Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study

Abstract

Background: Effective prevention is needed to combat the worldwide epidemic of type 2 diabetes. We investigated the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes prevention, originally shown during the 3-year Diabetes Prevention Program (DPP), and assessed whether these interventions reduced diabetes-associated microvascular complications.

Methods: The DPP (1996-2001) was a randomised trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk of developing diabetes. All participants were offered lifestyle training at the end of the DPP. 2776 (88%) of the surviving DPP cohort were followed up in the DPP Outcomes Study (DPPOS, Sept 1, 2002, to Jan 2, 2014) and analysed by intention to treat on the basis of their original DPP assignment. During DPPOS, the original lifestyle intervention group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin. The primary outcomes were the development of diabetes and the prevalence of microvascular disease. For the assessment of microvascular disease, we used an aggregate microvascular outcome, composed of nephropathy, retinopathy, and neuropathy.

Findings: During a mean follow-up of 15 years, diabetes incidence was reduced by 27% in the lifestyle intervention group (hazard ratio 0·73, 95% CI 0·65-0·83; p<0·0001) and by 18% in the metformin group (0·82, 0·72-0·93; p=0·001), compared with the placebo group, with declining between-group differences over time. At year 15, the cumulative incidences of diabetes were 55% in the lifestyle group, 56% in the metformin group, and 62% in the placebo group. The prevalences at the end of the study of the aggregate microvascular outcome were not significantly different between the treatment groups in the total cohort (placebo 12·4%, 95% CI 11·1-13·8; metformin 13·0%, 11·7-14·5; lifestyle intervention 11·3%, 10·1-12·7). However, in women (n=1887) the lifestyle intervention was associated with a lower prevalence (8·7%, 95% CI 7·4-10·2) than in the placebo (11·0%, 9·6-12·6) and metformin (11·2%, 9·7-12·9) groups, with reductions in the lifestyle intervention group of 21% (p=0·03) compared with placebo and 22% (p=0·02) compared with metformin. Compared with participants who developed diabetes, those who did not develop diabetes had a 28% lower prevalence of microvascular complications (relative risk 0·72, 95% CI 0·63-0·83; p<0·0001).

Interpretation: Lifestyle intervention or metformin significantly reduced diabetes development over 15 years. There were no overall differences in the aggregate microvascular outcome between treatment groups; however, those who did not develop diabetes had a lower prevalence of microvascular complications than those who did develop diabetes. This result supports the importance of diabetes prevention.

Funding: National Institute of Diabetes and Digestive and Kidney Diseases.

Figure 1

Diabetes Prevention Program Outcomes Study consort diagram

Figure 2

Cumulative incidence of diabetes by treatment group among the 2776 DPPOS participants. The DPP and DPPOS periods, and the overlap between them, are indicated. Over the entire study, the incidence rates for participants were 7.0%, 5.7% and 5.2% per year for placebo, metformin and lifestyle, respectively, 27% and 18% lower for lifestyle and metformin vs. placebo, respectively (p<0.0001 and p= 0.001). The difference between lifestyle and metformin was not significant (p=0.10). The number at risk at each time point is listed by treatment group.

Figure 3

Prevalence of aggregate microvascular complication and individual microvascular components by DPPOS end (2012–2013). Placebo (red solid), metformin (blue dotted pattern), lifestyle (green diagonal stripes). 3A. By treatment group. None of the treatment group differences achieved statistical significance for the aggregate or the microvascular components. The aggregate microvascular is expressed as the average prevalence among the 3 components of nephropathy, retinopathy and neuropathy. 3B. By pre-specified subgroups according to sex and diabetes status. Prevalence was greater in men than in women in each of the three treatment groups. In women, the prevalence of the aggregate microvascular outcome was 22% (relative risk 0.78, p=0.02) lower in the lifestyle intervention group compared with the metformin group and 21% (relative risk 0.79, p=0.03) lower than in the placebo group. There were no significant differences among the treatment groups in men. The prevalence of microvascular disease in participants who did not develop diabetes was 28% lower than that in those who developed diabetes in a treatment group adjusted model (p<0.0001).

Figure 4

The role of HbA1c and diabetes duration on microvascular disease and its components were assessed in separate GEE models which included 2 interactions terms for treatment group*glycemia measure and microvascular component*glycemia measure. The interactions of HbA1c with the individual microvascular components were significantly different (p <0.0001). HbA1c (panels a–d) was associated with nephropathy and retinopathy (both p<0.0001) but not neuropathy (p=0.69). The interactions of diabetes duration also differed among the microvascular components (panel e–h) (p=0.01) with longer diabetes duration associated with nephropathy and retinopathy (both p<0.0001) but not with neuropathy (p=0.57). Figure 4A. Aggregate Figure 4B. Nephropathy Figure 4C. Retinopathy Figure 4D. Neuropathy Figure 4E. Aggregate Figure 4F. Nephropathy Figure 4G. Retinopathy Figure 4H. Neuropathy