第一篇：CounterpointReflections-短期報(bào)告：2型糖尿病可逆性的治療人群反應(yīng)

Short Report: Treatment Population response to information on reversibility of

Type 2 diabetes 短期報(bào)告：2型糖尿病可逆性的治療人群反應(yīng)

S.Steven, E.L.Lim and R.Taylor S.史提芬，E.L.Lim和R.泰勒

Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 磁共振中心，紐卡斯?fàn)柎髮W(xué)醫(yī)學(xué)院，蜂窩，泰恩河畔紐卡斯?fàn)?，英?guó) Accepted 10 January 2013 接受10一月2013

1.Abstract摘要

1.1.Aims目的

Following publication of the Counterpoint Study(on the reversibility of Type 2 diabetes using a very low energy diet), the extent of public interest prompted the authors to make available, on a website, general information about reversing diabetes.Shortly thereafter, individuals began to feed back their personal experiences of attempting to reverse their diabetes.We have collated this information on the effects of energy restriction in motivated individuals with Type 2 diabetes that has been achieved outside a research setting.以下的對(duì)位研究出版（對(duì)2型糖尿病患者采用極低能量飲食的可逆性），公共利益的程度上促使作者提供，網(wǎng)站上，關(guān)于糖尿病的一般信息。此后不久，個(gè)人開始反饋他們的個(gè)人

此處替換為文檔標(biāo)題

經(jīng)歷，試圖扭轉(zhuǎn)他們的糖尿病。我們已經(jīng)整理了對(duì)動(dòng)機(jī)的2型糖尿病患者已經(jīng)實(shí)現(xiàn)外研究制定能源約束的影響這一信息。

1.2.Methods方法

Emails, letters and telephone communications received between July 2011 and September 2012 were evaluated(n = 77: 66 men, 11 women).Median diabetes duration was 5.5 years(3 months–28 years).Reversal of diabetes was defined as achieving fasting capillary blood glucose < 6.1 mmol/l and/or, if available, HbA1c less than 43 mmol/mol(6.1%)off treatment.收到的電子郵件，信件和電話之間的通信在七月2011和九月2012進(jìn)行了評(píng)價(jià)（77名：66名男子，11名婦女）。中位糖尿病病程5.5年（3個(gè)月，28年）。逆轉(zhuǎn)糖尿病被定義為實(shí)現(xiàn)空腹毛細(xì)血管血糖＜6.1 mmol/L和/或，如果可用，糖化血紅蛋白小于43毫摩爾/摩爾（6.1%）治療。

1.3.Results結(jié)果

Self-reported weight fell from 96.7 17.5 kg at baseline to 81.9 14.8 kg after weight loss(P < 0.001).Selfreported fasting blood glucose levels fell from 8.3 mmol/l(5.9–33.0)to 5.5 mmol/l(4.0–10.0)after the weight loss period(P < 0.001).Diabetes reversal was considered to have occurred in 61% of the population.Reversal of diabetes was observed in 80, 63 and 53% of those with > 20, 10–20 and < 10 kg weight loss, respectively.There was a significant correlation between degree of weight loss and reported fasting glucose levels(Rs –0.38, P = 0.006).Reversal rates according to diabetes duration were: short(< 4 years)= 73%, medium(4–8 years)= 56% and long(> 8 years)= 43%.自報(bào)體重從17.5公斤下降到81.9 96.7公斤，體重減輕14.8公斤（0.001）。問(wèn)卷訪空腹血糖水平從8.3 mmol/L下降（5.9–33）5.5毫摩爾/升（4–10）減肥期后（P＜0.001）。糖尿病逆轉(zhuǎn)被認(rèn)為是發(fā)生在61%的人口。觀察20、63、53%、10、80和的糖尿病逆轉(zhuǎn)情況，分別為20和10。有一個(gè)顯著的相關(guān)性程度的減肥和空腹血糖水平（盧比）-0.38，磷= 0.006）。根據(jù)糖尿病病程逆轉(zhuǎn)率：短（4年）= 73%，中（4104）。

Self-reported weight fell from 96.7 17.5 kg at aseline and was 81.9 14.8 kg after weight loss(P < 0.001).Selfreported fasting blood glucose levels fell from 8.3 mmol/l(5.9–33.0)to 5.5 mmol/l(4.0–10.0)after the weight-loss period(P < 0.001).Pre-and post-diet HbA1c was available in 20 subjects and fell from 58 mmol/mol(40–115)[7.5%(5.8–12.7)] to 45 mmol/mol(26–57)[6.3%(4.5–7.4)](P < 0.001).Diabetes reversal was considered to have occurred in 61% of the 同方股份有限公司

此處替換為文檔標(biāo)題

population.In the non-reversal group, improvements sufficient to allow discontinuation of anti-diabetic medications occurred in five individuals.自我報(bào)告的體重從96.7公斤到17.5從81.9下跌，14.8公斤減肥后（P＜0.001）。問(wèn)卷訪空腹血糖水平從8.3 mmol/L下降（5.9–33）5.5毫摩爾/升（4–10）減肥期后（P＜0.001）。前和后的飲食20者HbA1c可從58毫摩爾/摩爾下降（40–115）[ 7.5%（5.8–12.7）] 45毫摩爾/摩爾（26–57）[ 6.3%（4.5–7.4）]（P＜0.001）。糖尿病逆轉(zhuǎn)被認(rèn)為是發(fā)生在61%的人口。在非逆轉(zhuǎn)組中，有足夠的改善，使五個(gè)人的抗糖尿病藥物的停止發(fā)生。

Reversal of diabetes was observed in 80% of those with > 20 kg weight loss, 63% of those with weight loss 10–20 kg and in 53% of those with < 10 kg weight loss.The mean weight loss in individuals who reported diabetes reversal was 16.0 6.9 kg, and was 12.8 4.9 kg in those who did not achieve reversal of diabetes.There was a significant correlation between degree of weight loss(%)and reported fasting glucose levels(Rs –0.38, P = 0.006)(see Fig.1).Of those achieving loss of > 20% of body weight, only three people did not achieve reversal of diabetes.The reversal rates in the short, medium and long duration groups were 73, 56 and 43%, respectively, and in those losing > 15 kg in weight the reversal rates were 82, 64 and 75%, respectively.在80%的減肥者中有20的體重下降，63%的體重下降10，20公斤，53%的體重下降，其中10的人體重下降。在個(gè)人誰(shuí)報(bào)告糖尿病逆轉(zhuǎn)的平均體重?fù)p失為6.9，16公斤，并在那些沒有達(dá)到逆轉(zhuǎn)糖尿病4.9 12.8公斤。有一個(gè)顯著的相關(guān)性之間的重量損失（%）和空腹血糖水平（盧比-0.38，磷= 0.006）（見圖1）。其中20%的減肥者達(dá)到減肥，只有三人沒有達(dá)到逆轉(zhuǎn)糖尿病。短、中、長(zhǎng)時(shí)間組的逆轉(zhuǎn)率分別為73、56和43%，而在減肥中的逆轉(zhuǎn)率分別為82、和64，分別為15和75%。

Longer-term data from eight of these individuals are available, indicating a sustained benefit on blood glucose levels following cessation of tight energy restriction.These individuals, all male, undertook an 8-week period of energy restriction, with four individuals using a meal replacement product.Sustained reversal of diabetes was confirmed by HbA1c in six individuals and by oral glucose tolerance test in two individuals.Details on glycaemic control and weight change for these individuals are shown in Table 1.同方股份有限公司

此處替換為文檔標(biāo)題

從這些人中的八個(gè)較長(zhǎng)的長(zhǎng)期數(shù)據(jù)是可用的，表明持續(xù)的利益，對(duì)血糖水平停止嚴(yán)格的能量限制。這些人，全部為男性，進(jìn)行了能量限制8周，用代餐產(chǎn)品四個(gè)人。糖尿病持續(xù)逆轉(zhuǎn)證實(shí)了HbA1c在六個(gè)人和兩個(gè)人口服葡萄糖耐量試驗(yàn)。這些人在控制血糖及體重變化情況如表1所示。

FIGURE 1 Self-reported fasting blood glucose levels at the end of the diet period in relation to the degree of achieved weight loss.The solid line at 6.1 mmol/l represents the diagnostic cut-off for diabetes reversal.圖1自我報(bào)告的空腹血糖水平在結(jié)束時(shí)的飲食與體重減輕的程度有關(guān)。在6.1毫摩爾/升的固體線代表診斷截?cái)嗵悄虿∧孓D(zhuǎn)。

5.Discussion The data suggest that very significant improvements in blood glucose levels can be made by energy restriction undertaken by motivated individuals in their usual environment.This is possible with minimal or no support from a healthcare practitioner.It is still widely believed that long-duration Type 2 diabetes results in an inevitable and irreversible decline in insulin secretion, 同方股份有限公司

此處替換為文檔標(biāo)題

with the inevitable requirement for insulin therapy after an average of 10 years [4].Six individuals with long-duration disease(9–28 years)reported reversal of diabetes.討論的數(shù)據(jù)表明，在血液中的葡萄糖水平的非常顯著的改善，可以通過(guò)在其通常的環(huán)境中的動(dòng)機(jī)的個(gè)人進(jìn)行的能量限制。這是可能的，最小的或不支持的醫(yī)療保健醫(yī)生。它仍然被廣泛認(rèn)為，持續(xù)時(shí)間長(zhǎng)2型糖尿病的結(jié)果是不可避免的和不可逆的胰島素分泌下降，胰島素治療的必然要求，平均10年后[ 4 ]。六個(gè)人的長(zhǎng)期病程（9年）報(bào)告逆轉(zhuǎn)糖尿病。

This is in keeping with observations following bariatric surgery, that some individuals will achieve normalization of blood glucose levels, even although remission rates decrease when disease duration is more than 10 years [5].Although the use of very low energy diets tends to be followed by weight regain, some people are able to avoid this [6,7] and our data confirm this.Modification of dietary fat content may have a beneficial effect following intentional weight loss [8].Further work is needed to define the optimum method for maintaining normal glucose toleranceafter the return to normal eating.這是符合減肥手術(shù)后的觀察，一些人將實(shí)現(xiàn)血糖水平正常，即使當(dāng)病程超過(guò)10年[ 5 ]降低緩解率。雖然極低能量飲食的使用往往是由體重恢復(fù)，有些人能夠避免這個(gè)[ 6,7 ]和我們的數(shù)據(jù)證實(shí)了這個(gè)。膳食脂肪含量的修改可能有一個(gè)有益的影響以下故意減肥[ 8 ]。進(jìn)一步的工作是需要定義為維持正常血糖toleranceafter恢復(fù)正常飲食的最佳方法。

The study population represents a group of individuals motivated to regain their health, and this is an important point.The crucial factor which differentiates this dietary intervention from previous attempts is the clearly identified goal of becoming free of Type 2 diabetes.The distinction between the treatment of a potentially curable disease and that of a chronic progressive condition was made eloquently by one individual, who contrasted the often reported battle to ‘beat’ a life-threatening disease such as cancer with the learned helplessness induced by advice that diabetes was inevitably progressive.研究人群代表了一組個(gè)人的動(dòng)機(jī)，以恢復(fù)他們的健康，這是一個(gè)重要的觀點(diǎn)。的關(guān)鍵因素，區(qū)分這一飲食干預(yù)，從以前的嘗試是明確確定的目標(biāo)，成為自由的2型糖尿病。區(qū)別可同方股份有限公司

此處替換為文檔標(biāo)題

能治愈的疾病的治療之間，慢性進(jìn)展性條件是充分的一個(gè)人，他對(duì)比了經(jīng)常報(bào)道的戰(zhàn)斗，打敗一個(gè)危及生命的疾病，如與習(xí)得性無(wú)助的建議，糖尿病是不可避免的進(jìn)步引起的癌癥。

The responses clearly show that this minority of health-motivated people strongly resent being told that there is nothing that can be done to escape from Type 2 diabetes and that they must take medication.The overwhelming impression gained by doctors from their routine clinical practice is that people with Type 2 diabetes rarely succeed in losing weight, and the critical point that there is a subgroup who are strongly motivated by desire to regain health has not been widely recognized.Some doctors do know that occasionally people do reverse their diabetes, but this is not acknowledged by clinical guidelines [9].The pathophysiological basis for this has previously been described [10].反應(yīng)清楚地表明，這少數(shù)的健康動(dòng)機(jī)的人強(qiáng)烈不滿被告知，沒有任何可以做，以擺脫2型糖尿病，他們必須采取藥物。醫(yī)生從他們的日常臨床實(shí)踐中得到的壓倒性的印象是，2型糖尿病患者很少能成功地減肥，而關(guān)鍵的一點(diǎn)是，有一個(gè)亞組誰(shuí)是強(qiáng)烈動(dòng)機(jī)的愿望，恢復(fù)健康并沒有得到廣泛認(rèn)可。有些醫(yī)生確實(shí)知道，偶爾的人會(huì)改變他們的糖尿病，但這是不承認(rèn)的臨床指南[ 9 ]。以前被描述的病理生理基礎(chǔ)[ 10 ]。

Table 1 Sustained benefit on weight and blood glucose levels following a period of energy restriction in eight individuals 表1: 持續(xù)的獲益于體重和血糖水平, 在八個(gè)個(gè)體的能量限制期后

Observations in uncontrolled free-living populations make this study unique and reflect the prospects for what can be achieved beyond the research environment.However, the limitations 同方股份有限公司

此處替換為文檔標(biāo)題

inherent to this study design must be acknowledged.Firstly, there will have been self-referral bias, with the observations demonstrating proof of principle rather than any estimate of likely reversal rates.The precision of the diagnosis of Type 2 diabetes is uncertain.The inclusion of individuals with maturity-onset diabetes of youth or slow-onset Type 1 diabetes would result in an underestimation of rates of diabetes reversal using a very low energy diet.在不受控制的自由生活的人群的觀察，使這項(xiàng)研究獨(dú)特的反映所能取得的成就超越環(huán)境的研究前景。然而，固有的局限性，本研究設(shè)計(jì)必須承認(rèn)。首先，將有自我轉(zhuǎn)介偏見，與觀察證明的原則，而不是任何可能的逆轉(zhuǎn)率的估計(jì)。2型糖尿病診斷的準(zhǔn)確性是不確定的。與青年或緩慢起病的1型糖尿病發(fā)病的成年型糖尿病患者納入會(huì)導(dǎo)致低估率糖尿病逆轉(zhuǎn)用極低能量飲食。

The significant degree of heterogeneity in the intervention must also be acknowledged, including the degree of energy restriction(particularly in those who did not use a meal replacement product)and the length of diet period undertaken.Finally, diabetes reversal was mostly based on self-reported, unverified measurements of glycaemic control in the form of capillary blood glucose results, fasting plasma glucose results, HbA1c or oral glucose tolerance tests.在干預(yù)的顯著程度的異質(zhì)性，也必須承認(rèn)，包括限制的能量限制（特別是在那些沒有使用的膳食替代產(chǎn)品）和飲食期間的長(zhǎng)度進(jìn)行。最后，糖尿病逆轉(zhuǎn)主要是基于自我報(bào)告，在毛細(xì)管血糖結(jié)果形成血糖控制未經(jīng)證實(shí)的測(cè)量結(jié)果，空腹血糖，糖化血紅蛋白或口服葡萄糖耐量試驗(yàn)。

These data demonstrate that intentional weight loss achieved at home by health-motivated individuals can reverse Type 2 diabetes.Diabetes reversal should be a goal in the management of Type 2 diabetes in these individuals.The durability of the effect on glucose metabolism requires further study.Long-term avoidance of weight gain must be the top priority after reversal of diabetes, and the dietary regimen best able to achieve this must now be established.這些數(shù)據(jù)表明，故意減肥，實(shí)現(xiàn)在家中的健康動(dòng)機(jī)的個(gè)人可以逆轉(zhuǎn)2型糖尿病。糖尿病的逆轉(zhuǎn)應(yīng)該是一個(gè)目標(biāo)，在這些人的2型糖尿病的管理。對(duì)糖代謝的影響的耐久性需要進(jìn)一同方股份有限公司

此處替換為文檔標(biāo)題

步研究。長(zhǎng)期避免體重增加必須是糖尿病逆轉(zhuǎn)后的重中之重，而現(xiàn)在必須建立的飲食方案最好能達(dá)到這個(gè)。

Funding sources 資金來(lái)源 None.無(wú)。

Competing interests 競(jìng)爭(zhēng)利益 None declared.沒有聲明。

6.References 1 Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC,Taylor R.Reversal of type 2 diabetes is associated with decrease inpancreas and liver fat.Diabetologia 2011;54: 2506–2514.2 Taylor R.Reversing Type 2 Diabetes.2011.Available at http://004km.cnmendationon reporting results for blood glucose.ClinChimActa 2001;307: 205–209.4 UK Prospective Diabetes Study.Intensive blood glucose controlwith sulphonylureas or insulin compared with conventional treatmentand risk of complications in patients with type 2 diabetes(UKPDS 33).Lancet 1999;352: 837–853.5 Hall TC, Pellen MGC, Sedman PC, Jain PK.Preoperativefactors predicting remission of Type 2 diabetes mellitus after Rouxen-Y gastric bypass surgery for obesity.ObesSurg 2010;20:1245–1250.6 Paisey RB, Frost J, Harvey P, Paisey A, Bower L, Paisey RM et al.Five-year results of a prospective very low calorie diet or conventionalweight loss programme in type 2 diabetes.J Hum Nutr Diet2002;15: 121–127.同方股份有限公司

此處替換為文檔標(biāo)題 Ross HM, Laws R, Reckless J, Lean M, Counterweight Project T.Evaluation of the Counterweight Programme for obesity managementin primary care: a starting point for continuous improvement.Br J Gen Pract 2008;58: 548–554.8 Low CC, Grossman EB, Gumbiner B.Potentiation of effects ofweight loss by monounsaturated fatty acids in obese NIDDMpatients.Diabetes 1996;45: 569–575.9 National Institute for Health and Clinical Excellence.NationalCollaborating Centre for Chronic Conditions: Type 2 Diabetes:National Clinical Guideline for Management in Primary andSecondary Care.NICE-CG66(update).London: Royal College ofPhysicians, 2008.10 Taylor R.Pathogenesis of Type 2 diabetes: tracing the reverse routefrom cure to cause.Diabetologia 2008;51: 1781–1789.同方股份有限公司

第二篇：治療2型糖尿病新藥的心血管風(fēng)險(xiǎn)評(píng)價(jià)指導(dǎo)原則

治療2型糖尿病新藥的心血管風(fēng)險(xiǎn)評(píng)價(jià)指導(dǎo)原則

一、引言

本指導(dǎo)原則僅針對(duì)如何證明一種新的治療2型糖尿病的藥物不會(huì)造成不可接受的心血管風(fēng)險(xiǎn)的增加提出建議。

本指導(dǎo)原則僅視為推薦性的建議。

二、背景

近期糖尿病的發(fā)病率在中國(guó)及世界范圍內(nèi)已經(jīng)達(dá)到了流行的程度。與糖尿病相關(guān)的發(fā)病率和死亡率預(yù)計(jì)占醫(yī)療費(fèi)用支出的相當(dāng)大比例。盡管目前已有幾種糖尿病治療藥物可應(yīng)用，但仍然需要新的藥物用于糖尿病的預(yù)防和治療（例如：藥物和治療性生物制品的開發(fā)）。

糖尿病是一種以胰島素分泌不足、胰島素抵抗或者二者并存引起的高血糖癥為特征的慢性代謝性疾病。脂質(zhì)和蛋白質(zhì)代謝的改變也是胰島素分泌不足或作用缺陷的重要表現(xiàn)。

大部分糖尿病患者為1型糖尿?。庖呓閷?dǎo)的或特發(fā)性的）或者2型糖尿?。ň哂袕?fù)雜的病理生理學(xué)，合并有漸進(jìn)性的胰島素抵抗和β細(xì)胞衰竭）。1型和2型糖尿病均有遺傳基礎(chǔ)。糖尿病還可能與妊娠激素環(huán)境、遺傳缺陷、其他的內(nèi)分泌疾病、感染和某些特定藥物相關(guān)。

目前糖尿病患者的治療目標(biāo)出現(xiàn)了顯著變化，從預(yù)防近期死亡到緩解癥狀，再到目前公認(rèn)的目標(biāo)，旨在使血糖水平正常化或接近正常以預(yù)防糖尿病的并發(fā)癥。糖尿病控制與并發(fā)癥的臨床研究已經(jīng)明確證明，對(duì)1型糖尿病患者進(jìn)行嚴(yán)格的血糖控制可以顯著減少慢性糖尿病并發(fā)癥（例如：視網(wǎng)膜病變、腎臟病變和神經(jīng)病變）的發(fā)生和進(jìn)展。在糖尿病干預(yù)與并發(fā)癥的流行病學(xué)研究中（Epidemiology of Diabetes Interventions and Complications study，EDIC study），通過(guò)對(duì)這些患者進(jìn)行的長(zhǎng)期隨訪證實(shí)了血糖控制對(duì)大血管結(jié)局產(chǎn)生有益的作用。

2型糖尿病患者中也有足夠的證據(jù)支持長(zhǎng)期良好的血糖控制可以降低微血管并發(fā)癥的風(fēng)險(xiǎn)。這些研究中的血糖控制是通過(guò)糖化血紅蛋白（HbA1c）的變化來(lái)判定的。該終點(diǎn)指標(biāo)反映了糖尿病的直接臨床表現(xiàn)（高血糖及其相關(guān)癥狀）的獲益作用，降低HbA1c可以合理地預(yù)期降低微血管并發(fā)癥的長(zhǎng)期風(fēng)險(xiǎn)。因此，在批準(zhǔn)糖尿病高血糖治療藥物時(shí)，可以將HbA1c作為主要療效終點(diǎn)指標(biāo)。然而，與糖尿病相關(guān)的心血管疾病風(fēng)險(xiǎn)的升高，是導(dǎo)致這些人群心血管疾病發(fā)病和死亡的首要病因。盡管這種過(guò)高的心血管風(fēng)險(xiǎn)在1型和2型糖尿病患者中均存在，但是1型糖尿病患者胰島素的絕對(duì)缺乏使其必須將胰島素治療作為直接挽救生命的治療，對(duì)其進(jìn)行長(zhǎng)期的心血管風(fēng)險(xiǎn)評(píng)價(jià)可能不切合實(shí)際。對(duì)于2型糖尿病而言，在胰島素治療前更廣泛的控制高血糖的治療手段使得有機(jī)會(huì)去評(píng)價(jià)這些治療對(duì)心血管風(fēng)險(xiǎn)的影響，從而使在治療2型糖尿病方面做出更為明智的決策。

三、建議

為了確定治療2型糖尿病的新藥的安全性，并確保該治療將不會(huì)造成不可接受的心血管風(fēng)險(xiǎn)的增加，開發(fā)計(jì)劃應(yīng)當(dāng)包括下列幾點(diǎn)。

（一）對(duì)于處于計(jì)劃階段的新的臨床研究

? 申辦者應(yīng)當(dāng)建立一個(gè)獨(dú)立的心血管終點(diǎn)委員會(huì)，要預(yù)先確定用盲法對(duì)所有Ⅱ期和Ⅲ期試驗(yàn)的心血管事件進(jìn)行裁定。這些事件應(yīng)當(dāng)包括心血管疾病死亡率、心肌梗死和卒中，還可包括因急性冠脈綜合癥而住院治療、緊急血管再造術(shù)以及其他可能的終點(diǎn)指標(biāo)。

? 申辦者應(yīng)當(dāng)確保Ⅱ期和Ⅲ期臨床試驗(yàn)恰當(dāng)?shù)卦O(shè)計(jì)和實(shí)施，以便在這些研究完成時(shí)能夠進(jìn)行薈萃分析，對(duì)重要的研究設(shè)計(jì)特點(diǎn)、患者情況、研究水平的協(xié)變量給予合理的說(shuō)明。為了獲取足夠的終點(diǎn)事件以進(jìn)行有意義的風(fēng)險(xiǎn)評(píng)估，Ⅱ期和Ⅲ期的開發(fā)計(jì)劃應(yīng)當(dāng)入選具有較高心血管事件風(fēng)險(xiǎn)的患者，如相對(duì)晚期疾病的患者、老年患者和具有一定程度腎臟損害的患者。由于此類患者可能接受降糖藥物治療，如果獲得批準(zhǔn)，該人群比年輕和健康人群更加適合進(jìn)行藥物安全性試驗(yàn)的其他方面的評(píng)價(jià)。

? 申辦者還應(yīng)當(dāng)提供一個(gè)研究方案對(duì)擬定的薈萃分析的統(tǒng)計(jì)學(xué)方法進(jìn)行描述，包括擬評(píng)價(jià)的終點(diǎn)指標(biāo)。此時(shí)，合理的薈萃分析應(yīng)當(dāng)包括所有的安慰劑對(duì)照試驗(yàn)、聯(lián)合治療試驗(yàn)（即在標(biāo)準(zhǔn)治療基礎(chǔ)上加用藥物，進(jìn)行藥物與安慰劑的比較）以及陽(yáng)性對(duì)照試驗(yàn)；應(yīng)當(dāng)保證研究水平上的隨機(jī)化比較；但在薈萃分析時(shí)，若有可能，應(yīng)納入研究差異的重要指標(biāo)或其他因素（例如：劑量、暴露持續(xù)時(shí)間、附加藥物）。為了獲得足夠的事件，為了給慢性治療提供長(zhǎng)期心血管風(fēng)險(xiǎn)相關(guān)數(shù)據(jù)（例如：至少2年的數(shù)據(jù)），對(duì)照試驗(yàn)可能需要持續(xù)3到6個(gè)月以上。

? 申辦者應(yīng)當(dāng)針對(duì)Ⅱ期和Ⅲ期對(duì)照臨床試驗(yàn)的重要心血管事件進(jìn)行薈萃分析，若有可能，應(yīng)當(dāng)針對(duì)亞組（例如：年齡、性別、種族）之間的相似性和/或差異性進(jìn)行探索。

（二）對(duì)于已經(jīng)完成的研究，在提交新藥或新生物制品上市申請(qǐng)之前

? 申辦者應(yīng)對(duì)研究藥物組中重要的心血管事件的發(fā)生率與對(duì)照組中同類型事件的發(fā)生率進(jìn)行比較，以表明所估計(jì)的風(fēng)險(xiǎn)比的雙側(cè)95%臵信區(qū)間的上限低于1.8。可以通過(guò)幾種方法實(shí)現(xiàn)該目的。可以使用上述針對(duì)Ⅱ期和Ⅲ期臨床研究的綜合分析（薈萃分析）；或者，如果作為薈萃分析組成部分的所有研究數(shù)據(jù)的本身不能夠表明所估計(jì)風(fēng)險(xiǎn)比的雙側(cè)95%臵信區(qū)間的上限低于1.8，則應(yīng)當(dāng)進(jìn)行一項(xiàng)附加的單項(xiàng)、大規(guī)模的安全性研究（單獨(dú)進(jìn)行或加到其他的研究中），使在NDA/BLA提交前能夠滿足該上限的要求。無(wú)論采用何種方法，申辦者都應(yīng)當(dāng)考慮到可能風(fēng)險(xiǎn)增加的幅度與風(fēng)險(xiǎn)增加的臵信區(qū)間及點(diǎn)估計(jì)值保持一致。例如：即使95%臵信區(qū)間的上限低于1.8，也不保證點(diǎn)估計(jì)值是否到1.5（所謂的有統(tǒng)計(jì)學(xué)意義的增加）。

? 如果在上市前申請(qǐng)中，臨床數(shù)據(jù)表明所估計(jì)的風(fēng)險(xiǎn)增加（即，風(fēng)險(xiǎn)比）的雙側(cè)95%臵信區(qū)間的上限介于1.3與1.8之間，并且總體風(fēng)險(xiǎn)/受益分析支持批準(zhǔn)該申請(qǐng)，則通常需要進(jìn)行一項(xiàng)上市后研究以最終表明所估計(jì)的風(fēng)險(xiǎn)比的雙側(cè)95%臵信區(qū)間的上限低于1.3?？梢酝ㄟ^(guò)實(shí)施一項(xiàng)具有足夠統(tǒng)計(jì)效能的單獨(dú)臨床研究或者將上市前安全性研究的結(jié)果與類似設(shè)計(jì)的上市后安全性研究的結(jié)果合并來(lái)實(shí)現(xiàn)上述目標(biāo)。該臨床研究將是一項(xiàng)必需的上市后安全性研究。

? 如果上市前申請(qǐng)包含能夠表明所估計(jì)的風(fēng)險(xiǎn)增加（即，風(fēng)險(xiǎn)比）的雙側(cè)95%臵信區(qū)間的上限低于1.3的臨床數(shù)據(jù)，而且總體風(fēng)險(xiǎn)/受益分析支持批準(zhǔn)該申請(qǐng)，則通常不需要進(jìn)行上市后的心血管臨床研究。

? 本項(xiàng)薈萃分析的報(bào)告應(yīng)當(dāng)包括：充分的所有分析的細(xì)節(jié)；按研究、亞組和總體風(fēng)險(xiǎn)比繪制的薈萃分析結(jié)果的常規(guī)圖表；所有能夠用于對(duì)結(jié)果進(jìn)行驗(yàn)證的分析數(shù)據(jù)集。