The Combined Effect of Triple Therapy with Rosiglitazone, Metformin, and Insulin Aspart in Type 2 Diabetic Patients

Response to Poulsen et al.

I have some concerns regarding the results of Poulsen et al.’s (1) study, which suggested that triple therapy with insulin aspart, metformin, and rosiglitazone was superior to continuing treatment with NPH insulin alone or NPH plus regular insulin (referred to as the control group). These results should be interpreted with caution because of several limitations in the study’s design. First, I disagree with the authors for applying “identical” goals for metabolic control in both study groups. Although the glycemic target was similar in both arms, the timing of self-monitored blood glucose was different. Thus, the adjustment of the insulin dosage in the control group aimed at blood glucose levels between 5 and 7 mmol/l in the preprandial period, whereas in the triple therapy group, insulin adjustment targeted the same range of blood glucose but in the postprandial period. Clearly, setting a glycemic goal of 5–7 mmol/l for postprandial blood glucose was quite aggressive and substantially lower than the recommendations of the American Diabetes Association (<10.0 mmol/l) (2). This more stringent glycemic target in the triple therapy group compared with the control group may explain, at least in part, the superior metabolic control observed with the triple therapy regimen. In addition, the bias that favored the triple therapy group (e.g., providing closer follow-up and care) could not be excluded since the study was not blinded. Moreover, the investigators may have been reluctant to further increase insulin doses in the control group to achieve the study’s preprandial glycemic goal because of the concern over hypoglycemia. Second, some patients in the control group received NPH twice daily and others received a mixture of NPH plus regular insulin. These two treatment regimens are different and should not be included in a single group because diabetic subjects receiving NPH alone may have inadequate plasma levels of postprandial insulin. Third, one limitation of triple therapy is the high cost of treatment and related laboratory tests, a factor that was not clarified in the study presumably because the three drugs were provided at no cost by the respective companies.

Despite these limitations, this pilot investigation addressed an attractive therapeutic approach that targeted the three main defects in the pathophysiology of type 2 diabetes. In this respect, the study’s findings suggested that insulin resistance was probably the hardest abnormality to correct. Indeed, the combination of the two insulin-sensitizing agents, metformin and rosiglitazone, in maximum therapeutic doses resulted in only partial amelioration of insulin sensitivity after 6 months (1). It would be interesting to evaluate the long-term effects and cost-effectiveness of this form of triple therapy in type 2 diabetes in well-designed trials.