Recent developments in GLP‐1RA therapy: A review of the latest evidence of efficacy and safety and differences within the class

As of 2021, 9 % of the global population is now affected by type 2 diabetes mellitus (T2DM). In the United Kingdom, 20% of National Health Service in-patients suffer from diabetes as a co-morbidity, while 10% of healthcare expenditure is linked to diabetes. Failed attempts to reduce the diabetes epidemic are due to an inability to halt rising levels of obesity and sedentary lifestyle. This has led to the development of an abundance of therapeutic agents to control hyperglycaemia and in the United States, there are now 12 different classes of glucose-lowering medication. The glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) act in a glucose-dependent manner by enhancing insulin secretion and reducing production of glucagon. GLP-1RAs are peptides that are resistant to dipeptidyl peptidase and provide supra-physiological stimulation of the GLP-1 receptor. They also retard gastric emptying and increase satiety; these effects in tandem lead to weight loss in a substantial proportion of people with T2DM. Exenatide was the first GLP-1RA to be launched and was based on the exendin-4 molecule (isolated from Gila Monster lizard saliva) and is administered by twice-daily subcutaneous injection at meal times due to its short half-life. Subsequent GLP-1RAs were longer acting, once daily (OD) preparations (liraglutide and lixisenatide) administered without regard to meals. Then in 2011, the European Medicines Agency (EMA) issued authorisation for the first long-acting GLP-1RA, a once-weekly (QW) version of exenatide. Currently, the most widely prescribed GLP-1RA is liraglutide, however, the convenience of less frequent dosing has led to an expansion of new prescriptions of the once-weekly GLP-1RAs. Unfortunately, exenatide extended-release (ER) is manufactured as microspheres suspended in a vehicle of medium-chain triglycerides, which requires vigorous shaking (>15 seconds) prior to injection. Injection-site swelling is also a prevalent issue due to the slow clearance of the co-formulated polymer, which does not resolve itself until several weeks following injection. As a result, exenatide ER is less frequently prescribed and this review will focus on dulaglutide and semaglutide. Dulaglutide was launched in 2014 and is a polypeptide analogue of human GLP-1 covalently linked to the Fc arms of human immunoglobulin G4. This structure reduces immunogenicity and is soluble allowing for simple administration of a clear solution. Dulaglutide is administered in four doses (0.75, 1.5, 3.0 and 4.5 mg QW) and the lower two doses have no need for up-titration. More recently, the long-acting GLP-1RA semaglutide was approved (2018). This molecule is 94% homologous with human GLP-1, differing by only two amino acids. There is an 18-carbon fatty di-acid chain attached to amino acid 26 of the molecule that provides strong binding to albumin and facilitates prolonged activity. A benefit of the long-acting GLP1RA semaglutide is its administration as a clear solution that does not require resuspension. It is initiated at a dose of 0.25 mg QW titrated after 1 month to a maintenance dose of 0.5 mg with the option for further up-titration to 1.0 mg QW.