GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and eliminated (mainly by kidneys) too fast (half-life 1–2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement, were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications.
Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide q.w., all for s.c. injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality.
It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).
…Recently, an oral preparation of semaglutide has been developed, which contains semaglutide (identical to the compound used for s.c. injection) and an absorption enhancer, Sodium N-(8-(2-hydroxybenzoyl) Amino) Caprylat (SNAC), which locally raises pH, prevents degradation of semaglutide, and facilitates absorption, most likely through gastric mucosa (28). Note that the bioavailability is still low, and much more peptide needs to be ingested to achieve similar plasma concentrations and efficacy (up to 14 mg per day as compared to 1 mg per week in the case of semaglutide for s.c. injection, ie. a 98-fold difference). To compensate for low and variable absorption, this oral preparation of semaglutide is recommended to be taken once daily. Predictable absorption and exposure to the drug requires it to be taken after an overnight fast with a small volume of water. A 30-min interval between the ingestion of the drug and the subsequent meal is required, before more fluid, food or other medications can be taken (28). Nevertheless, the development of an oral drug is a remarkable achievement and innovation.