The increasing prevalence of type 2 diabetes provides impetus for both development of new drugs to improve glycemic control and for reconsideration of treatment strategies with existing agents. Combination therapy with complementary drug classes that act on different aspects of glycemic control has been a particularly effective strategy. This work reviews the published literature reporting efficacy and safety/tolerability of nateglinide, a rapid-onset insulinotropic agent with a predominant effect to reduce postprandial glucose, when combined with metformin, a first-line agent that suppresses hepatic glucose production and thereby reduces fasting plasma glucose. The nateglinide/metformin combination has consistently been found to be both efficacious and well tolerated, whether given as initial combination therapy in drug-naïve patients or when added to metformin monotherapy. Maximum efficacy (Δ glycosylated hemoglobin [HbA1c]= −1.4% to −1.9%, sustained for up to 2 years of treatment) was seen in studies of drug-naïve patients in whom pharmacotherapy was initiated with the combination of nateglinide and metformin, and modest reductions in HbA1c (Δ = −0.5% to −1.2%, sustained for up to 24 weeks) were found when nateglinide was added to ongoing metformin monotherapy
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