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EASD: Early Intensive Glucose Control Pays Dividends

Posted: Wednesday, September 17, 2008

A 10-year follow-up of a landmark trial of intensive glucose control in type 2 diabetes has suggested that the clinical benefit was more than durable and rose over time to a reduction or 15% for myocardial infarction and a 13% reduction in the relative risk of death from any cause.
A decade after patients randomized to intensive glucose control completed the trial, they still had evidence of significant microvascular benefit, said Rury R. Holman, F.R.C.P., of the Diabetes Trials Unit of the Oxford Centre for Diabetes in England.

What's more, a once-nonsignificant decrease in the risk of myocardial infarction had matured into a significant 15% reduction (P=0.01) and there was a 13% reduction in the relative risk of death from any cause (P=0.007), said Dr. Holman and colleagues.

The benefits, both microvascular and macrovascular, of early intensive diabetes control persisted despite the fact that 10 years of ordinary care erased the impressive between-group glycemic differences seen at the end of the active intervention.

Dr. Holman and co-investigators from the United Kingdom Prospective Diabetes Study (UKPDS) reported the findings at the European Association for the Study of Diabetes, and they were published online in two manuscripts today by the New England Journal of Medicine.

The findings represented 30 years of data -- 20 years of active intervention and 10 years of follow-up -- from 5,102 patients enrolled in the trial.

One of the NEJM papers dealt with a substudy that studied the carryover effect of tight blood pressure control. In this case, the investigators found that the microvascular and macrovascular benefit of tight control of blood pressure, evident at the end of the active treatment phase, were not sustained during the 10-year follow-up.

Acknowledging that there was no legacy-effect for blood pressure, the investigators concluded that although optimal blood pressure control is of "major importance" in reducing the risks of microvascular and macrovascular complications, maintaining the benefit requires ongoing, aggressive hypertension therapy.

Edwin Gale, M.D., of Bristol University in England, who was not involved in the trial, said the results represent a true legacy in that they reinforce the benefit of early, intensive glucose management.

But even more important than the drugs used, Dr. Gale said, was the timing of the intervention -- that all the patients were newly diagnosed. "The message is that while glucose control is important, early glucose control may be critical, " he said.

To gauge the clinical importance of early intervention, Dr. Gale contrasted the new findings with those of the VADT, reported at the American Diabetes Association meeting in June. The VADT found no benefit for intensive glucose management in a population that had established diabetes. (See: ADA: VA Diabetes Trial Appears to Vindicate Rosiglitazone (Avandia) Safety)

David R. Matthews, F.R.C.P., of the Oxford Centers for Diabetes, Endocrinology, and Metabolism, said the difference between early intensive glucose control versus late intervention can be likened to rebuilding an old car.

After intensive rebuilding of the engine, "you take the car out on the road, put your foot on the gas, and the back wheels fall off."

The UKPDS recruited 5,102 type 2 diabetes patients and randomized 4,209 to conventional therapy, meaning diet and exercise, or intensive glucose control with sulfonylurea or insulin or -- in the case of overweight patients -- metformin, all of which were considered cutting-edge treatments when the study was begun 30 years ago.

In the follow-up, 3,277 patients were asked to attend annual UKPDS clinics for five years, but there were no attempts to maintain their previously assigned treatment. During years six through 10, patients were asked to fill out questionnaires yearly.

Among the findings of the 10-year follow-up of the intensive glucose control analysis:

After 20 years of intensive therapy, patients assigned to sulfonylurea-insulin had significantly lower mean glycosyated hemoglobin and fasting plasma glucose (P<0.001 for both).
The between-group differences in mean glycated hemoglobin levels disappeared after year one of the follow-up, but there were similar improvements in glycosyated hemoglobin in both groups thereafter.
After five years, only 5% of patients were on diet alone, 46% of patients were receiving oral therapy, and 49% were on insulin (with or without oral therapy).
Sulfonylurea-insulin group patients had a 9% risk reduction in any diabetes-related endpoint (P=0.04) and a 24% risk reduction for any microvascular disease outcome (P=0.001).
The sulfonylurea-insulin group had a 17% reduction in risk of death due to diabetes (P=0.01).
Patients treated with metformin had a 21% reduction in risk of any diabetes endpoint (P=0.01), a 30% reduction in risk of diabetes-related death (P=0.01), a 33% reduction in risk of MI (P=0.005), and a 27% reduction in risk of all cause mortality (P=0.002).

Source: Diabetes In Control: New England Journal of Medicine: Holman RR, et al "Ten-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes" N Engl J Med 2008; 359: