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Type 2 diabetes mellitus (T2DM) is a chronic, progressive illness that requires continuing medical care to prevent acute complications and to reduce the risk of long-term complications, particularly cardiovascular events.[1] According to the recommendations of the American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD), the main therapeutic goal in T2DM is the achievement and maintenance of glycaemic levels as close to the nondiabetic range as possible (glycosylated haemoglobin [HbA1C] <7.0%).[2] In addition, a comprehensive approach to managing patients with T2DM requires targeting the associated cardiovascular risk factors such as overweight/obesity, hypertension and dyslipidaemia.[1,3,4] Based on the data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES), however, only 13.2% of patients with diagnosed T2DM achieved concurrent recommended treatment targets for glucose, lipid and blood pressure (BP) levels,[5] and a nationwide survey in Norway suggests that a similar pattern is likely to occur in European countries.[6] For these reasons, along with the increasing prevalence of T2DM, the high burden of its comorbid conditions, the lack of adequate long-term glycaemic control and the adverse effects often associated with traditional antidiabetic therapies (mainly weight gain and hypoglycaemia), a better use of available glucose-lowering drugs and hopefully the development of new pharmacological agents with better risk-benefit ratios and greater patient acceptability are warranted.[3,4,7,8] In particular, anti-diabetic agents that would beneficially affect, or at least not worsen, common comorbidities are highly desirable.[9]
Traditional antihyperglycaemic drugs include insulin and insulin analogues, insulin sensitizers (metformin and thiazolidinediones), insulin secretagogues (sulfonylureas and glinides) and agents that inhibit dietary carbohydrate breakdown (α-glucosidase inhibitors).[10] Novel antidiabetic drugs, developed on the basis of an improved understanding of the mechanisms that govern glucose homeostasis, include the incretin-based agents, namely glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors (also named 'gliptins').[8] These drugs enhance glucose-dependent insulin secretion from pancreactic β cells and glucose-dependent suppression of glucagon release from pancreatic α cells, respectively, by mimicking the glucoregulatory effects of endogenous GLP-1 (GLP-1 receptor agonists or incretin mimetics) or enhancing endogenous GLP-1 concentrations (DPP-4 inhibitors or incretin enhancers). Importantly, they do not cause hypoglycaemia or weight gain. In addition, preclinical studies and evaluation of markers of β-cell function in clinical trials of DPP-4 inhibitor efficacy have shown that these agents...