Context: Although intensive lifestyle change (ILS) and metformin reduce diabetes incidence in subjects with impaired glucose tolerance (IGT), their effects on lipoprotein subfractions have not been studied.

Objective: The objective of the study was to characterize the effects of ILS and metformin vs placebo interventions on lipoprotein subfractions in the Diabetes Prevention Program.

Design: This was a randomized clinical trial, testing the effects of ILS, metformin, and placebo on diabetes development in subjects with IGT.

Participants: Selected individuals with IGT randomized in the Diabetes Prevention Program participated in the study.

Interventions: Interventions included randomization to metformin 850 mg or placebo twice daily or ILS aimed at a 7% weight loss using a low-fat diet with increased physical activity.

Main outcome measures: Lipoprotein subfraction size, density, and concentration measured by magnetic resonance and density gradient ultracentrifugation at baseline and 1 year were measured.

Results: ILS decreased large and buoyant very low-density lipoprotein, small and dense low-density lipoprotein (LDL), and small high-density lipoprotein (HDL) and raised large HDL. Metformin modestly reduced small and dense LDL and raised small and large HDL. Change in insulin resistance largely accounted for the intervention-associated decreases in large very low-density lipoprotein, whereas changes in body mass index (BMI) and adiponectin were strongly associated with changes in LDL. Baseline and a change in adiponectin were related to change in large HDL, and BMI change associated with small HDL change. The effect of metformin to increase small HDL was independent of adiponectin, BMI, and insulin resistance.

Conclusion: ILS and metformin treatment have favorable effects on lipoprotein subfractions that are primarily mediated by intervention-related changes in insulin resistance, BMI, and adiponectin. Interventions that slow the development of diabetes may also retard the progression of atherosclerosis.