ADA 2009: Intensive Glycemic Control Not Directly Linked to Excess Cardiovascular Risk

Martha Kerr

June 11, 2009

June 11, 2009 (New Orleans, Louisiana) — Intensive glycemic control by itself does not account for the increase in cardiovascular deaths among patients randomized to that approach in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which was first reported a year ago.

Rather, rapid changes in glycemia appear to be linked to an increased risk for death, coinvestigator Matthew C. Riddle, MD, a member of the Glycemic Management Group of ACCORD and professor of medicine at Oregon Health & Science University in Portland, told attendees here at the American Diabetes Association (ADA) 69th Scientific Sessions.

The findings are the latest in a series of studies supporting the idea that older age and comorbidities drive up cardiovascular mortality rates in patients treated with intensive glucose control, and not low blood glucose levels per se.

ACCORD involved some 10,000 patients with type 2 diabetes randomized to intensive care (IC) with target hemoglobin A1c levels below 7%, or to standard care. Trial data presented at last year's ADA Scientific Sessions showed that cardiovascular mortality was higher among those randomized to IC.

Low A1c Alone Does Not Explain Death Risk

However, analysis of this group revealed that "an A1c below 7% alone does not appear to explain the excess deaths in the ACCORD trial and is not necessarily a predictor of mortality risk," Dr. Riddle reported. "Further, the rate of 1-year change in A1c showed that a greater decline in A1c was associated with a lower risk of death."

"We found a 20% higher risk of death for every 1% higher A1c level above 6%, suggesting that lower blood glucose levels may be a worthy target in some patients," Dr. Riddle said. However, "it appears that it is the rapid changes in glucose that may be harmful," Dr. Riddle told Medscape Diabetes & Endocrinology after his presentation.

"Patients with the [consistently] lowest A1c levels had the lowest risk. The excess mortality risk was in those patients who failed to achieve and sustain A1c levels between 6% and 7%.

"Those who easily achieved target A1c levels . . . had the lowest risk of death," Dr. Riddle said. "It is those who struggle to achieve low A1c levels that have the highest risk of death."

VADT Data Also Illuminate IC Impact

Findings from the Veterans Affairs Diabetes Trial (VADT) were presented next, by coinvestigator William C. Duckworth, MD, director of diabetes research at the Carl T. Hayden VA Medical Center in Phoenix and professor of clinical medicine at the University of Arizona.

That population was somewhat different from that in ACCORD. It was older (median age at baseline was 60 years), it was predominantly male, and patients had poor glucose control despite optimal medical therapy. But again, patients were randomized to IC or standard care.

Overall, "there was a 12% reduction in risk of cardiovascular events with intensive control, but that did not nearly reach statistical significance," Dr. Duckworth announced.

However, risk varied significantly among subgroups. Patients with diabetes of between 4 and 15 years' duration showed the greatest benefit with IC. The risk of having a primary cardiovascular event among patients with diabetes of 10 to 15 years' duration was reduced 40% with intensive glucose control.

In contrast, patients with a longer history of diabetes, with multiple comorbidities and complications, and who had difficulty achieving target A1c levels had the highest risk for death. If diabetes had been diagnosed more than 21 years previously, the risk for a primary cardiovascular event was more than doubled with IC.

"We had to change our target values a year and a half before the end of the trial," by increasing A1c target levels for older, sicker patients, Dr. Duckworth acknowledged.

"I definitely treat an older, sicker diabetic differently than I do a younger patient with fewer morbidities," Dr. Duckworth told Medscape Diabetes & Endocrinology. "We want to avoid hypoglycemia as best we can.

"I might treat a younger patient to a target A1c of less than 7%. For a patient with a [mid-range] risk, I might aim for an A1c of 8%, and for an older patient with a number of comorbidities and complications, my goal might be 9%."

"That may sound shocking to some people," Dr. Duckworth said, "but you want to avoid hypoglycemia whenever possible" in the frail elderly.

"The conclusion is to treat early but treat carefully," Dr. Duckworth said. "Any episode of hypoglycemia increases risk of cardiovascular events. Multiple [cumulative] episodes strongly increase risk. . . . There appears to be no additional benefit to lowering A1c below 8.4% in this older, sicker population.

"Type 2 diabetics are an extremely heterogeneous population. You might get different results with the same treatment approach between subgroups," the VA investigator stated.

Researchers with both trials agreed that the 2 trials cannot be compared too closely because the populations were so very different.

ACCORD is primarily sponsored by the National Heart, Lung, and Blood Institute, with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention. Dr. Riddle serves as a consultant for ConjuChem and Emisphere, and receives research support from Amylin Pharmaceuticals, Eli Lilly & Co, Sanofi-Aventis, and GlaxoSmithKline. VADT was sponsored by the VA Medical Centers. Dr. Duckworth has disclosed no relevant financial relationships.

American Diabetes Association (ADA) 69th Scientific Sessions: Abstract 468-P. Presented June 9, 2009.

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