BACKGROUND: Pre-diabetes is a risk factor for full-blown diabetes; it presents opportunities to prevent the actual diseases. It is therefore essential to identify effective preventive strategies, and to clarify the direction of future research. METHODS: PubMed, Embase and Cochrane Central Register of Controlled Trials were searched using key terms (supplementary table 1). We applied network meta-analysis to multiple comparisons among various diabetic preventive strategies, including lifestyle and pharmacological interventions; traditional meta-analysis for the synthesis of basal metabolic changes after interventions; and trial sequential analysis for determinations as to whether analysis conclusions meet expectations. RESULTS: We included 32 randomized controlled trials comprising 43,669 patients and 14 interventions in the meta-analysis. Both lifestyle modifications and anti-diabetic medications improved physical conditions, including weight loss, blood glucose, and blood pressure. Network meta-analysis suggested that the progression of diabetes could be delayed to varying degrees by lifestyle and pharmacological interventions, except for angiotensin-converting enzyme inhibitors, statins, sulfonylureas and vitamin D. The risk ratios (RR) (95% credible interval (CrI)) compared with control were: GLP-1RAs 0.28 (0.15 to 0.50), Orlistat 0.33 (0.18 to 0.55), TZM 0.33 (0.16 to 0.63), TZD 0.39 (0.27 to 0.53), LST 0.54 (0.32 to 0.88), lifestyle 0.58 (0.49 to 0.67), LSM 0.62 (0.45 to 0.80), GI 0.66 (0.46 to 0.88), SU 0.67 (0.40 to 1.00), vitamin D 0.91 (0.59 to 1.40), ACEI 0.93 (0.62 to 1.40), statins 1.20 (0.84 to 1.60). CONCLUSIONS: In adults with pre-diabetes, firm evidence supports the notion that lifestyle modifications and metformin reduces the incidence of diabetes with an average of 20% relative risk reduction, while statins increase the relative risk 20%. We found that lifestyle modifications, promising long-term strategies involving three factors (nutrition, exercise, and weight loss) contribute to health by reducing BMI, body weight, waist and hip circumference, systolic and diastolic pressure, fasting, and 2-h postprandial blood glucose, total cholesterol and by increasing HDL. We made this determination using TSA, avoiding further waste of experimental resources.

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