Accord trial: diabetes tipo 2
- leia a proposta do estudo
- notícia de suspensão por excesso de mortes no grupo intervenção (em letra roxa)
- The day after: repercussão do estudo pelo HeartWire
(atualizado em 08/02/08)
- reportagem do The New York Times (em letra roxa)
- posição da American Diabetes Society.
- estudo Advance ( despacho da Reuters em 13/02/08)
"há hoje uma crescente pressão da indústria farmacêutica para vender cada vez mais drogas que reduzam cada vez mais o índice glicêmico (sic)" ..."Muitas vezes os valores de normalidade na prática médica sem ter estudo mostrando eficácia e segurança..."
The overall goal of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is to address this challenge by testing three complementary medical treatment strategies for type 2 diabetes to enhance the options for reducing the still very high rate of major CVD morbidity and mortality in this disease.
The design is a randomized, multicenter, double 2 X 2 factorial design in 10,251 patients with type 2 diabetes mellitus. The trial is designed to test the effects on major CVD events of intensive glycemia control, of treatment to increase HDL-cholesterol and lower triglycerides (in the context of good LDL-C and glycemia control), and of intensive blood pressure control (in the context of good glycemia control). All 10,251 participants will be in the overarching glycemia trial. In addition, one 2 X 2 trial will also address the lipid question in 5,518 of the participants and the other 2 X 2 trial will address the blood pressure question in 4,733 of the participants.
The three specific primary ACCORD hypotheses are as follow. In middle-aged or older people with type 2 diabetes who are at high risk for having a cardiovascular disease (CVD) event because of existing clinical or subclinical CVD or CVD risk factors:
- does a therapeutic strategy that targets a HbA1c of < 6.0% reduce the rate of CVD events more than a strategy that targets a HbA1c of 7.0% to 7.9% (with the expectation of achieving a median level of 7.5%)?
- in the context of good glycemic control, does a therapeutic strategy that uses a fibrate to raise HDL-C/lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C?
- In the context of good glycemic control, does a therapeutic strategy that targets a systolic blood pressure (SBP) of < 120 mm Hg reduce the rate of CVD events compared to a strategy that targets a SBP of < 140 mm Hg?
The primary outcome measure for the trial is the first occurrence of a major cardiovascular disease event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
The ACCORD study is designed to have:
- 89% power to detect a 15% treatment effect of intensive glycemic control compared with standard glycemic control,
- 87% power to detect a 20% treatment effect of lipid control through LDL-C treatment and fibrates compared with lipid control using LDL-C treatment alone,
- 94% power to detect a 20% treatment effect of intensive blood pressure control compared with standard blood pressure control.
Secondary hypotheses include treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life, and cost-effectiveness.
The 10,251 participants will be treated and followed for about 4 to 8 years (approximate mean of 5.6 years) at 77 Clinical Sites administratively located within 7 Clinical Center Networks in the United States and Canada. Recruitment occurred in two non-contiguous periods: an initial period that began in January 2001 for the Vanguard Phase of the trial (during which 1174 participants were randomized) and then a subsequent period beginning in January 2003 and ending in October 2005. Follow-up is scheduled to end in June 2009, with the primary results announced in early 2010.
The following table presents the double 2x2 factorial study design and final number of participants randomized by treatment group:
|Blood Pressure Trial||Lipid Trial*|
|Glycemia||SBP < 120||SBP < 140||Group||Group|
|Trial||mm Hg||mm Hg||A||B|
|A1c < 6.0%||1178||1193||1383||1374||5128|
|7.0% <= A1c <= 7.9%||1184||1178||1370||1391||5123|
*Treatment Group Assignment Blinded Until End of Trial
Intensive-glycemic-control arm of ACCORD stopped
Bethesda, MD - The blood-glucose-lowering part of the ACCORD trial in patients with type 2 diabetes at especially high risk of heart disease has been stopped prematurely because of a higher rate of mortality in the patients in the intensive arm vs that in the standard arm .
Patients in the standard-treatment group will continue treatment without changes, but patients in the intensive-treatment group will now be transitioned to the standard treatment.
The trial was a study of strategy rather than specific drug therapy, and many diabetes agents were used to reach glycemic targets. The higher death rate in the intensive group was not due to episodes of hypoglycemia or to any single drug, including rosiglitazone, or to a combination of drugs, ACCORD investigators said.
ACCORD is an National Heart, Lung, and Blood Institute (NHLBI) study of approximately 10 000 patients with type 2 diabetes and either heart disease or two risk factors for heart disease. The trial has a double 2X2 factorial design. All patients were participating in the glycemic-control part of the trial, which was testing whether an intensive strategy that targets a HbA1c level of <6.0% reduces the rate of cardiovascular events more than a standard strategy that targets an HbA1c of 7.0% to 7.9%.
Then, depending on their blood-pressure and cholesterol levels, patients are assigned to two other parts of the trial. These are testing the combination of a fibrate (to raise HDL and lower triglycerides) and a statin (to lower LDL) vs a statin alone, and lowering systolic blood pressure to a target of below 120 mm Hg vs a target of 140 mm Hg. These blood-pressure and lipid arms of the study will continue until the study ends as planned, in June 2009.
In the glycemic-control part of the study, the median A1c level achieved in the intensive-treatment group was 6.4%, vs 7.5% in the standard group. The trial was stopped because of an excess of three deaths per 1000 participants per year in the intensive group vs the standard group, over an average of four years of treatment.
ACCORD: Deaths in intensive vs standard glycemic control groups
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In a conference call on February 6, Dr Elizabeth Nabel, director of the NHLBI, pointed out that the death rate in both arms was lower than that previously observed in individuals with type 2 diabetes at especially high risk for heart disease, who generally have a risk of death of approximately 50/1000 per year. She also reported that there was a trend toward benefit in the intensive arm in terms of nonfatal cardiovascular events, but that this was outweighed by the increased mortality.
"This is an important finding that shows that if you have type 2 diabetes and are at especially high risk for heart disease, very intensive glucose-lowering treatments aimed at normalizing blood glucose to an A1c of less than 6% may be detrimental," Nabel stated.
She stressed that these results were applicable only to those individuals who are similar to the ACCORD participants—who had had type 2 diabetes on average for 10 years at the time of enrollment, had higher HbA1c levels than most type 2 diabetes patients in the US today (average of 8.2% at baseline), and had known heart disease or at least two risk factors in addition to diabetes, including high blood pressure, high cholesterol levels, obesity, and smoking.
She added that patients should not change their diabetes treatment without consulting with their healthcare provider and that the NHLBI concurs with the general recommendation of the American Diabetes Association that patients with diabetes should aim for an A1c level of less than 7%. "However, for this special group of individuals with diabetes, as exemplified in the ACCORD population, who were average age of 62, had diabetes for an average of 10 years, and had known heart disease or were at high risk, less stringent A1c goals are likely appropriate, with an aim for around 7%."
Reduction in nonfatal events?
Expanding on the study findings, chair of the ACCORD steering committee, Dr William Friedewald (Columbia University, New York), said the intensive group showed approximately 10% fewer nonfatal cardiovascular events such as MIs compared with the standard-treatment group, but that it appeared that, if an MI did occur, it was more likely to be fatal. In addition, the intensive-treatment group had more unexpected sudden deaths.
Not linked to rosiglitazone
Friedewald noted that because of recent concerns about rosiglitazone, they had specifically analyzed the data to try to determine whether there was any link between this particular medication and the increased deaths in the intensive-treatment group, but so far no link has been found, and the use of rosiglitazone does not seem to explain the increased mortality.
Some benefits seen in other populations
Dr Hertzel Gerstein (McMaster University, Hamilton, ON), who led the group that designed the glycemic-control approaches used in ACCORD, gave some background to the study. He noted that a large body of research has shown that higher glucose levels predict a higher likelihood of fatal and nonfatal cardiovascular events and that studies have shown that lowering blood glucose levels can significantly lower the risk of certain complications of diabetes, such as eye, nerve, and kidney diseases. In addition, a major study in people with type 1 diabetes has suggested that intensive blood-sugar-lowering strategies reduce the risk of cardiovascular disease and death, and a study in patients with more recent onset of type 2 diabetes than ACCORD participants showed a trend toward a reduction in MI.
"This body of research strongly suggests that lowering glucose levels to levels that are typically observed in people without diabetes could reduce the risk of cardiovascular disease in people with established type 2 diabetes. But, until ACCORD, no major clinical trial had studied whether lowering a raised blood-sugar level to a level similar to that seen in people without diabetes reduces the risk of cardiovascular disease in people with type 2 diabetes. In addition, no clinical trial has studied the effects of intensive blood-sugar lowering in people with longstanding type 2 diabetes who already have cardiovascular disease or who have multiple risk factors for cardiovascular disease in addition to diabetes," Gerstein stated. This was the rationale for ACCORD.
How ACCORD differs from previous studies
Dr Judy Fradkin (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD) reviewed how ACCORD differs from earlier studies of intensive glycemic control. She noted that a crucial difference was that ACCORD studied the effects of lowering glucose to a near-normal level, a lower level than that targeted in earlier studies. In addition, patients enrolled into ACCORD were older (average 62 years), had had diabetes for a longer time (an average of 10 years), and were at a higher risk for cardiovascular disease than patients enrolled in earlier studies of intensive glucose control.
"It is not yet known whether controlling glucose to near-normal levels will prevent heart disease and extend life in other groups such as younger people with diabetes, those earlier in the course of disease and in whom glucose is easier to control, and those without established cardiovascular disease," she said. The results also cannot be extrapolated to patients with type 1 diabetes, she added.
from Heartwire — a professional news service of WebMD
February 7, 2008 (Bethesda, MD) – Experts within and outside of the ACCORD trial are equally flummoxed by the finding that the group receiving intensive glucose lowering showed a higher mortality rate than those receiving standard care.
The announcement that the glucose-lowering part of the trial was being stopped because of this mortality difference was made yesterday by the National Heart, Lung, and Blood Institute (NHLBI), the organization coordinating the study.
Chair of the ACCORD steering committee, Dr William Friedewald (Columbia University, New York), commented to heartwire: "The simple and honest answer is that we have done extensive analyses and not identified a cause for the increased mortality. We will now do even more extensive analyses with all of our investigators, who are now unblinded to the results, and prepare a paper with the data and our best impressions of the possible causes."
Buse: Three Possibilities
In an interview with heartwire, Dr John Buse (University of North Carolina, Chapel Hill), ACCORD steering committee member and president of medicine and science at the American Diabetes Association, suggested three basic possibilities that would explain the higher mortality rate in the intensively treated group: it could have been a spurious observation, and it might have disappeared with further follow-up; it could have been due to adverse effects of a particular drug or drug combination that has not yet been teased out; or it could be that the observation is true, that lowering blood-sugar levels too much in older diabetics with heart disease is a bad thing.
He added that it would be difficult to detect an adverse effect of one or two drugs, given the large array of therapies used in the study and that the power would be very much reduced when the population is "sliced and diced" so much.
Too Many Interventions?
Buse's personal belief is that the increased mortality may not have been due to the level of A1C but more to do with the intensity of the intervention. "The patients enrolled in this study were quite vulnerable in that they were relatively old (average age 62) and had heart disease or at least two or more other risk factors for heart disease. Maybe we just flogged them too hard to get their sugar levels down. The intensive group had extremely rigorous treatment, with some patients taking four shots of insulin and three pills and checking their blood-sugar levels four times a day. Perhaps this was just too many drugs at too high a dosage, and the effort required just stressed them out too much. I think our conclusion is therefore that we should not be zealots about lowering blood sugar at all costs. We must understand that there are risks and benefits and one size probably does not fit all patients," he said.
But he pointed out that both groups in ACCORD did very well compared with similar patients in real life, who have a mortality rate two to three times that seen in either group in this study. "Taking that into account, the difference in mortality between the two arms seems like a pretty small signal, but the [data safety and monitoring board] DSMB were in a very difficult position. They could have decided to carry on for longer but then would have faced criticism if the mortality difference had increased. I am not uncomfortable with the decision they made, but I do feel we need more data, and I'm glad there are other studies under way that may shed more light on this issue," he added.
And more information should become available fairly soon, as there are at least three more trials under way looking at intensive vs standard lowering of blood-sugar levels in diabetics (ORIGIN, ADVANCE, and the VA Diabetes trial), two of which are thought to be reporting later this year.
No Need for Panic
"My key message is that the ACCORD result is not a reason to panic. The kind of patients enrolled in this study are a minority in terms of diabetes patients, and the treatment given was exceptionally intensive, so the average diabetic patient need not worry about these results," Buse reiterated.
He noted that previous trials have shown mixed results on the benefits of lowering blood-sugar levels in diabetics. The DCCT trial in type 1 diabetics showed no major differences in the actual six-year study follow-up, but after 13 years of follow-up, there was a reduction in cardiovascular events in the original group whose blood sugar was lowered most. But in that study, A1C levels went from around 9 to around 7 and so were higher than in ACCORD, and this was in a different patient population from ACCORD, he explained. And the UKPDS trial showed benefits of intensive blood-sugar lowering in terms of a reduction in retinopathy and kidney damage in patients with type 2 diabetes, and there was some suggestion of a benefit on MI but no effect on mortality. A smaller VA cooperative study had suggested an increase in mortality with more intensive glucose lowering, but this was underpowered and generally dismissed as "bad luck," Buse added.
Others Surprised and Disappointed
Observers from outside the trial also had little to offer in the way of possible explanations, all saying they needed to see more data from the study in the form of a published paper. But all were surprised by the result.
Dr Steve Nissen (Cleveland Clinic) commented to heartwire: "This result really does defy conventional wisdom." Noting that benefit has been seen in lowering blood sugar in terms of diabetic complications but the effect on major cardiovascular events and mortality is not known, he added: "I suppose it wouldn't have been a major surprise if there was no effect, but to show harm is really a big surprise. This effect could have been due to some of the drugs being used to lower glucose levels, which may have other effects that cause harm. We know that rosiglitazone increases MI risk, so others may do this too." He said not enough data on rosiglitazone use in ACCORD had been released to establish whether it could have played a role in the adverse outcome. "We don't even know what percentage of people in each group were on rosiglitazone. So we can't answer that question yet. All in all, this trial has raised a lot more questions than it has answered."
Was it the Low Sugar Levels or the Multiple Treatments?
Dr Rury Holman (Churchill Hospital, Oxford, UK) who led the UKPDS trial, told heartwire: "We need to see what medications the patients who died were taking and the causes of death to come up with explanations, but I suspect that because so many different treatments were used in both groups, it will be hard to come up with any clear-cut answers."
He said that the main question was whether the low sugar levels or the multiple treatments were the cause of the excess deaths and that in this regard it would be important to establish whether the patients who died had the lowest blood-sugar levels. "The intensive arm was aiming for an A1c level of 6, and they got to an average of 6.4, so some patients would have gone quite a way below 6. It would be interesting to know if more deaths occurred in these patients who went very low. If so, then it could be the low A1c. But they haven't released that information yet."
Holman also suggested that the observation that patients in the intensive arm of ACCORD were less likely to have an MI, but if they did have an MI it was more likely to be fatal, might provide some clues, adding that "if you have an MI, the chances of surviving depend on your background metabolic status."
Low Mortality Rates in Both Groups
Holman also emphasized the low mortality rates in the study. "These mortality rates are lower than we saw in the UKPDS trial in newly diagnosed and younger diabetic patients, so the standard of care was very good in ACCORD. For me, the message to patients remains that near-normal glucose levels are still better than high levels." He said that the UKPDS trial (in which A1c levels were reduced from 9 to 7) had shown that lowering sugar levels did reduce microvascular complications, and that was important to remember.
Califf: "No Shortcuts"
Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), who is cochairing (with Holman) a large diabetes-prevention trial testing nateglinide, repeated his mantra that surrogate end points are never a replacement for clinical outcomes and that ACCORD is another example of that. "I'm afraid I have to make the same points I've made over and over. An epidemiologic relationship between glucose level and risk of cardiovascular events does not mean lowering glucose levels with an intervention will have the desired effect. This is the same story as [premature ventricular complexes] PVCs and sudden death, low cardiac output and inotropes, HDL cholesterol and torcetrapib, LDL cholesterol and HRT; you name it. All this is reaffirmation that there are no shortcuts. We just don't know what we're doing until an adequate randomized trial is done."
Califf agreed with many others polled that the two main explanations for the excess mortality were probably hypoglycemic spells or other drug toxicities. "Either is possible, but from the discussion so far, I don't think we'll be able to tell," he said.
Dr Darren McGuire (University of Texas Southwestern Medical Center at Dallas) also expressed disappointment at the result. "Once again, the most sound of scientific and biologic plausibility has been refuted by a large clinical-outcomes trial, and for both patients with type 2 diabetes and for those of us who care for them, this is a very disappointing result," he told heartwire. And he made similar points to Califf's on the importance of appraising therapies with regard to overall clinical-outcome effects, regardless of how promising the science on which they are based. "We cardiologists have learned similar lessons to this time and again about the disconnect between intermediate markers of disease risk and clinical outcomes, and this has led to the critical clinical-outcomes trial appraisal of virtually every domain of cardiology. Hopefully, observations such as these, added now to the recent rosiglitazone observations and the failure of the first CETP antagonist, will continue to drive the endocrinology/metabolism clinical, pharmaceutical, and regulatory community toward a mandate for the generation and application of true clinical-outcomes data for existing and certainly for emerging metabolic therapies," he added.
Diabetes Health Goes Beyond Blood Sugar < xml="true" ns="urn:schemas-microsoft-com:office:office" prefix="o" namespace="">
The study, announced Wednesday, showed that an intensive program to lower blood sugar actually increased risk of death. The findings were so surprising that the study was stopped early, and they seemed to undercut the accepted wisdom that people with diabetes should do everything possible to get their blood sugar down to normal.
But the methods used in the study, called Accord (for Action to Control Cardiovascular Risk in Diabetes), bear little resemblance to the techniques most doctors and patients use to manage blood sugar levels. And the patients in the study were typically far sicker than many people with diabetes today.
“The intensity of what we did is done virtually nowhere on the planet,” said Dr. John Buse, vice chairman of the study’s steering committee and the president of medicine and science at the American Diabetes Association. “It’s far beyond what’s common in clinical practice.” Dr. Buse called the study’s regimen to lower blood sugar a “brutal program.”
Still, doctors are likely to reconsider their emphasis on lowering blood sugar at all costs, because it is becoming clear that other factors influence the overall health of patients with diabetes.
The New England Journal of Medicine published a study this week showing that a three-pronged approach of managing sugar, blood pressure and cholesterol — combined with low doses of aspirin — prolonged the lives of people with diabetes. The patients who did best in that study did not reach the nearly normal sugar levels that were the aim of the Accord study. Instead, their levels were just slightly higher than normal.
In the Accord study, the group of patients who were randomly assigned to lower their blood sugar levels to nearly normal had 54 more deaths than the group whose levels were less rigidly controlled. The patients were in the study for an average of four years when investigators stopped the intense regimen and put all of them on the less intense one.
“When we look at mortality in patients with Type 2 diabetes, it’s not only the blood sugar,” said Dr. Joel Zonszein, director of the Clinical Diabetes Center at Montefiore Medical Center in the Bronx. “What the study shows is that just lowering blood sugar is not protecting you from dying sooner. Blood sugar is important, but so is blood pressure and cholesterol.”
Patients with newly diagnosed diabetes still appear to have much to gain by keeping their blood sugar levels as close to normal as possible through healthful eating and exercise. But patients who have had a heart attack and have other risk factors need not feel guilty if they cannot get their blood sugar to normal levels, Dr. Buse said.
“The most important thing is get your blood pressure controlled, cholesterol controlled, and do a reasonable job on your diabetes, but don’t go wild,” he said. “We are backing away from notion that we always have to push, push, push to get blood sugar lower.”
Today, many patients with diabetes take two or three drugs to manage their blood sugar levels. In the Accord study, many patients took multiple drugs and insulin shots, adhered to strict diets and regularly met with counselors and doctors who monitored them. No single drug treatment was prescribed; doctors used whatever combination of various treatments that appeared to work best in each patients.
The researchers still have to sift through the data on those who died to find out whether there was any pattern that might help explain why patients in the intense treatment group fared worse. It may be that they were simply sicker to begin with. It may have been the number of drugs they used or the pace at which their blood sugar dropped.
Dr. Buse said one little-discussed issue was the sheer stress of the treatment program itself. He noted that the program demanded a lot of effort from patients but that it was still exceedingly difficult for any of them to achieve the blood sugar levels that had been set for them. Many patients with diabetes feel stressed when they fail to meet blood sugar goals set by their doctors.
“At some level I just wonder if some of them were just overwhelmed by this psychologically,” Dr. Buse said. “Could it be the stress of ‘I’m trying so hard, but I can’t get it done’?”
FOR IMMEDIATE RELEASE
ACCORD data raises concerns; Group advises patients with diabetes to maintain good control of blood glucose and talk to their doctor.
ALEXANDRIA, VA (February 6, 2008) – In response to today’s announcement by the National Heart, Lung, and Blood Institute, which sponsors the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Trial to stop the intensive blood glucose (sugar) control sub-study in ACCORD due to safety concerns, the American Diabetes Association strongly encourages people with diabetes not to alter their course of treatment without first consulting with their health care team. The American Diabetes Association continues to encourage good control of blood glucose for the management of diabetes and its complications.
The ACCORD trial randomized patients with diabetes and vascular disease or multiple cardiovascular risk factors to an intensive treatment program targeting normal blood glucose values and an A1C less than 6 percent or a standard treatment program with an A1C between 7 percent and 7.9 percent. The intensive participants in ACCORD are now being switched to the standard treatment program because of an increased death rate in the intensive treatment program (14 deaths per 1000 patients per year versus 11 per 1000 patients per year in the standard treatment program; a difference of 0.3 deaths per 100 patients per year).
The American Diabetes Association continues to advise people with diabetes to strive for an A1C (a measure of long-term blood glucose control) of less than 7 percent. Recent data indicates that more than half of the population with diabetes in the U.S. have an A1C less than 7 percent and this overall level of glucose control appears to be of great benefit rather than harm.
The importance of glucose control in diabetes is firmly established. Evidence from the landmark Diabetes Control and Complications Trial (DCCT), and the U.K. Prospective Diabetes Study (UKPDS) show that improved glucose control to a level of approximately 7 percent reduces the complications of diabetes dramatically.
The Association’s treatment guidelines also state that treatment should be tailored to the individual patient and that for some people with diabetes, intensive glucose control may not be warranted. Of note, the American Diabetes Association (in its Standards of Medical Care) states: “Less stringent A1C goals may be appropriate for patients with a history of severe hypoglycemia, patients with limited life expectancies, children, individuals with comorbid conditions, and those with longstanding diabetes and minimal or stable microvascular complications.”
This recent announcement by ACCORD investigators suggests that very intensive glucose lowering treatment aimed at normalizing blood glucose (A1C<6%) may be detrimental, at least in middle-aged and older adults with vascular disease or multiple risk factors for vascular disease. The exact reason for the increased death rates with intensive treatment that occurred in ACCORD are not yet known. However, an analysis of the ACCORD data indicates that the detrimental effect of intensive therapy was not due to hypoglycemia or any specific combination of drug therapies.
The American Diabetes Association looks forward to more analysis of the data from ACCORD, as well as other ongoing studies that may shed more light on this issue. However, at this time, the American Diabetes Association advises people with diabetes who have existing cardiovascular disease (CVD), or multiple CVD risk factors, to consult with their health care team about their treatment goals and to ensure that their blood pressure and cholesterol are appropriately managed.
(Editing by Bill Trott)
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