Does intensive therapy of type 2 diabetes help or harm? Seeking accord on ACCORD
ABSTRACTThe Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial tested the hypothesis that intensive glucose-lowering (with a hemoglobin A1c target of less than 6.0%) would reduce the incidence of atherosclerotic disease events and death compared with standard treatment (with a hemoglobin A1c target of 7.0% to 7.9%) in more than 10,000 patients with type 2 diabetes at high risk of cardiovascular events. The study was terminated early because more people had died in the intensive-treatment group than in the standard-treatment group (257 vs 203). The ACCORD results should not substantially alter our usual approach to glucose-lowering, which should still be “as low as we can get it safely” while avoiding hypoglycemia, significant weight gain, complex regimens, and, perhaps, the “stress” of maintaining glycemic control, especially in patients at high risk of coronary heart disease.
KEY POINTS
- No obvious cause, including hypoglycemia proximate to death or the use of any particular medication, clearly explained the excess deaths, although hypoglycemia occurred more often in intensively treated participants.
- The death rates in ACCORD were lower than in population studies and in other intervention trials. It is likely that multiple approaches to reducing the risk of cardiovascular disease contributed to this low mortality rate.
IMPLICATIONS OF ACCORD
In practice, most clinicians believe that the target glucose level in patients with type 2 diabetes should be as low as safely possible. This approach does not need to be modified on the basis of current information from ACCORD.
To be safe, regimens should be associated with a low risk of hypoglycemia and a low risk of weight gain. Use of combinations of medications that work by different mechanisms is still prudent. Agents should be used that may have favorable effects on other cardiovascular risk factors (eg, lipids, blood pressure, visceral fat).
Hemoglobin A1c targets below 7% are not precluded in all patients on the basis of the ACCORD results, though values lower than 6% may not have much added benefit for cardiovascular risk reduction. We should note that hemoglobin A1c was reduced in all ACCORD participants and that death rates were lower than in many other type 2 diabetic cohorts. Pending data on other outcomes in ACCORD (nephropathy, retinopathy, dementia, fracture risk), I believe it is premature for organizations to change their proposed hemoglobin A1c targets,36,37 as none have proposed values as low as the target in the ACCORD intensive-treatment group. At present, no class of glucose-lowering agents needs to be excluded from consideration on the basis of the ACCORD data.
The overall low rates of death in this population at high risk of coronary heart disease deserve comment. Not only are they lower than in other glucose-lowering trials, but they are also lower than in a number of studies of mortality in diabetes cohorts. As noted above, multiple risk factors for coronary heart disease and death were (and are) addressed in the ACCORD study participants, including repeated recommendation for lifestyle modification, intervention arms with lipid and blood pressure therapy, encouragement of aspirin use, and regular follow-up with health care providers for risk factors not managed by the ACCORD trial protocol. It is likely that multiple approaches to reducing the risk of cardiovascular disease contributed to this low mortality rate and that similar approaches will reduce the risk of coronary disease and death in regular clinical practice.
The ACCORD lipid and blood pressure arms are continuing, with results expected in 2010. The future results from ACCORD as well as from several glucose-lowering trials currently in progress (ADVANCE,32,33 Veteran’s Administration,34 Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI-2D]38) will likely help refine our understanding of the effects of glucose-lowering, glucose-lowering strategies and targets, and multiple interventions on coronary events and all-cause mortality.
For now, any strategy that lowers glucose and is associated with a low risk of hypoglycemia and does not cause excessive weight gain should be considered appropriate in patients with type 2 diabetes.
