FAQ
Intensive glycemic control may be detrimental for patients with type 2 diabetes: results of the ACCORD trial
Type 2 diabetes mellitus (DM-2) is a disease that affects millions of Americans and confers an increased risk of cardiovascular disease and mortality. This risk can be associated with the glycosylated hemoglobin (A1C), a value that is correlated with a patients’ average glucose level in the preceding 2 to 3 months. For every percent above 5% a patient’s A1C is, their risk of cardiovascular disease increases by approximately 20%. Currently the Centers for Disease Control and Prevention (CDC) estimates that there are more than 20 million patients in the United States with DM-2. It is predicted that the number of patients with a diagnosis of diabetes will be nearly 40 million by the year 2050. While care for patients with diabetes has improved, as of 2000 it was estimated that less than 5% of patients with diabetes were compliant with all 5 methods of reducing diabetic complications. These methods include glycemic control, blood pressure control, lipid control, smoking cessation, and daily aspirin use. The cost of diabetic complications is a considerable burden to the healthcare industry, and direct medical costs are well over $100 billion annually.
In response to the association of DM-2 with cardiovascular disease, the National Heart, Lung, Blood Institute (NHBLI) sought to determine if intensive glycemic control, as determined by the A1C, would reduce cardiovascular morbidity and mortality. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was designed to assess the effect of intensive glycemic control as well as improved control of dyslipidemia and improved hypertension control on cardiovascular morbidity and mortality in patients with DM-2 at high risk for cardiovascular disease. It was a randomized, 2 x 2 factorial trial conducted at 77 clinical centers in the United States and Canada. This trial was initiated in 1999 with a plan to conclude data collection in 2009. On February 6, 2008, the NHBLI announced that they were discontinuing the intensive glycemic control arm of the ACCORD trial 18 months earlier than expected in response to a significantly increased mortality rate with this group. The results that led to this decision may be viewed on the NHBLI website (http://www.nhlbi.nih.gov/health/prof/heart/other/accord/). The results have not peen published yet.
The ACCORD trial included 10 251 patients who had DM-2 for 10 years on average with an average A1C of about 8.2% on entry into the trial. Participants also must have had evidence of heart disease or at least 2 risk factors for heart disease, including hypertension, hyperlipidemia, obesity, and smoking. Participants were randomized into either the intensive glycemic control group (goal A1C <6.0%) or standard glycemic control group (goal A1C 7.0% to 7.9%). To achieve these A1C goals study physicians were allowed to use all anti-diabetic agents currently available. Glycemic control was evaluated frequently initially, and then every 2 months and every 4 months for the intensive glycemic control group and standard glycemic control group, respectively. The study incorporated a planned follow-up of 4 to 8 years to assess primary and secondary endpoints. The primary endpoint was a composite consisting of time to nonfatal MI, nonfatal stroke, or cardiovascular death and was assessed throughout the study. Secondary endpoints included total mortality, diabetic complications, quality of life, and cost-effectiveness. Interim analysis of data was conducted by the data and safety monitoring board approximately every 6 months during data collection. One such interim analysis led to the decision to discontinue the intensive glycemic control arm of the ACCORD study prior to the end of the trial. All patients previously enrolled in this study arm were transitioned to the standard glycemic control protocol.
Investigators noted that patients in the intensive glycemic control group did achieve lower average A1C values than their counterparts in the standard glycemic control group. The median A1C values for the intensive glycemic control group and standard glycemic control group were 6.4% and 7.5% respectively. However, what was troubling to investigators was the significant increase in mortality with the intensive glycemic control group. In the intensive group there were 257 deaths, compared with 203 deaths in the standard glycemic control group. This equates to an increase of 3 deaths per 1000 participants per year over an average of 4 years in the intensive glycemic control group as compared to the standard glycemic control group. Extensive sub-group analyses of data have demonstrated that increased mortality is not due to episodes of hypoglycemia, use of any single drug, including rosiglitazone, or any specific combination of drugs.
The NHLBI emphasizes that it is important to note that in this trial both groups experienced lower death rates than has been previously observed in patients with DM-2 who were at high risk for cardiovascular disease. From these data, the NHLBI concludes that intensive glycemic control, with a goal A1C of <6%, may be detrimental to those patients with DM-2 and significant risk for cardiovascular disease.
As a result of these findings, the NHLBI recommends the following with regard to management of DM-2:
References
National Heart Lung and Blood Institute, ACCORD Blood Sugar Treatment Strategy Announcement - http://www.nhlbi.nih.gov/health/prof/heart/other/accord/ - accessed 03/14/2008
Goff DC, Gerstein HC, Ginsberg HN, et al. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the action to control cardiovascular risk in diabetes (ACCORD) trial. Am J Cardiol. 2007; 99(suppl):4i-20i.
The ACCORD study group. Action to control cardiovascular risk in diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007; 99(suppl):21i-33i.
Gerstein HC, Riddle MC, Kendall DM, et al. Glycemia treatment strategies in the action to control cardiovascular risk in diabetes (ACCORD) trial. Am J Cardiol. 2007; 99(suppl):34i-43i.
By: R. Carlin Walsh, PharmD