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.