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Microvascular Residual Risk Studies

8 October 2015
Diabetes Prevention Program Outcomes Study reaffirms the importance of lifestyle intervention
In the Diabetes Prevention Program Outcomes Study, lifestyle intervention was associated with significant reduction in new-onset diabetes over 15 years. However, reduction in microvascular outcomes was only observed in women.
Diabetes Prevention Program Research Group. 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. Lancet Diabetes Endocrinol 2015; Published Online September 14, 2015
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.
Efficacity measures

There were two primary outcomes:

  • Development of diabetes (fasting plasma glucose ³7·0 mmol/L or 2 hour concentration ³ 11·1 mmol/L, confirmed by a repeat test within 6 weeks)
  • Prevalence of microvascular disease, based on an aggregate outcome including three components of diabetes-related microvascular disease: nephropathy, retinopathy, and neuropathy (see below).
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.

  • Nephropathy: albuminuria ³30 mg/g creatinine in a spot urine collection on two consecutive tests, an estimated glomerular filtration rate (eGFR) <45 mL/min/1·73 m² on two consecutive tests, or renal failure (end-stage renal disease, dialysis, or transplantation). Subjects receiving antihypertensive pharmacotherapy at the final visit who did not meet albuminuria or eGFR criteria at that time were regarded as having reached the nephropathy outcome if the nephropathy criteria were met previously at two consecutive visits.
  • Retinopathy: evaluated with seven-field stereoscopic fundus photography if the Early Treatment Diabetic Retinopathy Study grade was ³20 in either eye, or with treatment of retinopathy with laser or intravitreal injections.
  • Neuropathy: loss of light touch sensation (<8 of 10 applications detected on the dorsum of the great toe in either foot), measured with a 10 g Semmes-Weinstein monofilament.

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.

  • The mean follow-up period was 15 years. Over this time, there were significant reductions in diabetes incidence compared with placebo in both the lifestyle intervention group and the metformin group (see Table 1). However, in both groups, the benefit of intervention decreased over time.
  • For the total cohort, there was no significant difference in the aggregate microvascular outcome at the end of the study. However, women in the lifestyle group had a lower prevalence of the microvascular aggregate outcome than those in either the placebo or metformin groups (Table 1)


Table 1. Impact of lifestyle intervention or metformin on development of diabetes or microvascular outcomes at 15 years



Lifestyle intervention


Diabetes incidence, %




Reduction vs. Placebo

   hazard ratio (95% CI)


0·73 (0·65–0·83)

0·82 (0·72–0·93)





Aggregate microvascular outcome, %

Point estimate (95% CI) of relative risk

12·4% (11·1–13·8)

11·3% (10·1–12·7)

13·0% (11·7–14·5)


11·0% (9·6–12·6)

8·7% (7·4–10·2)

11·2 (9·7–12·9)

Reduction vs. placebo


21% (p=0·03)


Reduction vs. metformin


22% (p=0·02)


CI confidence interval


  • Across all groups, there was a lower prevalence of the microvascular outcome in subjects who did not develop diabetes than in those who did (relative risk 0·72, 95% CI 0·63–0·83; p<0·0001 for all treatment groups combined).
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