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CME/CE

Intensive-Glycemic-Control Arm of ACCORD Stopped

  • Authors: News Author: Sue Hughes
    CME Author: Charles Vega, MD
  • CME/CE Released: 2/12/2008
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 3/4/2010
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Target Audience and Goal Statement

This article is intended for primary care clinicians, endocrinologists, cardiologists, and other specialists who care for patients with diabetes.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Compare metformin and intensive lifestyle intervention with placebo among patients with impaired glucose tolerance.
  2. Identify the reason for early discontinuation of the Action to Control Cardiovascular Risk in Diabetes trial.


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Author(s)

  • Sue Hughes

    Sue Hughes is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000. Previously, she was science editor of Scrip World Pharmaceutical News. Graduating in pharmacy from Manchester University, UK, she started her career as a hospital pharmacist before moving as a journalist to a UK pharmacy trade publication. She can be reached at [email protected]

    Disclosures

    Disclosure: Sue Hughes has disclosed no relevant financial relationships.

Editor(s)

  • Brande Nicole Martin

    Brande Nicole Martin is the News CME editor for Medscape Medical News.

    Disclosures

    Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

CME Author(s)

  • Charles P Vega, MD

    Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

    Disclosures

    Disclosure: Charles Vega, MD, has disclosed an advisor/consultant relationship to Novartis, Inc.


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CME/CE

Intensive-Glycemic-Control Arm of ACCORD Stopped

Authors: News Author: Sue Hughes CME Author: Charles Vega, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME/CE Released: 2/12/2008

Valid for credit through: 3/4/2010

processing....

February 12, 2008 — The blood-glucose-lowering part of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in patients with type 2 diabetes at especially high risk of heart disease has been stopped prematurely because of a higher rate of mortality in the patients in the intensive arm vs that in the standard arm [1].

Patients in the standard-treatment group will continue treatment without changes, but patients in the intensive-treatment group will now be transitioned to the standard treatment.

The trial was a study of strategy rather than specific drug therapy, and many diabetes agents were used to reach glycemic targets. The higher death rate in the intensive group was not due to episodes of hypoglycemia or to any single drug, including rosiglitazone, or to a combination of drugs, ACCORD investigators said.

ACCORD is an National Heart, Lung, and Blood Institute (NHLBI) study of approximately 10,000 patients with type 2 diabetes and either heart disease or two risk factors for heart disease. The trial has a double 2X2 factorial design. All patients were participating in the glycemic-control part of the trial, which was testing whether an intensive strategy that targets a hemoglobin A1c (HbA1c) level of <6.0% reduces the rate of cardiovascular events more than a standard strategy that targets an HbA1c of 7.0% to 7.9%.

Then, depending on their blood-pressure and cholesterol levels, patients are assigned to two other parts of the trial. These are testing the combination of a fibrate (to raise high-density lipoprotein [HDL] and lower triglycerides) and a statin (to lower low-density lipoprotein [LDL]) vs a statin alone, and lowering systolic blood pressure to a target of below 120 mm Hg vs a target of 140 mm Hg. These blood-pressure and lipid arms of the study will continue until the study ends as planned, in June 2009.

In the glycemic-control part of the study, the median A1c level achieved in the intensive-treatment group was 6.4%, vs 7.5% in the standard group. The trial was stopped because of an excess of three deaths per 1000 participants per year in the intensive group vs the standard group, over an average of four years of treatment.

ACCORD: Deaths in intensive vs standard glycemic control groups

  Standard glycemic control Intensive glycemic control
Deaths, n 203 (11/1000/y) 257 (14/1000/y)


In a conference call on February 6, Dr Elizabeth Nabel, director of the NHLBI, pointed out that the death rate in both arms was lower than that previously observed in individuals with type 2 diabetes at especially high risk for heart disease, who generally have a risk of death of approximately 50/1000 per year. She also reported that there was a trend toward benefit in the intensive arm in terms of nonfatal cardiovascular events, but that this was outweighed by the increased mortality.

"This is an important finding that shows that if you have type 2 diabetes and are at especially high risk for heart disease, very intensive glucose-lowering treatments aimed at normalizing blood glucose to an A1c of less than 6% may be detrimental," Nabel stated.

She stressed that these results were applicable only to those individuals who are similar to the ACCORD participants — who had had type 2 diabetes on average for 10 years at the time of enrollment, had higher HbA1c levels than most type 2 diabetes patients in the US today (average of 8.2% at baseline), and had known heart disease or at least two risk factors in addition to diabetes, including high blood pressure, high cholesterol levels, obesity, and smoking.

She added that patients should not change their diabetes treatment without consulting with their healthcare provider and that the NHLBI concurs with the general recommendation of the American Diabetes Association that patients with diabetes should aim for an A1c level of less than 7%. "However, for this special group of individuals with diabetes, as exemplified in the ACCORD population, who were average age of 62, had diabetes for an average of 10 years, and had known heart disease or were at high risk, less stringent A1c goals are likely appropriate, with an aim for around 7%."

Reduction in nonfatal events?

Expanding on the study findings, chair of the ACCORD steering committee, Dr William Friedewald (Columbia University, New York), said the intensive group showed approximately 10% fewer nonfatal cardiovascular events such as myocardial infarctions (MIs) compared with the standard-treatment group, but that it appeared that, if an MI did occur, it was more likely to be fatal. In addition, the intensive-treatment group had more unexpected sudden deaths.

Not linked to rosiglitazone

Friedewald noted that because of recent concerns about rosiglitazone, they had specifically analyzed the data to try to determine whether there was any link between this particular medication and the increased deaths in the intensive-treatment group, but so far no link has been found, and the use of rosiglitazone does not seem to explain the increased mortality.

Some benefits seen in other populations

Dr Hertzel Gerstein (McMaster University, Hamilton, ON), who led the group that designed the glycemic-control approaches used in ACCORD, gave some background to the study. He noted that a large body of research has shown that higher glucose levels predict a higher likelihood of fatal and nonfatal cardiovascular events and that studies have shown that lowering blood glucose levels can significantly lower the risk of certain complications of diabetes, such as eye, nerve, and kidney diseases. In addition, a major study in people with type 1 diabetes has suggested that intensive blood-sugar-lowering strategies reduce the risk of cardiovascular disease and death, and a study in patients with more recent onset of type 2 diabetes than ACCORD participants showed a trend toward a reduction in MI.

"This body of research strongly suggests that lowering glucose levels to levels that are typically observed in people without diabetes could reduce the risk of cardiovascular disease in people with established type 2 diabetes. But, until ACCORD, no major clinical trial had studied whether lowering a raised blood-sugar level to a level similar to that seen in people without diabetes reduces the risk of cardiovascular disease in people with type 2 diabetes. In addition, no clinical trial has studied the effects of intensive blood-sugar lowering in people with longstanding type 2 diabetes who already have cardiovascular disease or who have multiple risk factors for cardiovascular disease in addition to diabetes," Gerstein stated. This was the rationale for ACCORD.

How ACCORD differs from previous studies

Dr Judy Fradkin (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD) reviewed how ACCORD differs from earlier studies of intensive glycemic control. She noted that a crucial difference was that ACCORD studied the effects of lowering glucose to a near-normal level, a lower level than that targeted in earlier studies. In addition, patients enrolled into ACCORD were older (average 62 years), had had diabetes for a longer time (an average of 10 years), and were at a higher risk for cardiovascular disease than patients enrolled in earlier studies of intensive glucose control.

"It is not yet known whether controlling glucose to near-normal levels will prevent heart disease and extend life in other groups such as younger people with diabetes, those earlier in the course of disease and in whom glucose is easier to control, and those without established cardiovascular disease," she said. The results also cannot be extrapolated to patients with type 1 diabetes, she added.

Source

  1. National Heart, Lung, and Blood Institute. ACCORD telebriefing prepared remarks. February 6, 2008. Available at: http://www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Clinical Context

Patients with impaired glucose tolerance and type 2 diabetes are at significantly increased risk for cardiac events, but there is limited research to support the concept that tight control of these conditions reduces cardiovascular morbidity or mortality. In a study published in the April 2005 issue of Diabetes Care, Ratner and colleagues randomized patients with impaired glucose tolerance to receive intensive lifestyle intervention, metformin, or placebo. They found that the incidence of hypertension was reduced with lifestyle interventions but not with metformin or placebo. They also demonstrated that intensive lifestyle intervention improved triglyceride levels, but the other interventions did not affect the lipid profile. After an average of 3 years of follow-up, there was no difference in the rate of cardiovascular events based on treatment group.

The ACCORD trial was designed to test whether tighter control of serum glucose levels, blood pressure, and lipid levels among patients with type 2 diabetes could reduce the risk for cardiovascular events. The methodology of this important trial and the reasoning behind the early discontinuation of the blood glucose–lowering part of the study are summarized in the Study Highlights section.

Study Highlights

  • The ACCORD trial enrolled 10,251 adults with established type 2 diabetes. The study was conducted at 77 clinical sites in the United States and Canada. Participants also had established cardiovascular disease or at least 2 of the following risk factors for cardiovascular disease: high levels of low-density lipoprotein cholesterol, high blood pressure, smoking, or obesity.
  • The trial randomized patients to a standard or intensive glycemic-lowering group. The goal HbA1c among subjects in these 2 groups was 7% to 7.9% and less than 6%, respectively. Concurrently, 2 other trials are examining standard vs intensive lowering of blood pressure and lipid treatments, and these trials are continuing.
  • All diabetes medications were allowed to achieve glycemic goals during the study, with preference given to metformin, the thiazolidinediones, and insulin.
  • 10,251 adults participated in the ACCORD trial. The mean age of subjects was 62 years, and the average duration of type 2 diabetes was 10 years.
  • Half of subjects in the intensive-treatment group achieved an HbA1c level less than 6.4% vs a reduction to 7.5% or less in half of the standard-treatment group.
  • During a mean of approximately 4 years of follow-up, there were 257 deaths in the intensive-treatment group vs 203 deaths in the standard-treatment group. This 20% difference in the mortality rate led researchers to discontinue the intensive glycemic-lowering part of the study.
  • Approximately half of study deaths were from cardiovascular causes. Intensive treatment was associated with a higher rate of both overall and cardiovascular mortality vs standard treatment.
  • However, intensive treatment was associated with a lower risk for nonfatal MI.
  • Researchers could not find any specific cause for the higher death rate among participants receiving intensive therapy. Given a recent report describing a higher rate of cardiovascular events with rosiglitazone treatment, the use of this thiazolidinedione was particularly scrutinized. However, rosiglitazone did not appear to significantly affect mortality rates.

Pearls for Practice

  • A previous trial demonstrated that intensive lifestyle interventions can reduce cardiovascular risk factors to a greater degree than metformin or placebo among patients with impaired glucose tolerance, but none of these interventions was effective in reducing cardiovascular events after 3 years of follow-up.
  • A part of the ACCORD trial has been stopped prematurely because of a higher risk for mortality among participants receiving intensive blood glucose–lowering vs standard treatment.

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