Oral Semaglutide Equal to or Better Than Injectable in Combo With Insulin, Study Says

Oral semaglutide, when used with basal insulin, is as effective or better than the injectable version in treating type 2 diabetes (T2) while providing similar tolerability.

When used with basal insulin, oral semaglutide is as effective or better than the injectable version in treating type 2 diabetes (T2) while providing similar tolerability, according to a recent study.

Researchers performed a literature review of 7 randomized clinical trials to compare efficacy and safety outcomes of 14 mg once daily of oral semaglutide (sold under the brand names Ozempic and Rybelsus), against doses of the injectable version as well as 4 other injectable versions of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) after approximately 26 weeks.

The review, published in Diabetes Therapy, found oral semaglutide was associated with significantly greater reductions in hemoglobin A1c (HbA1c) than all other types of GLP1-RAs (treatment differences, 0.42 to –1.32%); the differences with its own injectable version (0.5 mg and 1 mg) were not statistically significant.

Oral semaglutide also was associated with similar odds of side effects of nausea, vomiting, and diarrhea. As far as weight reduction, it was associated with significantly greater results than exenatide 2 mg and lixisenatide 20 μg (–2.21 and –2.39 kg, respectively); weight reductions also were higher compared with all other injectables except 1 mg of injectable semaglutide, but the differences were not statistically significant. Performance in driving HbA1c below targets of less than 7.0% and less than 6.5% were similar to oral semaglutide.

Given the progressive nature of T2D, physicians often intensify efforts to control glucose levels and reach the targets of less than 7.0% or less than 6.5%, the authors said. For patients who fail to achieve glycemic control after initial treatment with metformin, GLP1-RAs are among the options available. Others recommended by the American Diabetes Association and the European Association for the Study of Diabetes are sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors.

Some patients still require insulin treatment—typically basal insulin—despite intensive noninsulin therapy, the authors said. Most receiving basal insulin across Europe (78.1%) and the United States (72.2%) still fail to achieve adequate glycemic control 3 and 24 months after start of treatment. At that point, the options are adding quick-acting bolus insulin, other antidiabetic drugs, or GLP-1 RAs. The combination with GLP-1 RAs has been effective in bringing in controlling glucose levels without causing increased instances of hypoglycemia or weight gain compared to adding mealtime insulin.

Once-daily oral semaglutide 14 mg was associated with significantly higher odds of achieving HbA1c <7% vs. once-weekly dulaglutide 1.5 mg, twice-daily exenatide 10 μg, once-weekly exenatide 2 mg and once-daily lixisenatide 20 μg. The odds of achieving HbA1c <7% with once-daily oral semaglutide 14 mg were greater, although not statistically significant, when compared with once-daily liraglutide 1.8 mg and once-weekly injectable semaglutide 0.5 mg. Once-weekly injectable semaglutide 1 mg was associated with greater odds, although not statistically significant, of achieving HbA1c <7% vs. once-daily oral semaglutide 14 mg.

Oral semaglutide was not associated with significantly different odds of experiencing nausea or diarrhea compared with the other drugs. The odds of vomiting with oral semaglutide 14 mg were significantly lower compared with once-weekly dulaglutide 1.5 mg and once-daily lixisenatide 20 μg.

Once-daily oral semaglutide is the first GLP-1 RA in tablet form for the treatment of T2D in adults. The Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) phase 3 clinical program demonstrated efficacy and safety for early- to late-stage disease.

The authors considered the findings of their literature review to be robust based on the quality and homogeneity of the trials examined.


Chubb B, Gupta P, Gupta J, et al. Once-daily oral semaglutide versus injectable GLP-1 RAs in people with type 2 diabetes inadequately controlled on basal insulin: Systematic review and network meta-analysis. Diabetes Ther. Published online March 16, 2021. doi:10.1007/s13300-021-01034-w

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