San Diego, CA - Intensive glucose control aimed at achieving near-normal glucose levels not only reduces microvascular disease but also decreases cardiovascular events, including nonfatal MI, stroke, and cardiovascular mortality, according to the results of a recent study. The beneficial effect of intensive therapy appears to be mediated by changes in glycemia and cannot be explained entirely by the reduction in kidney disease or other cardiovascular-disease risk factors, report investigators.

Dr David Nathan

"The effects of controlling glucose and lowering hemoglobin A1_c [HbA1_c] levels are pretty profound," lead investigator Dr David Nathan (Massachusetts General Hospital, Boston) told heartwire. "If you are able to get hemoglobin A1_c levels down with intensive therapy, there are benefits beyond decreasing eye, kidney, and nerve disease common among patients with type 1 diabetes. What we saw was that intensive therapy significantly and dramatically reduced cardiovascular-disease events in this type 1 diabetic population."

The data, from the Epidemiology of Diabetes Interventions and Complications (EDIC) study group, an extension study of the landmark Diabetes Control and Complications Trial (DCCT), were presented this week at the American Diabetes Association (ADA) 2005 annual meeting.

Dr Richard Kahn

Dr Richard Kahn, the chief scientific and medical officer of the ADA, told reporters during a morning press conference that the results are "the most important news story to emerge from the meeting." Referring back to an earthquake that shook the convention floor earlier in the week, Kahn said the findings are "a 9 on the Richter scale," adding that clinicians now have evidence that intensive glycemic control early in type 1 diabetic patients translates into better long-term cardiovascular outcomes.

More than 90% of patients tracked from the DCCT

The DCCT was a National Institutes of Health study comparing a strategy of intensive management of blood glucose, with glucose monitoring several times per day and requiring patients to keep their HbA1_c levels as close to 6% as possible, with a conventional control strategy. More than 1400 patients with type 1 diabetes, aged 13 to 39 years, were enrolled in the study between 1983 and 1989. After 10 years, researchers reported that the complications of type 1 diabetes—nephropathy, retinopathy, and neuropathy—were reduced by 50% to 75% in the group assigned to the more intensive strategy. Based on those results, the day-to-day management of diabetes has changed dramatically.

When the results were published, the DCCT data hinted at a difference between the groups in the occurrence of MI, amputations for peripheral vascular disease, and stroke, but the numbers were too small to be conclusive. Follow-up with these patients, part of the EDIC study presented in 2001 and reported by heartwire at that time, showed that intensive control of blood glucose reduced the progression of atherosclerosis as measured by carotid intima-media thickness.

Nathan explained that because the number of cardiovascular events in DCCT/EDIC was small, investigators waited until 50 subjects in the conventional-treatment arm had a cardiovascular event, giving them enough statistical power to detect a reduction in cardiovascular events between the two treatment groups. Cardiovascular events were defined a priori and included nonfatal MI, stroke, cardiovascular death, subclinical MI, angina confirmed by exercise testing or angiography, and revascularization requiring bypass, stenting, or angioplasty.

Nearly 22 years after the first patient was enrolled, the DCCT/EDIC investigators report that intensively treated patients had significantly fewer cardiovascular events than the conventionally treated patients. Overall, 31 patients in the intensive-treatment arm had a cardiovascular event compared with 52 patients in the conventional strategy.

Reduction in risk associated with intensive glycemic control

End point	Relative risk reduction (%) (95% CI)	p
Cardiovascular events	42 (19-63)	0.016
Nonfatal MI, stroke, and cardiovascular death	57 (12-79)	0.018

After adjusting for renal disease, microalbuminuria, and albuminuria, the importance of aggressively lowering HbA1_c levels early in type 1 diabetics remained. "Even after you control for the decrease in kidney disease, there is still some other benefit. The most potent mechanism that we have so far identified is the lowering of glucose," said Nathan.

Nathan noted that the benefits of the original six years of intensive control persisted despite the fact that the HbA1_c values in both treatment groups leveled off at 8% after the initial DCCT study was completed. The cardiovascular-event reductions not only underscore the importance of early, tight, blood sugar control but also suggest that early high blood glucose causes changes that are not prevented by the conventional treatment, said Nathan.

"We've now studied these patients for twice as long as the patients were enrolled in the original DCCT study, but the complications continue to reflect the initial period of therapy," said Nathan. "This is the real mystery. We know that the hemoglobin A1_c measurement takes advantage of the fact that blood sugar sticks to red blood cells, but glucose also sticks to a whole bunch of other tissues and proteins and stays there for a very long time, taking years to go away. The question is whether this profound long-term effect is based on the fact that we were able to lower glucose early and prevent it from sticking to these cells."

Both Kahn and Nathan pointed out that the 57% reduction in nonfatal MI, stroke, and cardiovascular death in type 1 diabetic patients is larger than the risk reductions observed in the aggressive management of hypertension and hypercholesterolemia in other populations.