Preserve-β: Two-year Efficacy and Safety of Initial Combination Therapy with Nateglinide or Glyburide Plus Metformin

Gerich J, Raskin P, Jean-Louis L, Purkayastha D, Baron M. Diabetes Care. 2005;28:2093-2099.

Type 2 diabetes is characterized by a deterioration of β-cell function, which necessitates the use of multiple agents to maintain adequate glycemic control. Nateglinide and glyburide are two agents that may be used to combat diabetes-related β-cell dysfunction. The purpose of this study was 2-fold: 1) to test the hypothesis that the combination of nateglinide and metformin will provide glycemic control with a decreased incidence of hyperglycemia and weight gain compared with the combination of glyburide and metformin, and 2) to compare the 2-year efficacy of nateglinide/metformin and glyburide/metformin in type 2 diabetes patients.

A total of 428 subjects with type 2 diabetes participated in this randomized, multicenter, 2-year study. Inclusion criteria included: 1) drug-naïve patients, 2) aged 18-77, 3) baseline A1C beween 7.0% and 11.0%, 4) fasting plasma glucose (FPG) ≤15 mmol/L, and 5) BMI between 22 and 45 kg/m². Patients were randomized into one of 2 groups: 1) a combination therapy group with nateglinide plus metformin (Nate/Met group), or 2) a combination therapy group with glyburide plus metformin (Glyb/Met group). Each treatment group had a corresponding placebo group. Treatment for the first 4 weeks consisted of either 120 mg AC nateglinide or 1.25 mg glyburide before breakfast and 200mg open-label metformin before the evening meal, followed by a 12-week titration period, during which patients received either 120 mg AC nateglinide or treatment with glyburide (titrated to a maximum of 10 mg daily, in 1.25 mg increments) and metformin titrated to a maximum of 2,000 mg daily as necessary. An 88-week monitoring period followed. A1C, glycemic control, postprandial glucose excursions (PPGE), and FPG were measured at weeks -2, 0, and 4, and again at weeks 20, 28, 40, 52, 64, 76, 88, 96, and 104.

The results from the 2 groups were similar in terms of glycemic control. The mean change in A1C from baseline was -1.2±0.1% in the Nate/Met group and -1.5±0.1% in the Glyb/Met group (P = 0.1730). A total of 39% of the Nate/Met group and 43% of the Glyb/Met groups had maintained the American Diabetes Association’s recommended A1C goal of ≤7.0% at the end of 2 years. The mean change in FPG from baseline to week 104 was -0.6±0.2 mmol/L in the Nate/Met group (P<.0001) and -2.4±0.2 mmol/L in the Glyb/Met group.

Although the results were similar in terms of glycemic control, there were some important differences observed in terms of side effects. Body weight in the Nate/Met group decreased slightly (∆ = -4.0±0.4 kg), whereas body weight in the Glyb/Met group increased slightly (∆ = 0.8±0.5 kg). This difference was statistically significant. One or more episodes of hypoglycemia was reported by 8.2% of the Nate/Met group vs 17.7% of the Glyb/Met group (P = .003).

The results of this trial suggest that combination therapy with both an insulinotropic and an insulin-sensitizing agent is an efficacious method for maintaining glycemic control. Within this study, both the Nate/Met and the Glyb/Met groups produced similar results. It should be noted, however, that the Glyb/Met group exhibited a more than 2-fold incidence of hypoglycemia in relation to the Nate/Met goup.