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Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study
March 15, 2010
ACCORD Blood Sugar Clinical Trial
ACCORD Blood Pressure Clinical Trial
ACCORD Lipid Clinical Trial
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The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study (www.accordtrial.org) was a large clinical trial of adults with established type 2 diabetes who are at especially high risk of cardiovascular disease (CVD). Type 2 diabetes is a complex metabolic disease characterized by high blood glucose (sugar) levels. People with this form of diabetes have insulin resistance and a progressive loss of the ability to produce insulin. Insulin is needed so that sugar in the blood (which comes from eating food) can enter the cells of the body in order for the body to function. CVD includes heart attacks, strokes, and deaths from conditions of the heart and blood vessels.
The ACCORD study was designed to determine if a strategy of intensive lowering of blood sugar levels, intensive lowering of blood pressure, or treatment of blood lipids with a fibrate drug plus a statin drug, can reduce the risk of major CVD events in patients with type 2 diabetes who are at especially high risk of CVD. Thus, the ACCORD study was designed to answer three complementary questions about treatment of adults with diabetes.
However, no previous clinical trial had tested the effects of lowering blood sugar or blood pressure to near-normal levels in patients with type 2 diabetes, and no previous clinical trial had tested the effects of treating multiple blood lipids compared to treating only LDL-cholesterol in people with diabetes.
After providing written informed consent, the participants were randomly (i.e., by chance) assigned to intensive blood sugar-lowering strategy or to standard blood sugar-lowering strategy. Blood sugar levels are measured by a blood test called A1C, which reflects a person's average level of blood sugar in the previous two to three months. Participants in ACCORD's standard blood sugar group were treated to a target A1C level of 7 to 7.9 percent, which is about that achieved in the U.S. and lower than the participants' levels when they joined the study. Therapy for those in the intensive blood-sugar group sought to achieve an A1C of less than 6 percent, a level of blood sugar that is similar to that of a person without diabetes. Participants were asked to perform home blood glucose monitoring and learned about preventing, recognizing, and treating hypoglycemia (very low blood sugar). Hypoglycemic events were monitored carefully and, if necessary, medications were adjusted to minimize severe hypoglycemic reactions.
Before launching the full-scale ACCORD study, NHLBI funded a Vanguard Phase of ACCORD to determine the safety and feasibility of implementing the study protocol. The ACCORD Vanguard Phase treated and followed 1,174 participants for at least one year, with an average treatment duration of about 1˝ years. There were no safety concerns identified in the Vanguard Phase.
A DSMB is an independent group of experts who regularly examine the study outcomes and safety data. The DSMB was appointed by the National Heart, Lung, and Blood Institute – part of the federal National Institutes of Health and the study sponsor. The ACCORD DSMB included 10 experts in diabetes, CVD, statistics, ethics, epidemiology, and clinical trials. The DSMB was responsible for providing recommendations concerning starting, continuing, and/or stopping the clinical research study under review. The DSMB’s recommendations are based on safeguarding the interests of study participants, assessing the safety and efficacy of study procedures, and monitoring the overall conduct of the study. Since the study began in 2001, the ACCORD DSMB met regularly, generally every six months, to monitor study conduct and to review data from ACCORD.
All three ACCORD clinical trials have ended. The National Heart, Lung, and Blood Institute (NHLBI) stopped the intensive blood sugar lowering strategy on February 6, 2008, due to safety concerns. Participants in the intensive blood sugar treatment strategy group were transitioned to the standard treatment strategy. The blood pressure and lipid treatment trials continued until the planned end of the study in June 2009.
Now that the study is over, what kinds of questions are left to be answered?
Researchers will continue to analyze the ACCORD data to try to understand why these “intensive” interventions did not reduce the rates of cardiovascular outcomes as hypothesized. They will examine characteristics of the participants to determine if some (and which ones) had increased risks of adverse effects and/or benefited. They will explore the contribution of various drugs and combinations of drugs on outcomes. These analyses may generate ideas for future studies.
Many other analyses are currently under way or planned. Some of the most important will address the effect of intensive lowering of blood sugar, intensive lowering of blood pressure, and treatment with a fibrate plus a statin on the rates of microvascular (eye, nerve and kidney) disease, on quality of life and on cognitive (brain) function. Researchers hope to publish some of the most important results in the coming months. Also, a longer observational follow-up of the ACCORD participants is planned to examine any longer term effects of the interventions tested in ACCORD.
The ACCORD study was sponsored by the federal government through the National Heart, Lung, and Blood Institute (NHLBI), which is one of the Institutes at the federal National Institutes of Health. The NHLBI funded the sites through contracts and inter-agency agreements. Other components of the NIH, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute contribute funding. The Centers for Disease Control and Prevention funded substudies within ACCORD on cost-effectiveness and health-related quality of life. The total cost of the study was about $300 million.
The results of ACCORD apply only to patients at particularly high risk of cardiovascular disease and established diabetes. ACCORD participants had diabetes on average for 10 years, over a third had existing cardiovascular disease, and the rest had at least 2 additional risk factors (like high blood pressure, high blood cholesterol, or obesity). Different levels of risk factors control may be recommended depending on each patient’s individual risk profile. These results do not apply to patients with type 2 diabetes who are younger, whose diagnosis is more recent, or who have a lower risk of CVD than participants studied in the ACCORD trials. It is not known what effect more intensive therapy might have on CVD in younger people with type 2 diabetes or in patients with a lower risk of CVD than were studied in ACCORD.
Since cardiovascular disease is still a major threat to people with type 2 diabetes, what can patients do to lower their risks of heart attack, stroke, or death from cardiovascular disease?
Patients should continue to use treatments and strategies that have proven to be effective in reducing the risk of cardiovascular disease. These include treating elevated blood pressure levels and controlling elevated LDL cholesterol levels as currently recommended. (See NHLBI cholesterol guidelines and blood pressure guidelines)
ACCORD Blood Sugar Clinical Trial
A large body of research in which adults were followed for several years had shown that diabetes increases the risk of developing CVD. In addition, the higher the blood sugar, the greater the future risk of CVD, and the lower the blood sugar, the lower the risk of CVD. However, most studies were "observational," rather than more rigorous randomized clinical trials that test interventions or treatments, so they do not prove whether lowering blood sugar levels reduces CVD risk. Although observational studies are important to advancing our understanding of health and disease, well-conducted randomized clinical trials are considered the gold standard for determining safe and effective treatments.
However, no previous major clinical trial had studied whether lowering a raised blood sugar level to a level similar to that of people without diabetes reduces the risk of CVD. In addition, no previous clinical trial had studied the effects of intensive blood sugar lowering in people with longstanding type 2 diabetes who already have CVD or have multiple risk factors for CVD in addition to diabetes.
Which drugs were used to lower blood sugar in ACCORD?
All major classes of drugs approved by the FDA to treat diabetes were used to treat blood sugar in both groups of the ACCORD blood sugar trial – those in the intensive strategy group that targeted a near-normal blood sugar level as well as those in the standard blood sugar strategy group.
Why was the blood sugar treatment in the ACCORD trial changed?
In its regular review of the available study data, the ACCORD Data and Safety Monitoring Board (DSMB) noticed an unexpected increase in total deaths from any cause among participants who had been randomly (by chance) assigned to the intensive blood sugar strategy group compared to those assigned to the standard blood sugar strategy group. The data analyses showed that over an average of 3.5 years of treatment (ranging from about 2 years to about 7 years), 257 participants in the intensive group died, compared to 203 in the standard group – a difference of 54 deaths, or an excess of about 3 deaths per 1,000 participants treated for a year. This translates to a statistically significant 22% higher rate of death in the intensive than the standard group.
Did the ACCORD trial meet its treatment goals for blood sugar level?
In general, intensive-group participants achieved lower blood sugar levels than standard-group participants. An A1C level less than 6.4% was achieved in half of the intensive-group participants and a level less than 7.5% in half of the standard group participants. These levels were maintained over the average 3.5 year study period. The level achieved in the intensive group required substantial effort on the part of ACCORD clinicians and patients, including multiple medications, frequent clinic visits (at least every 2 months), and frequent self-monitoring of blood sugar levels, sometimes multiple times a day.
Why did more people in the intensive blood sugar treatment group die?
ACCORD researchers have extensively analyzed the available data and have not been able to identify to date any specific cause for the higher death rate among the intensive blood sugar treatment group. Based on analyses done to date, there is no evidence that any medication or combination of medications is responsible for the higher risk. In addition, although the number of severe hypoglycemic events was greater in the intensive blood sugar strategy group, this does not appear to account for the difference.
What were the causes of death in those assigned to intensive blood sugar treatment compared to those in the standard blood sugar treatment group?
About half of the deaths were from cardiovascular diseases, such as heart attack, sudden cardiac death, stroke, heart failure, or another cardiovascular disease condition. Of the total 460 total deaths, there were 229 deaths from cardiovascular causes – 135 in the intensive treatment group and 94 in the standard treatment group. This difference resulted in a significant 35 percent higher cardiovascular death rate in the intensive strategy group. The remainder of the deaths was from other causes such as cancer. Differences between the intensive and standard treatment groups were present in overall death from any cause as well as deaths from combined cardiovascular causes.
What other adverse effects were seen from the intensive blood sugar treatment?
There was a greater rate of seriously low blood sugar (called hypoglycemia) events in the intensive group than in the standard group: about 10% of intensive participants and about 3.5% of standard participants had a hypoglycemia event that needed care from a medical professional. There was more fluid retention in the intensive than the standard group: 71% compared with 67%. About 28% of participants in the intensive group gained more than 10 kg (22 pounds) of body weight, compared with about 14% of participants in the standard group.
Were there any benefits from the intensive blood sugar treatment?
As noted above, analyses suggest that participants who were assigned to a strategy of blood sugar lowering aiming for an A1C less than 6.0 percent had a lower risk of a nonfatal heart attack.
However, it appears that, if a heart attack did occur, it may have been more likely to have been fatal.
Were there any differences in outcomes in different types of people?
As noted above, participants’ characteristics at enrollment did not impact their risk of death from the intensive blood sugar strategy. However, for the primary outcome of any CVD event, including nonfatal events, there were some differences. Participants who did not already have a CVD diagnosis (that is, no history of heart attack or stroke) at enrollment were less likely to have a cardiovascular event (fatal and nonfatal heart attacks or strokes) if they were in the intensive group than if they were in the standard group. A similar result was seen in participants who had lower A1C levels at baseline (8.0% or lower). These findings, however, are only suggestive and are not definitive.
What do the blood sugar results mean for people with type 2 diabetes?
Patients with type 2 diabetes should not be alarmed by these blood-sugar findings of the ACCORD trial. Most individuals with type 2 diabetes who are similar to the participants in ACCORD are not being treated to the very low blood sugar goal of the study’s intensive treatment group. This goal of less than 6 percent A1C is very hard to reach for most patients who have had diabetes for several years, often requiring multiple medications. Even the achieved level of A1C of about 6.4% is often difficult to achieve in such patients. The ACCORD participants were at particularly high risk of a CVD event or already had CVD at enrollment, and the results may not apply to lower-risk patients. who are not like the ACCORD participants.
What implications does the blood sugar trial have for people with type 1 diabetes?
These results do not apply to patients with type 1 diabetes. ACCORD participants had type 2 diabetes, which is quite different from Type 1 diabetes.
ACCORD Blood Pressure Clinical Trial
Why was ACCORD looking at lowering blood pressure far below what is now recommended for such patients?
Many observational studies have shown that there is a continuous relationship between blood pressure level and risk of cardiovascular disease, such as heart attacks or stroke. This relationship goes all the way down to levels of blood pressure considered normal – below 120 mm Hg of systolic blood pressure (the top number in a blood pressure reading). In other words, there were data suggesting that lower systolic blood pressure is better for patients with type 2 diabetes. However, there was no evidence from randomized clinical trials of treatment interventions to definitely show that lowering systolic blood pressure to such “normal” levels would reduce cardiovascular events in patients with diabetes and elevated blood pressure. It was necessary to conduct a rigorous randomized clinical trial to compare a lower goal to a more standard goal that was consistent with prior evidence.
Which drugs were used to lower blood pressure?
ACCORD did not test any new drugs. ACCORD used all classes of FDA-approved blood pressure lowering medications. These included common classes of blood pressure lowering medications such as diuretics, angiotensin converting enzyme inhibitors, beta-blockers, and calcium channel blockers. Most patients in ACCORD needed several medications to control their blood pressure to the levels being targeted.
Did the ACCORD trial meet its treatment goals for blood pressure?
Yes. Patients were randomly assigned (a procedure similar to the flip of a coin) to the intensive or the standard blood pressure treatment groups. In the intensive group, an average systolic blood pressure of less than 120 mm Hg – the goal for treatment – was achieved at the end of the first year of treatment and stayed under 120 for the rest of the trial. In the standard group, systolic blood pressure averaged around 134 mm Hg – consistent with the goal of less than 140 mm Hg. So, the standard group was treated similar to current standards, and the intensive group was treated to about a 14 mmHg lower level.
What were some of the adverse effects of the intensive blood pressure lowering?
Serious adverse effects were relatively uncommon. However, there were more cases of hypotension (blood pressure too low) and bradycardia (low heart rate) in the intensive group. Also, there were more cases of low and high blood potassium levels, which can cause severe heart rhythm problems, as well as more cases of changes in kidney function. But there was no increase observed in the number of cases of dialysis or kidney failure in the intensive group compared to the standard group during the study.
What were the results of the ACCORD blood pressure trial?
There was no significant difference in the primary study outcome between the intensive and standard blood pressure treatment groups. The primary outcome was the time to first occurrence after randomization of a heart attack, a stroke, or a cardiovascular death. Thus, the primary hypothesis of the ACCORD BP trial was not supported. There was, however, a significant reduction in the rate of strokes, although the numbers were relatively small. This reduction in stroke was consistent with previous blood pressure lowering trials. Overall, however, the findings from the ACCORD blood pressure trial suggest that, on average, the standard treatment for blood pressure lowering treatment was just as good as the intensive lowering treatment for cardiovascular outcomes.
ACCORD Lipid Clinical Trial
Why was ACCORD looking at adding a fibrate drug to statin medication for type 2 diabetes patients?
People with type 2 diabetes very often have a combination of high blood levels of LDL cholesterol, low HDL cholesterol, and high triglycerides. LDL cholesterol is a major risk factor for CVD in general and in patients with type 2 diabetes in particular. Statin medications are very effective at reducing the levels of LDL cholesterol. Many clinical trials have shown that treatment with statins lowers the rates of heart attacks and cardiovascular death. On the other hand, fibrate medications are used to increase the blood levels of the “good” HDL cholesterol as well as reduce triglycerides (another form of fat made in the blood). Unlike the statins, which are used to lower LDL cholesterol, there was no definitive evidence from previous clinical trials that using a fibrate to increase HDL cholesterol and decrease triglyceride levels in combination with a statin to control LDL cholesterol would reduce the risk of heart attacks and strokes in patients with type 2 diabetes. A clinical trial was needed to answer this question.
Which drugs were used to treat lipids?
The statin drug simvastatin (Zocor™) was given to all participants as necessary to control their level of LDL cholesterol according to current treatment guidelines. Participants were randomly assigned to receive either the fibrate drug fenofibrate (Tricor™) or a matching placebo (pill with no active drug). Neither the participant nor the researcher knew whether the patient was receiving active drug or placebo during the course of the trial (except in case of a medical emergency requiring this knowledge for treatment).
Did the ACCORD lipid trial meet its treatment goals for raising HDL, or “good cholesterol,” and for lowering triglycerides?
There were no specific target levels for HDL or triglycerides. However, there were significant differences between the levels of HDL cholesterol and triglycerides between the group that received the fenofibrate as compared to the group that received the placebo. So in this way the trial achieved its goal of a difference in multiple blood lipids between the two groups.
What were the results of the ACCORD lipid trial?
Overall, the fibrate and the placebo groups did not differ in the rates of the combined outcome of heart attacks, strokes, or cardiovascular death. The results, however, suggest that men may benefit from this treatment, but there was a trend toward more cardiovascular problems in women receiving the combination therapy compared to those who received statins only. Also, the group of patients who at the start of the trial had the lowest level of HDL cholesterol combined with the highest level of triglycerides (which represented only 17% of the ACCORD participants) may have benefitted from this combined drug treatment. However, when there is no difference overall, any positive result on a subgroup of patients must be interpreted with a lot of caution as it could occur by chance alone. These results must be looked at in more detail and considered in the context of results from other studies. They shouldn’t be, by themselves, the basis of individual treatment decisions. Patients currently on a fibrate, or considering getting on this treatment, should talk to their health care provider.
What were some of the adverse effects of using a fibrate plus a statin?
This treatment was very safe with very few serious adverse effects. An already known adverse effect on biologic signs of kidney function was noted at the beginning of fibrate treatment, but there was no increase in the rate of dialysis or serious kidney disease, and few patients had to discontinue their treatment because of side effects.
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Where can I find more information about the ACCORD trial?
Where can I find more information about diabetes and cardiovascular disease?
Last Updated May 2011