Linagliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, has a favourable pharmacokinetic profile in terms of its predominantly non-renal elimination. It shows highly selective, potent, dose-dependent inhibition of DPP-4, with ≥ 80% inhibition of DPP-4 throughout the 24-hour dosing interval. In two double-blind, multicentre trials (n >350 evaluable patients/trial) in adult patients with inadequately controlled type 2 diabetes mellitus, oral linagliptin monotherapy (5 or 10 mg once daily) was significantly more effective than placebo in improving glycaemic control and several parameters of pancreatic function, with placebo-corrected adjusted mean changes in glycosylated haemoglobin (HbA(1c)) levels of -0.69% to -0.88% after 12 or 24 weeks. Linagliptin 5 or 10 mg once daily was also significantly more efficacious than voglibose 0.2 mg three times daily in terms of improving glycaemic control in a 26-week, double-blind, multicentre trial (n >450 evaluable patients). In several similarly designed trials (n >250 evaluable patients/trial) of 12-24 weeks' duration in adult patients with inadequately controlled type 2 diabetes, oral linagliptin (5 mg once daily) as add-on therapy to metformin, a sulfonylurea drug or metformin plus a sulfonylurea drug, or in combination with pioglitazone, improved glycaemic control significantly more than placebo plus the respective oral antihyperglycaemic therapy, with improvements in adjusted mean HbA(1c) levels considered clinically relevant. Linagliptin, as monotherapy or in combination with other oral antihyperglycaemic drugs, was generally well tolerated in clinical trials, having neutral or minimal effects on bodyweight and generally being associated with a very low incidence of hypoglycaemia.