ACCORD Clinical Trial Publishes Results
A Therapeutic Strategy Targeting Blood Sugar to Near-Normal
Levels Does Not Reduce Cardiovascular Events But Increases Mortality
in Persons with Diabetes at High Risk
Intensively targeting blood sugar to near-normal levels in adults
with type 2 diabetes at especially high risk for heart attack and
stroke does not significantly reduce the risk of major cardiovascular
events, such as fatal or nonfatal heart attacks or stroke, but
increases risk of death, compared to standard treatment. Researchers
from the ACCORD (Action to Control Cardiovascular Risk in Diabetes)
clinical trial compared a medical strategy aimed at near-normal
blood sugar levels — below current recommendations — to
a strategy to reach more standard blood sugar levels. Supported
by the National Institutes of Health, the study evaluated the effects
of intensively targeting blood sugar control among adults with
established diabetes, high blood sugar levels, and pre-existing
heart disease or at least two cardiovascular disease risk factors
in addition to diabetes.
The first published results of the ACCORD trial of over 10,000
participants appear online in the New England Journal of Medicine
(NEJM) today and will be in the June 12 NEJM print
edition. The results are being presented at the American Diabetes
Association's 68th Annual Scientific Sessions in San Francisco
on June 10.
In February, the NIH's National Heart, Lung, and Blood Institute
(NHLBI) stopped the intensive blood sugar strategy after an average
of 3.5 years of treatment, instead of the planned 5.6 years, due
to safety concerns. The intensive strategy group had a 22 percent
higher risk of death — or 54 more deaths — compared
to the standard group. The increased risk began emerging within
1 to 2 years after the strategy began to aggressively lower the
participantsí blood sugar levels. All participants now follow a
medical strategy to reach the standard blood sugar levels while
other components of the study continue.
"ACCORD is providing important evidence to help guide treatment
recommendations for adults with established type 2 diabetes who
have had a heart attack or stroke or who have two or more risk
factors for cardiovascular disease in addition to diabetes," said
NHLBI Director Elizabeth G. Nabel, M.D. "For these individuals,
intensively lowering blood sugar to near-normal levels appears
to be too risky."
The researchers caution that the results might not apply to patients
who are at lower risk of cardiovascular disease than the ACCORD
participants or to patients with more recently diagnosed type 2
diabetes. On average, ACCORD participants had been diagnosed with
diabetes for 10 years at enrollment.
ACCORD's ongoing studies of the effects of aggressively lowering
blood pressure and treating multiple blood lipids (cholesterol
and triglycerides) in high-risk diabetic patients are expected
to continue through June 2009.
"Adults with type 2 diabetes are two to four times more likely
than adults without diabetes to die from heart disease, so identifying
the safest and most effective ways to help them lower their risk
of heart disease, stroke, and death is critical," Nabel noted.
An estimated 21 million Americans have diabetes and 284,000 die
from it each year. Sixty-five percent of deaths in persons with
diabetes are from cardiovascular causes.
Conducted at 77 sites nationwide and in Canada, ACCORD randomly
assigned 10,251 participants between the ages 40 and 79 (average
age 62) to standard or intensive blood sugar treatment goals. Therapy
in both groups included patient education and counseling, and treatment
with any of the major classes of Food and Drug Administration-approved
diabetes medications, as prescribed by their study clinician: metformin,
thiazolidinediones (TZDs, primarily rosiglitazone), insulins, sulfonylureas,
exanatide, and acarbose. Combinations of medications could be used
as needed to reach the treatment goals.
Hemoglobin A1C levels, a standard measure of average blood sugar
levels over the preceding two to three months, were used to monitor
participants' blood sugar. The standard strategy group (5,123 participants)
aimed to lower blood sugar levels to an A1C of 7 to 7.9 percent — a
target similar to what is achieved, on average, by individuals
treated for type 2 diabetes in the United States. The intensive
strategy group (5,128 participants) had an A1C blood sugar target
of less than 6 percent — similar to that found in adults
without diabetes. To join the study, participants needed to have
an A1C level of 7.5 percent or higher; at study enrollment, one-half
of the participants had an A1C level over 8.1 percent.
Half of the participants in the standard strategy group achieved
an A1C less than 7.5 percent, and half of the intensive strategy
group achieved an A1C less than 6.4 percent. On average, participants
in both groups achieved these levels within the first year of the
study and maintained them throughout the study.
After an average of 3.5 years, 257 people in the intensive strategy
group died, compared to 203 participants in the standard strategy
group. This difference of 54 deaths resulted in a 22 percent increased
death rate in the intensive group. Causes of death were similar
in each group, with about half from cardiovascular conditions,
such as heart attack, sudden cardiac death, stroke, or heart failure.
However, the intensive group had 41 more cardiovascular deaths
than the standard group, resulting in a 35 percent higher cardiovascular
"Despite detailed analyses, we have been unable to identify the
precise cause of the increased risk of death in the intensive blood
sugar strategy group," noted lead author Hertzel C. Gerstein, M.D.,
M.Sc. "Our analyses to date suggest that no specific medication
or combination of medications is responsible. We believe that some
unidentified combination of factors tied to the overall medical
strategy is likely at play." Gerstein holds the Population Health
Research Institute Chair in Diabetes and is director of the Division
of Endocrinology & Metabolism and Diabetes Care and Research Program
at McMaster University and Hamilton Health Sciences, Hamilton,
To meet their more aggressive targets, participants in the intensive
group used more medications, were more likely to use combinations
of medications, and changed medications and/or doses of medications
more frequently than those in the standard group. For example,
52 percent of participants in the intensive strategy group were
on three oral medications plus insulin compared with 16 percent
of participants in the standard strategy group. The intensive strategy
was associated with more adverse side effects from medications,
hypoglycemia (low blood sugar) events, weight gain, and fluid retention.
The researchers also studied whether participants' characteristics
at enrollment had an impact on their outcomes. They compared persons
with and without existing cardiovascular disease, women and men,
those older and younger than age 65, those with A1C levels lower
and higher than 8 percent, and white and non-white participants.
Death rates were consistently higher in the intensive strategy
group regardless of baseline characteristics. However, compared
to participants in the standard group, those in the intensive group
who began the study with no history of heart attack or stroke,
or with lower blood sugar levels (A1C level 8 percent or less)
had fewer combined cardiovascular events — fatal and nonfatal
heart attacks or strokes — during the study.
The increased risk of death from the intensive strategy surprised
researchers and other experts because earlier studies had shown
that blood sugar at near-normal levels was associated with lower
cardiovascular disease risk in people with type 2 diabetes. However,
these were observational studies, rather than randomized clinical
trials, as they did not test treatments to reduce blood sugar.
In addition, intensive blood sugar control has been shown in clinical
trials to reduce microvascular complications from diabetes — including
eye, kidney, and nervous system diseases — in people with
type 1 or type 2 diabetes, and to lower cardiovascular disease
risk in people with type 1 diabetes. However, the levels tested
in other studies were not at as low as the level targeted in the
ACCORD intensive treatment group.
The American Diabetes Association's clinical guidelines recommend
that most people with type 2 diabetes reach and maintain an A1C
of less than 7 percent. The guidelines also state that treatment
should be individualized. For example, a less stringent A1C goal
should be considered for people with severe or frequent low blood
sugar or with other medical conditions.
"The ACCORD results can now be considered when doctors are tailoring
blood sugar strategies for adults with type 2 diabetes who are
at especially high risk for cardiovascular disease," said Denise
G. Simons-Morton, M.D., Ph.D., a coauthor and NHLBI project officer
Future analyses from ACCORD will determine the effects of the
intensive blood sugar strategy on microvascular diseases, cognition,
quality of life, and other outcomes in the study participants.
ACCORD is primarily funded by NHLBI, with additional funding and
scientific expertise contributed by the National Institute of Diabetes
and Digestive and Kidney Diseases. Other components of the NIH — the
National Institute of Aging and National Eye Institute — as
well as the Centers for Disease Control and Prevention, support
substudies. The following companies provided study medications,
equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical,
AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare
Inc., GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Inc.,
Merck & Co., Inc., Novartis Pharmaceuticals, Inc., Novo Nordisk,
Inc., Omron Healthcare, Inc., and Sanofi-Aventis U.S.
To interview an ACCORD spokesperson, please contact the NHLBI
Communications Office at (301) 496-4236 or email email@example.com.
To speak with Dr. Gerstein, please contact Veronica McGuire at
905-525-9140, ext. 22169, or firstname.lastname@example.org.
Part of the National Institutes of Health, the National Heart,
Lung, and Blood Institute (NHLBI) plans, conducts, and supports
research related to the causes, prevention, diagnosis, and treatment
of heart, blood vessel, lung, and blood diseases; and sleep disorders.
The Institute also administers national health education campaigns
on women and heart disease, healthy weight for children, and other
topics. NHLBI press releases and other materials are available
online at www.nhlbi.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Questions and Answers About the ACCORD Clinical Trial, http://www.nhlbi.nih.gov/health/prof/heart/other/accord/q_a.htm
February 6, 2008, ACCORD Blood Sugar Treatment Strategy Announcement, http://www.nhlbi.nih.gov/health/prof/heart/other/accord/
National Diabetes Information Clearinghouse, http://diabetes.niddk.nih.gov/
National Diabetes Education Program, http://ndep.nih.gov/
Your Guide to Living Well With Heart Disease, http://www.nhlbi.nih.gov/health/public/heart/other/your_guide/living_well.htm
ACCORD clinical trial website, http://www.accordtrial.org/public/index.cfm