ADA: Intensive Diabetes Treatment to Blame for Excess Mortality Risk

By Crystal Phend
SAN FRANCISCO, 12 june 2008-- The elevated mortality seen among patients with type 2 diabetes in a major trial of intensive glucose management cannot be pegged to either rosiglitazone (Avandia) or hypoglycemia, researchers said here.
Rather, they suggested, it was the multiple-agent treatment and rapid decrease in glycosylated hemoglobin levels to a target 6.5% that increased mortality 22% (1.41% versus 1.14% per year, P=0.04) compared with a standard approach targeting 7% in the ACCORD trial.
The results of ACCORD and two other large, randomized trials of tight glucose control made waves at the American Diabetes Association meeting. Subgroup analyses of ACCORD found no single factor that could account for the higher death rate, said Robert P. Byington, Ph.D., of Wake Forest University in Winston-Salem, N.C., and colleagues in an extensive panel discussion of the results.
"I think this is the price one pays for more intensive control," he said.
Notably, rosiglitazone tended to be protective against mortality, reported Michael E. Miller, Ph.D., also of Wake Forest University.
The only agents associated with significantly higher mortality were bolus and premixed insulin with a strong trend for basal insulin as well. All three increased risk about 25%, but an analysis did not find significant interactions with rosiglitazone for any of the three (P=0.53).
Dr. Miller noted, though, that premixed insulin was used more frequently in the standard glycemia treatment group and bolus insulin showed no difference between treatment groups.
A similar analysis of the Veterans Affairs Diabetes Trial, also reported here, showed that, if anything, there was a trend toward lower event rates with rosiglitazone. However, some researchers were skeptical of these post-hoc subgroup analyses, including Steven Nissen, M.D., of the Cleveland Clinic, who first brought to light the increased MI and other cardiovascular risks associated with the drug.
Not only were the trials not designed to answer questions about rosiglitazone, Dr. Nissen commented, but also the drug was used frequently across treatment groups and patients who took the drug were less likely to have pre-existing heart disease.
The ACCORD researchers likewise were circumspect about the significance of their subgroup findings, suggesting only hypotheses for further study.
The VA trial researchers identified severe hypoglycemia as one of the strongest predictors of cardiovascular events (HR 2.062, 95% CI 1.132 to 3.756, P=0.018).
But the ACCORD analysis did not confirm this as a factor in the increased mortality risk with intensive glycemic control, Dr. Byington reported.
Severe hypoglycemia more than doubled the risk of mortality but was linked to a higher rate of mortality in the standard treatment arm than in the intensive therapy arm (2.8% versus 4.9% per year, adjusted hazard ratio 0.52).
In patients who had never had a severe hypoglycemic event in the trial, the trend was the same as in overall mortality (1.3% versus 1.1% per year, adjusted HR 1.22).
"People keep asking us what was the cause of the higher mortality," said Denise G. Simons-Morton, M.D., Ph.D., of the National Heart, Lung, and Blood Institute in Bethesda, Md., another ACCORD investigator. "It's the strategy."
The reason for the significant increase in mortality in ACCORD but not the VA trial or the third trial reported here -- ADVANCE -- was likely the more rapid drop in glycosylated hemoglobin, she said."The biggest problem from my perspective is the fact that you're dealing with a regimen that's extremely intense in patients who had atherosclerosis for a long time," agreed Robert Sherwin, M.D., of Yale, who commented on the findings in a separate panel discussion of results from all three trials.
He noted that the regimens used in ACCORD typically included three to five oral agents and at least one insulin, which is rare in clinical practice and has never been tested in trials in such extensive combinations. "With ACCORD they just went too far, I think."
Clinical practice will likely continue as is but "maybe not push as hard" for the near normal glycosylated hemoglobin levels, commented Sue Kirkman, M.D., of the ADA in New York, who spoke at the same session. "It probably matters how you get there."
ACCORD was funded by the National Institutes of Health, the CDC, and General Clinical Research Centers. Medications, equipment, and supplies were provided by Abbott, Amylin, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline, King, Merck, Novartis, Novo Nordisk, Omron, sanofi-aventis, and Schering-Plough.
The ACCORD researchers who were presenting reported no potential conflicts of interest.
Dr. Kirkman reported no conflicts of interest. Dr. Sherwin reported conflicts of interest for Amylin, Merck, Lilly, Boehringer Ingelheim, and Bristol-Myers Squibb with a possible future role with Pfizer as well. Dr. Nissen reported no conflicts of interest.

Primary source: American Diabetes Association meetingSource reference:Kirkman S, et al "ACCORD trial -- study results" ADA Meeting 2008. Additional source: American Diabetes Association meetingSource reference: Lebovitz H, et al "Panel discussion -- glycemic control and heart disease -- implications for clinical practice" ADA Meeting 2008.