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Friday, June 6, 2008
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 participants’ 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 death rate.
"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, Canada.
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 for ACCORD.
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.
About the National Institutes of Health (NIH): 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. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH…Turning Discovery Into Health®
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