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Meta分析方法当今医学研究飞速发展，在全球范围内对于同一个研究问题所进行的医学研究往往有很多，但往往研究对象、设计方案、干预措施、结局变量、样本含量、随访时间等多个方面并不完全相同，研究结果也不完全一致。
除了传统的系统文献综述(review)和述评（editorial）等研究外，一些研究者希望对综述的各个研究的结果进行定量综合统计学分析——Meta分析。
本文将举例介绍Meta分析的基本概念和常用的Meta分析方法。
Meta分析中的基本概念例1 为了研究Aspirin预防心肌梗塞(MI)后死亡的发生，美国在1976年－1988年间进行了7个关于Aspirin预防MI后死亡的研究，其结果见表16.1，其中6次研究的结果表明Aspirin组与安慰剂组的MI后死亡率的差别无统计意义，只有一个研究的结果表明Aspirin在预防MI后死亡有效并且差别有统计意义。
具体结果如表1所示。
表1 Aspirin预防心肌梗塞后死亡的研究结果研究Aspirin组安慰剂组编号观察人数死亡人数死亡率P E(%) 观察人数死亡人数死亡率P C(%) P值OR*1 615 49 7.97 624 67 10.74 0.094 0.7202 758 44 5.80 771 64 8.30 0.057 0.6813 832 102 12.26 850 126 14.82 0.125 0.8034 317 32 10.09 309 38 12.30 0.382 0.8015 810 85 10.49 406 52 12.81 0.229 0.7986 2267 246 10.85 2257 219 9.70 0.204 1.1337 8587 1570 18.28 8600 1720 20.00 0.004 0.895在例1中，涉及到的主要概念如下：1、研究人群：对每个研究而言，在干预前，根据研究者在设计时，考虑确定研究人群为某地区的心肌梗死患者，通过干预上述研究人群分为两个研究人群：该地区服用Aspirin的心肌梗死人群和该地区服用安慰剂的心肌梗死人群。
循证医学的“证”循证医学核心理念是临床实践应基于证据。
那么什么是循证医学的证据呢？循证医学认为，所有已经完成的和正在进行的医学研究都可以成为证据。
但是，对大样本随机对照试验和其他相关随机对照研究进行系统综述(systematic reviews, SR)后所得出的结果，是关于某种疗法有效性和安全性的最佳证据，是金标准。
因此，在进行临床决策时，应尽可能收集相关的随机对照研究，并对它们进行系统综述以获得最强有力的证据。
一般的，循证医学的"证”可以按由强至弱的顺序分级如下：A级la: RCTs的系统综述lb:单项RCT(95%可信区间的宽度较窄者为优)lc:全或无，即必须满足下列要求(1) 用传统方法治疗，全部患者残疾或治疗失败：而用新的疗法后，有部分患者存活或治愈。
(2) 用传统方法治疗，许多患者死亡或治疗失败：而用新疗法无一死亡或治疗失败。
B级2a:队列研究的系统综述2b:单项队列研究(包括质量较差的RCT,随访率＜80%)2c:结局研究3a:病例对照研究的系统综述3b:单项病例对照研究C级4:系列病例分析及质量较差的病例对照研究D级5:没有分析评价的专家意见循证医学的实施可以大致上槪括为以下步骤(Rosenberg and Donald. 1995)：1. 针对病人的某种具体情况提岀一个淸晰明了的临床问题：2. 搜寻相关的临床论文文献：3. 严格评价论文文献结果的有效性和实用性；4. 对各个论文结果进行综合分析5. 将综合分析的研究结果应用于临床实践。
三、循证医学与MeS分析之间的关系如上所述，相关研究或相关研究的系统综述结果是循证医学的所谓的证据，其中相关随机对照研究的系统综述结果更是循证医学中的最强证据。
系统综述指的是全面收集所有相关研究并进行科学的立量合成，从而得出综合可靠结论的过程。
苴科学性体现在可用一些系统的方法来尽可能地减少单个研究所可能存在的偏倚和随机误差。
而Meta分析是汇总多个研究结果而进行总体效应评价的一种分析方法。
The effect of fructose consumption on plasma cholesterol in adults: a meta-analysis of controlled feeding trials1,2,3Tao An4,5, Rong Cheng Zhang4,5, Yu Hui Zhang4, Qiong Zhou4, Yan Huang4, Jian Zhang4, *.4 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China5Tao An and Rong Cheng Zhang contributed equally to this study.3 Supplemental Table 1 and supplemental Figures 1-4 are available as Online Supporting Material with the online posting of this paper at RUNNING TITLE: Fructose and cholesterolWORD COUNT: 5618; NUMBER OF FIGUREA: 3; NUMBER OF TABLES: 2 SUPPLEMENTARY MATERIAL: Online Supporting Materials: 5AUTHOR LIST FOR INDEXING: An, Zhang, Zhang, Zhou, Huang, Zhang1 The study was supported by the Ministry of Science and Technology of China with grant of the National High-tech Research and Development Program of China to Dr Jian Zhang.2 Author disclosures: T. An, R.C. Zhang, Y.H. Zhang, Q. Zhou, Y. Hung, J. Zhanghave no conflicts of interest.* To whom correspondence should be addressed. Mailing address: Heart FailureCenter, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of MedicalSciences and Peking Union Medical College, 167 Beilishilu, Beijing, China; Zip code: 100000; Telephone number: 86-10-88396180; Fax number: 86-10-88396180; E-mail: Fwzhangjian62@PROSPERO REGISTRATION NUMBERS: CRD420120033511ABSTRACT2Fructose is widely used as a sweetener in production of many foods, yet the relation 3between fructose intake and cholesterol remains uncertain. We performed a systematic 4review and meta-analysis of human controlled feeding trials of isocaloric fructose 5exchange for other carbohydrates to quantify the effects of fructose on total 6cholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in adult 7humans. Weighted mean differences were calculated for changes from baseline 8cholesterol concentrations by using generic inverse variance random-effects models. 9The Heyland Methodological Quality was used to assess study quality. Subgroup 10analyses and meta-regression were conducted to explore possible influence of study 11characteristics. Twenty-four trials (with a total of 474 subjects) were included in our 12meta-analysis. In an overall pooled estimate, fructose exerted no effect on TC, LDL-C 13and HDL-C. Meta-regression analysis indicated that fructose dose was positively 14correlated with the effect sizes of TC and LDL-C. Subgroup analyses showed that 15isocaloric fructose exchange for carbohydrates could significantly increase TC by 1612.97 mg/dL (95%CI: 4.66, 21.29; P = 0.002) and LDL-C by 11.59 mg/dL (95%CI: 174.39, 18.78; P = 0.002) at >100g fructose/d but had no effect on TC and LDL-C when 18fructose intake was ≤100g/d. In conclusion, very high fructose intake (>100g/d) 19could lead to significantly increase in serum LDL-C and TC. Larger, longer and 20higher-quality human controlled feeding trials are needed to confirm these results.21Key words: fructose, cholesterol, meta-analysis2223INTRODUCTION24Hyperlipidemia is a common risk factor for coronary heart disease (CHD), with 2544.4% of adults in the United States having abnormal TC values and 32% having 26elevated LDL-C levels (1). Compared to subjects with normal blood lipid, those with 27hyperlipidemia have a 3-fold risk of heart attacks (2). Lifestyle modification should be 28initiated in conjunction both primary and secondary prevention of CHD. More 29consideration exists as to what constitutes healthy eating.30Fructose is the most naturally occurring monosaccharide, and has become a major 31constituent of our modern diet. Fruit, vegetables, and other natural sources provide 32nearly one-third of dietary fructose, and two-thirds come from beverages and foods in 33the diets (eg, candies, jam, syrups, etc) (3). Fructose is preferred by many people, 34especially those with diabetes mellitus because of its low glycemic index (23% versus 35glucose 100%) (4). After intestinal uptake, fructose is mainly removed from the blood 36stream by the liver in an insulin-independent manner, and is used for intrahepatic 37production of glucose, fatty acids or lactate. Cross-sectional studies in human suggest 38that excessive fructose consumption can lead to adverse metabolic effects, such as 39dyslipidemia and increased visceral adiposity (5-7). The Dietary Guidelines for 40Americans, 2010, point out that it is lack of sufficient evidence to set a tolerable upper 41intake of carbohydrates for adults (8). Although The Candian Diabetes Association 42suggests consumption of no more than 60g of added fructose per day by people with 43diabetes for its triglyceride-raising effect (9), the threshold dose of fructose at which 44the adverse influence on cholesterol is controversial.45To determine the effect of fructose on cholesterol, a substantial number of clinical 46trials have been performed on adult humans with different health status (diabetic, 47obese, overweight, hyperinsulinemic, impaired glucose-tolerant and healthy). These 48trials used various intake levels of fructose and different protocols. Thus, it is difficult 49to reach a consistent conclusion across these studies. Therefore, we conducted a 50systematic review of the scientific literature and meta-analysis of controlled feeding 51trials to evaluate the effect of isocaloric oral fructose exchange for carbohydrates on 52cholesterol and to clarify the active factors of fructose.53Materials and Methods54This meta-analysis followed the Preferred Reporting Items for Systematic Reviews 55and Meta-analyses (PRISMA) criteria (10).56Search strategy.We searched PubMed (/pubmed; from 571966 to December 2012), Embase (; from 1966 to December 582012) and the Cochrane Library database () by using the 59following search terms: fructose and (lipemia or lipaemia or lipids or cholesterol or 60“total cholesterol”or “LDL cholesterol” or “HDL cholesterol”) in English. We also 61searched China National Knowledge Infrastructure () and Wangfang 62database () in Chinese according to the search strategy. The 63search was restricted to reports of trials on humans.64Study selection.All clinical trials using fructose and indexed within the above 65databases were collected. Two independent reviewers (T.A., R.C.Z) screened the 66abstracts and titles for initial inclusion. If this was not sufficient, full texts articles 67were obtained and reviewed by at least two independent reviewers (T.A., R.C.Z, Q.Z., 68Y.H.). The reference lists of retrieved articles also used to supplement the database.69Any disagreements were resolved through discussion. We included controlled feeding 70trials investigating the chronic effect of fructose on blood cholesterol, from both 71randomized and nonrandomized studies, if they met the following criteria: subjects 72must have been administered fructose for at least 2 weeks; studies investigated the 73effect of oral free (unbound, monosaccharide) fructose when compared with isocaloric 74control diet with another carbohydrate in place of fructose; studies were performed in 75human adults with either a parallel or crossover design; subjects in both experimental 76groups and control groups were instructed to consume isocaloric diets. If the study 77reported any comparisons, we included all such comparisons in the meta-analysis.78Data extraction and quality assessment.Two reviewers (T.A., R.C.Z) independently 79extracted relevant data from eligible studies. Disagreements were resolved by one of 80the two authors (Y.H.Z., J.Z.). These data included information on study features 81(author, year of publication, study design, randomization, blinding, sample size, 82comparator, fructose form, dose, follow-up and macronutrient profile of the 83background diet), participant characteristics (gender, age and healthy status) and 84baseline and final concentrations or net changes of total cholesterol, LDL-C and 85HDL-C. Data initially extracted were converted to system international unit (eg, TC: 1 86mmol/L converted to 38.6 mg/dL). For multi-arm studies, only intervention groups 87that met inclusion criteria were used in this analysis. If blood lipid concentrations 88were measured several times at different stages of trials, only final records of lipid 89concentrations at the end of the trials were extracted for this meta-analysis.90The quality of each study was assessed with the Heyland Methodological Quality 91Score (MQS) (11), generalized as follows: randomization; analysis; blinding; patient 92selection; comparability of groups at baseline; extent of follow up; treatment protocol;93co-intervention; outcomes. The highest score for each area was two points. Higher 94numbers represented a better quality (MQS≥8).95Data synthesis.Statistical analyses were performed with Stata software (version 11.0;96StataCorporation, TX, USA) and REVMAN software (version 5.2; Cochrane 97Collaboration, Oxford, United Kingdom). Separate pooled analyses were conducted 98by using the generic inverse variance random-effects models even where there was no 99evidence of between-study heterogeneity because these models give more 100conservative summary effect estimates in the presence of undetected residual 101heterogeneity than fixed-effects models. The different changes from baseline between 102fructose and carbohydrate comparators for total cholesterol, LDL cholesterol and 103HDL cholesterol were used to estimate the principle effect. We applied paired 104analyses to all crossover trials according to the methods of Elbourne and colleagues 105(12). Weighted mean differences of fructose consumption on cholesterol 106concentrations and corresponding 95% CIs were calculated. A 2-sided P value <0.05 107was set as the level of significance for an effect. The variances for net changes in 108serum cholesterol were only reported directly in two trials (29, 31). We calculate net 109changes for other studies by using the means±SDs cholesterol concentrations at 110baseline and at the end of intervention period (13). SDs were calculated from SEs 111when they were not directly given. If these data were unavailable, we extrapolated 112missing SDs by borrowing SDs derived from other trials in this meta-analysis (14). In 113addition, we assumed a conservative degree of correlation of 0.5 to impute the 114change-from-baseline SDs, with sensitivity analyses performed across a range of 115possible correlation coefficients (0.25 and 0.75) (13). For crossover trials in which 116only final measurements were included, the differences in mean final measurements 117were assumed on average to be the same as the differences in mean change scores 118(13). Inter-study heterogeneity was tested by the Cochrane’s Q-test (P < 0.1), and was 119quantified by the I2statistic, where I2 ≥ 50% was evidence of substantial heterogeneity. 120To explore the potential effects of factors on the primary outcomes and investigate the 121possible sources of heterogeneity, we performed meta-regressions and predefined 122subgroup analyses stratified by comparator, dose, study duration, randomization, 123health status, study design and study quality. As for studies used a range of fructose 124doses, the average doses calculated on the basis of the average reported energy intake 125or weight of participants (28.5 calories per kilogram of body weight). Sensitivity 126analyses were also performed according to the Cochrane Handbook for Systemic 127Review. Funnel plots and Egger’s linear regression test were conducted to detect 128publication bias.129RESULTS130Based on our search criteria, 1602 eligible studies were identified, and 1565 131studies were excluded on review of the titles and abstracts. The remaining 37 studies 132were retrieved and fully reviewed. Fifteen of these did not meet the inclusion criteria 133and were excluded in the final analysis. A total of 22 studies (providing data for 24 134trials) involving 474 subjects (15-36) were included in the meta-analysis 135(Supplemental Fig. 1, Table 1).136The reports of Koh and Reiser (22, 23) included two trials (bringing the total 137number of trials to 24). Eleven trials were randomized (17, 18, 20, 21, 25, 27-29, 31, 13834, 36). Nineteen trials used crossover (15-19, 21-32), and five used parallel designs 139(20, 33-36). As for the 19 cross-over trials, 10 trials have reported the washout period 140(16, 18, 22, 25, 27-31), 9 trials did not have washout period (15, 17, 19, 21, 23, 24, 26, 14132). The trials varied in size, from 8 to131 subjects. The mean age of trial participants 142ranged from 26.7 to 64.4 years. Seventeen trials (15, 17-23, 25, 27, 28, 30, 31, 34, 36) 143were performed in outpatient settings, 3 trials (26, 29, 32) in inpatient settings, and 4 144trials in both outpatient and inpatient settings (16, 24, 33, 35). Nine trials were 145conducted on diabetic subjects (19-21, 24-27, 29, 30), 8 trials in healthy subjects (17, 14618, 22, 23, 28, 31, 34, 35), 3 trials in overweight/obese subjects (32, 33, 36), 2 trials in 147hyperinsulinemic subjects (16, 23), 1 trial in those who were impaired 148glucose-tolerant (22), and 1 trial in subjects with type IV hyperlipoproteinaemia (HLP) 149(15). Background diets were 42-55% carbohydrate, 25-38% fat, and 13-20% protein. 150The carbohydrate comparators choose starch in 13 trials (15, 16, 21, 23-25, 27-30, 32, 15136), glucose in 6 trials (22, 31, 33-35), sucrose in 3 trials (17, 18, 26), and mixed 152carbohydrates in two trials (19, 20). Four trials used fructose in crystalline (16, 18, 20, 15321), 5 trials in liquid (19, 32-35), and 15 trials in mixed form (15, 17, 22-31). The 154reported mean baseline serum TC ranged from 170 to 230.8 mg/dl, LDL-C ranged 155from 90.7 to 157 mg/dl, and HDL-C ranged from 35.1 to 57.1 mg/dl. Nineteen trials 156reported the fructose intake among background diet was not different between the 157fructose and control groups, in which 15 trials reported the background fructose intake 158account for ≤3% of total energy (9 to 24g) (15-23, 29, 32, 33, 35), while 4 trials did 159not report the proportion of it (24, 25, 26, 34). Four trials used background fructose ≤3% 160(3.2 to 18g) of total energy in the control groups, but put total fructose into 161consideration in the fructose group (27, 28, 30-31). Only o ne trial reported less than 16220g (4.3 % of total energy) fructose was consumed among basal diet (36). The baseline 163values were not provided in 5 trials (19, 22, 23). The median fructose dose in the 164available trials included in our meta-analysis was 79.25 g/d (range: 30-182 g/d), and 165the duration varied from 2 to 26 weeks.166The quality scores of each study ranged from 6 to 9. Fifteen trials were classified 167as high quality (MQS≥8),and 8 trials were of low quality (17, 19, 26, 30, 32-35). 168Only three trials were blinded, one single-blinded (34) and 2 double-blinded (29, 35). 169Eight trials (19, 21, 24, 26-30) received industry funding. Three studies with four 170trials (15, 16, 22) did not report any information about financial conflicts of interest. 171Effect of fructose on cholesterol172Total cholesterol.Twenty-two trials (16-34, 36) reported the value of TC, and the 173pooled estimate was 2.47 mg/dL (95% CI: -3.04, 7.98; P = 0.38) without statistically 174heterogeneity (heterogeneity Chi2 = 28.14, I2= 25%, P = 0.14) (Fig. 1). The residual 175sources of heterogeneity were investigated by meta-regression models. Univariate 176meta-regression showed that the fructose dose was positively related to TC, even after 177adjusted for study duration and health status(regression coefficient = 0.18; 95% CI: 1780.06, 0.31, P = 0.008)(Table 2). The dose-response relation between fructose 179consumption and TC largely explained the residual heterogeneity of the effect. 180Subsequently, we stratified fructose dose ≤60, >60 to 100, and >100 as moderate, 181high, and very high, respectively, according to Candian Diabetes Association and 182reference ranges for fructose (9, 37, 38). Fructose could significantly increase TC by 18312.97 mg/dL (95%CI: 4.66, 21.29; P= 0.002) when fructose intakes were >100g/d 184but had no effect on TC if fructose was given lower than 100g. Predefined subgroup 185analyses were conducted by study characteristics (Supplemental Table 1). Sensitivity 186analyses according to possible correlation coefficients (0.25 and 0.75) and 187systematically removal of each individual trial did not alter the overall analysis and 188analyses stratified by dose.189LDL cholesterol.The mean change for LDL cholesterol in nineteen trials (15, 16, 18, 19020, 22, 23, 25-35) was 3.76 mg/dL (95% CI: -1.07, 8.6; P = 0.13) without statistically 191heterogeneity (heterogeneity Chi2 = 19.85, I2= 9%, P = 0.34) (Fig. 2). The residual 192sources of heterogeneity were investigated by meta-regression models. Univariate 193meta-regression showed that the fructose dose was positively related to LDL-C, even 194after adjusted for comparators, study duration and health status(regression coefficient 195= 0.15; 95% CI: 0.03, 0.28, P = 0.02)(Table 2). The dose-response relation between 196fructose consumption and LDL-C largely explained the residual heterogeneity of the 197effect. We stratified fructose dose according to CDA and reference ranges for fructose 198(9, 37, 38). Fructose intake >100g/d could significantly increase LDL-C by 11.59 199mg/dL (95%CI: 4.39, 18.78; P= 0.002). Predefined subgroup analyses were 200conducted by other study characteristics (Supplemental Table 1). Sensitivity analyses 201across possible correlation coefficients (0.25 and 0.75) did not alter the overall 202analysis and analyses stratified by dose. The removal of Cybulska et al resulted in a 203significant LDL-C-raising effect in the overall analysis (P = 0.03).204HDL cholesterol.The result of HDL cholesterol was calculated based on 24 trials 205(15-36), the mean difference was -0.56 mg/dL (95% CI: -2.05, 0.93; P = 0.46) without 206heterogeneity (heterogeneity Chi2 = 21.85, I2= 0%, P= 0.53) (Fig. 3). 207Meta-regression analysis did not show significant effect modifier of HDL-C. 208Predefined subgroup analyses were conducted by study characteristics (Supplemental 209Table 1). Sensitivity analyses according to possible correlation coefficients (0.25 and 2100.75) and systematically removal of each individual trial did not alter the overall 211analysis.212Publication bias213Funnel plots and Egger’s test indicated no significant publication bi as in the 214meta-analyses of TC, LDL cholesterol, and HDL cholesterol (TC Egger’s test: P= 2150.881; LDL cholesterol Egger’s test: P= 0.815; HDL cholesterol Egger’s test: P= 2160.484) (Supplemental Figs. 2-4).217DISCUSSION218This meta-analysis of 24 controlled feeding trials with 477 subjects found no 219effect on TC, LDL-C and HDL-C when fructose was substituted for other 220carbohydrates. Residual heterogeneity was detected by meta-regression for this 221outcome that fructose dose was positively correlated with the effect sizes of TC and 222LDL-C.223The present meta-analysis is consistent with a prospective 2-year trial on chronic 224effect of fructose from Turku sugar studies XI, which did not report any change in 225cholesterol for those individuals who consumed more than 100g fructose/d (39). 226Aeberli et al reported another prospective, randomized, 3-week controlled crossover 227trial in which healthy young men were fed 80 g/d free fructose, and found a 228significant atherogenic LDL subclass distribution (40). However, there was an average 229of 34g combined fructose consumed among basal foods in this study, which meant 230subjects consumed fructose over 110g/d. The median dose of fructose available in our 231meta-analysis was ≈79.25 g/d, it was higher than 90th percentile (78 g/d) and lower 232than 95th percentile (87 g/d) in the United States, reported by the National and Health 233and Nutrition Examination Survey III (41). As for subjects with diabetic mellitus, 234Sievenpiper et al did not report cholesterol-raising effect if the fructose dose was >60 235g/d (median: 97.5 g/d) in their meta-analysis (42). The result of our study and 236intervention trials may be supported the idea that fructose did not increase cholesterol 237for the subjects with generalizable levels of exposure.238The results of subgroup analyses showed that the effects of fructose intake on TC 239and LDL-C were significant as the fructose dose > 100g/d. An intake of 100g/d is 240approximately equal to 400kcal/d or 20% of energy intake for a sedentary person with 241an energy requirement of 2000 kcal/d. The doses for cholesterol-raising effect account 242for less than 10 percent of intake in males and females aged 19 to 22 years, the group 243with the highest level of exposure in the United States (41). Another study found that 244the upper quintile of Americans consume more than 110g fructose daily as added 245sugar or as high-fructose corn syrup (43). Although a small number of people 246consume fructose at very high dose, it is necessary to advise them to change their 247lifestyle.248The dose-dependent effect on triglyceride was also reported in a recent 249meta-analysis that concluded the same dose threshold of 100g/d for a 250triglyceride-increasing effect of fructose on fasting triglyceride level in adult humans 251(38). For healthy subjects who consumed 150g of fructose/day, endogenous 252cholesterol synthesis and the fat content of viscera and liver have been shown to 253increase (44). All evidences have proved that fructose is proposed to have adverse 254effects at very high or excessive doses. The mechanism of the cholesterol increase by 255fructose might be due to increased levels of advanced glycation end products, which 256cause damage to LDL and make it poorly recognized by lipoprotein receptors and 257scavenger receptors (45). Furthermore, excess exposure to fructose can damage the 258function of adipocytes and may reduce the recycling of cholesterol extracted from 259serum LDL. Studies have shown that elevated uric acid might contribute to LDL-C 260increases, and this effect can be reduced by allopurinol (46).261Based on the composition of added sugars in the United States where the fructose: 262glucose ratio is close to 0.43, and the NHANES 1999–2004 estimates (41), the 263increase of fructose consumption is always accompanied with an increase in total 264energy intake. Persons consuming >100g/d of sugars are potentially eating in excess 265of their energy requirement (47), and then overweight and obesity could result. So we 266can not suggest that it is safe to only limit fructose to <100g/d in coronary heart 267disease management and prevention. It may need to take into account the other 268components of foods that accompany the fructose. This dose threshold effects on TG 269and LDL-C can only help better inform nutritional guidance and avoid inappropriate 270marketing of carbohydrates.271Our meta-analysis did not show significant effect of fructose on HDL-C. 272However, Perez-Pozo et al (46) reported a significant HDL-C-lowing effect in 74 273adult men fed with 200g fructose/d in a randomized, 2-week crossover trial, 274suggesting that excessive fructose dose intake can also affect HDL-C. Further trials 275are needed to find the threshold of fructose on HDL-C.276There are several limitations to our work. First, many trials had a relatively small 277sample size, and most of them were funded by industry which can affect the quality of 278studies. Second, the change of fructose in the background diet can affect the practical 279utility of the outcomes of meta-analyses. However, most of trials used the background 280diet with ≤ 3% of total energy derived from fructose (15-23, 27-33, 35), others trials 281did not report the proportion of fructose in the background (24, 25, 26, 34). It was 282hard to make sure the dose of background fructose in every trial. Third, the data 283provided by Reiser et al (23) must be interpreted with caution. Although this study 284met all of our inclusion criteria, they choose a low P:S (polyunsaturated : saturated) 285rate of the fat as the background diet, which might change the metabolism of fructose 286as diets high in saturated fatty acids can enhance intestinal fructose absorption (48). 287Fourth, some of included trials lack test statistics, baseline values and SDs. We 288overcame these problems according to the methods proposed by Cochrane Handbook 289for Systematic Reviews of Interventions. Finally, it is difficult to differentiate effects of 290other modifiers, such as exercise and age, from those included trials. These factors can 291also influence the final result. Fructose can indeed be metabolized during exercise, 292and the rate of metabolism is different between exercise and sedentary lifestyle. Most 293of participants were requested to follow a designed regiment at home, but it is not 294easy to maintain the activity intensity. On the plus size, the age of participants in our 295meta-analysis ranged from 18 to 72 years old. Evidence from animal experiments 296shows that fructose absorption may affected by age, as older rats showed decreased 297fructose absorption (49). However, no human trial has been done to assess the 298difference in fructose effect among different age groups. Therefore, further studies 299should attempt to limit or isolate the degree of heterogeneity present in the study 300population to better assess the effect of age.301In conclusion, our meta-analysis shows that fructose used as a sweetener in 302isocaloric exchange for other carbohydrates has significant increasing effects on TC 303and LDL-C in individuals with very high fructose (>100g). This effect seems not to be 304dose-dependent when fructose is given at moderate or high dose of fructose (<100g). 305Further studies should concentrate on larger, longer and higher-quality human 306controlled feeding trials, which provide a better assessment of the effect of fructose on 307cholesterol.308Acknowledgements309Tao An, Rong Cheng Zhang and Jian Zhang designed the research; Tao An, Rong 310Cheng Zhang, Yu Hui Zhang and Jian Zhang preformed the research; Tao An and 311Rong Cheng Zhang summarized the data and had primary responsibility for the 312accuracy of the analysis; Rong Cheng Zhang wrote the manuscript. All the authors 313had full access to the data. None of the authors declared a conflict of interest.314。
联合运用降脂通脉胶囊治疗血脂异常疗效及安全性的Meta分析赵哲俊,孙元隆,王肖龙,李琳,黄程新,贾美君摘要目的:评价联合运用降脂通脉胶囊治疗血脂异常的临床疗效及安全性㊂方法:计算机检索维普(VIP)㊁中国知网(CNKI)㊁万方(WanFang Data)㊁中国生物医学文献数据库(CBM)㊁PubMed㊁the Cochrane Library㊁EMbase等收录的有关联合运用降脂通脉胶囊治疗血脂异常的随机对照试验(RCT)㊂检索时限为建库至2022年9月采用Cochrane评价手册中的偏倚风险评估工具进行评估,并使用RevMan5.4.1与Stata14.0软件进行Meta分析,系统评价降脂通脉胶囊对总胆固醇(TC)㊁三酰甘油(TG)㊁低密度脂蛋白胆固醇(LDL-C)㊁高密度脂蛋白胆固醇(HDL-C)㊁颈动脉内中膜厚度(IMT)及颈动脉斑块积分的影响㊂结果:共纳入11项RCT,涉及914例血脂异常病人㊂采用降脂通脉胶囊联合常规西药治疗的试验组TC[MD=-0.69,95%CI(-0.98,-0.40),P<0.00001]㊁LDL-C[MD=-0.52,95%CI(-0.74,-0.31),P<0.00001]㊁TG[MD=-0.47,95%CI(-0.67,-0.26),P<0.00001]㊁IMT[MD=-0.27, 95%CI(-0.33,-0.22),P<0.00001]与颈动脉斑块积分[MD=-1.43,95%CI(-2.33,-0.63),P=0.0004]水平较采用常规西药治疗的对照组明显降低,HDL-C[MD=0.20,95%CI(0.07,0.32),P=0.002]水平与临床疗效[OR=3.49,95%CI(2.11,5.76),P<0.00001]较对照组明显提高㊂两组不良反应发生率比较差异无统计学意义[OR=1.25,95%CI(0.59,2.65),P=0.57]㊂结论:现有证据表明,加用降脂通脉胶囊治疗血脂异常效果优于单纯西药常规治疗㊂关键词高血脂;血脂异常;降脂通脉胶囊;Meta分析d o i:10.12102/j.i s s n.1672-1349.2024.07.007Efficacy and Safety of Jiangzhi Tongmai Capsule for the Treatment of Dyslipidemia:a Meta-analysisZHAO Zhejun,SUN Yuanlong,WANG Xiaolong,LI Lin,HUANG Chengxin,JIA MeijunShuguang Hospital of Shanghai University of Traditional Chinese Medicine,Shanghai201203,China Corresponding Author JIA Meijun,E-mail:****************Abstract Objective:To assess the clinical effectiveness and safety of Jiangzhi Tongmai Capsule for the treatment of dyslipidemia. Methods:VIP,China National Knowledge Infrastructure(CNKI),WanFang Data,China Biology Medicine Disc(CBM),PubMed,the Cochrane Library,and EMbase were searched for randomized controlled trials(RCT)of Jiangzhi Tongmai Capsule for the management of dyslipidemia.The retrieval time limit is from the establishment of the databases to September2022.The Cochrane systematic review manual bias risk assessment tool was used to evaluate the bias risk of the included study.The Stata14.0software was used for Meta analysis.Results:A total of11RCT were included,involving914cases.Meta-analysis showed that total cholesterol(TC)(MD=-0.69, 95%CI-0.98--0.40,P<0.00001),low density lipoprotein cholesterol(LDL-C)(MD=-0.52,95%CI-0.74--0.31,P<0.00001), triglyceride(TG)(MD=-0.47,95%CI-0.67--0.26,P<0.00001),carotid intima-media thickness(IMT)(MD=-0.27,95%CI-0.33--0.22, P<0.00001),and carotid plaque score(MD=-1.43,95%CI-2.33--0.63,P=0.0004)in experimental group were lower than those in control group.The high density lipoprotein cholesterol(HDL-C)(MD=0.20,95%CI0.07-0.32,P=0.002)and clinical efficacy(OR=3.49, 95%CI2.11-5.76,P<0.00001)in experimental group were higher than those in control group.There was no statistically significant difference in the occurrence of adverse reactions between the experimental and control groups(OR=1.25,95%CI0.59-2.65,P=0.57). Conclusion:Available evidence indicates that combined application of Jiangzhi Tongmai Capsule is superior to conventional western medicine alone in improving the clinical efficacy of dyslipidemia.Keywords hyperlipidemia;dyslipidemia;Jiangzhi Tongmai Capsule;Meta-analysis血脂异常已成为现代社会一种常见的代谢性疾病,主要表现为总胆固醇(TC)㊁三酰甘油(TG)㊁低密度脂蛋白胆固醇(LDL-C)升高和高密度脂蛋白(HDL)降低,是导致动脉粥样硬化疾病发展的独立危险因素与病理基础[1-2]㊂同时,其代谢紊乱亦会引起一系列代谢性疾病,如冠心病㊁肥胖㊁脂肪肝等[3]㊂一项2012年的全国调查显示,血脂异常成人总体患病率达40.40%,基金项目国家自然科学青年基金项目(No.81603381);第七批全国老中医药专家学术经验继承工作项目,编号:国中医药人教函 2022 76号;上海市临床重点专科项目(No.shslczdzk05301);国家自然科学基金面上项目(No.82174152)作者单位上海中医药大学附属曙光医院(上海201203)通讯作者贾美君,E-mail:****************引用信息赵哲俊,孙元隆,王肖龙,等.联合运用降脂通脉胶囊治疗血脂异常疗效及安全性的Meta分析[J].中西医结合心脑血管病杂志, 2024,22(7):1204-1212.且发病率仍在逐年升高[4]㊂研究表明,血清LDL-C水平每降低1mmol/L将使心血管事件发生率降低20%~ 25%[5-6]㊂另一方面,颈动脉是动脉粥样硬化最易发生部位,颈动脉斑块积分对复发性缺血性脑卒中具有预测价值,而颈动脉内中膜厚度(IMT)可作为心血管事件的强相关预测因子[7-9]㊂因此,降低LDL-C血清水平及控制颈动脉斑块积分与IMT于正常值尤为重要㊂现临床上仍首选他汀类药物改善病人血脂水平,其可降低血浆胆固醇,减少心肌梗死发生率[10]㊂他汀类药物主要通过抑制羟甲基戊二酰辅酶A(HMG-CoA)还原酶来调控脂质代谢[11]㊂但长期服用存在肝功能异常㊁横纹肌溶解等不良反应,亦可增加新患糖尿病风险[12-14]㊂对于他汀类药物不耐受病人,常出现胃肠道反应㊁皮肤潮红㊁头痛等症状,降低了病人的依从性[15-16]㊂临床上存在因此类负担而过早停止使用他汀类药物的现象,一定程度上影响了该药物的疗效[17]㊂因此,需要探索更加有效㊁安全的降脂药物㊂许多研究报道中医药在降脂治疗方面具有一定优势,因此,本研究将研究视角转移至中成药领域[18-19]㊂中医学中并无血脂异常的病名,但在中医经典著作中有相似的论述,如‘灵枢㊃卫气失常“中最早提出膏浊理论,并将肥胖分为3型, 人有脂㊁有膏㊁有肉 ㊂虞抟进一步丰富了膏浊理论,指出 津液稠黏,血为止浊 ㊂中医学中以 膏浊 血浊 血瘀 等病名描述血脂异常㊂病人常由素体脾胃虚弱,复加嗜食膏粱厚味,喜逸恶劳或情志不畅等因素致使痰浊内生,胶于体内,发为本病㊂本病基本病机为本虚标实㊁痰瘀互结[20-22],治疗上以健脾化痰㊁活血化瘀为法[23]㊂降脂通脉胶囊由三七㊁决明子㊁泽泻㊁姜黄㊁铁线草5味药组成,具有化痰祛湿㊁活血通脉的功效,符合血脂异常的基本病机,为临床上常用于治疗血脂异常痰瘀互结证的中成药㊂临床研究已证实该药有效性及安全性较好,因此,本研究纳入降脂通脉胶囊治疗血脂异常病人的随机对照试验(RCT),关注药物对基础血脂指标影响的同时,还纳入颈动脉斑块积分与IMT作为结局指标,系统评价降脂通脉胶囊治疗血脂异常的有效性及安全性,为临床用药选择提供循证依据㊂1资料与方法1.1文献检索计算机检索中国知网(CNKI)㊁维普(VIP)㊁万方(WanFang Data)㊁中国生物医学文献数据库(CBM)及PubMed㊁the Cochrane Library㊁EMbase㊂检索自建库至2022年9月降脂通脉胶囊联合常规西药治疗血脂异常相关的RCT㊂检索式为:(降脂通脉胶囊OR 优克OR Jiangzhi Tongmai Capsule)AND(膏浊OR 血脂异常OR高脂血症OR高胆固醇血症OR dyslipidemia OR hyperlipidemias OR hypercholesterolemia OR hypolipoproteinemias OR TC OR LDL-C),其中 优克 为商品名㊂1.2纳入标准1.2.1文献选择降脂通脉胶囊联合常规西药治疗血脂异常的RCT㊂1.2.2研究对象1)年龄ȡ18岁;2)诊断为血脂异常,符合‘中国成人血脂异常防治指南(2016年修订版)“[4,24]㊁‘2021加拿大心血管疾病协会(CCS)指南:成人心血管疾病预防中血脂异常的管理“[15]评判标准;3)可包括合并疾病有冠心病与动脉粥样硬化,其中结局指标需包含血脂相关指标㊂1.2.3干预措施试验组采用降脂通脉胶囊联合常规西药进行治疗,治疗剂量与疗程不限制;对照组采用常规西药进行治疗㊂1.3排除标准1)综述及动物实验;2)数据资料错误㊁缺漏的文献;3)与本研究目的无关的文献;4)涉嫌抄袭的文献;5)文献质量较低的文献㊂1.4结局指标1)TC;2)LDL-C;3)TG;4)高密度脂蛋白胆固醇(HDL-C);5)IMT;6)颈动脉斑块积分;7)临床总有效率;8)不良反应㊂1.5资料提取由2名研究人员分别独立阅读文献的标题和摘要,根据预先确定的纳入和排除标准来筛选文献㊂对于符合纳入和排除标准的文献,对其全文质量进行评估,并从中提取相关信息㊂资料提取内容包括文献第一作者与发表年份㊁试验设计与结局指标等相关内容㊂若在提取数据过程中意见不同,需与第3位研究者商讨,统合意见㊂1.6文献质量评价采用Cochrane手册评估文献风险偏倚,1)选择偏倚:随机序列生成(随机方法是否合理),分配隐藏;2)实施偏倚:实施者与参与者设盲;3)归因偏倚:结局指标完整程度;4)报告偏倚:选择性报告;5)其他偏倚㊂对每项标准做出高风险㊁低风险㊁风险不明确3种评价结果,颜色分别区分为红色㊁绿色㊁黄色㊂1.7统计学处理本研究使用RevMan5.4.1软件进行Meta分析㊂通过χ2检验和I2值分析纳入研究的异质性㊂如果异质性结果P<0.05或I2>50%,表明各研究间存在较大异质性,需要分析异质性原因,并采用随机效应模型㊂以比值比(OR)与95%置信区间(CI)作为二分类变量的效应量,均方差(MD)与95%CI作为连续性变量的效应量㊂连续性变量中均方差与标准差均为治疗前后的变化值[25]㊂最终结果采用森林图表示㊂采用Stata14.0软件进行发表偏倚与敏感性分析,运用Begg's检验和Egger's检验分析各研究间偏倚情况㊂2结果2.1文献检索流程与结果根据设定的主题词,共检索到相关文献451篇,导入NoteExpress3.6去重后剩余126篇文献;阅读题目与摘要后剔除113篇文献,剔除内容主要为综述及动物实验类文献㊂初步筛选后获得文献13篇;阅读全文后剔除2篇文献,其中1篇文献试验设计无对照组,另1篇文献数据有误㊂最终纳入11篇RCT[26-36]图1文献筛选流程与结果2.2纳入研究的基本特征经过严格筛选,本研究最终纳入11篇文献,涉及914例病人,其中试验组458例,对照组456例㊂所有文献内药物服用方法均为口服㊂1项研究[32]试验组降脂通脉胶囊服用剂量不明㊂1项研究[28]对照组他汀类药物服用次数不明㊂1项研究[33]的治疗疗程分为4周与8周㊂1项研究[28]为长疗程12周,3项研究[27,34,36]为长疗程6个月㊂在数据处理时,肖波(1)代表4周疗程,肖波(2)代表8周疗程㊂详见表1㊂表1纳入研究的基本特征纳入研究疾病类型样本量(例)T C干预措施T C疗程结局指标卢火木[26]2021高脂血症4646在对照组治疗基础上应用降脂通脉胶囊1.5g,每日3次辛伐他汀钙片20mg,每日1次1个月①②③④⑦⑧沈延宝等[27]2021冠心病合并颈动脉粥样硬化4040在对照组治疗基础上应用降脂通脉胶囊1.5g,每日3次瑞舒伐他汀钙片10mg,每晚1次6个月①②③④⑤⑥张鸿生等[28]2019冠心病4644在对照组治疗基础上应用降脂通脉胶囊2.0g,每日3次阿托伐他汀钙片20mg或瑞舒伐他汀钙片10mg(不明次数)12周①②③④张琢[29]2018高脂血症4747在对照组治疗基础上应用降脂通脉胶囊1.0~2.0g,每日3次瑞舒伐他汀钙片5mg,每晚1次4周⑦潘春奇等[30]2016高脂血症4545在对照组治疗基础上应用降脂通脉胶囊1.5g,每日3次依折麦布片1片,每日1次4周①②③④⑦⑧饶春燕等[31]2015高脂血症5959在对照组治疗基础上应用降脂通脉胶囊2.0g,每日3次阿托伐他汀钙片10mg,每日1次4周①②③④⑦尤秀梅[32]2015高脂血症3030在对照组治疗基础上应用降脂通脉胶囊(不明剂量)阿托伐他汀钙片20mg,每晚1次8周①②③④⑦肖波[33]2014高脂血症4040在对照组治疗基础上应用降脂通脉胶囊1.5g 阿托伐他汀钙片20mg,每晚1次4㊁8周①②③④⑦⑧陈宏[34]2013冠心病4545在对照组治疗基础上应用降脂通脉胶囊1.5g,每日3次辛伐他汀钙片20mg,每日1次6个月①②③④⑤⑥刘凤阁等[35]2011高脂血症3030在对照组治疗基础上应用降脂通脉胶囊1.0g,每日3次阿托伐他汀钙片20mg,每晚1次30d①②③④散兴忠等[36]2011颈动脉粥样硬化3030在对照组治疗基础上应用降脂通脉胶囊1.5g,每日3次拜阿司匹林100mg,每日1次6个月①②③④⑤⑥注:T为试验组;C为对照组㊂①为TC;②为TG;③为HDL-C;④为LDL-C;⑤为IMT;⑥为颈动脉斑块积分;⑦为临床疗效;⑧为不良反应㊂2.3文献方法学质量评价本研究纳入文献均为中文文献,均进行了偏倚风险评估㊂3项研究[27-28,32]采用随机数字表法进行分组,选择偏倚为低风险,1项研究[33]采用就诊先后顺序分组,1项研究[30]采用病历ID末尾数字奇偶分组,此2项研究选择偏倚均为高风险,其余未明确说明随机分组具体方法;所有文献均未提及分配隐藏及盲法;所有文献均无病例失访或退出;所有研究数据均完整㊂纳入研究的偏倚风险评价见图2㊁图3㊂图2偏倚风险比例图图3偏倚风险汇总图2.4Meta分析结果2.4.1临床疗效6篇文献[26,29-33]报道了血脂异常的临床疗效,各研究间异质性可接受(P=0.31,I2=17%),采用固定效应模型进行Meta分析,结果显示,试验组与对照组临床疗效比较差异有统计学意义[OR=3.49,95%CI (2.11,5.76),P<0.00001]㊂详见图4㊂表明联合降脂通脉胶囊缓解血脂异常的临床疗效更好㊂图4两组临床疗效比较的Meta分析森林图2.4.2TC10篇文献[26-28,30-36]报道了血清TC水平的变化,各研究间异质性较大(P<0.00001,I2=86%),采用随机效应模型进行Meta分析,结果显示,试验组与对照组TC水平比较差异有统计学意义[MD=-0.69,95%CI (-0.98,-0.40),P<0.00001],表明降脂通脉胶囊联合常规西药降低血清TC水平作用更明显㊂详见图5㊂图5两组TC水平比较的Meta分析森林图2.4.3LDL-C10篇文献[26-28,30-36]报道了血清LDL-C水平的变化,各研究间异质性较大(P<0.00001,I2=89%),采用随机效应模型进行Meta分析,结果显示,试验组与对照组LDL-C水平比较差异有统计学意义[MD=-0.52,95%CI(-0.74,-0.31),P<0.00001],表明降脂通脉胶囊联合常规西药降低血清LDL-C水平作用更明显㊂详见图6㊂但各组间异质性较大,需进一步行敏感性分析寻找异质性原因㊂图6两组LDL-C水平比较的Meta分析森林图2.4.4TG10篇文献[26-28,30-36]报道了血清TG水平的变化,各研究间异质性较大(P<0.00001,I2=85%),采用随机效应模型进行Meta分析,结果显示,试验组与对照组TG水平比较差异有统计学意义[MD=-0.47, 95%CI(-0.67,-0.26),P<0.00001],表明降脂通脉胶囊联合常规西药降低血清TG水平作用更显著㊂详见图7㊂2.4.5HDL-C10篇文献[26-28,30-36]报道了血清HDL-C水平的变化,各研究间异质性较大(P<0.00001,I2=95%),采用随机效应模型进行Meta分析,结果显示,试验组与对照组HDL-C水平比较差异有统计学意义[MD=0.20, 95%CI(0.07,0.32),P=0.002],表明降脂通脉胶囊联合常规西药治疗高脂血症血清HDL-C水平升高更显著㊂详见图8㊂图7两组TG水平比较的Meta 分析森林图图8两组HDL-C水平比较的Meta分析森林图2.4.6IMT3篇文献[27,34,36]报道了IMT的变化,各研究间异质性可接受(P=0.20,I2=38%),采用固定效应模型进行Meta分析,结果显示,试验组与对照组IMT比较差异有统计学意义[MD=-0.27,95%CI(-0.33,-0.22), P<0.00001],表明降脂通脉胶囊联合常规西药降低IMT作用更显著㊂2.4.7颈动脉斑块积分3篇文献[27,34,36]报道了颈动脉斑块积分的变化,各研究间异质性较大(P<0.0001,I2=91%),采用随机效应模型进行Meta分析,结果显示,两组与对照组颈动脉斑块积分比较差异有统计学意义[MD=-1.43, 95%CI(-2.33,-0.63),P=0.0004],表明降脂通脉胶囊联合常规西药降低颈动脉斑块积分作用更显著㊂2.4.8不良反应3篇文献[26,30,33]报道了药物导致不良反应情况,症状均轻,均无严重肝肾损伤㊂各研究间异质性可接受(P=0.30,I2=17%),采用固定效应模型进行Meta 分析,结果显示,两组不良反应发生率比较差异无统计学意义[OR=1.25,95%CI(0.59,2.65),P=0.57],表明联合应用降脂通脉胶囊不会增加不良反应㊂各研究具体不良反应情况见表2㊂表2降脂通脉胶囊联合常规西药治疗血脂异常导致不良反应情况纳入研究试验组对照组卢火木[26]20211例头痛,3例呕吐,2例恶心1例头痛,2例呕吐,1例恶心潘春奇等[30]20163例腹痛㊁腹胀,3例轻度头痛,2例疲乏无力4例腹痛㊁腹胀,3例轻度头痛,3例疲乏无力肖波[35]20143例腹胀㊁恶心无明显不良反应2.5发表偏倚分析使用Stata14.0软件分析各结局指标发表偏倚㊂针对治疗血脂异常临床疗效漏斗图的结果显示散点大致分布于漏斗图中下部,等效线左右两侧,表明出现发表偏倚的可能性较小㊂而有些项目各研究间有显著异质性,因各研究间疾病类型不同,故使用Egger's检验与Begg's检验进行发表偏倚分析㊂结果显示,结局指标TC㊁LDL-C㊁TG㊁HDL-C均存在一定的偏倚,在按照疾病类型的不同分组后,各研究间偏倚水平明显下降,分析偏倚主要来自不同的疾病类型㊂详见表3㊂表3各结局指标发表偏倚根据不同疾病类型分组前后具体情况(P值)结局指标分组前(血脂异常+冠心病)Egger's Begg's分组后(血脂异常)Egger's Begg'sTC0.0430.0430.4360.548 LDL-C0.0040.2130.037 1.000 TG0.0420.0350.453 1.000 HDL-C0.0130.1610.5480.0992.6敏感性分析本研究发现LDL-C异质性水平较高,采用随机效应模型对其行进一步敏感性分析,方法为逐一剔除法,分析剩余文献所得新的合并效应量的点估计值偏倚情况,详见图9㊂分析显示,剔除潘春奇等[30]的研究后异质性水平明显下降,提示异质性较大的原因可能来源于此项研究㊂该文献运用依折麦布片作为基础用药㊂区别于他汀类药物,依折麦布片为血脂管理的二线用药,为尼曼-匹克C1型类似蛋白1(NPC1L1)抑制剂,通过阻断小肠刷状边缘对胆固醇的吸收而发挥作用[37]㊂但依折麦布片对LDL-C的不同疗效可能是导致此异质性的原因㊂图9LDL-C敏感性分析3讨论3.1文献质量评价优质的随机㊁双盲㊁安慰剂㊁平行设计临床试验是为临床应用提供可靠指导的必要条件[38-39]㊂然而,中药临床研究在实践中往往难以遵循这些原则㊂本研究纳入的文献存在以下缺陷:1)在随机分组方面,只有3项研究明确了其随机化方法,2项研究的随机化方法出现错误,剩余研究未详细描述随机分配策略,导致随机性的可靠性和质量受到质疑,同时也使研究结果的重复性受到影响;2)各研究均未开展样本量预估;3)所有研究均未提及是否采用盲法㊂而纳入的文献均局限于中文,缺乏外文文献,且均为阳性报道,存在明显的发表偏倚㊂3.2降脂通脉胶囊的疗效现中医学对于血脂异常已有系统认识,如脏腑辨证从肝㊁脾㊁肾三脏入手[40];或从‘脾胃论“气机升降与元气为基础,探讨脾胃在血脂异常发展过程中的重要性[41];也有学者强调 玄府理论 ,以平衡玄府的正常功能为治疗原则[42]㊂分析以上理论,血脂异常的中医病机离不开气机失常,久之则产生膏㊁脂㊁痰㊁瘀等病理产物,而这些病理产物又会成为病因加重病情㊂根据血脂异常的基本病机,现中医对血脂异常的治疗方法可归纳为3类,即涤痰化湿㊁行气消食㊁活血化瘀[43]㊂降脂通脉胶囊由决明子㊁姜黄㊁泽泻等5味药组成㊂其中,决明子降脂降压㊁清肝明目;姜黄破血行气㊁通络止痛;泽泻利水渗湿㊁化浊降脂;三七活血散瘀㊁补虚壮强;铁线草清热解毒㊁利尿通淋㊂全方共奏化痰祛湿㊁活血通脉之功,囊括了化痰㊁行气㊁活血化瘀三法,符合血脂异常治疗的基本理法㊂现代药理学对于中药功效有进一步认识㊂决明子含有化合物包括蒽醌类和苯并吡酮类,可拮抗高脂饮食所致的动脉粥样硬化,主要涉及信号通路包括血管内皮生长因子(VEGF)㊁肿瘤坏死因子(TNF)㊁花生四烯酸代谢等[44]㊂姜黄中姜黄素可以有效降低TG㊁胆固醇以及游离脂肪酸水平,亦可通过调节多种炎症通路降低炎症反应[45-46],其与阿托伐他汀钙片联合运用可更有效地降低血清TC㊁TG㊁LDL-C水平[47]㊂泽泻中泽泻醇A等活性成分可显著降低油酸诱导的TC㊁TG 高水平,主要机制与抑制脂质合成关键转录因子(SREBPs)的转录活性相关[48]㊂三七中三七总皂苷可以调控caveolae/Cav1抑制细胞增殖,以抗血管新生,发挥抗动脉粥样硬化作用[49]㊂铁线草乙醇提取物能显著降低高血糖大鼠模型血糖㊁胆固醇㊁TG水平[50]㊂在临床上,三七提取物三七总皂苷已作为中成药广泛使用,如血塞通胶囊,江小萍等[51]试验表明其可有效减缓动脉粥样硬化进展,效果与阿托伐他汀钙片相当㊂而通过数据挖掘,泽泻在以 痰瘀 论治的中药组方中出现的频率达到了第三[52]㊂可见,基础和临床研究均已证实降脂通脉胶囊组方中各味单药已具有降血脂的作用与机制㊂因此,降脂通脉胶囊具备一定的血脂异常治疗效果㊂本研究对降脂通脉胶囊治疗血脂异常的临床疗效进行了系统评价㊂研究过程中遵循了现代指南对血脂异常病人的基础治疗要求,包括使用一线用药他汀类㊂采用这种方法有助于保证纳入研究的一致性和科学性,进而使研究结果在现实和实际应用方面具有指导价值㊂本研究共纳入11篇文献,涉及914例血脂异常病人,Meta分析结果显示,采用降脂通脉胶囊联合常规西药治疗后TC㊁LDL-C㊁TG㊁IMT与颈动脉斑块积分均低于单用常规西药治疗,HDL-C水平与临床疗效均高于单用常规西药治疗,差异均有统计学意义,表明联合降脂通脉胶囊较单用常规西药进一步降低了血脂异常病人的血脂水平,降低伴有颈动脉粥样硬化斑块病人IMT和斑块钙化积分㊂尽管血脂异常病人的长期治疗效果是临床研究的关键指标,但本研究所涵盖的文献中关于长期疗效的观察较为有限,仅有3篇文献涉及6个月的观察期,且各研究的随访时间存在较大差异,因此,在合并分析时未发现统计学差异㊂3.3降脂通脉胶囊的安全性分析在安全性方面,与对照组相比,试验组不良反应发生情况差异无统计学意义,表明联合降脂通脉胶囊不会增加不良反应㊂其中3项研究[26,30,33]报道了在用药阶段出现的不良反应,包括头痛㊁腹痛腹胀㊁呕吐等㊂然而本研究纳入文献的干预手段均为在常规西药治疗基础上加用降脂通脉胶囊,无法判断不良反应为联合用药或是单纯西药产生的㊂只有1项研究[33]单纯西药组无不良反应,而联合用药组出现3例恶心㊁呕吐㊂姜黄素对肠道具有健康调节作用[53],而三七总皂苷可保护阿司匹林对胃黏膜造成的损伤[54]㊂结合Meta分析结果,该项研究的不良反应不能确定是由降脂通脉胶囊造成的,还需要更深入的研究证明是否存在与他汀类药物的相互作用㊂上述不良反应均在对症处理后减轻,且试验过程并无病人因不适而退出,因此,可以认为加用降脂通脉胶囊具有较好的安全性㊂4小结本次Meta分析显示,加用降脂通脉胶囊在提高血脂异常病人临床疗效方面优于单纯西药常规治疗,且不会增加不良反应,但在远期疗效方面数据不够充足㊂本研究结果存在一定局限性,在进一步研究中,期待更大量的样本与更高质量的RCT补充证实降脂通脉胶囊对血脂异常的有效性,尤其是对血清LDL-C水平的影响,为临床应用提供更可靠的循证医学依据㊂参考文献:[1]ANDERSON 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