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|Objective:||To investigate whether the beneficial effects of lifestyle intervention and metformin on diabetes prevention, previously shown at 3 years of the Diabetes Prevention Program (DPP), were still evident after 15 years follow-up, and if so, there was also benefit in diabetes-associated microvascular complications.|
|Study design:||The DPP (1996–2001) was a randomised controlled trial comparing an intensive lifestyle intervention or masked metformin with placebo in subjects at very high risk of developing diabetes. Surviving patients were followed up in the DPP Outcomes Study; the original lifestyle intervention group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin.|
|Study population:||Of the 3,149 surviving members of the DPP, 2,776 (88%) were enrolled in the DPP Outcomes Study. Across both DPP and DPP Outcomes Study there was a slight excess of females (~67-69%), and over 50% of patients were white.|
There were two primary outcomes:
|Secondary||Adverse events (AEs), assessed by a standard questionnaire. Sprains or fractures needing medical attention were predefined as a non-severe AE of special interest.|
Microvascular complications were defined as specified below.
The primary outcomes were analysed on an intention-to-treat basis on the basis of subjects’ original DPP treatment assignment. The aggregate microvascular outcome was analysed with the global test using general estimating equation models to estimate average prevalence and account for correlations among the individual outcomes.
Table 1. Impact of lifestyle intervention or metformin on development of diabetes or microvascular outcomes at 15 years
CI confidence interval
|Authors’ conclusion:||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|
The results of the DPP Outcomes Study show that prolonged lifestyle intervention, or metformin, prevent diabetes in at-risk individuals over the long-term. Lifestyle intervention also appeared to reduce hyperglycaemia-related microvascular disease in women over 15 years. It is pertinent that other studies such as the Look AHEAD Study have also shown a sex difference with respect to the effects of lifestyle intervention in preventing the development of diabetic nephropathy (1). It is not possible to discern a specific benefit of lifestyle intervention on the individual components of the microvascular outcome. This may relate to the duration of follow-up, as in the Da Qing study (2), the benefit of lifestyle intervention on diabetes prevention, retinopathy, and cardiovascular and all-cause mortality were evident after 23 years follow-up.
The DPP Outcomes Study has a number of strengths, including the size of the cohort, the consistent nature of follow-up, and complete data collection over the 15 years. However, the authors also recognise that the possibility of therapeutic cross-over is a limitation of the study.
Ultimately, the key message from this study is that preventing diabetes reduces the long-term risk of microvascular complications; prevalence was 28% lower in individuals who did not develop diabetes than in those who did. This finding has important public health implications, given that management of microvascular complications is associated with substantial cost, which increases as the severity of disease progresses (3,4). However, while lifestyle intervention is clearly relevant, it does not significantly impact the prevalence of microvascular complications for the total cohort. Indeed, at 15 years, more than one in 10 subjects in the lifestyle intervention group had objective evidence of diabetic retinopathy, nephropathy and/or neuropathy. These findings therefore highlight the need for additional interventions, including lipid-modifying therapy beyond statins, to reduce the residual risk of diabetes-related microvascular outcomes in at-risk individuals.
1. Look AHEAD Research Group. Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomized clinical trial. Lancet Diabetes Endocrinol 2014; 2: 801–9.
2. Li G, Zhang P, Wang J et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing diabetes prevention study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80.
3. Ward A, Alvarez P, Vo L, Martin S. Direct medical costs of complications of diabetes in the United States: estimates for event-year and annual state costs (USD 2012). J Med Econ 2014;17:176-83.
4. Clarke PM, Glasziou P, Patel A et al. Event rates, hospital utilization, and costs associated with major complications of diabetes: a multicountry comparative analysis. PLoS Med 2010;7(2):e1000236.
|Key words||diabetes; microvascular outcomes; lifestyle intervention; prevention; retinopathy, nephropathy, neuropathy|