The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients: response to Poulsen et al.

OBJECTIVE Type 2 diabetes is caused by reduced insulin secretion and insulin resistance in skeletal muscle and liver. We tested the combination therapy with insulin aspart, rosiglitazone, and metformin with the purpose of treating all three defects in order to test the hypothesis that this "triple therapy" will normalize glucose metabolism. RESEARCH DESIGN AND METHODS Sixteen obese type 2 diabetic outpatients on human NPH or MIX (regular + NPH insulin) insulin twice daily were randomized to either triple therapy, i.e., insulin aspart (a rapid-acting insulin analog) at meals, metformin (which improves hepatic insulin sensitivity), and rosiglitazone (which improves peripheral insulin sensitivity), or to continue their NPH or MIX insulin twice daily for 6 months. Insulin doses were adjusted in both groups based on algorithms. HbA(1c), insulin dose, hypoglycemic episodes, insulin sensitivity (clamp), hepatic glucose production (tracer), and diurnal profiles of plasma glucose and insulin were used in evaluating treatment. RESULTS In the triple therapy group, HbA(1c) declined from 8.8 to 6.8% (P < 0.01) without inducing severe hypoglycemic events. Postprandial hyperglycemia was generally avoided, and the diurnal profile of serum insulin showed fast and high peaks without any need to increase insulin dose. In the control group, the insulin dose was increased by 50%, but nevertheless both HbA(1c) and 24-h blood glucose profiles remained unchanged. Insulin sensitivity improved in both skeletal muscle and the liver in the triple therapy group, whereas no change was observed in the control group. CONCLUSIONS We conclude that treatment of the three major pathophysiological defects in type 2 diabetic subjects by triple therapy significantly improved glucose metabolism in obese type 2 diabetic subjects.