Oral semaglutide: A technical triumph, with caveats
We know that injectable GLP‑1 receptor agonists (GLP‑1RAs) are effective treatments for type 2 diabetes, with robust effects on glucose lowering and also significant weight reduction, an important benefit for the high proportion of people with type 2 diabetes who are overweight or obese.
Since the first GLP‑1RA, exenatide, became available in 2007 as a twice-daily injectable preparation, there have been steady advances in the duration of action, efficacy, and ease of use of this class of medicines. The most common new treatment initiations are now for once-weekly preparations, namely exenatide modified release, dulaglutide, and semaglutide. These GLP‑1RAs have all been shown to be safe from a cardiovascular perspective, and dulaglutide and semaglutide have shown lower cardiovascular events than placebo in the high-risk patients enrolled in cardiovascular outcome trials.
The GLP‑1RA class now has a firm place in the armamentarium of treatments for type 2 diabetes. However, uptake is relatively low in comparison to oral treatments, partly due to cost and associated limitations on use, but also because patients may be reluctant to use an injectable medication. Will the availability of an oral preparation of semaglutide make a difference?
An important technical advance…
The ability to achieve significant absorption of a peptide hormone from the stomach by using sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) to protect the molecule from acid and enzymatic degradation is undoubtedly an important technical advance. Oral semaglutide is absorbed sufficiently from the stomach to be effective at lowering glucose; it has been shown to be more effective than commonly used oral glucose-lowering treatments such as the dipeptidyl peptidase-4 (DPP‑4) inhibitor sitagliptin and the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin in head-to-head trials. Like the injectable preparations it does cause some weight loss; however, it should be noted that these therapeutic benefits were achieved using the highest dose of 14 mg daily, and are not as great as is seen with injectable semaglutide at the 1 mg once-weekly dose.
What about cardiovascular benefit?
The PIONEER 6 cardiovascular outcome trial was relatively small and confirmed safety, but not superiority, for reduction in major adverse cardiovascular events. There was, however, a nominally significant reduction in cardiovascular death, and a recent patient-level meta-analysis of data from PIONEER 6 and SUSTAIN 6 (the cardiovascular outcome trial with subcutaneous semaglutide) suggested cardiovascular benefit.
Convenience vs efficacy
The convenience of oral administration does have some limitations. Oral semaglutide should be taken once-daily on an empty stomach, with 100 mL of water, and patients should wait 30 min before eating. So in clinical practice, effects may be attenuated compared with trials if this guidance is not strictly followed. The adverse effect profile is similar to the injectable preparations, with nausea early in treatment that wanes over time being the major issue, so there is no particular advantage from an adverse effect perspective.
Thus overall, oral semaglutide is slightly less efficacious than the injectable preparation, requires daily compared with weekly administration, with careful attention to detail in relation to administration, and does not currently have data that unequivocally support cardiovascular benefit.
Who is this medication for?
Hence, for those patients where a GLP-1RA is being used for cardiovascular benefit, the current evidence supports the use of an injectable agent with proven efficacy for cardiovascular prevention (currently liraglutide, dulaglutide and semaglutide). For others oral semaglutide may be an alternative option for those who are averse to injections, and when the superior efficacy of the injectable preparation is not needed.
In summary, oral semaglutide is a technical triumph, but its advantages for most patients with type 2 diabetes over once-weekly injectable GLP-1RA are limited.
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