Effect of Regression From Prediabetes to Normal Glucose Regulation on Long-Term Reduction in Diabetes Risk: Results From the Diabetes Prevention Program Outcomes Study

Study Questions:

What is the degree of diabetes risk reduction in individuals who return to normal glucose regulation at least once compared with those who consistently meet criteria for prediabetes?


The Diabetes Prevention Program Outcomes Study (DPPOS) is an ongoing observational study of participants from the Diabetes Prevention Program (DPP) randomized 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 randomized treatment group. Cox proportional hazards modeling and generalized linear mixed models were used to quantify the effect of previous (DPP) glycemic status on risk of later (DPPOS) diabetes and normal glucose regulation status, respectively, per standard deviation in change. Included in this analysis were 1,990 participants of DPPOS who had been randomly assigned to treatment groups during DPP (736 intensive lifestyle intervention, 647 metformin, 607 placebo).


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% confidence interval [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 beta-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 beta-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.


The authors concluded that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention.


The current study reports that the strategy used for diabetes prevention (lifestyle or pharmacological) is unimportant as long as the intervention is early (when someone has prediabetes) and can restore normal glucose regulation, even if transiently. Furthermore, maintenance of prediabetes despite the potent glucose-lowering effects of intensive lifestyle modification represents a high-risk state and might warrant additional preventive strategies. These data support a shift in the standard of care to early and aggressive glucose-lowering treatment, particularly in patients at highest risk, for example, individuals who remain with prediabetes despite lifestyle intervention.

Keywords: Catabolite Repression, Incidence, Prediabetic State, Insulin-Secreting Cells, Life Style, Risk Reduction Behavior, Blood Glucose, Metformin, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Transcription Factors, Insulin Resistance

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