Successful treatment of prediabetes in clinical practice: targeting insulin resistance and β-cell dysfunction.

OBJECTIVE: To determine the effectiveness of targeted pharmacologic interventions to reverse documented pathophysiologic abnormalities in prediabetes. METHODS: Patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) were treated with insulin sensitizers (pioglitazone + metformin) or insulin sensitizers + exenatide on the basis of oral glucose tolerance testing-derived indices of insulin resistance and impaired β-cell function. Patients who declined pharmacologic therapy received lifestyle modification only. RESULTS: One hundred five patients with IGT and/or IFG were treated with insulin sensitizers (pioglitazone + metformin) (n = 40), insulin sensitizers + exenatide (n = 47), or lifestyle modification only (n = 18). After a mean follow-up period of 8.9 months, the lifestyle modification group demonstrated no significant changes in fasting plasma glucose, plasma glucose area under the curve during oral glucose tolerance testing, insulin sensitivity, or β-cell function. In the pioglitazone + metformin group (24 hours off medication), fasting plasma glucose fell from 109 to 102 mg/dL; plasma glucose area under the curve decreased by 12.0%; insulin sensitivity and β-cell function improved by 42% and 50%, respectively (all P<.001); 14.3% converted to normal glucose tolerance; and no patient developed diabetes. In the pioglitazone + metformin + exenatide group (24 hours off medication), fasting plasma glucose fell from 109 to 98 mg/dL; plasma glucose area under the curve decreased by 21.2%; insulin sensitivity and β-cell function improved by 52% and 109%, respectively (all P<.001); 59.1% of patients with IGT reverted to normal glucose tolerance; and no patient developed diabetes. CONCLUSIONS: Targeted pathophysiologic therapy based on oral glucose tolerance test-derived measures of insulin sensitivity and β-cell function can be implemented in general internal medicine and endocrine practice and is associated with marked improvement in glucose tolerance and reversion of prediabetes to normal glucose tolerance in more than 50% of patients.