Statins are widely used to reduce cardiovascular risk. Unfortunately, some 
patients still experience cardiovascular events though prescribed with 
high-intensity statins. Metformin, an anti-diabetic drug, was reported to 
possess anti-atherosclerotic effects. Therefore, the experiments were designed 
to evaluate whether combined use of metformin and atorvastatin can achieve 
additional benefits. In rabbits fed a high-cholesterol diet, we evaluated the 
effects of the combination therapy on atherosclerotic plaques, lipid profiles, 
blood glucose levels, liver and kidney functions. Effects of combination therapy 
on cholesterol efflux and the expression of related transporters were studied in 
vitro. Our results showed that the combination therapy induced a more 
significant decrease in atherosclerotic lesion area than atorvastatin without 
additional lipid-lowering effect. The combination therapy significantly 
increased the percentage of large high-density lipoprotein subfraction. The 
intravenous glucose tolerance test showed that atorvastatin-treated rabbits had 
an increased area under the curve for time-dependent glucose levels after a 
bolus injection of glucose, which was completely reversed by metformin 
treatment. In cultured macrophages, co-treatment with metformin and atorvastatin 
promoted cholesterol efflux and up-regulated expression of ATP-binding cassette 
transporters A1 and G1. Taken together, our results suggest that 
atorvastatin/metformin combination therapy may achieve additional 
anti-atherosclerotic benefits likely through increasing cholesterol efflux in 
macrophages.