What is the role of semaglutide (Ozempic and Rybelsus) in the treatment of type 2 diabetes mellitus (DM)?

Updated: Jul 13, 2021
  • Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
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In December 2017, the FDA approved once-weekly semaglutide SC (Ozempic), a GLP-1 receptor agonist, as a glycemic control–improvement agent in adults with type 2 diabetes. It is administered as a subcutaneous injection once weekly. Meant as an adjunct to diet and exercise, semaglutide was approved following eight phase 3a studies (the SUSTAIN trials). 

Semaglutide SC gained FDA approval in January 2020 for risk reduction of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and heart disease. Results from the 2-year randomized study SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) led to approval for the new indication. In the trial, 3297 adults with type 2 diabetes and established cardiovascular disease (CVD) received either injectable semaglutide or placebo, in addition to stand-of-care therapy. [223, 224]

Risk for the primary composite outcome—first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke—for patients treated with semaglutide SC was a significant 26% below that for placebo patients. However, cardiovascular risk reduction primarily resulted from declines in nonfatal stroke (39%) and nonfatal myocardial infarction (26%), with cardiovascular death rates being similar between the semaglutide and placebo patients. [223, 224, 225]

In September 2019, the FDA approved the first oral GLP-1 receptor agonist, a form of semaglutide available under the brand name Rybelsus. It is administered as a once-daily oral tablet. Approval of the oral tablet was based on results from the phase 3 PIONEER trials (n=9543). The trials included head-to-head studies of oral semaglutide compared with sitagliptin (DP4 inhibitor), empagliflozin (sodium-glucose cotransporter–2 [SGLT2] inhibitor), and liraglutide 1.8 mg (GLP-1 agonist). A1c reduction was found with oral semaglutide, as well as, via a secondary endpoint, body weight reduction. [226, 227, 228]

In January 2020, the FDA updated the clinical studies section of Rybelsus’s prescribing information, with results added from the randomized, placebo-controlled study PIONEER 6 (Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes), which were released in June 2019. The report found oral semaglutide to be associated with a nonsignificant 21% reduction in three-component MACE. The information added to Rybelsus’s label related to cardiovascular safety, not benefit. [229, 224]

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