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Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study

March 15, 2010

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Contents


ACCORD Blood Sugar Clinical Trial


ACCORD Blood Pressure Clinical Trial


ACCORD Lipid Clinical Trial


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What was the ACCORD study?

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study (www.accordtrial.orgexternal link) 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.

Type 2 diabetes increases the risk of a number of complications, especially CVD, which is the leading cause of early death in people with diabetes. Many people with diabetes are overweight and have high blood pressure and lipid or cholesterol problems – conditions that further add to their CVD risk. Adults with type 2 diabetes are two to four times more likely to die of heart disease and stroke than adults without diabetes, and about 65 percent of people with diabetes die from heart disease or stroke.

The ACCORD study was primarily composed of three clinical trials, which tested treatment approaches to determine the best ways to decrease the high rate of major CVD events – heart attack, stroke or death from CVD – among people with type 2 diabetes who are at especially high risk of having a CVD event, like a heart attack or stroke. These three treatment approaches were: intensive lowering of blood sugar levels compared to a more standard blood sugar treatment; intensive lowering of blood pressure compared to standard blood pressure treatment; and treatment of multiple blood lipids with two drugs—a fibrate plus a statin – compared to one drug, a statin alone.

The study began enrolling participants in 2001 and took place in 77 clinical sites across the United States and Canada. A total of 10,251 adults with established type 2 diabetes participated in ACCORD. At enrollment, study participants were between the ages 40 and 79 (average age 62), had diabetes for an average of 10 years, and were at especially high risk for CVD events because they already had pre-existing CVD, evidence of subclinical CVD, or at least two CVD risk factors in addition to type 2 diabetes. The other CVD risk factors could be high low-density lipoprotein (LDL) cholesterol, high blood pressure, smoking, or obesity.

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What questions did the ACCORD study seek to answer?

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.

The primary outcome measure for all three questions was the first occurrence after randomization of a major CVD event, specifically nonfatal heart attack, nonfatal stroke, or CVD death. Secondary outcomes include total mortality (death), microvascular outcomes (e.g., eye, kidney, and nerve complications), health-related quality of life, and cost-effectiveness.

Previous clinical trials in patients with type 2 diabetes have shown that:

  • Blood sugar lowering reduces eye, kidney, and nerve complications of diabetes;
  • Blood pressure lowering reduces CVD, eye, and kidney complications of diabetes; and
  • LDL cholesterol (the “bad” cholesterol) lowering with statins reduces CVD events, like heart attacks and strokes.

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.

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How was the ACCORD study designed?

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.

In addition to being randomized to one of the blood sugar strategy groups, participants were enrolled in one of two other randomized clinical trials. One trial compared intensive lowering of blood pressure – to near-normal levels – to standard blood pressure lowering. The other trial examined the effects of treating multiple blood lipids by using two drugs – a fibrate plus a statin to raise HDL ("good") cholesterol, lower triglyceride levels, and lower LDL ("bad") cholesterol – compared to only a statin to lower LDL cholesterol. Participants did not know whether they were on a fibrate or on a matching placebo (pill with no active drug). The blood pressure and lipid trials also assigned participants randomly to each trial’s treatment groups.

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What steps did the ACCORD study take to assure the safety of participants?

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.

From the time ACCORD was launched, a Data and Safety Monitoring Board (DSMB) monitored trial data regularly (about every 6 months). Data on many safety parameters were collected and reviewed, including serious adverse events, measures of liver and kidney function, fluid retention, heart failure occurrence, and overall mortality.

Participants visited study sites at least every 2 months for the intensive group participants, and every 4 months for the standard group participants. They learned about managing diabetes, self-monitoring their blood sugar levels, and preventing and treating hypoglycemia (low blood sugar) episodes. They were provided diabetes care and monitored for hypoglycemia and heart failure. They also learned about treating their blood pressure or their blood lipids, depending on which other trial they were in. At these visits their health status was reviewed, any side effects of medications were discussed, adjustments in dosages were made, and medical tests were taken. They were provided results of their tests and notified of any abnormal findings, so they could take those results to their private physicians.

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What is a Data and Safety Monitoring Board (DSMB)?

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.

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What is the status of the ACCORD study?

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.

The New England Journal of Medicine published the results of the blood sugar trial online on June 6, 2008, and in the print edition on June 12, 2008. The results were presented on June 10, 2008, at the American Diabetes Association’s 68th Annual Scientific Sessions.

The New England Journal of Medicine published the results of the lipid and the blood pressure trials online on March 14, 2010. Results are expected to be published in the print edition in April, 2010. The results were presented at the American College of Cardiology meeting on March 14, 2010.

After the trial interventions ended in June 2009, consenting participants have continued to be followed regularly to determine whether any differences seen during the ACCORD trials in outcomes – deaths, CVD events, and microvascular diseases – persist or change over time and whether other differences emerge.

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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.

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What other analyses are being done based on ACCORD data? When will these results be available?

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.

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How was the ACCORD study funded and what was the cost?

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 following companies donated study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare Inc., GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Inc., Merck & Company, Inc., Novartis Pharmaceuticals, Inc., Novo Nordisk Pharmaceuticals, Inc., Omron Healthcare, Inc., Sanofi-Aventis U.S., and Takeda Pharmaceuticals, Inc.

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To whom do the ACCORD study results apply?

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.

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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)

Patients with type 2 diabetes should continue to pay special attention to controlling their weight and having a healthy lifestyle (healthful diet and regular exercise), which can improve blood sugar, blood pressure, and blood lipid levels. They also should not smoke, which increases risk of disease.

Other clinical trials in type 2 diabetes, such as the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) international trial and the VADT (Veterans Administration Diabetes Trial), have recently reported their findings. The findings from ACCORD and these other studies will be analyzed together to help determine appropriate evidence-based treatment approaches for people with diabetes.

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ACCORD Blood Sugar Clinical Trial

Why was ACCORD studying intensive blood sugar lowering in patients with type 2 diabetes?

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.

Some clinical trials, have tested the effects of reducing blood sugar through medical treatments. The United Kingdom Prospective Diabetes Study (UKPDS), the NIH-supported Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, and other clinical trials have demonstrated benefits of lowering blood sugar in persons with diabetes. Such studies have shown, for example, that

  • For every percentage point drop in A1C blood test results (from 8.0 percent to 7.0 percent, for example), the risk of diabetic eye, nerve, and kidney disease is reduced by 40 percent. Lowering blood sugar reduces these microvascular complications in both type 1 and type 2 diabetes.
  • Intensive blood sugar control in people with type 1 diabetes (average A1C of 7.4%) reduces the risk of any CVD event by 42 percent and the risk of heart attack, stroke, or death from CVD by 57 percent (source: DCCT/EDIC, reported in December 22, 2005, issue of the New England Journal of Medicine.) Note: Although type 2 diabetes is similar to type 1 diabetes (previously known as “juvenile” diabetes) in that both involve high blood sugar levels due to inadequate insulin, the two forms of diabetes are different in many ways, and results from studies in one type may not be relevant to the other type.
  • In adults with more recent onset of type 2 diabetes than the ACCORD participants, the UKPDS showed a trend toward reduced CVD events, particularly heart attacks. However, the results are not considered conclusive.

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.

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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.

Medications used included (in order of frequency of use): metformin; thiazolidinediones, or TZD’s (rosiglitazone, pioglitazone); injectable insulins; sulfonylureas (gliclazide, glimepiride, glipizide, glyburide); acarbose and exenatide. Combinations of medications could be used to achieve the A1C goals.

The type, number and dosages of these drugs varied, depending on participants’ individual needs and their A1C goals. For example, metformin was used in about 95% of intensive-group participants, and in about 87% of standard group participants. Insulin was used in about 77% of intensive-group participants, and in about 55% of standard-group participants.

Participants in the intensive group were more likely to be on combinations of drugs than participants in the standard group. For example, 52% of participants in the intensive strategy group were on three oral medications as well as insulin, compared to 16% of those in the standard group.

For more information on diabetes medications, see http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm.

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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.

There was a trend toward lower (10% lower) rate of primary outcome events, primarily nonfatal heart attacks, in the intensive compared to the standard treatment group. However, the DSMB recommended discontinuing intensive blood sugar treatment because the harm of the intensive strategy outweighed the potential benefit. NHLBI accepted the DSMB’s recommendation and decided to transition all participants to the standard blood sugar strategy. This transition enabled ACCORD to fulfill its commitment to provide diabetes therapy to the participants until 2009, and, at the same time, to enable the other two questions (blood pressure and lipids) to be answered.

On the whole, the death rates in both blood sugar strategy groups were lower than those seen in similar type 2 diabetes patients with similar characteristics. That is, although the death rate was higher in the intensive treatment group than the standard group, it was still lower than death rates reported in other studies of type 2 diabetes. This difference is likely because ACCORD participants received excellent care for their diabetes, and because participants in clinical trials generally have excellent adherence to their treatment regimens.

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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.

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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.

Because of the recent concerns with rosiglitazone (Avandia), which is one of several medications used in ACCORD, researchers specifically reviewed data to determine whether there was any link between this particular medication and the increased deaths. To date, no link has been found. (For more on this issue, see http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=287.)

ACCORD researchers will continue to monitor participants and conduct additional analyses to try to explain the findings. However, the main conclusion at this time is that the treatment strategy is responsible for the findings, not any specific component of the strategy.

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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.

In addition, death rates were consistently higher in the intensive strategy group regardless of participant characteristics at study enrollment, such as whether the participants had existing cardiovascular disease (versus multiple CVD risk factors), were male or female, were older or younger than 65 years, had an A1C level lower or higher than 8 percent, or were of white or non-white race/ethnicity.

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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.

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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.

ACCORD investigators are analyzing the effects of this therapeutic strategy on other serious health consequences of diabetes such as eye and kidney diseases.

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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.

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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.

Current guidelines for diabetes treatment recommend maintaining an A1C level of less than 7 percent for most people with type 2 diabetes, based on the proven benefits of blood sugar control in preventing eye, kidney, and nerve diseases. However, treatment should be tailored to the individual patient.

As always, patients with diabetes should not make any treatment changes without first consulting with their physician.

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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.

The risk of heart disease is about 10 times higher in people with type 1 diabetes than in those without diabetes. The NIH-funded Diabetes Control and Complications Trial (DCCT) in type 1 diabetes patients showed that intensive blood sugar control aimed at a near-normal A1C level reduced complications of the eyes, nerves, and kidneys. In 2005, the long-term follow-up of DCCT participants showed that intensive blood sugar control also lowers by about half the risk of heart disease and stroke in people with type 1 diabetes. These results strongly suggest that patients with type 1 diabetes should begin intensive blood sugar control as early as possible. This recommendation has not changed. For young people without complications, the guidelines recommend an A1C goal as close to normal as possible without significant hypoglycemia.

It should be noted that participants in the DCCT received intensive treatment early in the course of disease and before the onset of CVD. Researchers have not studied the risks and benefits of intensive therapy in type 1 diabetes patients with established CVD.

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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.

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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.

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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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For More Information

Where can I find more information about the ACCORD trial?

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Where can I find more information about diabetes and cardiovascular disease?

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Last Updated May 2011

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