SAN FRANCISCO – Glycemic control has remained stable for an average of 15 years after initial randomization for patients in the Diabetes Prevention Program.
No significant differences in early microvascular complications were seen among interventions on intention to treat analysis, although intensive lifestyle intervention was effective in reducing microvascular complications in women.
Those are two key findings from an analysis of long-term outcomes from the Diabetes Prevention Program Outcomes Study (DPPOS), which were presented at the annual scientific sessions of the American Diabetes Association.
Doug Brunk/Frontline Medical News
Dr. William Knowler, Dr. Jill Crandall, and Dr. Kieren Mather discuss the results of the DPPOS trial.*
DPPOS is a follow-up to the Diabetes Prevention Program (DPP), a randomized clinical trial of intensive lifestyle and metformin, compared with placebo for the prevention of diabetes. Launched in 1996, the trial took place at 27 centers in the United States and was designed to determine whether the development of diabetes could be prevented or delayed in high-risk patients. A total of 3,234 patients were randomized to either an intensive lifestyle intervention to reduce their weight by 7% through a low-fat diet and increased physical activity, or standard advice on diet and exercise plus metformin, or standard advice on diet and exercise plus placebo.
The DPP ended 1 year ahead of schedule after an average of 3 years of study. The lifestyle intervention program, which had accomplished its goal of 7% weight loss at 1 year, and then maintained about a 5% weight loss over the remaining time of the study, resulted in a 58% reduction in diabetes. The metformin group reduced diabetes development by 31%.
"To put these reductions in perspective, approximately 11% per year of participants in the placebo group developed diabetes," Dr. David M. Nathan, chair of the DPP and DPPOS and professor of medicine at Harvard Medical School, Boston, said during a press briefing. "That was reduced to about 8%/year in the metformin group, and less than 5%/year in the lifestyle group."
The DPP results were "widely heralded and reported," Dr. Nathan continued, "but they only covered a very brief period: Three years in what is in fact a life-long disease or risk state." DPPOS was designed to examine "whether the diabetes development that we demonstrated was delayed over a brief period of time, would continue to be delayed or prevented over a longer period of time."
Of the original 3,234 DPP participants, 2,776 (86%) continued in DPPOS. Their average age at the first visit was 56 years and 68% were women. Their average age is now 67 years and 31% have developed diabetes since enrollment in DPP.
The annual diabetes incidence rates among the original DPP placebo and metformin groups have declined to approximately equal the rate in the lifestyle group, "which have remained remarkably stable, at approximately 5% per year over time," said Dr. William C. Knowler, chief of diabetes epidemiology and clinical research at the National Institute of Diabetes and Digestive and Kidney Diseases. While the reasons for this decline were not clear, one possibility is that an effective lifestyle intervention was offered to all study participants, he said.
Despite the convergence of the annual diabetes rates in long-term follow-up, the differences between groups obtained in the first 3 years of DPP "resulted in continued lower overall long-term incidence of diabetes over the 15 years of follow-up, during which the diabetes incidence rate overall was 18% lower in the metformin group and 27% lower in the original lifestyle group, than in the original placebo group."
Even though diabetes prevention or delay was substantial with lifestyle or metformin over 15 years, all three treatment groups maintained good glycemic control on average. HbA1c averages over follow-up were 6.1%, 6.0%, and 6.0% in the original placebo, metformin, and lifestyle groups, respectively.
"While these differences are statistically significant, they are very small and of questionable clinical importance," Dr. Knowler said. "The good news is that all three groups maintained good glycemic control on average, perhaps as a result not only of our interventions, but [also as] a result of rapid diagnosis and intensive treatment of diabetes once it developed."
As for microvascular outcomes such as retinopathy and neuropathy, Dr. Kieren J. Mather, professor of medicine at Indiana University, Indianapolis, reported that the average prevalence of microvascular disease at year 15 following DPP randomization was 12.4% in the placebo group, 13% in the metformin group, and 11.3% in the lifestyle group. While these differences between groups did not reach statistical significance, the mean prevalence of microvascular outcomes was about 50% higher in men than in women.