Combination of nateglinide with thiazolidinediones in Type 2 diabetes

Insulin sensitivity and insulin secretion are reciprocally related such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. Treatment of Type 2 diabetes should aim to restore and sustain the normal relationship between insulin sensitivity and secretion. Nateglinide is a rapid-onset, short-acting insulin-secretion enhancer that restores early-phase insulin secretion, reduces postprandial glucose excursions and prevents long-term hyperinsulinemia. Given its mechanism of action, it is evident that nateglinide would be more effective when used in combination with an insulin sensitizer, such as the thiazolidinediones. Thiazolidinediones do not stimulate insulin release and, therefore, are potentially suitable candidates for combination therapy with an insulin-secretion enhancer, such as nateglinide. Combination therapy of thiazolidinediones with nateglinide is effective, carries low risk of hypoglycemia and is suitable for patients with moderate renal impairment, although weight gain and edema are common side effects. Further studies are needed to determine whether nateglinide in combination with thiazolidinediones will help clinicians better achieve their treatment goals in targeting Type 2 diabetes. Moreover, comparative studies between nateglinide and medications targeting postprandial glycemia, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, are necessary. This article summarizes data concerning the mechanism of action, efficacy and safety of therapy with nateglinide and thiazolidinediones as monotherapy and in combination treatment, and aims at a better understanding of the substrate defects their synergy hopes to defy.