ACCORD Trial Update

As the seventh leading cause of death in the United States, Diabetes affects an estimated
24 million Americans. Adults with type 2 diabetes are more than twice as likely to die from
heart disease compared to adults without diabetes. In fact, 65 percent of deaths in people with
diabetes are due to cardiovascular disease.

It is from these staggering statistics, that the ACCORD (Action to Control Cardiovascular
Risk in Diabetes) clinical trial was launched. The overarching goal of this study was to address
cardiovascular disease event rates in people with diabetes, which was accomplished by testing
the effectiveness of medical therapies. The specific cardiovascular disease (CVD) events
included heart attack, stroke or death related to cardiovascular disease. CVD is a class of
diseases that affect the heart and blood vessels (veins and arteries). By examining these
therapies, the trial hoped to find the best treatments for reducing CVD death rates among people
with type 2 diabetes.

Study Set-Up

The ACCORD study included 10,251 participants, making it one of the largest studies
ever conducted in adults with type 2 diabetes. These individuals were at especially high risk for
CVD events (heart attack, stroke, or death from CVD). The trial tested three possible methods
for lowering the risk of these events in people with type 2 diabetes:

1. Controlling blood sugar intensively compared to in standard fashion

2. Controlling blood pressure intensively compared to in standard fashion
3. Treatment of multiple blood lipids (HDL & LDL cholesterol and triglycerides) compared
to treatment of LDL cholesterol alone

The participants in the ACCORD trial had type 2 diabetes for an average of ten years and
were between the ages of 40 and 79. The participants were considered to be at a high risk of
CVD events because they had at least one of the following:

● Pre-existing cardiovascular disease

● Evidence of subclinical cardiovascular disease (the person has yet to experience
symptoms)
● In addition to diabetes, at least two CVD risk factors such as smoking

All of the trial participants were enrolled in the ACCORD blood sugar treatment clinical
trial. Iin addition about half were enrolled in the blood pressure trial and the other half in the
lipid trial. During the study, the participants maintained good control of blood sugar levels and
were treated and followed for an average of five years.

Blood Sugar Trial Results

The National Institutes of Health’s National Heart, Lung and Blood Institute prematurely
stopped the arm of the ACCORD trial aimed at intensive) glucose-lowering. Concern over the
number of deaths in participating patients caused the early end to this part of the ACCORD trial.
The goal of this section was to reduce blood sugar levels to near normal in adults with type 2
diabetes who were at especially high risk for heart attack and stroke. However, deaths in people
who underwent the rigorous treatment were 22 percent higher than those who underwent the
standard treatment. Researchers have yet to fully determine what caused the higher amount of
deaths; however, they think that a combination of factors related to the overall intensive strategy
could have been the culprit. Although intensive treatment patients had lower average blood
glucose (HbA1c) levels and more hypoglycemic events, neither of these appeared to explain the
increased death rate.

Released in 2008 after 3.5 years of follow-up, the results of this section showed that the
more ambitious glucose treatment did not significantly reduce the risk of major CVD events in
the diabetic patients. However, compared with the standard treatment, the more rigorous
approach increases the risk of death. After the intensive group patients were switched to standard
treatment, the trial completed its 5 year planned follow-up and the results did not change.

Blood Pressure Trial Results

The blood pressure portion of the ACCORD trial was the largest clinical trial ever to test
the effect of systolic blood pressure (top number in a blood pressure reading) below 120 mmHg
(normal) compared to below 140 mmHg on CVD events. The current blood pressure guidelines
advise that adults with type 2 diabetes should aim for this number to be less than 130 mmHg.
Previous non-randomized clinical trials have suggested that systolic blood pressures below 120
mmHg might reduce CVD rates in type 2 diabetic adults. Thus, a randomized clinical trial was
needed to find out what treatment effects would emerge if this number was brought to 120
mmHg in type 2 diabetic patients.

For this part of the ACCORD trial, 4,733 participants with high blood pressure were
randomly assigned to a target systolic blood pressure of either less than 120 mmHg (intensive
group) or less than 140 mmHg (standard group). In order to reach these goals, a variety of FDA
approved blood pressure lowering medications was used in both groups. The participants
received follow up for an average period of 5 years.

Researchers found that there were no significant differences between the intensive group
(target: less than 120 mmHg) and the standard group (less than 140 mmHg) in terms of rates for
heart attack, stroke and cardiovascular disease death. However, lowering the systolic blood
pressure below 120 mmHg decreased the risk of stroke by 40 percent, a potential benefit for
patients at high risk of stroke.. The results were not fully promising, though. This was because
participants who targeted a blood pressure of 120 mmHg or below were somewhat more likely to
have complications such as abnormally low blood pressure, high levels of potassium in their
blood or a modest reduction in kidney function.

Given this information, it is important that patients talk to their doctor about what their
own systolic blood pressure should be. The risks and benefits of the various treatments to lower
blood pressure should be considered at that time.

Lipid Trial Results

 The third and final section of the ACCORD trial studied whether adding a fibrate to a
statin is more effective at controlling triglyceride, HDL (good) and LDL (bad) cholesterol levels
(lowering the risk of CVD events) compared to treatment with a statin alone. Fibrates are a class
of drugs that work to lower triglyceride levels but also have the ability to raise HDL levels. A
different class of drugs called statins work to suppress the body’s ability to make LDL
cholesterol. Often statins and fibrates are used together to maintain proper levels of these blood
lipids, since high triglyceride and low HDL levels are common in type 2 diabetic patients.

This section of ACCORD involved 5,518 participants and was the first large clinical trial
to compare the cardiovascular effects of a statin versus the effects of a statin and fibrate
combination. Overall, researchers found that the combination of statins with fibrates was safe.
However, researchers discovered that the combination therapy did not result in lower risks for a
heart attack or death from cardiovascular disease compared to treatment with statins alone.

The study did show that type 2 diabetic patients with the lowest levels of HDL
cholesterol and the highest levels of triglyceride were least likely to experience cardiovascular
disease events if they received the combination therapy compared to the statin alone. Adding the
fibrate to the statin also had some benefit on diabetic retinopathy (eye complications). It was
also discovered that women undergoing the statin and fibrate combination appeared to have more
cardiovascular problems than those on just statins.

The people who participated in the ACCORD study were at especially high risk for
cardiovascular disease events; therefore you should talk to your doctor to determine your own
personal risk and how best to manage it.. Results from the ACCORD clinical trial may not apply
to younger patients of lower cardiovascular disease risk or to patients recently diagnosed with
type 2 diabetes. Another study, UKPDS, conducted in patients starting at the time of their
diabetes diagnosis showed long term CVD benefit from a lesser reduction in blood glucose and
in blood pressure.

Information for this article is based on a National Institutes of Health (NIH) press release dated
March 15, 2010. More information regarding the ACCORD study and the NIH can be found at
http://www.nih.gov/news/health/mar2010/nhlbi-15.htm.