Comparison of Repaglinide and Nateglinide in Combination With Metformin: Response to Raskin et al.

I believe there are significant limitations in the study by Raskin et al. (1) in the June issue of Diabetes Care that preclude broad conclusions about the relative efficacy of nateglinide and repaglinide. They presented the results of a “head-to-head assessment of the relative efficacy and safety of repaglinide versus nateglinide, under conditions of combination therapy with metformin.”

The authors concluded that when both agents were compared in combination with metformin, repaglinide lowered fasting plasma glucose and HbA_1c significantly better than nateglinide and with a similar safety profile. The design of the study precludes drawing conclusions about the comparable efficacy of these agents. Patients were titrated to 2 g/day of metformin (if they were currently taking metformin) or switched from either a sulfonylurea or Glucovance to metformin, which was titrated to 2 g/day. Titration to the final metformin dose occurred over 4 weeks, at which point either repaglinide or nateglinide was added.

Combination therapy is usually initiated as either first-line therapy in drug-naïve patients or added to stable doses of current therapy if glycemic goals are not met. This study was neither a head-to-head comparison of initial combination therapy with repaglinide/metformin versus nateglinide/metformin nor a true comparison of repaglinide and nateglinide added to metformin. In order to compare the efficacy of these agents as add-on therapy to metformin over a 16-week period, patients should have been maintained on the final dose of metformin for a sufficient period to allow their glycemic control to stabilize and establish a clear baseline.

The most important limitation of the study is that the nateglinide/metformin treatment arm was biased by including patients recently treated with sulfonylureas. The nateglinide label states that patients should not be switched from a sulfonylurea to nateglinide. Over one-third (33 of 96) of patients receiving the nateglinide/metformin combination had been on sulfonylurea monotherapy or Glucovance before being switched to the combination and were therefore treated outside of product labeling.

In addition, the underlying assumptions and relevant background information whereby the imputation method was chosen to handle missing data are not provided. Imputation is generally considered exploratory in nature, whereas the last observation carried forward approach is conservative and appropriate when reductions in the parameter under consideration reflect the improvement of disease.

Finally, the authors conclude that repaglinide achieved improved glycemic control with no difference in safety compared with nateglinide; however, there was a 3.5-fold increase in the incidence of hypoglycemia with repaglinide compared with nateglinide.

We believe that for the appropriate patient, nateglinide is a valuable treatment option to control postmeal glucose and reduce HbA_1c and trust that physicians will continue to exercise discretion in evaluating product comparisons before making clinical decisions.