[PHNUTR-L] 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

[Kathrynne Holden]

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Public release date: 6-Jun-2008
http://www.eurekalert.org/pub_releases/2008-06/nhla-act060608.php

Contact: NHLBI Communications Office
NHLBI_news at nhlbi.nih.gov
301-496-4236
NIH/National Heart, Lung and Blood Institute

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 â€" 
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 â€" 
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 â€" 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 â€" 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 â€" 
fatal and nonfatal heart attacks or strokes â€" 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 â€" including 
eye, kidney, and nervous system diseases â€" 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.

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.

Resources:

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
-- 
Kathrynne Holden, MS, RD
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"Eat well, stay well with Parkinson's disease"
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