, men had smaller HDL particles than women. Multiple regression linear analyses showed that the FH/Control status accounted for 20.3% of the variance in the integrated HDL size. These results suggest that the FH/control status was independently associated with variations in HDL particle size and that these variations could contribute to the development of premature atherosclerosis in these patients.     

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia

Background and aimsXanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR).Method and results40 Non-related subjects with FCH and 30 control subjects were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose, insulin, uric acid, XO activity, malondialdehyde (MDA), IL-6 and hsCRP in plasma and NFkB activity in circulating mononuclear cells. Patients with FCH showed significantly higher levels of uric acid, XO activity, MDA, NFkB activity, IL-6 and hsCRP than controls. XO activity was independently related to NFkB activity with an odds ratio of 4.082; to IL-6 with an odds ratio of 4.191; and to IR with an odds ratio of 3.830. Furthermore, mean NFkB activity, IL-6 levels, and IR were highest in the highest percentile of XO activity.ConclusionsSubjects with FCH showed increased XO and NFkB activities and low grade inflammatory markers related to atherosclerosis. XO activity was correlated with higher inflammatory activity and IR. These data could explain, in part, the high cardiovascular disease risk present in these patients.     

家族性高胆固醇血症家系低密度脂蛋白受体活性及其基因突变分析

目的:对1例临床诊断为家族性高胆固醇血症(FH)纯合子患者家系进行低密度脂蛋白受体(LDL-R)活性研究及其基因突变分析,旨在探讨其分子病理机制。方法:对先证者及其父母进行血脂、颈动脉超声等检查;采用流式细胞仪检测先证者及其父母外周血淋巴细胞LDL-R表达量和功能;以先证者基因组DNA为模板,扩增载脂蛋白B100(ApoB100)基因3500区域片断,PCR产物进行核苷酸序列分析,排除由该突变导致家族性ApoB100缺陷症;用降落式PCR方法,在同一程序中分别扩增LDL-R基因的启动子和全部18个外显子片段,扩增产物进行核苷酸序列分析;发现突变后验证其父母是否存在相同基因突变。结果:先证者血清TC和LDL水平明显升高、颈动脉内中膜明显增厚;LDL-R的表达量和结合功能显著下降(分别为正常人的13.6%和21.1%);ApoB100基因3500区域未见突变,LDL-R基因第1864位碱基T取代了G发生纯合错义突变,导致第601位氨基酸天冬氨酸变成脯氨酸(D601Y)。其父母LDL-R基因发现了相同的杂合突变,经检索该突变在我国未见报道。结论:证实家系先证者存在LDL-R基因突变,分别来源于父系和母系的遗传,该突变可能是家系发病的分子基础;D601Y也可能是我国FH患者LDL-R基因一种新的突变类型。     

Effect of pravastatin on LDL particle concentration as determined by NMR spectroscopy: a substudy of a randomized placebo controlled trial.

AIM: Recent data suggests that LDL particle concentration, as determined by Nuclear Magnetic Resonance (NMR) spectroscopy, may be associated with cardiovascular risk. We sought to determine the effect of randomization to pravastatin therapy on LDL particle concentration-NMR, among a primary prevention population. METHODS AND RESULTS: LDL particle concentration-NMR, LDL size-NMR, and standard chemical lipid parameters were measured at baseline and after 12 weeks among 500 individuals without overt coronary disease randomly allocated to pravastatin 40mg (n=256) or placebo (n=244). Randomization to pravastatin therapy caused a 19% reduction in median LDL particle concentration-NMR at 12 weeks, as compared to a 4.2% increase among those randomized to placebo (P<0.001 for pravastatin group compared to placebo). Pravastatin therapy caused a median 24.9% reduction in LDL cholesterol measured chemically compared to a 0.9% increase in the placebo group (P<0.001). Pravastatin therapy did not cause a significant change in median LDL size-NMR (0.5% increase in pravastatin group vs 0.0% in placebo group; P=0.25). The change in LDL particle concentration with pravastatin correlated inversely with baseline LDL size (r=-0.24; P<0.001) such that the largest reduction in LDL particle concentration-NMR was among those with the smallest LDL size-NMR at baseline (median% change =21.4% for tertile 1 of LDL size, 19.9% for tertile 2, and 16.5% for tertile 3; P=0.03). In contrast, pravastatin-induced changes in LDL cholesterol did not correlate with baseline LDL size-NMR (r=-0.05; P=0.47). CONCLUSION: Among individuals without overt hyperlipidemia or known coronary artery disease, randomized allocation to pravastatin (40mg) therapy for 12 weeks caused a reduction in LDL particle concentration-NMR, the magnitude of which was dependent on baseline LDL size-NMR.     

Comparison of the effects of atorvastatin or fenofibrate on nonlipid biochemical risk factors and the LDL particle size in subjects with combined hyperlipidemia

Background Combined hyperlipidemia (CH) is an increasingly prevalent risk factor for premature heart disease, and its treatment is troublesome. The aim of this study was to compare the effects of atorvastatin and fenofibrate on nonlipid biochemical risk factors and the low-density lipoprotein (LDL) particle size in subjects with CH. Methods Twenty-nine middle-aged men with CH were randomly assigned to open-label therapy with atorvastatin (10 mg daily) or micronized fenofibrate (200 mg daily); they were sequentially treated with both drugs, with crossover of medication after 10 weeks. Results Atorvastatin was more efficient in the reduction of total cholesterol, whereas fenofibrate was more efficient in the reduction of triglycerides. Only atorvastatin led to a significant reduction of LDL cholesterol and apolipoprotein B. Only fenofibrate increased high-density lipoprotein cholesterol. Neither drug influenced lipoprotein(a). Mean LDL particle size increased both after fenofibrate (3.08%) and atorvastatin (1.77%). Fenofibrate increased serum homocysteine (HCY) by 36.5%. Atorvastatin had no effect on HCY. Only atorvastatin increased fibrinogen by 17.4%. Only fenofibrate reduced C-reactive protein by 51.7%. Neither drug influenced HOMA (homeostasis model assessment) index of insulin resistance. The plasma level of thiobarbituric acid reactive substances, an index of oxidative stress, decreased after both treatments. Conclusions Both atorvastatin and fenofibrate had similar beneficial effects on LDL particle size and on oxidative stress. The effects of both drugs on other parameters such as triglycerides, total and high-density lipoprotein cholesterol, fibrinogen, or HCY differed significantly. These differences, together with the risk profile of a patient, should be considered during selection of a particular lipid-lowering modality. (Am Heart J 2002;144:e6.)     

Fluvastatin increases LDL particle size and reduces oxidative stress in patients with hyperlipidemia

The effects of fluvastatin on levels of urinary 8-iso-prostaglandin F2alpha (iPF2alphaIII), a marker of oxidative stress, and low-density lipoprotein (LDL) particle size in serum were investigated in patients with hypercholesterolemia. After 6 months of fluvastatin therapy, levels of urinary iPF2alphaIII decreased from 1720.1 +/- 392.0 to 539.6 +/- 75.5 pg/mg (p < 0.01), and LDL particle size increased from 24.3 +/- 0.3 to 26.5 +/- 0.2 nm (p < 0.001). These changes from the treatment of fluvastatin were not correlated with those of the serum LDL cholesterol (LDL-C) levels. The results imply that fluvastatin, with its unique antioxidant property among statins, reduces oxidative stress and increases LDL particle size simultaneously in hyperlipidemic patients.     

阿托伐他汀联合氯吡格雷对急性冠脉综合征血小板聚集率的影响

目的:探讨急性冠脉综合征(ACS)患者急性期负荷剂量氯吡格雷联合阿托伐他汀或普伐他汀对血小板聚集率和主要不良心血管事件发生率的影响。方法:102例ACS患者被随机分成两组:普伐他汀组(P组)和阿托伐他汀组(A组),两组均予氯吡格雷300mg顿服后,75mg/d维持。P组予普伐他汀。入院后24h内和第14天分别测定TC、HDL-C、LDL-C、血小板聚集率(PAR)、肝功能,并统计两组主要不良心血管事件的发生率。结果:(1)两组TC、HDL-C、LDL-C水平在基础状态和第14d,差异无显著性(P>0.05);(2)P组或A组PAR在治疗后和基线相比,差异有显著性(P<0.05);但P、A两组在治疗后相比,差异无显著性(P>0.05);(3)心血管死亡、再发心肌梗塞复合终点发生率在两组间差异无显著性(P>0.05)。结论:阿托伐他汀或普伐他汀与负荷剂量氯吡格雷联合治疗急性冠脉综合征安全有效,两组效果相似,无显著差异。     

Effects of atorvastatin and pravastatin on malondialdehyde-modified LDL in hypercholesterolemic patients.

The aim of the present study was to compare the effects of atorvastatin and pravastatin on lipid parameters and the concentration of malondialdehyde-modified low-density lipoprotein (MDA-LDL) in hypercholesterolemic patients. A total of 17 patients (10 men, 7 women; mean age, 68+/-9 years) who were indicated for drug therapy based on the National Cholesterol Education Program II underwent an 8-week regimen of atorvastatin (10 mg/day) or pravastatin (10 mg/day) with a 4-week washout period between drugs. After an overnight fast, lipid parameters and MDA-LDL concentration were measured before and after the 8-week treatment with each drug. Both atorvastatin and pravastatin produced significant reductions in low-density lipoprotein (LDL) cholesterol and MDA-LDL concentrations, with a significant increase in high-density lipoprotein cholesterol concentration. The percent reductions in LDL cholesterol and MDA-LDL concentration were significantly greater with atorvastatin than pravastatin (46 +/-6% vs 24+/-10%, p<0.0001, and 44+/-10% vs 14+/-13%, p<0.0001, respectively). The ratios of percent reductions in MDA-LDL concentrations and percent reductions in LDL cholesterol concentrations were significantly greater for atorvastatin than pravastatin (0.96+/-0.19 vs 0.59+/-0.55, p<0.0001). In conclusion, atorvastatin reduced serum concentrations of LDL cholesterol and MDA-LDL to a greater degree than pravastatin, indicating that atorvastatin not only has stronger lipid-lowering effects, but also stronger antioxidative effects than pravastatin.     

Long-term efficacy of upstream therapy with lipophilic or hydrophilic statins on antiarrhythmic drugs in patients with paroxysmal atrial fibrillation: comparison between atorvastatin and pravastatin

There is little information available on the benefits of selection of statins as upstream therapy for the prevention of paroxysmal atrial fibrillation (AF). We compared the efficacy and safety of atorvastatin (A-group, n = 43) and pravastatin (P-group, n = 41) as upstream therapy in patients with paroxysmal AF and dyslipidemia. A total of 84 patients (45 men, mean age, 66 ± 9 years, mean follow-up, 49 ± 32 months) were retrospectively assigned to receive atorvastatin (n = 41;10 mg/day) or pravastatin (n = 43 ; 10 mg/day). Survival rates free from AF recurrence at 1, 6, 12, and 24 months were 93%, 74%, 60%, and 53% in A-group, and 88%, 49%, 37%, and 29%, respectively, in P-group (P = 0.029, A-group versus P-group). Survival rates free from conversion to permanent AF at 12, 36, 60, and 90 months were 100%, 100%, 98%, and 95% in A-group, and 100%, 95%, 88%, and 83%, respectively, in P-group (P = 0.063, A-group versus P-group). Using a logistic regression model, atorvastatin was found to be associated with a significantly reduced risk of AF recurrence in comparison to pravastatin (unadjusted odds ratio [OR] = 0.27, 95% confidence interval 0.11-0.68, P = 0.005). This association remained significant after adjustment for potentially confounding variables (OR = 0.26, 95% CI 0.08-0.86, P = 0.027). Using a logistic regression model, atorvastatin was not associated with a significantly reduced risk of converting to permanent AF in comparison to pravastatin (unadjusted OR = 0.29, 95% CI 0.05-1.50, P = 0.138), but this association did show a significant difference after adjustment for potentially confounding variables in a multivariate model (OR = 0.08, 95% CI 0.06-0.96, P = 0.046). Adverse effects requiring discontinuation of statins were observed in 1 case (2%, myalgia) in A-group, and 1 case (2%, elevation in CPK level ≥ 500 IU/L) in P-group, respectively (P = NS, A-group versus P-group). Atorvastatin, a lipophilic statin, was considered to be more effective in preventing recurrence of paroxysmal AF and conversion to permanent AF than pravastatin, a hydrophilic statin.     

Atherogenic lipoprotein phenotype and LDL size and subclasses in women with gestational diabetes

Aims Women with gestational diabetes are more likely to develop Type 2 diabetes and cardiovascular disease after pregnancy; however, the exact nature of the lipid alterations present is not clear. In Mediterranean women with gestational diabetes, we measured low‐density lipoprotein (LDL) size and all seven subclasses, as well as the ‘atherogenic–lipoprotein phenotype’[ALP, e.g. concomitant presence of elevated triglycerides, reduced high‐density lipoprotein (HDL)‐cholesterol and increased small, dense LDL]. Methods In 27 women with gestational diabetes and 23 healthy pregnant women matched for age, weeks of gestation and body mass index, we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis between 24 and 28 weeks of gestation. Results Although no significant differences were found in the concentrations of any of the plasma lipids, compared with control subjects women with gestational diabetes had lower LDL size (P = 0.0007) due to reduced LDL‐I (P = 0.0074) and increased LDL‐IVA (P = 0.0146) and ‐IVB (P < 0.0001) subclasses. Correlation analysis revealed that fasting glucose, homeostasis model assessment and glycated haemoglobin were inversely correlated with LDL‐I and positively with LDL‐IVA and ‐IVB (all P < 0.05). ALP due to high HDL‐cholesterol levels was not seen in either group, whereas elevated small, dense LDL were more common in women with gestational diabetes than control subjects (33% vs. 4%, P = 0.0107). Conclusions Increased levels of small, dense LDL are common in Mediterranean women with gestational diabetes. Whether these findings affect the atherogenic process and clinical end‐points in these women remains to be determined by future prospective studies.     

阿托伐他汀治疗混合型高脂血症的疗效和安全性

目的　评估红惠医药发展公司生产的阿托伐他汀 (Atorvastatin)治疗高脂血症 ,特别是混合型高脂血症的疗效和安全性。方法　试验组 (阿托伐他汀 10mg d) 5 2例和对照组 (舒降之 10mg d) 5 3例 ,进行随机单盲平行对照试验 ,观察两组降脂疗效和不良反应发生情况。结果　经过 8周治疗 ,阿托伐他汀组TC、LDL C、TG和 (TC HDL C) HDL C分别下降 30 % ,40 % ,30 %和 36 % (P <0 .0 1) ,HDL C虽有升高 (5 % ) ,但差异无显著性意义 (P >0 .0 5 )。组间比较 ,阿托伐他汀降LDL C和TG作用明显优于辛伐他汀 (P <0 .0 5 ) ,降TC作用则两组相似。两组不良反应均很轻微和少见。结论　阿托伐他汀 10mg d治疗混合型高脂血症可以明显降低TC、LDL C ,TG和 (TC HDL C) HDL C ;阿托伐他汀降低LDL C和TG的作用大于同剂量辛伐他汀 ;阿托伐他汀的不良反应轻微 ,耐受性好。     

Qualitative effect of fenofibrate and quantitative effect of atorvastatin on LDL profile in combined hyperlipidemia with dense LDL.

INTRODUCTION: The association of elevated plasma triglyceride concentrations, decreased HDL-cholesterol, and dense LDL (dLDL) is referred to as the atherogenic lipoprotein phenotype. dLDL particularly plays a role in the metabolic syndrome and type 2 diabetes and may be one of the factors responsible for the increased risk for coronary artery disease in these patients. The effect of fenofibrate and atorvastatin on the LDL subfraction profile in patients with combined hyperlipidemia and a preponderance of dLDL was studied in a sequential design. METHODS: Six male patients with combined hyperlipidemia and dLDL received 160 mg/die supra-bioavailable fenofibrate. After a washout phase of 8 weeks all patients received 10 mg/die atorvastatin for another 8 weeks. At baseline, after fenofibrate, and after atorvastatin treatment LDL subfractions were analyzed by equilibrium density gradient ultracentrifugation. RESULTS: Treatment with atorvastatin and fenofibrate reduced serum cholesterol by 30 % and 21 % (p = 0.046) (p-values for differences between treatment groups), triglycerides by 32 % and 45 %, LDL cholesterol by 28 % and 16 %, and increased HDL cholesterol by 3 % and 6 %, respectively. Atorvastatin and fenofibrate treatment resulted in the following changes of apoB and LDL subfractions: LDL-1 (1.019 - 1.031 kg/L) - 31 % and + 15 % (p = 0.028); LDL-2 (1.031 - 1.034 kg/L) - 14 % and + 57 % (p = 0.028); LDL-3 (1.034 - 1.037 kg/L) - 20 % and + 30 % (p = 0.028); LDL-4 (1.037 - 1.040 kg/L) - 25 % and - 6 %; LDL-5 (1.040 - 1.044 kg/L) - 29 % and - 38 %; and LDL-6 (1.044 - 1.063 kg/L) - 39 % and - 55 % (p = 0.028). As a consequence, fenofibrate reduced LDL density significantly (p = 0.028 versus atorvastatin). CONCLUSIONS: Atorvastatin decreased all LDL-subfractions to a similar extent (quantitative effect) whereas fenofibrate reduced predominantly dLDL and changed the LDL profile towards medium dense LDL-particles (qualitative effect). Since medium dense LDL have a higher affinity to the LDL-receptor fenofibrate may have a higher antiatherogenic potential than assessed by the reduction of total LDL-cholesterol and triglycerides alone.