DPPOS Shows Long-Term Diabetes Prevention with Lifestyle and Metformin Intervention; Preventing Diabetes Lowers Risk of Vascular Complications
Presenters: David M. Nathan, MD; Mark Molitch, MD; Ronald B. Goldberg, MD; Brandy Heckman-Stoddard, PhD, MD; and Jose A. Luchsinger, MD, MPH
Long-term follow-up of 2,779 people enrolled in the Diabetes Prevention Program Outcomes Study (DPPOS) indicates a continued significant reduction in the participants’ risk of developing type 2 diabetes mellitus (T2DM) through intensive lifestyle intervention or use of metformin.
The DPPOS is the long-term follow-up of the Diabetes Prevention Program (DPP), a multicenter trial conducted from 1996 to 2001, in which lifestyle intervention aimed at achieving weight loss reduced the risk of development of T2DM by 58% and metformin use reduced the risk by 31%, both compared with placebo, after an average of 3 years, in persons considered to have pre-diabetes. The intensive lifestyle intervention was particularly effective in individuals ≥60 years old (71% reduction in risk), whereas metformin was particularly effective in younger, more obese patients (54% reduction in risk).
At the conclusion of the DPP, 88% of the surviving 3,234 participants enrolled in the DPPOS, including the DPP participants who had developed T2DM and those who still had not developed diabetes.
After an average of 22 years of study, 75% of the DPP participants who are still alive have continued to be evaluated, including those who have developed diabetes and those who have not. Some 47% of the total cohort and 61% of those who have developed T2DM are still on metformin. As of 2020, the mean age of the participants is 72 years, mean HbA1c level is 6.4%, mean systolic blood pressure is 124 mm Hg, mean level of low-density lipoprotein cholesterol is 93 mg/dL, and 56% are on statin treatment.
An overview of the latest findings from DPPOS was provided by DPPOS chair David M. Nathan, MD, director of the Clinical Research Center and Diabetes Center at Massachusetts General Hospital and professor of medicine at Harvard Medical School, Boston.
“The current results indicate that prevention of type 2 diabetes is possible and has important clinical benefits. The long-term benefits of the two DPP interventions on diabetes development, still present many years after they were started, are a testament to the power of these interventions and reinforce their importance in the reduction of diabetes,” said Dr. Nathan, in a statement prepared by the ADA.
New findings from DPPOS:
- Prevention effects in the original lifestyle and metformin treatment groups remain at 22 years, with a 25% and 18% reduction in the risk of developing T2DM, respectively, compared with the original placebo group, as presented by Dr. Nathan.
- The median time to T2DM development was delayed in the experimental arms: 9.5 years in the placebo arm versus 12 years in the metformin arm and 14 years in the intensive lifestyle arm.
- Among all participants and those with diabetes, HbA1c levels were lower in the intervention groups compared with placebo.
- Participants who did not develop diabetes had a significant 57% and 37% lower risk of developing retinopathy and kidney disease, respectively, and a 39% lower risk of major cardiovascular (CV) disease endpoints than those who developed diabetes, as presented by Mark Molitch, MD, professor emeritus of medicine (endocrinology), Northwestern University Feinberg School of Medicine, Chicago.
- The original group assignment did not affect the ultimate development of retinopathy over a mean follow-up of 20 years. There was also no significant benefit to lifestyle intervention or metformin on CV disease endpoints or the development of kidney disease, although favorable trends were observed with metformin on stroke and CV events in the subgroup of people who started the study before age 45. “Since avoidance of diabetes was associated with a lower risk for cardiovascular disease, the absence of benefit from the individual interventions is perplexing,” said Ronald B. Goldberg, MD, professor of medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine.
- Diabetes status (prediabetes vs. diabetes) did not affect cancer incidence. Metformin was associated with a nonsignificant 12% lower risk of cancer compared with placebo. “If metformin does affect cancer risk, the effect is smaller than epidemiologic studies initially suggested, which would require either a larger study or longer follow-up to determine,” said Brandy Heckman-Stoddard, PhD, MD, chief, Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Institutes of Health.
- The intensive lifestyle intervention group had a long-term reduction in the development of frailty, as presented by Jose A. Luchsinger-Stuart, MD, MPH, professor of medicine and epidemiology, Columbia University Medical Center, New York City.
- The only long-term negative effect observed with either intervention was a modest increase in kidney disease with metformin, which appeared only in the oldest group of participants.
David M. Nathan, MD; Ronald B. Goldberg, MD; and Brandy Heckman-Stoddard, PhD, MD had nothing to disclose. Mark Molitch, MD, disclosed advisory panel fees from Janssen Pharmaceuticals, Inc., Merck & Co., and Inc., Pfizer Inc.; consultant fees from AstraZeneca; and research support from Novartis Pharmaceuticals Corporation and Novo Nordisk Inc. Jose A. Luchsinger-Stuart, MD, MPH, disclosed consultant fees from vTv