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Back: ACCORD Trial
“Some Random Thoughts About ACCORD" 


Jeff Unger Picture

 

   Jeff Unger, MD
   PCMG Steering Committee Member
   Charlotte, North Carolina 
   The Unger Primary Care Medical Center
   Associate Director for Metabolic Studies
   Catalina Research Institute
   Chino, Californina



Not long ago, I attended several “high level” diabetes symposia in various parts of the country. The question was always brought up as to how low clinicians should target their patient’s A1C values. The speakers reminded their audience that “although the American Diabetes Association suggests lowering one’s A1C to the safest level, we are anxiously awaiting the results of the ACCORD study to confirm how low we should really go.”  So, what is the ACCORD trial and what happened to the subjects who participated in this study which has caused so many experts in the field of diabetes to re-think their patients’ personal glycemic targets?

ACCORD Demographics and Methodology

ACCORD (Action to Control Cardiovascular Risk in Diabetes) is a large clinical study of adults with established type 2 diabetes (T2DM) who are at especially high risk of cardiovascular disease (CVD). T2DM increases the risk of a number of complications, especially CVD, which is the leading cause of early death in people with diabetes. Many patients with T2DM also have co-existing hypertension and hyperlipidemia further adding to their cardiovascular risk. The ACCORD trial is testing three treatment approaches to determine the best ways to decrease the high rate of major CVD events--heart attack, stroke or death from CVD--among people with type 2 diabetes who are at especially high risk of CVD. These treatment approaches are: intensive lowering of blood sugar levels compared to a more standard blood sugar treatment; intensive lowering of blood pressure compared to standard blood pressure treatment; and treatment of blood lipids by a fibrate plus a statin compared to a statin alone.

The study began enrolling participants in 2001 and is taking place in 77 clinical sites across the United States and Canada. A total of 10,251 adults with established T2DM are participating in the ACCORD trial. At enrollment, study participants were between the ages 40 and 82 (average age 62), had diabetes for an average of 10 years, and were at especially high risk for CVD events because they either already had diagnosed CVD or they had at least two CVD risk factors in addition to type 2 diabetes. The other CVD risk factors could be high cholesterol (high low-density lipoprotein cholesterol, or LDL), high blood pressure, smoking, or obesity. ACCORD participant treatment was scheduled to end in 2009 with final statistical results published in 2010.

The A1C targets for ACCORD were as follows:

Intensive A1C Target                         Standard A1C Target

< 6.0 %                                                            7.0 -7.9 %

All routinely used medications for the treatment of T2DM could be administered to patients in ACCORD. These drugs included: rosiglitazone, pioglitazone, metformin, insulins, sulfonylureas, acarbose and exenatide.

ACCORD Intensive Glycemic Control Study Arm Is Halted!

In February 2008, the National Heart, Lung and Blood Institute, which sponsors ACCORD, announced that the intensive blood glucose arm in the study had been stopped. These patients were being transitioned to the same “standard treatment group protocol.” In its regular review of the available study data, the ACCORD DSMB (Data and Safety Monitoring Board) noticed an unexpected increase in total deaths from any cause among participants who had been randomly assigned to the intensive blood sugar treatment group compared to those assigned to the standard blood sugar treatment group. The data analyses showed that over an average of almost four years of treatment 257 participants in the intensive-treatment group died, compared with 203 within the standard-treatment group - a difference of 54 deaths, or an excess of about 3 deaths per 1,000 participants treated for a year. This translates to a 20% higher rate of death in the intensive than the standard group.

The primary outcome measure for the trial is the first occurrence after randomization of a major CVD event, specifically nonfatal heart attack, nonfatal stroke, or CVD death. Secondary outcomes include total mortality (deaths), microvascular outcomes (eg, eye, kidney, and nerve complications), health-related quality of life, and cost-effectiveness.

Interestingly, the intensive group had a 10 % lower rate of primary acute myocardial events when compared with the standard treatment arm. However, the increase in overall mortality in the intensive group appeared to outweigh the potential benefits.

Why were there so many more deaths in the intensively treated group of ACCORD? The statistical analyses are still being run. ACCORD researchers have extensively analyzed the available data and have not been able to identify to date any specific cause for the higher death rate among the intensive blood sugar treatment group. Based on analyses done to date, there is no evidence that any medication or combination of medications is responsible for the higher risk. In addition, although the number of severe hypoglycemic events was greater in the intensive blood sugar treatment group, this does not appear to account for the difference.

About half of the deaths in the intensive cohort of ACCORD were from cardiovascular diseases, such as heart attack, sudden cardiac death, stroke, heart failure, or another cardiovascular disease condition. The remainder of the deaths were from other causes such as cancer. Differences between the intensive and standard treatment groups were present in overall death from any cause as well as deaths from combined cardiovascular causes.

As stated above, lowering the A1C in the intensive cohort to < 6 % actually reduced the likelihood of having a myocardial event. However, if a heart attack did occur in those who were intensively treated, chances were higher that the event would prove to be fatal.

The ACCORD study is continuing to treat all participants for their diabetes; however, all participants will now be treated according to the ACCORD protocol for standard blood sugar control. Participants formerly randomized to the intensive blood sugar treatment are being transitioned to the ACCORD standard blood sugar protocol, aiming for an A1C of 7 to 7.9 percent.

Dr. Unger’s Views On ACCORD

After reading reviews of the ACCORD data, I have decided to list my personal thoughts below. Please note that these views are certainly NOT evidenced based. All clinicians who manage patients with diabetes anxiously await guidance from the ACCORD scientific committee to help us understand these outcome data more clearly. Only then will we be able to counsel our patients on how best to intensify management of type 2 diabetes.

Perceived Lessons Learned From ACCORD 

  1. The death rate in the intensively treated cohort, although slightly higher than in the individuals treated a bit less aggressively, was still ~70% lower than the death rate expected in patients with diabetes and a comparable degree of heart risk. We still do not know what the most appropriate A1C target might be for patients with T2DM.
  2. Remember, upon randomization, ACCORD patients already had multiple complications. ACCORD was a study involving high risk patients. As such, their likelihood of having an acute myocardial event would be higher than patients who were complication free at the time of entry into the trial. Statistically speaking, 80% of patients with diabetes will succumb to cardiovascular disease!
  3. Whereas enrollees in the UKPDS had a median age of only 53 years, the average age of ACCORD subjects was 62! ACCORD participants also had heart disease or at least two or more other risk factors for heart disease. Perhaps these patients were too aggressively treated in an attempt to improve their overall metabolic control! The intensive group was subject to extremely rigorous treatment. Some patients were taking 4 injections of insulin daily and monitoring their glucose levels 4 times each day. Perhaps achieving ideal glycemic control in ALL patients is just not necessary. One treatment plan is probably not appropriate for all patients. Treatment must be individualized rather than generalized.  
  4. I believe that we should be spending more time and effort identifying and managing patients who have PREDIABETES. In so doing, these individuals will be able to preserve their endogenous pancreatic beta cell function, minimize peripheral insulin resistance, aggressively pursue healthy lifestyle changes, and reduce their risk factors for developing microvascular and macrovascular complications. The perfect recipe for living a long and healthy life would include 30 minutes of daily exercise, 7-10 lbs of weight reduction, initial use of metformin plus pioglitazone plus an incretin mimetic as soon as one’s 2 hour postprandial glucose level exceeds 180 mg/dL. (See March 2008’s blog).

Please share your thoughts on ACCORD, management of prediabetes or any other metabolic issues with me through my monthly PCMG blog.

Jeff Unger, MD