Abstract
Despite the availability of at least nine differently acting classes of glucose-lowering agents, many people with type 2 diabetes do not achieve or maintain sufficiently tight glycaemic control to avoid the complications of chronic hyperglycaemia. This narrative review examines the prospects for future non-insulin agents and therapeutic approaches in early development that aim to improve glycaemic control in type 2 diabetes. Such therapies will ideally enhance glucose lowering through existing mechanisms or by targeting different aspects of disease pathophysiology. They will avoid overt hypoglycaemia and facilitate weight control and be convenient to use, have minimal adverse effects, provide benefits against common comorbidities and have a commendable overall safety profile. Particularly promising therapies in development are the co-agonist and multi-agonist incretin-based and amylin-based synthetic peptides that improve glycaemic control and body weight regulation. Initial studies suggest that such therapies can improve insulin secretion, assist pancreatic beta cell preservation and enhance insulin-mediated glucose metabolism while reducing glucagon secretion and risk of fatty liver disease. Antibodies and small molecules that interact with incretin targets are also being developed, as well as agents to modulate mitochondrial function, fatty acid receptors and receptors for selected gastrointestinal and adipocyte peptides that affect appetite or pathways of nutrient metabolism. Multiomics, miRNAs, gene-editing technologies and epigenetic targets have received considerable attention but have yet to deliver usable therapies. Directing therapeutic agents to specific organs or tissues and avoiding unwanted off-target effects continue to challenge the application of laboratory innovations into viable clinical agents. However, recent successes with weight-lowering incretin-based medicines have raised expectations for pharmaceutical pipelines to transform the management of type 2 diabetes.