Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes

SUMMARY Objective: To assess the efficacy and tolerability of the combination of nateglinide (120 mg, ac) and metformin (500 mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM). Research design and methods: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24-week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA1c between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120 mg, ac), metformin (500 mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA1c, and fasting plasma glucose (FPG) levels of approximately 58 years, 30 kg/m2, 4 years, 8.2%, and 10.2 mmol/L, respectively. Results: In patients receiving initial CT, HbA1c decreased substantially ( = -1.6 ± 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 ± 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies ( p < 0.001); whereas, in placebo-treated patients, HbA1c increased modestly ( = +0.3 ± 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA1c of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3 mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 ± 0.3 mmol/L and -0.5 ± 0.2 mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 ± 32 pmol/L ( p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. Gastrointestinal side effects occurred in 27% of patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose ≤ 2.8 mmol/L) occurred in 3.4% of patients receiving CT. Conclusions: Initial CT with the rapid-acting insulinotropic agent, nateglinide, and metformin, an agent with insulin-sensitizing effects in the liver and periphery, is a safe and effective means of achieving glycemic targets in TN patients with T2DM.