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

Summary

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.

Introduction

In the USA, 12·3% of the adult population has diabetes, with 1·7 million new cases diagnosed per year.¹ Most have type 2 diabetes. The economic cost of diabetes and prediabetes was estimated to be US$322 billion in 2012.² When the Diabetes Prevention Program (DPP; 1996–2001) was planned in the mid-1990s,³ the goal was to determine whether a behavioural lifestyle intervention programme designed to address the two major environmental risk factors for type 2 diabetes, overweight or obesity and sedentary lifestyle, or the most commonly used drug to treat diabetes, metformin, would reduce the development of the disease in a population selected to be at very high risk. The large beneficial short-term effects, and especially the lifestyle intervention, shown in DPP⁴ and in other studies5, 6 prompted many translation projects internationally.⁷

The ultimate worth of diabetes prevention is in the reduction of long-term morbidity or mortality, compared with waiting for the disease to develop and then treating it. The DPP Outcomes Study (DPPOS; Sept 1, 2002, to Jan 2, 2014) was designed to examine the effects of the original DPP interventions, beyond the 3-year average treatment during DPP, on the further development of diabetes and on microvascular complications.⁸

Research in context

Evidence before this study

The US Diabetes Prevention Program (DPP, 1996–2001) was initiated at a time when the worldwide epidemic of type 2 diabetes was increasing at a rapid rate. A fairly small study of lifestyle interventions to prevent diabetes in China, the Da Qing Study, had been completed and another small study in Finland (Finnish Diabetes Prevention Program) was underway when the DPP was initiated. The DPP was the largest and most comprehensive study of diabetes prevention. It was done in a diverse cohort representative of the population at very high risk for diabetes in the USA and included both lifestyle intervention and drug treatment (metformin) groups, with the aim of preventing or delaying the onset of diabetes. After 3 years, the DPP results showed a 58% reduction in the development of diabetes with the lifestyle intervention and a 31% reduction with metformin. The DPP lifestyle intervention results extended the previous findings from the Chinese and Finnish populations.

Added value of this study

The DPP Outcomes Study (DPPOS; 2002–13) was a continuation of the DPP. DPPOS was initiated to establish the longer-term effects of the DPP interventions on the development of diabetes and on the downstream microvascular complications of diabetes and cardiovascular risk factors. We published an interim report in 2009 reflecting 10 years of total follow-up. It showed continued reduction in diabetes development, albeit with reduced efficacy, and a reduction of cardiovascular risk factors in the lifestyle intervention group. In the current report, we show that diabetes prevention persists over as long as 15 years. Although microvascular complications were not reduced in the total cohort with either intervention, they were significantly reduced in the women in the lifestyle intervention group. Moreover, microvascular complications were significantly less frequent in those patients who did not develop diabetes compared with those who did.

Implications of all the available evidence

Understanding the effects of prevention, beyond the reduction in biochemical diabetes, is crucial for identifying whether prevention efforts will reduce the long-term public health burden of diabetes. DPPOS has shown the long-term prevention of diabetes and other added benefits of the lifestyle intervention and metformin, such as reduced cardiovascular risk factors, improved quality of life, and even cost savings (with metformin); however, establishing whether long-term microvascular or cardiovascular complications are reduced by the interventions will need further study.

The limited 3-year duration of the DPP precluded an understanding of longer-term effects of the interventions on diabetes prevention or on the development of complications associated with diabetes. Understanding the timecourse of the development of complications has been hampered in previous studies by a poor ascertainment of the actual time of diabetes onset, since the prevalence of complications is related to diabetes duration and exposure to hyperglycaemia. Longer follow-up of the DPP cohort was necessary to determine whether preventing or delaying diabetes onset would reduce the development of complications. Interim analyses of the 10-year combined DPP and DPPOS follow-up revealed a continued reduction of diabetes development with the lifestyle intervention and metformin, albeit with decreased efficacy.⁸

Here we report the main outcomes of the DPPOS, focusing on the long-term prevention of diabetes and the effects of the original, randomly assigned DPP interventions and the development of diabetes on microvascular complications over a mean follow-up of 15 years.