For Safety,
NHLBI Changes Intensive Blood Sugar Treatment Strategy in Clinical Trial of
Diabetes and Cardiovascular Disease
The National Heart, Lung, and Blood
Institute (NHLBI) of the National Institutes of Health has stopped one
treatment within a large, ongoing North American clinical trial of diabetes and
cardiovascular disease 18 months early due to safety concerns after review of
available data, although the study will continue.
In this trial of adults with type 2 diabetes
at especially high risk for heart attack and stroke, the medical strategy to
intensively lower blood glucose (sugar) below current recommendations increased
the risk of death compared with a less-intensive standard treatment
strategy. Study participants receiving intensive blood glucose lowering
treatment will now receive the less-intensive standard treatment.
The ACCORD (Action to Control Cardiovascular
Risk in Diabetes) study enrolled 10,251 participants. Of these, 257 in the
intensive treatment group have died, compared with 203 within the standard
treatment group. This is a difference of 54 deaths, or 3 per 1,000 participants
each year, over an average of almost four years of treatment. The death rates
in both groups were lower than seen in similar populations in other studies.
“A thorough review of the data shows that
the medical treatment strategy of intensively reducing blood sugar below
current clinical guidelines causes harm in these especially high-risk patients
with type 2 diabetes,” said Elizabeth G. Nabel, M.D.,
director, NHLBI. “Though we have stopped this part of the trial, we will
continue to care for these participants, who now will receive the
less-intensive standard treatment. In addition, we will continue to monitor the
health of all participants, seek the underlying causes for this finding, and
carry on with other important research within ACCORD.”
In stopping this part of the trial, Nabel accepted the recommendation of the 10-member Data and
Safety Monitoring Board (DSMB) – an independent advisory group of experts in
diabetes, cardiovascular disease, epidemiology, patient care, biostatistics,
medical ethics, and clinical trial design that has been monitoring ACCORD since
it began. A specific charge of any DSMB is to monitor participant safety.
ACCORD participants will continue to receive
blood sugar treatment from their study clinicians until the planned trial
conclusion in June 2009. Those participants in the intensive treatment group
will now be treated to the same A1C goals as those already in the standard
treatment group.
The intensive treatment group had a target
blood sugar goal, measured by hemoglobin A1C, of less than 6 percent. This is
similar to blood sugar levels in adults without diabetes. The standard
treatment group aimed for a target similar to what is achieved, on average, by
those with diabetes in the United States (A1C of 7 to 7.9 percent) and lower
than at study entry.
“The ACCORD findings are important, but will
not change therapy for most patients with type 2 diabetes. Few patients with
high cardiovascular risk like those studied in ACCORD are treated to blood
sugar levels as low as those tested in this study, “ said Judith Fradkin, M.D., director, Division of Diabetes,
Endocrinology, and Metabolic Diseases at the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK). “People with diabetes should never
adjust their treatment plan or goals without consulting their health care
providers.”
In ACCORD, intensive treatment group
participants achieved, on average, A1C values lower than standard treatment
group participants. Half of the participants in the intensive treatment group
achieved an A1C of less than 6.4 percent, and half of the participants in the
standard treatment group achieved an A1C of less than 7.5 percent. The
average blood sugar levels for both groups were lower than when they entered
the study.
The ACCORD trial was designed to determine
whether intensively lowering blood sugar would reduce the risk of
cardiovascular events such as heart attack, stroke, or death from
cardiovascular disease, specifically in people with type 2
diabetes who are at particularly high risk for a cardiovascular event.
Prior studies suggested that reducing blood sugar to levels found in
non-diabetic adults may reduce the rate of cardiovascular diseases among those
with diabetes. However, a randomized clinical trial was needed to determine
whether that hypothesis is accurate.
“ACCORD is an important study intended to
find new answers to help people with type 2 diabetes reduce their high risk of
heart disease,” said Denise G. Simons-Morton, M.D., Ph.D., NHLBI project
officer for ACCORD and a member of the ACCORD steering committee. “Hypotheses
about treatments to prevent cardiovascular disease in people with type 2
diabetes need to be tested in clinical trials such as ACCORD. The ACCORD
results, along with results from other studies, will contribute to determining
what the treatment goals should be in patients with various characteristics.”
Conducted at 77 sites nationwide and in
Canada, the trial includes adults between the ages of 40 and 82 at enrollment
who, in addition to type 2 diabetes, also have two or more other risk factors
for heart disease or had been diagnosed with heart disease before entering the
study. Thus, participants were included in the ACCORD trial because they were
at especially high risk—more risk than is associated with diabetes alone—for
having a heart attack, stroke, or of dying from cardiovascular disease.
Participants, who on average had diabetes for 10 years at enrollment, were
randomly assigned to either standard (5,123 participants) or intensive (5,128)
blood sugar treatment goals. They were also enrolled in one of two other
ACCORD randomized clinical trials examining effects of treatments for blood
pressure or blood lipids; those study components will continue.
Participants had been followed for 2 years to 7 years at the time the intensive
blood sugar control treatment was stopped.
These results from ACCORD do not apply to
patients with type 1 (juvenile) diabetes, according to Fradkin.
It is also unclear whether the results apply to patients with recently
diagnosed type 2 diabetes or those whose cardiovascular risk is lower than the
participants studied in ACCORD.
Extensive analyses by ACCORD researchers
have not determined a specific cause for the increased deaths among the
intensive treatment group. Based on analyses conducted to date, there is no
evidence that any medication or combination of medications is responsible.
Most participants in the intensive treatment
group achieved their lower blood sugar goals with combinations of Food and Drug
Administration-approved diabetes medications. For both the intensive and
standard treatment groups, study clinicians could use all major classes of
diabetes medications available: metformin, thiazolidinediones (TZDs,
primarily rosiglitazone), insulins,
sulfonylureas, exanatide,
and acarbose.
“Because of the recent concerns with rosiglitazone, our extensive analysis included a specific
review to determine whether there was any link between this particular
medication and the increased deaths. We found no link,” said William T. Friedewald, M.D., ACCORD Steering Committee Chair and
Clinical Professor of Medicine and Public Health at
ACCORD researchers will continue to monitor
participants and conduct additional analyses to try and explain the findings.
Investigators are preparing a report of the findings for a peer-reviewed
publication.
An estimated 21 million Americans have
diabetes and 284,000 die from it each year. Sixty-five percent of the deaths
are related to cardiovascular causes. Type 2 diabetes increases the risk
for heart disease 2 to 4 times.
The National Diabetes Education Program, a
program of the NIDDK and the Centers for Disease Control and Prevention (CDC),
promotes the diabetes care guidelines of the American Diabetes Association
(ADA), which recommend an A1C goal of less than 7 percent for most people with
type 2 diabetes. The
NIDDK contributed funding and scientific
expertise to ACCORD. The NIH’s National
Institute of Aging and National Eye Institute, as well as the CDC, are also
contributing in order to conduct sub-studies in ACCORD. The following
companies provided study medications, equipment, or supplies: Abbott Laboratories,
Amylin Pharmaceuticals, AstraZeneca
LP, Aventis Pharmaceuticals, Inc., Closer Healthcare,
GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Inc., MediSense Products (Division of Abbott Laboratories), Merck
& Company, Inc., Novartis Pharmaceuticals, Inc.,
Novo Nordisk Pharmaceuticals, Inc., and Omron
Healthcare, Inc.
To arrange an interview with an NHLBI
spokesperson, please contact the NHLBI Communications Office at (301) 496-4236
or email nhlbi_news@nhlbi.nih.gov.
To interview Dr. Friedewald on Wednesday, please
contact NHLBI; after February 6, contact Randee Sacks
Levine at Columbia University Office of Communications at 212-305-8044.