Several researchers from the Diabetes Prevention Program Outcomes Study (DPPOS) shared new data on clinical outcomes from the largest and longest follow-up to the Diabetes Prevention Program (DPP) study during the Virtual 80th Scientific Sessions.
Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, DPP was conducted from 1996 to 2001 at 25 centers across the U.S. and examined the effect of intensive lifestyle changes and metformin on the development of type 2 diabetes in a diverse, high-risk population. It showed that lifestyle changes reduced diabetes onset by 58% and metformin reduced diabetes onset by 31%.
DPPOS, which began in 2002, continues to follow most of the DPP cohort to determine whether the relatively short-term benefits of delaying diabetes demonstrated in the DPP study translate to long-term benefits. Roughly 88% of the eligible surviving DPP participants are enrolled in DPPOS.
The current phase of DPPOS is scheduled to run through 2021 and is examining the long-term effects of metformin on cardiovascular disease and cancer outcomes. DPPOS investigators are also studying the consequences of diabetes on aging, including cognitive and physical dysfunction and frailty. The average age in the DPPOS cohort is 72.
The virtual presentation at the Scientific Sessions featured researchers who have been involved with DPPOS since at least 2012, as well as study leaders who have directed DPP since its inception in 1996. The researchers plan to publish more detailed results from this phase of DPPOS soon.
DPPOS Chair David M. Nathan, MD, Director of the Diabetes Center at Massachusetts General Hospital, said that while the benefits of the original interventions have decreased over time, both the metformin and intensive lifestyle groups still show a reduction in the development of diabetes compared to the original placebo group. A reduction in diabetes development was associated with reductions in the development of eye disease, kidney disease, and major adverse cardiovascular events. No reduction was found in the outcomes for cancer or age-related cognitive or physical dysfunction.
Intention-to-treat analyses for metformin versus placebo were the primary aim regarding cardiovascular disease and cancer outcomes. Lifestyle versus placebo analyses were also performed.
Mark Molitch, MD, Professor Emeritus of Medicine (Endocrinology) at Northwestern University Feinberg School of Medicine, reported that although a reduction in diabetes was associated with reduced risk for eye and kidney disease, there were no significant effects of the lifestyle and metformin interventions on kidney disease or eye disease.
Ronald B. Goldberg, MD, Professor of Medicine at the University of Miami Miller School of Medicine, reported that although metformin showed a trend to reduce the risk of stroke, there was no significant beneficial effect of either metformin or lifestyle on the aggregate cardiovascular outcome, which included heart attacks, stroke, and fatal cardiovascular disease.
Brandy M. Heckman-Stoddard, PhD, MPH, Chief in the Division of Cancer Prevention at the National Cancer Institute, part of the National Institutes of Health, discussed the effects of metformin and lifestyle on cancer outcomes. Metformin showed a non-significant reduction in cancer compared with placebo.
“Initial epidemiologic reports of metformin’s beneficial effects on cancer risk may have been overestimated,” she said. “Our results suggest that if metformin has a significant beneficial effect, the effect is smaller than first anticipated, which would require longer or larger studies to demonstrate.”
Intensive lifestyle changes reduced frailty, according to Jose A. Luchsinger-Stuart, MD, MPH, Associate Professor of Medicine and Epidemiology at Columbia University Medical Center, but the current analyses didn’t indicate any significant effects on cognitive function. However, higher glycated hemoglobin levels, indicating higher average blood sugars, at the time of cognitive testing were related to worse cognitive function.
Dr. Nathan noted a “DPP/DPPOS paradox” in the results reported at the Scientific Sessions. The interventions reduced diabetes development, and the reduction in diabetes led to fewer complications, but the evidence didn’t indicate that the interventions themselves reduced complications, he said.
Possible explanations for this paradox are being explored. Some possible explanations include: Intervention benefits may have been masked by competing factors such as frequent use of risk-reducing medications such as statins; substantial use of non-study metformin by patients who developed diabetes during the study may have reduced the study metformin’s apparent effects; and some of the outcomes, like more advanced eye and kidney disease and the cognitive and physical outcomes that accompany aging, may require more study time to detect benefits.
“The DPPOS population is now entering the age period when many of these complications ‘take off,’” Dr. Nathan said.
Editor’s note: This session was only made available to the ADA for presentation on June 16. It is not included in the content being made available for 90 days post-event on ADA2020.org.
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