Regression from pre-diabetes to normal glucose regulation in the diabetes prevention program

Abstract

Objective: Participants in the Diabetes Prevention Program (DPP) randomized to intensive lifestyle modification (ILS) or metformin had a significantly reduced incidence of diabetes compared with those randomized to placebo, yet most were still at risk because they had pre-diabetes. We explored the effect of baseline characteristics, weight change, ILS, and metformin on regression from pre-diabetes to the lowest-risk state of normal glucose regulation (NGR) defined by American Diabetes Association criteria.

Research design and methods: The DPP was a prospective randomized trial. Cox proportional hazards modeling was used to identify predictors of regression from pre-diabetes to NGR over 3 years of follow-up.

Results: Lower baseline fasting (hazard ratio 1.52, P < 0.01) and 2-h (1.24, P < 0.01) glucose predicted regression to NGR, as did younger age (1.07, P < 0.01) and greater insulin secretion (1.09, P = 0.04). ILS (2.05, P < 0.01) and weight loss (1.34, P < 0.01) had significant and independent effects on regression. A nonsignificant trend for regression was also observed for metformin (1.25, P = 0.06), male sex (1.17, P = 0.08), and insulin sensitivity (1.07, P = 0.09). In those entering the study with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), male sex and insulin sensitivity predicted regression to isolated IFG, whereas ILS, metformin, female sex, and greater insulin secretion predicted regression to isolated IGT.

Conclusions: Insulin secretion, and other biologic processes retained with younger age, are key in restoring NGR in people with pre-diabetes. However, NGR may also be attained through weight loss and additional aspects of ILS.

Figure 1

Flowchart for primary data analysis illustrating handling of the data from years 1 to 3. IFG, fasting glucose = 5.6–6.9 mmol/l; IGT, 2-h glucose = 7.8–11.1 mmol/l; NGR, fasting glucose <5.6 mmol/l; and 2-h glucose <7.8 mmol/l. Data “not included” were censored from subsequent analyses due to regression to NGR (in year prior), isolated IFG or IGT, progression to diabetes, or missing data.

Figure 2

Cumulative incidence of NGR according to treatment group, adjusted for baseline age, sex, ethnicity, weight, fasting and 2-h glucose concentrations, as well as insulin sensitivity (1/fasting insulin) and secretion (CIR).