Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes considered for injectable GLP-1 receptor agonist therapy or currently on insulin therapy

Abstract

Injectable therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin are high-efficacy options for people with type 2 diabetes (T2D) who require treatment intensification. In addition to high glycemic efficacy, GLP-1RAs offer weight loss benefits, and some agents have been shown to reduce cardiovascular risk. This article summarizes data from two clinical studies with the first oral GLP-1RA, oral semaglutide, in situations where injectable therapy is often considered, and provides guidance on use in primary care. PIONEER 4 compared oral semaglutide 14 mg with an injectable GLP-1RA, liraglutide 1.8 mg, or placebo in patients uncontrolled on oral glucose-lowering therapies. PIONEER 8 compared oral semaglutide with placebo in patients with T2D already on insulin therapy. Treatment with oral semaglutide gave similar reductions in glycated hemoglobin (HbA 1c) compared with liraglutide at 26 weeks, and significantly greater reductions at 52 weeks. Changes in body weight with oral semaglutide were significantly greater compared with liraglutide after 26 and 52 weeks. Adding oral semaglutide 7 or 14 mg to insulin resulted in significant reductions in HbA 1c and body weight at both 26 and 52 weeks compared with placebo, and facilitated a decrease in total daily insulin dosage. Oral semaglutide was associated with low proportions of patients experiencing severe or blood-glucose-confirmed symptomatic hypoglycemia when added to oral glucoselowering therapies, and did not increase the incidence of such events when added to insulin. The tolerability profile of oral semaglutide was consistent with that seen for injectable GLP-1RAs, with gastrointestinal side effects seen most frequently; most were transient and tended to occur during dose escalation. For patients requiring treatment intensification after oral therapy or as add-on to insulin, oral semaglutide provides effective glucose lowering and body weight loss, with low risk of hypoglycemia, thus broadening the range of therapeutic options for treatment of T2D in primary care.

Meeting the Challenge of Virtual Diabetes Care: A Consensus Viewpoint on the Positioning and Value of Oral Semaglutide in Routine Clinical Practice

“…Semaglutide improves hyperglycaemia by stimulating beta-cell insulin secretion and reducing alpha-cell production of glucagon secretion in both the fasting and post-fed state [ 20 , 21 ]. Lower glucagon levels result in a reduction in post-hepatic glucose production.…”

“…Lower glucagon levels result in a reduction in post-hepatic glucose production. Additionally, the drug slows gastric emptying and improves satiety, thereby favouring weight loss [ 20 , 21 ]. Furthermore, semaglutide also demonstrates a beneficial effect on plasma lipids, lowering systolic blood pressure and reducing inflammation [ 22 , 23 ].…”

“…After at least 1 month of 7 mg tablets once daily, the dose can be increased to a maintenance daily dose of 14 mg tablets to further improve glycaemic control if required (taking two 7 mg tablets to achieve the effect of one 14 mg dose has not been studied, but would increase the cost, and so is not recommended). This escalation will minimise gastrointestinal adverse reactions during the initial stages of treatment [ 21 ]. While these reactions are typically mild to moderate and abate over time [ 20 , 21 ], monitoring of renal function in people with T2D experiencing severe gastrointestinal reactions is recommended in case of potential dehydration.…”

Structural basis of peptidomimetic agonism revealed by small molecule GLP-1R agonists Boc5 and WB4-24

“…With the established therapeutic effects that derive mainly from potentiation of glucose-dependent insulin secretion and suppression of appetite (5), considerable efforts have been made in developing orally available GLP-1R agonists. Semaglutide (Rybelsus ® ) is the first and only one noninjectable formulation in the clinic in spite of its low bioavailability and frequent gastrointestinal complaints, such as nausea and vomiting (6,7). To circumvent these problems, search for non-peptidic agonists suitable for oral administration has never stopped.…”

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

“…Despite the therapeutic success, currently available GLP-1R agonists are suboptimal due to poor patient compliance caused by subcutaneous injections and several side-effects such as nausea and vomiting 4,5 . Oral-delivery of GLP-1 mimetics have been pursued for many years, with semaglutide being the first and only one in the clinic albeit its low bioavailability and frequent gastrointestinal complaints 6,7 . Thus, development of orally active small molecule GLP-1R modulators remains an attractive strategy and a few compounds have progressed to clinical trials 8 .…”