The Clinical Impact of GLP-1 Receptor Agonists in Type 2 Diabetes: Focus on the Long-Acting Analogs

Abstract

GLP-1 receptor agonists (GLP-1 RAs), introduced for clinical use in 2005, have excellent potency in reducing HbA1c and mean glucose, improving fasting plasma glucose, inducing weight loss or protecting against the weight gain associated with insulin therapy, reducing appetite, and delaying gastric emptying. Two of these medications, liraglutide and semaglutide, appear to have cardioprotective effects as reflected in cardiovascular outcomes studies. The GLP-1 RAs are associated with gastrointestinal side effects that tend to diminish over time. They have very low risk of hypoglycemia unless used in conjunction with insulin or insulin secretagogues. Two coformulations of GLP-1 RAs together with long-acting basal insulin are available for daily use. The original GLP-1 RA, exenatide, requires twice-daily injections; two short-acting analogs are given once daily. Three currently available long-acting GLP-1 RAs are injected once weekly, providing greater convenience and potentially improving patient adherence. Semaglutide appears to be the most effective in terms of HbA1c reduction and weight loss. GLP-1 RAs can be combined with all classes of antihyperglycemic agents except DPP-4 inhibitors. Current studies are exploring the use of an implantable osmotic pump for long-term administration of a rapid acting analog (exenatide), an oral preparation of semaglutide, benefits for management of obesity and nonalcoholic steatohepatitis, and mechanisms of cardioprotective effects.