Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.

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By Kristina Fiore, Staff Writer, MedPage Today Published: May 22, 2009 Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner LITTLE FALLS, N.J., May 22 -- Researchers attempting to clarify the debate over intense glucose control through meta-analysis concluded that it does reduce cardiovascular risk among type 2 diabetes patients, but not overall mortality.

Their meta-analysis of five studies found that the approach reduces the risk of nonfatal myocardial infarction by 17%, and coronary heart disease events by 15%, according to Kaushik K. Ray, M.D., of Strangeways Research Lab in Cambridge, England, and colleagues.

But the treatment had no effect on stroke or all-cause mortality, the group reported in the May 23 issue of The Lancet.

"Intensive glucose-lowering treatment has cardiovascular benefit compared with standard treatment for individuals with type 2 diabetes," concluded the researchers, who will present their findings at the American Diabetes Association meeting in New Orleans in June. Action Points

But it appears considerably less significant than controlling blood pressure and cholesterol, they said.

There have been conflicting reports on the effectiveness of intensive glucose control in reducing macrovascular events and all-cause mortality in patients with type 2 diabetes. But the researchers said many trials have been underpowered to show clinical benefit.

So they conducted a meta-analysis of five prospective trials -- including ADVANCE and ACCORD -- involving a total of 33,040 patients.

Over 163,000 person-years of follow-up, there were 1,497 nonfatal myocardial infarction events, 2,318 coronary heart disease events, 1,127 fatal and nonfatal stroke events, and 2,892 deaths from any cause.

The researchers found that there were 2.3 fewer myocardial infarctions and 2.9 fewer coronary heart disease events for every 200 patients on intensive glucose control treatment for five years.

That translates to a number-needed-to-treat of 87 and 69, respectively.

"This benefit is much more modest than is that from a per-mmol/L reduction in LDL cholesterol or from a 4-mm Hg lower blood pressure," the researchers said.

Intensive glycemic control resulted in a 17% reduction in events of nonfatal myocardial infarction (OR 0.83, 95% CI 0.75 to 0.93) and a 15% reduction in coronary heart disease events (OR 0.85, 95% CI 0.77 to 0.93).

There was no significant effect on stroke or all-cause mortality.

Additionally, almost twice as many patients on intensive glycemic control had a hypoglycemic episode as those on standard treatment.

Therefore, a practical clinical approach "might be to reduce HbA1c concentration steadily with care taken to avoid severe hypoglycemia," the researchers said.

Those on intensive control also gained more weight -- an average of 2.5 kg more than those on standard treatment.

The meta-analysis was limited by the methodological rigor of the assessed studies, as well as the possibility of publication bias. Also, the researchers could not assess the effects of intensive glycemic control among different patient subgroups.

An additional limitation was the inability to assess different treatment regimens.

Still, they concluded that their "quantitative analysis of randomized controlled trials provides reliable large-scale evidence of a consistent beneficial effect of intensive treatment on nonfatal myocardial infarction and coronary heart disease, without increased risk of all-cause mortality."

In an accompanying editorial, Theodore Mazzone, M.D., of the University of Illinois at Chicago, said the findings suggest a need for additional clinical trial data about the effect of controlling blood sugar on coronary heart disease risk in patients with type 2 diabetes.

Dr. Mazzone said that intensive glucose-control efforts "might need to be started sooner after onset of diabetes, and extended follow-up could be required."

He noted that tight glucose control does not have as great an impact as blood pressure and cholesterol control. But he said that given an "urgent need to address residual risk of coronary heart disease in a rapidly expanding population with type 2 diabetes, it is premature to conclude that glucose control has no part to play."