Safety and efficacy of nateglinide/metformin combination therapy in the treatment of type 2 diabetes

Abstract

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 (Delta glycosylated hemoglobin [HbA(1c)]= -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 HbA(1c) (Delta = -0.5% to -1.2%, sustained for up to 24 weeks) were found when nateglinide was added to ongoing metformin monotherapy.

Conclusion: the combination of nateglinide and metformin provides a sustained degree of glycemic control not achievable with either agent given as monotherapy.

Keywords: combination therapy; metformin; nateglinide; postprandial hyperglycemia; type 2 diabetes.

Figure 1

Adjusted mean change from baseline in glycosylated hemoglobin (HbA_1c), fasting plasma glucose (FPG), and glucose area under the curve (AUC) after Sustacal challenge. All parameters were significantly reduced from baseline (p ≤ 0.0001) in the active treatment groups. All values were significantly reduced compared to placebo (p ≤ 0.0001) except for glucose AUC with metformin monotherapy (not significant, NS). *p ≤ 0.01; **p ≤ 0.001; ***p ≤ 0.0001. Open bars = placebo; light gray bars = nateg-linide monotherapy; dark gray bars = metformin monotherapy; black bars = nateglinide plus metformin (Horton et al 2000). Copyright © 2000 American Diabetes Association. From Diabetes Care®, Vol 23, 2000; 1660–1665. Reprinted with permission from The American Diabetes Association.

Figure 2

Time course of HbA_1c in drug-naïve patients with type 2 diabetes randomized to the nateglinide/metformin combination (closed triangles) or the glyburide/metformin combination (open circles). Mean ± SE, intention-to-treat population (Gerich et al 2005). Copyright © 2005 American Diabetes Association. From Diabetes Care^®, Vol 28, 2005; 2093–2099. Reprinted with permission from The American Diabetes Association.