Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Treatment with Oral Drugs

Till the turn of the century, treatment of hyperglycemia in Type 2 diabetes was limited to two main classes of oral agents: sulfonylureas and biguanides. In the meantime, better understanding of the pathophysiology of hyperglycemia in Type 2 diabetes has been gained and the identification of several pathogenitic mechanisms has enabled moving from serendipitous discovery – as for sulfonylureas and metformin – to the development of agents with more targeted modes of action. Current guidelines concur in recommending metformin at diagnosis of diabetes. Selection of the second drug therapy should be made on the basis of an educated process tacking into consideration efficacy, risk of hypoglycemia, effect on body weight, costs of different drugs, as well as patient’s characteristics. With more clinical data generated, other features of the available oral agents should be taken into account such as durability, predominant effect on fasting vs. postprandial glucose, as well effects beyond their glucose lowering capacity