Long-term Effects of Lifestyle Intervention or Metformin on Diabetes Development and Microvascular Complications: the DPP Outcomes Study

BACKGROUND: The worldwide epidemic of type 2 diabetes requires effective prevention. We determined the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes prevention, originally demonstrated during the 3-year Diabetes Prevention Program (DPP), and whether diabetes-associated microvascular complications are reduced. METHODS: The DPP (1996–2001) was a randomized trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk to develop diabetes. All participants were offered lifestyle training at DPP-end. 2776 (88%) of the surviving DPP cohort were followed in the DPP Outcome Study (DPPOS 2002–2013) and analyzed by intention-to-treat based on original DPP assignment. During DPPOS, the lifestyle group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin. FINDINGS: During 15 years of average follow-up, lifestyle intervention and metformin reduced diabetes incidence rates by 27% (p<0.0001) and 18% (p=0.001), respectively, compared with the placebo group, with declining between group differences over time. At year 15, the cumulative incidences of diabetes were 55, 56 and 62%, respectively. The prevalences at study-end of the aggregate microvascular outcome, composed of nephropathy, neuropathy, and retinopathy, were not significantly different among the treatment groups (11–13%) in the total cohort. However, in women (n=1887) lifestyle intervention was associated with a lower prevalence (8.7%) than in the placebo (11%) and metformin (11.2%) groups, with 21% (p=0.03) and 22% (p=0.02) reductions with lifestyle compared with placebo and metformin, respectively. Compared with participants who progressed to diabetes, those who didn’t progress had a 28% lower prevalence of microvascular complications (p<0.0001). INTERPRETATION: Lifestyle intervention or metformin significantly reduce diabetes development over 15 years. There were no overall differences in the aggregate microvascular outcome among treatment groups; however, those who did not progress to diabetes had a lower prevalence of microvascular complications than those who progressed. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)