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

Postgrad Med. 2020 Nov;132(sup2):26-36. doi: 10.1080/00325481.2020.1798127. Epub 2020 Sep 8.


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 (HbA1 c) 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 HbA1 c 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 glucose-lowering 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.

Keywords: Oral semaglutide; comparative studies; glucagon-like peptide-1 receptor agonist; injectable therapy; insulin; treatment escalation; type 2 diabetes.

Publication types

  • Review
  • Video-Audio Media

MeSH terms

  • Administration, Oral
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptides / administration & dosage*
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Insulin / therapeutic use
  • Placebos
  • Randomized Controlled Trials as Topic


  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulin
  • Placebos
  • semaglutide
  • Glucagon-Like Peptides