UKPDS provides answers, fuel for debate

By Ralph Hall, MD
Diabetes Management Consulting Editor
Emeritus Professor of Medicine
University of Missouri-Kansas City School of Medicine

The results of the long-awaited United Kingdom Prospective Diabetes Study (UKPDS) are now available, and they may best be summed up by the title of an accompanying editorial by David Nathan, "Some answers, more controversy, from UKPDS."

These findings of the UKPDS were presented in four papers published in the Lancet and British Medical Journal in September.

The first of the studies (UKPDS 33), "The Intensive Blood-Glucose Control with Sulfonylureas or Insulin Compared with Conventional Treatment and Risks of Complications in Patients with Type II Diabetes," covered a period of 10 years. The HbA1c was 7% in the intensive group compared to 7.9% in the conventional group.

The risks for any diabetes-related endpoint were the evaluation measurements used in the study. These risks were sudden death from hyperglycemia or hypoglycemia, fatal or nonfatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye or peripheral vascular disease, and all-cause mortality.

Compared with the conventional group, the risk in the intensive group was 12% lower for any diabetes-related endpoint, 10% for any diabetes-related death, and 6% lower for all-cause mortality. Most of the risk reduction was due to a reduction in microvascular endpoints. None of the individual drugs has an adverse effect on cardiovascular outcomes.

An important finding was that the intensive group had a reduction in albuminuria accompanied by a 67% risk reduction in patients who had a two-fold increase in plasma creatinine. This is critical because of the high incidence of renal failure in Type II diabetes patients.

A more controversial part of the study, according to Nathan and Richard Kahn, chief scientific and medical officer of the American Diabetes Association, was "The Effect of Intensive Blood Glucose Control with Metformin on Complications in Overweight Patients with Type II Diabetes" (UKPDS 34). The mean HbA1c was 7.4% in the metformin group and 8% in the conventional group. Those allocated to metformin had risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death, and 36% for all-cause mortality. However, when metformin was added early in treatment to sulfonylurea-treated groups, it was associated with an increased risk of diabetes-related deaths. The UKPDS study concluded that because of less weight gain and a decrease in diabetes-related endpoints, metformin may be the first line of pharmacological therapy of choice for obese diabetes patients.

Because the addition of metformin to the sulfonylureas early on in treatment is associated with a less favorable outcome and the use of metformin alone results in a more favorable outcome, there is cause for concern that there is a statistical problem with the complicated analyses of these studies. This will be a topic of debate for some time.

The studies reported in the British Medical Journal were aimed at measuring the effect of tight blood pressure control on the risk of macrovascular and microvascular complications in Type II diabetes (UKPDS 38) and the efficacy of atenolol and captopril in reducing macrovascular as well as microvascular complications in Type II diabetes (UKPDS 39).

These studies showed that tight control of hypertension with atenolol or captopril decreased risks significantly. Heart failure risk was reduced by 56%, stroke by 44%, and death from diabetes-related causes by 32%.

The findings of UKPDS add to the findings of the the DCCT studies, which documented that improved control decreases microvascular diseases in Type I diabetes by demonstrating that improved blood glucose control also lowers the risk of microvascular diseases in Type II diabetes.

The metformin findings, although somewhat confusing, are important. Metformin, unlike sulfonylureas, does not promote vasoconstriction. Metformin does promote favorable changes in the quality of the lipoproteins, changing small dense lipoproteins to a more buoyant and less atherogenic form. Others have found more favorable outcomes with metformin albeit it in small and less well-structured trials. The Alexandria, VA-based American Diabetes Association’s (ADA) representatives, however, feel that this aspect of the study needs verification before these observations are used in clinical practice.

Two issues are clear, however. There is no longer an excuse for poor diabetes blood glucose control, and hypertension in all diabetics should be treated vigorously with beta-blockers and/or angiotensin-converting enzyme inhibitors.

All of these findings mean there will have to be a greater effort to manage diabetes more effectively, Kahn said in his statement for the ADA. This means more physician and patient education, more frequent office visits, closer monitoring, and more counselling.

The results of such efforts are likely to improve every aspect of the diabetic’s well-being as well as lowering the cost of care.