The Diabetes Prevention Program and Its Outcomes Study: NIDDK's Journey Into the Prevention of Type 2 Diabetes and Its Public Health Impact

Abstract

The current-day epidemic of type 2 diabetes, largely driven by increased adiposity and reduced physical activity in the setting of genetic susceptibility, is a major public health challenge. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) presciently proposed the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial, designed by investigators in conjunction with NIDDK staff and initiated in 1996. The primary goal of DPP was to determine whether an intensive lifestyle intervention (ILS) or metformin in comparison with placebo would reduce the development of diabetes in a high-risk population with prediabetes. After mean 2.8 years, ILS reduced diabetes risk by 58% and metformin by 31%, leading to study termination ahead of schedule due to demonstrated efficacy of both interventions. In 2002, an extension of the DPP study, the Diabetes Prevention Program Outcomes Study (DPPOS), was initiated for examination of the longer-term course and consequences of diabetes prevention. Over 21 years of median total follow-up, in comparison with the placebo group, cumulative diabetes incidence was reduced by 24% and 17% in the original ILS and metformin groups, respectively, with median increases in diabetes-free survival of 3.5 and 2.5 years/person. During long-term follow-up, there were no significant effects of the original DPP interventions on microvascular or cardiovascular outcomes. However, compared with prevalence of microvascular outcomes among participants who progressed to diabetes, prevalence among those who did not progress was significantly lower. Longer-term follow-up of the cohort continues with examination of relationships between diabetes and prediabetes and an expanded array of diabetes- and aging-related morbidities.

Graphical abstract

Figure 1

History of the DPP and DPPOS with milestones for aims, results, and impact. DM, diabetes mellitus; MET, metformin; RFA, request for appplications.

Figure 2

Cumulative incidence of diabetes during DPP and DPPOS (31). The DPP (1996–2002) was conducted for an average of 2.8 years (range 1.8–4.6), after which DPP participants were invited to join the DPPOS (2003–present).

Figure 3

Effects of lifestyle and metformin on diabetes development by subgroups categorized according to baseline measurements (6). The solid squares and lines represent point and 95% CI of the estimated HRs for the effects of ILS vs. placebo (left) and metformin vs. placebo (right). There were significant interactions (P < 0.05) between metformin and BMI and between metformin and fasting glucose. None of the other subgroup-by-treatment interactions were statistically significant.