Elsevier

The Lancet

Volume 379, Issue 9833, 16–22 June 2012, Pages 2243-2251
The Lancet

Articles
Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study

https://doi.org/10.1016/S0140-6736(12)60525-XGet rights and content

Summary

Background

Our objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) in participants who returned to normal glucose regulation at least once during the Diabetes Prevention Program (DPP) compared with those who consistently met criteria for prediabetes.

Methods

DPPOS is an ongoing observational study of participants from the DPP randomised trial. For this analysis, diabetes cumulative incidence in DPPOS was calculated for participants with normal glucose regulation or prediabetes status during DPP with and without stratification by previous randomised treatment group. Cox proportional hazards modelling and generalised linear mixed models were used to quantify the effect of previous (DPP) glycaemic status on risk of later (DPPOS) diabetes and normal glucose regulation status, respectively, per SD in change. Included in this analysis were 1990 participants of DPPOS who had been randomly assigned to treatment groups during DPP (736 intensive lifestyle intervention, 647 metformin, 607 placebo). These studies are registered at ClinicalTrials.gov, NCT00004992 (DPP) and NCT00038727 (DPPOS).

Findings

Diabetes risk during DPPOS was 56% lower for participants who had returned to normal glucose regulation versus those who consistently had prediabetes (hazard ratio [HR] 0·44, 95% CI 0·37–0·55, p<0·0001) and was unaffected by previous group assignment (interaction test for normal glucose regulation and lifestyle intervention, p=0·1722; normal glucose regulation and metformin, p=0·3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of a participant reaching normal glucose regulation status in DPPOS. Specifically, previous achievement of normal glucose regulation (odds ratio [OR] 3·18, 95% CI 2·71–3·72, p<0·0001), increased β-cell function (OR 1·28; 95% CI 1·18–1·39, p<0·0001), and insulin sensitivity (OR 1·16, 95% CI 1·08–1·25, p<0·0001) were associated with normal glucose regulation in DPPOS, whereas the opposite was true for prediction of diabetes, with increased β-cell function (HR 0·80, 95% CI 0·71–0·89, p<0·0001) and insulin sensitivity (HR 0·83, 95% CI 0·74–0·94, p=0·0001) having a protective effect. Among participants who did not return to normal glucose regulation in DPP, those assigned to the intensive lifestyle intervention had a higher diabetes risk (HR 1·31, 95% CI 1·03–1·68, p=0·0304) and lower chance of normal glucose regulation (OR 0·59, 95% CI 0·42–0·82, p=0·0014) than did the placebo group in DPPOS.

Interpretation

We conclude that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention. Reversion to normal glucose regulation, even if transient, is associated with a significantly reduced risk of future diabetes independent of previous treatment group.

Funding

US National Institutes of Health.

Introduction

Estimates from the US Centers for Disease Control and Prevention suggest that roughly 79 million Americans have impaired fasting glucose or impaired glucose tolerance (or both), collectively termed prediabetes.1 Screening for prediabetes is advocated because the disorder is a very high risk state for future type 2 diabetes and itself carries risk of diabetic complications.2, 3, 4, 5 Clinical trials of diabetes prevention worldwide have largely enrolled participants with untreated prediabetes because every year roughly 11% of this group will acquire diabetes, when both fasting and postprandial plasma glucose concentrations are raised.6, 7, 8, 9, 10, 11, 12 Even when overt diabetes is delayed or prevented, both microvascular and macrovascular disease are more prevalent in those with prediabetes compared with their normoglycaemic peers.2, 3, 4, 5 Thus, there is reason to believe that true prevention of diabetes and its complications probably resides in the reversal of prediabetes and the restoration of normal glucose regulation.

Several clinical trials have examined the feasibility and efficacy of lifestyle changes or drugs, or both, for prevention of diabetes in people with prediabetes.6, 7, 8, 9, 10, 11, 12, 13, 14, 15 Together, these studies have shown reductions between 25% and 72% in incidence of diabetes during 2·4–6 year intervention periods, with most participants remaining with prediabetes. Less often discussed are the 20–50% of participants who not only did not progress to diabetes, but in fact reverted to normal glucose regulation (fasting glucose <5·6 mmol/L and 2-h glucose <7·8 mmol/L).7, 8, 9, 10 Three of these studies—STOP NIDDM,7 DREAM,9 and ACT NOW13—make particular mention of a subgroup who achieved normal glycaemic status, but offer no detail as to the demographic characteristics or predictive factors. We previously reported a post-hoc analysis from the Diabetes Prevention Program (DPP) examining predictors for the restoration of normal glucose regulation.16 This analysis revealed that improved β-cell function and young age, as well as weight loss and intensive lifestyle intervention—independent of one another—were related to regression to normal glucose regulation. After completion of DPP, the Diabetes Prevention Program Outcomes Study (DPPOS) was initiated, which afforded a unique opportunity to establish the perseverance of predictors of normal glucose regulation—treatment-related or otherwise—and to quantify long-term diabetes risk reduction in participants who achieved normal glucose regulation. In pursuit of this objective, we postulated that participants reaching normal glucose regulation would have a significant and enduring decreased risk of incident diabetes compared with those with persistent prediabetes.

Section snippets

Trial design

DPPOS was an observational follow-up study to a randomised clinical trial undertaken at 27 centres involving 2761 participants who were at high risk of developing diabetes. The detailed methods have been reported17 and the protocol is available online. Institutional review boards at each centre approved the protocol, and all participants gave written informed consent before participation.

Participants

Participants were followed up for a median 3·2 years during the intervention phase of DPP, which formally

Results

The average number of lifestyle sessions attended during the bridge period between DPP and DPPOS was 2·87 (SD 4·73, 95% CI 0–14) in the intensive lifestyle intervention group, 5·35 (SD 5·95, 95% CI 0–16) in the metformin group, and 5·34 (SD 5·99, 95% CI 0–15) in the placebo group. Participants who had attained normal glucose regulation during DPP (n=894) attended more sessions (mean 4·61, SD 5·71) than did those who remained with prediabetes (n=1096) during DPP (mean 4·28, SD 5·63; p=0·0086 vs

Discussion

Although there is widespread consensus that diabetes prevention is crucially important,24 there is less agreement with respect to the particular intervention. Several studies have shown the efficacy of lifestyle modification for diabetes prevention.8, 10, 12, 15, 25 Long-term compliance with these lifestyle changes has proven difficult, however, and the benefits wane with weight regain.17 Various pharmacological agents also prevent diabetes, but the cost-effectiveness and risk–benefit ratio for

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