06-JUN-2008

World's Largest Trial of Intensive Glucose Control in Type 2 Diabetes Finds Significant Reduction in Serious Complications -- 21% Reduced Kidney Disease Risk

SAN FRANCISCO, CA, Jun 06, 2008 (MARKET WIRE via COMTEX) -- The world's largest diabetes trial has shown intensive blood glucose control in type 2 diabetes reduces the risk of complications -- notably a 21% reduction in risk for kidney disease. The study also showed no evidence of any increased risk of death when blood glucose was intensively controlled, according to reports presented here today at the American Diabetes Association's 68th Annual Scientific Sessions.

"The results clearly demonstrate that intensive control of blood glucose, as recommended by most current clinical guidelines, has an important role in the prevention of renal complications of type 2 diabetes. The other major finding of the trial was that major macrovascular events -- heart attack, stroke and death from cardiovascular disease -- were not significantly reduced with intensive glucose control, although there was a trend towards improvement in these outcomes. However, the results suggest that a multifactorial approach addressing all the major risk factors including blood pressure and blood lipids is required to prevent macrovascular disease," said Anushka Patel, MBBS, SM, PhD, Study Director of the ADVANCE trial, and Director, Cardiovascular Division, The George Institute for International Health, which conducted the study, in a recent interview. "The key message is that the study confirms the current approach that intensively controlling blood glucose has an important role in the prevention of the microvascular complications of diabetes."

There was no evidence of an increased risk of death among ADVANCE patients receiving intensive treatment to lower blood glucose, in contrast to the similar ACCORD trial in the U.S., which was discontinued prematurely earlier this year due to an increased rate of death in its intensive arm.

"Overall, we found that the intensive control strategy reduced the combined risk of macrovascular and microvascular complications by 10%, but that was driven largely by the microvascular results," said Dr Patel. "Further, the 14% reduction in microvascular risk was driven mainly by nephropathy rather than retinopathy. We found that intensively controlling blood glucose reduces risk of the development or progression of kidney disease by 21%."

ADVANCE did not show a statistically significant effect of intensive glucose control on cardiovascular disease (10% in the intensively treated group vs., 10.6% in the standard group). "We believe a protective effect remains plausible since we were aiming for a 1% difference in A1C levels between the standard and intensive groups, but achieved an average of a 0.7% difference over the course of the trial," said Dr. Patel. "Further, the rate of cardiovascular events was only 2.2% per year rather than the expected 3% per year, possibly due to more aggressive treatment of blood pressure and lipids." She also noted that the wide confidence interval in the trial's results does not exclude the benefits that epidemiologic evidence predicts.

A1C is a measure of blood glucose over the prior two to three months.

Trial Design

The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) trial was an international study involving 11,140 high-risk patients with type 2 diabetes based at 214 centers in 20 countries worldwide.

"ADVANCE was designed to address two of the major uncertainties in the prevention of the vascular complications of diabetes: whether important clinical benefits would result from reducing A1C to 6.5% or lower and from intensive blood pressure lowering, whether or not the patient had had hypertension," said Stephen MacMahon, DSc, PhD, MPH, Co-Principal Investigator of the study, Principal Director of The George Institute for International Health. He is also a Professor of Cardiovascular Medicine and Epidemiology at the University of Sydney. In a factorial design, patients received blood-pressure-lowering treatment with a fixed-dose combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide or a placebo, and diabetes treatment with gliclazide MR, plus other anti-diabetic drugs as needed.

The average age of participants was 66, with 46% coming from Europe, 37% from Asia, 13% from Australia and New Zealand, and 4% from North America. At the outset, 32% of the participants had already had a cardiovascular event, such as a stroke or heart attack, and the balance were already at high risk due to such risk factors as a history microalbuminuria (protein in the urine), proliferative diabetic retinopathy, current cigarette smoking, elevated total cholesterol, or low HDL (the "good" cholesterol).

"The key objective was to get the intensive group patients down to an A1C of 6.5%, which the trial achieved," said Dr. MacMahon. The investigators did not have a particular target for the standard group so they did not have control of what the standard group would achieve.

"At baseline, the average A1C of all participants was 7.5%," said Dr. MacMahon. "Physicians treating those in the standard group could give them any medications they chose according to the guidelines in the local country. Physicians treating those in the intensive group were required to use gliclazide MR first and then up to three oral agents, followed by insulin in order to reach the goal of an A1C of 6.5% or lower. Sulfonylureas, thiazolidinediones, acarbose, metformin, and insulin were commonly used in both arms of the study. Aside from gliclazide MR, all medication choices were left to the treating physician."

"At the end of the five years of follow-up, the average A1C in the intensive group was 6.5% and in the standard group was 7.3%," he reported. "However, the average difference in A1C over the course of the trial was 0.7%."

There were two primary outcomes: first, a composite of death and macrovascular complications -- death, cardiovascular death, nonfatal heart attacks, and nonfatal stroke; second, a composite of microvascular complications -- new or worsening renal disease (nephropathy) or diabetic eye disease (retinopathy). It was prespecified that the outcomes would be analyzed both jointly and separately.

"As expected, patients in the intensive group had more hypoglycemia (episodes of low blood glucose), but the overall incidence was actually quite low," he said. The incidence of severe hypoglycemic events was 2.7% in the intensive group and 1.5% in the standard group, and this difference was statistically significant.

Translating the Results to Action

"It's more challenging today than it has ever been in the past to demonstrate a benefit for glucose control first because the standard group was in such good control. Patients getting standard treatment are already in good glycemic control today and are also getting good treatments for cholesterol and blood pressure and are getting aspirin," said Dr. MacMahon. "So the overall rate of heart attacks is low, which means we might need a much larger group and a much longer study to detect the effects of glucose lowering on macrovascular outcomes."

"If there is any effect of glucose control using currently available drugs on heart attacks, it's going to be small, and therefore the key message with heart attacks and strokes is that diabetes patients need comprehensive treatment to control all risk factors including blood pressure and cholesterol," said Dr. MacMahon.

Nearly 21 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputations. It is the fifth leading cause of death by disease in the United States. Type 2 diabetes involves insulin resistance -- the body's inability to properly use its own insulin. Type 2 used to occur mainly in adults who were overweight and ages 40 and older. Now, as more children and adolescents in the United States become overweight and inactive, type 2 diabetes is occurring more often in young people. Globally, there are approximately 250 million people with diabetes, and that number is estimated to rise to 380 million in 2025.

Results of the blood pressure component of the trial, already published in the Lancet in September 2007 showed that a fixed combination of perindopril and indapamide given to patients with type 2 diabetes, regardless of baseline blood pressure, reduced the risks of vascular events by 9% over the course of five years. The relative risk of cardiovascular death was reduced by 18%.

ADVANCE was designed, conducted, monitored, analyzed and reported by an international collaborative medical research group. The study was led by The George Institute for International Health, funded by the Australian Government's National Health and Medical Research Council and by Servier, and carried out independently of the government and industry sponsors.

The George Institute for International Health seeks to improve the health of millions of people worldwide by providing the best research evidence to guide global health decisions and applying this research to health policy and practice. The George Institute is a leader in clinical trials, health policy and capacity-building areas and works in collaboration with medical institutions around the world.

The American Diabetes Association is the nation's leading voluntary health organization supporting diabetes research, information and advocacy. Founded in 1940, the Association has offices in every region of the country, providing services to hundreds of communities. For more information, please call the American Diabetes Association at 1-800-DIABETES (1-800-342-2383) or visit www.diabetes.org. Information from both these sources is available in English and Spanish.

Symposium, Friday, 2:00 pm PDT

NOTE TO EDITOR:

英语水平不够哦

全英文的啊，看的好累啊

研究生看的也累啊

The study also showed no evidence of any increased risk of death when blood glucose was intensively controlled, according to reports presented here today at the American Diabetes Association's 68th Annual Scientific Sessions.
我觉得这句话比题目更有价值。

其实，在第68届ADA年会上面，美国的全国大型糖尿病研究课题（ACCORD)结果表明，他们第一次发现了与标准组糖化7.0％-7.5％，强化组尽量控制到6.5%以下，甚至到6％左右），强化组的病人死亡率要增加了1％左右。
--------------------------------------------------------------------------------
06-JUN-2008

Previously Unrecognized Harm of Intensified Glucose Lowering Reported in High Risk Patients With Type 2 Diabetes


SAN FRANCISCO, CA, Jun 06, 2008 (MARKET WIRE via COMTEX) -- For the first time a previously unrecognized harm due to a strategy of intensified glucose lowering in high risk patients with type 2 diabetes has been identified, according to a report here today at the American Diabetes Association's 68th Annual Scientific Sessions.

The news came in a report on the Action to Control Cardiovascular Risk in Diabetes trial, known as ACCORD, sponsored by the National Heart, Lung, and Blood Institute. The trial had been studying whether a strategy of intensive control of blood glucose in type 2 diabetes could reduce the risk of cardiovascular disease. A safety review terminated its intensive treatment arm in February due to an increased death rate in the intensive treatment group.

All-cause mortality reported today indicated that the intensive group had a 22% higher relative risk of death compared to the standard group, which translates into an absolute mortality increase of about 1% during the average 3.5 years of treatment and follow-up.

The goal of the intensive group was to reach an A1C level of less than 6%, while the standard group goal was between 7 and 7.9%. In fact, at the time of termination, the median A1C was 6.4% in the intensive group vs. 7.5% in the standard group. A1C is a measure of blood glucose over the prior two to three months.

"The major clinical implication is that there is some risk associated with this level of intensification of glycemic control in high risk cardiovascular patients with type 2 diabetes similar to ACCORD patients and that has to be considered by clinicians in the management of the disease," said Robert Byington, PhD, head of the ACCORD coordinating center and Professor of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston Salem, NC, in a recent interview. He noted that all ACCORD patients were at high risk: 35% had had a CVD event such as a heart attack or stroke prior to entering the trial; the balance had subclinical cardiovascular disease or major cardiovascular risk factors.

Other Trial Findings

"Despite the fact that we achieved a good 1.1% difference in A1C levels between the two treatment groups, the intensive group patients only had a non-significant 10% lower risk of our primary outcome measure, the first occurrence of a major fatal or non-fatal cardiovascular event during follow-up. In ACCORD, we defined this as having a nonfatal heart attack, a nonfatal stroke, or dying from a cardiovascular cause," said Dr. Byington. "Specifically, 6.9% of intensives vs. 7.2% of the standard patients had one of these events during the 3.5 years of treatment and follow-up."

The following secondary outcomes were also assessed in ACCORD.

The rate of cardiovascular death due to events such as heart attacks, heart failure, and arrhythmias was 35% higher in the intensive group, a significant finding.

In contrast, there was good news in another secondary outcome. Those in the intensive group had a 24% lower risk of nonfatal heart attacks, which was also a significant finding. However, there was no difference between the two groups in the rate of nonfatal strokes and heart failure.

The 22% higher total mortality in the intensive group -- the reason for trial cessation -- was also a secondary outcome. Dr. Byington reported that 5% of intensive participants compared to 4% of standard participants died during the 3.5 years of follow-up. This reflected the deaths of 257 intensive patients compared to 203 standard patients who died, a difference of 54 people. Patients in both groups died of a variety of causes.

A significant question remains in that the researchers were unable to date to identify any subgroup among the intensive patients as more likely to die in response to intensive therapy, despite analyses by age, gender, ethnicity, comorbidities, glycemic control, current or severe hypoglycemia, drugs used (including rosiglitazone), or combinations of these factors.

"All we can say at this time is that it appears that a strategy of intensive glycemic lowering itself, compared to a standard approach, in a population of people with type 2 diabetes at high risk for cardiovascular disease, increases mortality over the course of three and a half years of treatment," said Dr. Byington.

"We will be continuing to follow all of the patients who have been in the study for at least another 18 months, when the study was scheduled to end in 2009, and we will reanalyze the results at that time," he said.

Trial Design and Strategy

ACCORD, sponsored by the National Heart, Lung, and Blood Institute, enrolled 10,251 adults at 77 clinics in the U.S. and Canada. Among the participants, 61% were men; 19% were African-Americans; 7% were Hispanic; and the rest were Caucasian. The average age at study entry was 62 years. The 35% who had prior CVD events (heart attacks and strokes) were the secondary prevention group, while the balance who were at high risk for such events had problems such as left ventricular hypertrophy, microalbuminuria, or at least two of the following risk factors: high LDL (the "bad" cholesterol), low HDL (the "good" cholesterol), high blood pressure, an elevated BMI (an indicator of overweight or obesity), or were smokers.

"ACCORD was designed to address the high rates of CVD in type 2 diabetes by testing three complementary strategies for treating the disease," said Hertzel Gerstein, MD, MSc, Chair of ACCORD's Glycemia Group and Principal Investigator of its Canadian Network, in a recent interview. He is a Professor of Medicine and the Population Health Institute Chair in Diabetes Research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

"We were testing an intensive strategy of glycemic control versus a standard strategy, so intensive group patients had more frequent clinic visits and were required to do more frequent self-monitoring of blood glucose, because they modified certain medications themselves in response to self-monitoring results," explained Dr. Gerstein. Intensive patients were seen every two months and standard patients every four months. Intensives were required to self-monitor their blood glucose levels two to four times per day if their A1C was above the target, while the standard group was required to self-test only once a day.

"The same menu of medications was available to physicians treating both groups, but patients in the intensive group tended to be prescribed more of them," said Dr. Gerstein. A broader comparison is that 52% of intensive patients were likely to be on insulin plus three oral agents versus 16% of those in the standard group. However, he also gave examples of particular medications.

"The treating physicians were told to use any drugs they wanted to get to the target, enabling them to use their clinical judgment to determine the order and types of medication to be used," said Dr. Gerstein. "Because all intensive and standard patients had the same drugs but those in the intensive therapy group had more of them, we must say that it is the intensive strategy that was associated with the higher mortality."

Although the arm of the study under discussion at the American Diabetes Association's Scientific Sessions is the glycemia trial, embedded within it are two other studies. Approximately 45% of each of the intensive and standard glycemic control group patients were given either intensive or standard blood pressure control. Similarly, approximately 55% of each of the intensive and standard glycemic control group patients were given (in addition to background simvastatin to lower LDL cholesterol) a placebo or fenofibrate to raise HDL and lower triglycerides. The blood pressure and lipid trials will close in June 2009.

Nearly 21 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputations. It is the fifth leading cause of death by disease in the U.S. Type 2 diabetes involves insulin resistance ---the body's inability to properly use its own insulin. Type 2 occurs mainly in adults who are overweight and ages 40 and older.

The American Diabetes Association is the nation's leading voluntary health organization supporting diabetes research, information and advocacy. Founded in 1940, the Association has offices in every region of the country, providing services to hundreds of communities. For more information, please call the American Diabetes Association at 1-800-DIABETES (1-800-342-2383) or visit www.diabetes.org. Information from both these sources is available in English and Spanish.

Symposium Tuesday, 7:30 am PDT

[ 本帖最后由 平衡行者 于 2008-6-7 09:39 PM 编辑 ]

ACCORD针对的是晚期已经有并发症的DM患者，得出的结果。这个说明前期更应该严格控制血糖，错过了时机，想补救而强化控制，可能适得其反。（偶的理解）
DM初哥当然更应该严格控制血糖水平！

谢谢alfa大哥的回复。您的回复促使我再次阅读ADANCE的新闻报告。ACCCORD是一个国际大项目合作研究，受试者总共11，140个2型糖尿病患者，全世界20个国家，214个中心参与研究。ADVANCE实验设计想解决在预防血管并发症方面的两个悬而未决的问题：1）重要的临床益处是否归因于把糖化血红蛋白降到6.5％，或者更低同时强化降压的结果；另外已有的高血压对2型患者后期的并发症的影响。血压的管理主要用ACEIperindopril和the diuretic indapamide，对照用安慰剂。ADVANCE的受试对象的平均年龄是66岁，其中46％来自欧洲，37％来自亚洲，13％来自澳大利亚和新西兰，4％来自北美洲。刚开始，32％的参与者已经罹患心血管事件，比如中风和心脏病，剩下的受试者也有高风险罹患心血管事件，他们有以下危险因子，比如微量白蛋白尿，增值性糖尿病视网膜病变，或者总胆固醇水平升高，或者HDL偏低等。
    ACCORD是全美心脏、肺和血管研究所发起的研究项目，总共招募了10，251个成年2型DM，包括了美国和加拿大共77个临床中心。参与者中，61％是男性，19％属于非裔美国人，7％西班牙裔，剩下的是高加索的白种人，患者的平均年龄是62岁，其中35％已经发生过心血管CVD事件（心脏病和中风)，这些人群属于二级预防组，剩余患者也对CVD事件发生有高风险性，他们有高LDL，低HDL，或者高血压，以及偏高的BMI指数和吸烟者。
    从以上把ADVANCE和ACCORD的受试对象特点进行比较，我觉得两者差异不大。
但是我本人更相信ADVANCE的研究结果，比较它是国际20多个国家的研究结果，但是ACCORD的研究结果也很重要，其中列出了以前被忽视的重要结果。（以上是我的个人理解，以抛砖引玉）。

[ 本帖最后由 平衡行者 于 2008-6-8 09:52 AM 编辑 ]

糖尿病患者真的需要更加积极地降糖？——ACCORD研究降糖治疗分支提前终止带来的思考
作者：李勇　朱雯　 复旦大学附属华山医院 2008-4-23
http://www.h-ceo.com/article.asp?id=7817

新近相继发表了两篇令人深思的重要文献：其一，美国心脏协会（AHA）发布了题为“高血糖与急性冠状动脉综合征（ACS）”的声明（Circulation
published online Feb 25, 2008），意在提高心脏科医生对ACS患者高血糖的重视，并敦促进行更多的临床研究以探索两者关系。

        其二，ACCORD（Action to Control Cardiovascular Risk in
Diabetes）研究中针对2型糖尿病患者血糖控制分支试验发现，强化治疗组较标准治疗组患者死亡率增高，该分支试验被提前终止。这个结果引起相当大的震动，使得学者们迷惑不解。

ACCORD研究

        强化降糖增加死亡风险，否定了降糖治疗对冠心病患者的益处？

        ACCORD研究是由NHLBI（National Heart, Lung, and Blood Institution）组织的，共纳入了10
000例2型糖尿病患者，入选标准为同时存在冠心病或有2个冠心病危险因素。该研究采用双2×2的阶乘研究设计。所有患者都参与血糖控制分支部分，目的是比较强化治疗策略（HbA1C目标值为<6.0%）与

标准治疗策略（HbA1C目标值为7.0%~7.9%）在减少心血管事件方面的优劣。结果表明，在该研究的血糖控制部分，强化治疗组达到的平均HbA1C为6.4%，而标准治疗组则为7.5%。在平均4年的治疗中，发

现强化治疗组的每年每1000人死亡人数较标准治疗组多3人（14/1000/y
vs 11/1000/y）。故而该分支研究提前终止，所有强化血糖控制组的患者都转入了标准控制组。

        
事实上，ACCORD研究中强化治疗组与常规治疗组的死亡率均低于临床上在UKPDS研究中所观察到的新诊断的及较年轻的糖尿病患者，而现实生活中高危患者的死亡率是ACCORD研究中任何一组的2~3倍。如

此比较，强化血糖控制组与标准血糖控制组的区别就不再显得如此惊人了。

        
那么，引起强化治疗组不理想结果的原因何在？ACCORD研究的结果是不是否定了强化降糖治疗对冠心病患者的益处？尽管AHA的“高血糖与ACS”声明针对的是ACS患者，仍然对我们理解ACCORD的结果有相

当大的作用。

高血糖与ACS声明

        肯定了高血糖与ACS的不良预后相关，目前不能确定理想的血糖目标值，避免降糖治疗导致低血糖。

        
在这一声明中，专家组通过大量的流行病学证据，肯定了高血糖与ACS的不良预后相关。那么，这种关联到底是由于高血糖本身所引起的？抑或高血糖仅是其他危险因素的一个标志？事实上，已经有大量

的研究证实高血糖能通过多种途径损害缺血心肌，例如减少侧支循环、增加梗死面积、促进缺血细胞凋亡、导致内皮功能紊乱、促凝、促进炎症反应等等。

        
那么，有没有随机对照临床研究能证实降低血糖对于ACS患者的益处呢？尽管先前的随机对照研究主要局限于糖尿病患者，且结果并不一致，但仍能给我们很大的启示。Original
DIGAMI研究纳入了620例糖尿病或入院时血糖>11.1 mmol/L（200
mg/dl）的患者，比较胰岛素治疗和常规治疗对预后的影响。胰岛素强化治疗组的血糖得到了更好的控制（胰岛素治疗组治疗后24小时血糖平均值为9.6
mmol/L（173 mg/dl），对照组则为11.7 mmol/L（210 mg/dl）；同时，强化治疗组的1年死亡率较对照组显著下降（19% vs
26%，P=0.011）。除了Original
DIGAMI研究之外，还有3个临床试验与该主题相关，即DIGAMI-2研究、HI-5研究及CREATE-ECLA研究。然而这些研究中干预组和对照组间的血糖水平及死亡率差异无统计学意义。

        最后，该声明认为，目前仍没有足够的证据，能确定ACS患者理想的血糖目标值。只是建议：不论患者既往是否有糖尿病病史，对于血糖明显增高>10.0
mmol/L（180
mg/dl）的患者都要进行降糖治疗。同时，专家们认为对于血糖略偏高的ACS患者进行降糖治疗的证据仍不够充分。至于降糖治疗的准确目标值，目前仍不能确定，只能说接近于正常的血糖较为合理

2.8~7.8
mmol/L（50~140 mg/dl）。

        另外，该声明指出，既往的流行病学研究发现，低血糖对于ACS患者的预后是不利的。因此建议避免降糖治疗导致低血糖。

ADVANCE研究

        ADVANCE研究命运与ACCORD不同，是否HbA1C目标值的差距或是降糖的幅度引起的？答案有待ADVANCE研究最终结果的正式发表。

        研究对象及试验设计均与ACCORD研究的血糖控制部分十分相似的ADVANCE（Action in Diabetes and Vascular
Disease）研究负责人则表示，ADVANCE研究的中期结果并没有显示出与ACCORD研究类似的趋势。

        ADVANCE研究纳入了11140例高危的2型糖尿病患者，随机分配到标准血糖控制组或强化血糖控制组。由于ADVANCE研究与ACCORD研究的相似性，以及ACCORD研究的提前终止，ADVANCE研究的负责人

提前发表声明，表示目前的初步研究结果并未发现对2型糖尿病患者进行强化血糖控制会增加患者的死亡率。

        
当然，ADVANCE研究和ACCORD研究还存在一定的区别：ACCORD研究中允许使用任何一种降糖治疗来达到目标血糖，而ADVANCE研究则要求所有强化治疗组的患者使用缓释的格列齐特作为初始治疗；ADVANCE

研究中患者的平均年龄较大（66岁 vs ACCORD研究为62岁）；ADVANCE的研究人群平均患病时间较短（8年 vs ACCORD研究为10年）；
ADVANCE的研究人群相比ACCORD的人群来说，基线HbA1C水平略低，而血压略高；最后，也可能是最重要的一点，ACCORD研究强化治疗的目标为<6.0%，而ADVANCE研究则为6.5%。

        
ADVANCE研究与ACCORD研究的不同命运是否为HbA1C目标值的差距或是降糖的幅度所引起的？这使得我们回到了AHA“高血糖与ACS”声明中提出的同一个问题“理想的血糖目标值到底为多少”。ADVANCE研

究最终结果的正式发表，将有助于这个问题的解答。

      　

最早看到比较两个大型研究不同的文章，是国内某大牌学者，观点跟偶上面的相似，文章的出处一时找不到了 。

看了平衡同学的回复，今天再去搜索了一下，这篇文章的观点可能更加客观。

PF同学们的钻研精神