Patients with type 2 diabetes have multiple defects contributing to hyperglycaemia including insulin resistance, inadequate insulin secretion and excessive hepatic glucose production. Oral antihyperglycaemic agents (OHA) that target any of these metabolic defects will improve glucose levels . Metformin, the most commonly prescribed OHA, targets excessive hepatic glucose output and insulin resistance [2,3]. While defective at the time of diagnosis, β-cell function continues to deteriorate over time in patients with type 2 diabetes, leading to progressive failure of insulin secretion. This progressive loss of β-cell function may explain why many patients who initially achieve glycaemic control fail to maintain control at levels consistent with current guidelines [e.g. haemoglobin A1c (HbA1c) < 7 or <6.5%] and hence require additional therapies . Sulfonylureas, which act as insulin secretagogues, are the most common next therapeutic step when patients do not achieve or maintain glycaemic control on metformin . Glycaemic efficacy is similar across sulfonylurea agents [5,6]. Sulfonylurea stimulation of insulin secretion is not strictly glucose dependent . Although generally well tolerated, these agents are associated with hypoglycaemia because of continued stimulation of insulin secretion with falling glucose concentrations . Weight gain is another common side effect of sulfonylurea treatment, potentially related to the sulfonylurea-induced increase in insulin concentrations . An agent that can provide efficacy similar to a sulfonylurea but with a better safety profile could provide a useful alternative.
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a novel treatment for type 2 diabetes that improves glycaemic control through a new mechanism, enhancement of the incretin axis [8–10]. Sitagliptin inhibits the enzymatic degradation and inactivation of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) [11,12]. These incretins augment glucose-induced insulin secretion after meals. In addition, GLP-1 suppresses glucagon release, delays gastric emptying and increases satiety [13–15]. Notably, incretin-induced stimulation of insulin release and the suppression of glucagon release by GLP-1 occur in a glucose-dependent fashion. Studies have shown, for example that at normal or elevated glucose levels, GLP-1 potently stimulates insulin secretion and inhibits glucagon release – effects that disappear when glucose levels approach normal concentrations . Single doses of sitagliptin have been shown to increase active GLP-1 and GIP levels, enhance insulin secretion and suppress glucagon release in patients with type 2 diabetes . In prior clinical studies, sitagliptin added to ongoing metformin monotherapy significantly improved fasting and postprandial glycaemic control and measures of β-cell function in patients with type 2 diabetes [17,18]. Moreover, in these trials, sitagliptin was well tolerated with a neutral effect on body weight and a low risk of hypoglycaemia and gastrointestinal adverse experiences. The present 52-week study in patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy was designed to compare the glycaemic efficacy and safety of the addition of sitagliptin with that of a standard sulfonylurea agent, glipizide.