The target hemoglobin A1c of less than 7% should remain the general goal for nonpregnant adults with diabetes, despite recent results from three large randomized trials showing that intensive glucose lowering did not reduce the risks of cardiovascular disease in people with longstanding type 2 diabetes.
But glycemic targets that are either more or less stringent than that standard may be prudent for certain individuals with diabetes, according to a position statement issued jointly last month by the American College of Cardiology, American Diabetes Association, and American Heart Association and published online in the journals of each organization: the Journal of the American College of Cardiology, Diabetes Care, and Circulation.
“The ADA/AHA/ACC position statement is very well thought out and very well articulated. The authors should be commended for their concise analysis of the available data,” Dr. J. Michael Gonzalez-Campoy, medical director and chief executive officer, Minnesota Center for Obesity, Metabolism, and Endocrinology, said in an interview.
The three organizations conducted a careful reexamination of glycemic control guidelines in light of the findings from the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT). All showed no significant reduction in cardiovascular outcomes with intensive glucose control, but the ACCORD caused particular concern—and was halted early—because it showed a 22% increase in mortality among subjects randomized to a strategy of very intensive glycemic control with a target HbA1c of less than 6% (N. Engl. J. Med. 2008;358:2545–9).
Nonetheless, “The evidence from ACCORD, ADVANCE, and VADT does not suggest the need for major changes in glycemic control targets, but rather additional clarification of the language that has consistently stressed individualization,” wrote Dr. Jay S. Skyler and his associates (Diabetes Care 2009;32:187–92).
The clarifications include the following:
▸ To prevent microvascular and neuropathic complications in people with both type 1 and type 2 diabetes, the HbA1c goal for nonpregnant adults in general remains less than 7%. This recommendation is based on robust data from long-term studies including the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS).
▸ The general HbA1c goal of less than 7% also “appears reasonable” for prevention of macrovascular disease among those with recent onset of diabetes, based on long-term follow-up of the DCCT and UKPDS cohorts.
▸ For selected individual patients, even lower HbA1c goals than the general goal of less than 7% might be reasonable, provided that this target can be achieved without significant hypoglycemia or other adverse effects of treatment. Such individuals might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. This recommendation was based on subgroup analyses of the DCCT, UKPDS, and the microvascular evidence from the ADVANCE trial, which showed a reduction in albuminuria with intensive glucose lowering.
▸ Conversely, less stringent HbA1c goals may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management and education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin.
▸ For primary and secondary cardiovascular risk reduction in patients with diabetes, providers should continue to follow the evidence-based recommendations for blood pressure treatment, lipid lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors delineated in the ADA Standards of Medical Care in Diabetes (Diabetes Care 2008;31[suppl 1]:s12–54) and the AHA/ADA guidelines for primary CVD prevention (Circulation 2007;115:114–126).
Dr. Gonzalez-Campoy, who serves on the board of directors of the American Association of Clinical Endocrinologists, agrees with the recommendations. “The ACCORD, ADVANCE, and VADT emphasize the need to individualize care. … The recent publications that show no benefit in cardiovascular outcomes with attempts at normalizing glycemic control were all done on people with type 2 diabetes that had been longstanding. Therefore, these findings are not applicable to people with type 1 diabetes, nor do they apply to people with new onset diabetes mellitus. People with type 2 DM who may achieve normal A1c values with lifestyle changes alone, or with weight management, should not increase their A1c values. … There is good epidemiological data that relates increasing A1c values to an increased risk of death,” he said.
A substudy of VADT presented at the ADA's annual meeting in June suggested patients earlier in their history of type 2 diabetes had the most benefit of improved glycemic control, said Dr. Daniel Einhorn, head of the Sharp Diabetes Treatment and Research Center, San Diego.
“The key is not to throw out the baby with the bathwater. The VADT and ACCORD suggest that some populations may not benefit from tight glycemic control and there may be risks associated with tight control in these same populations, i.e., with cardiovascular disease and/or increased risk of hypoglycemia. This does not detract from the wealth of information that good glycemic control confers benefit on microvascular disease and, given a long enough window, cardiovascular disease,” said Dr. Einhorn, also on the AACE board of directors.
Proving a CVD benefit from glycemic control takes much longer than does blood pressure or lipid control, he added.
Dr. Gonzalez-Campoy noted that insulin and sulfonylureas, which are associated with hypoglycemia, may have incurred a greater risk for cardiovascular events than agents which do not increase the hypoglycemic risk. In any case, “Patients should always be counseled on the benefits of physical activity, medical nutrition therapy, and behavior modification. Patients should be reminded that active involvement on their part is essential to success.”
Seven of the eleven members of the document's writing committee disclosed financial dualities of interest with companies that manufacture diabetes-related products. Dr. Skyler, of the University of Miami, reported receipt of fees totaling $10,000 per year or more from Amylin Pharmaceuticals, Dexcom Corp., Novo Nordisk, and Nutrition 21. Dr. Gonzalez-Campoy receives all grant support from the MNCOME Foundation.
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