In uncontrolled type 2 diabetes, adjunctive semaglutide reduced HbA1c and body weight vs sitagliptin

The trial showed that an oral glucagon-like peptide-1–receptor analogue improved glycemic control compared to a dipeptidyl peptidase 4 inhibitor, but gastrointestinal side effects and cost remain barriers to use of the former class.


Compared to oral sitagliptin at 100 mg/d, oral semaglutide at 7 or 14 mg/d, but not 3 mg/d, led to greater improvements in glycemic control in patients whose type 2 diabetes was previously uncontrolled with metformin, with or without a sulfonylurea, an industry-funded study found. The randomized trial included 1,864 adults from 206 sites in 14 countries and found larger reductions in HbA1c level and body weight with semaglutide than sitagliptin.

The study was published on March 23 by JAMA and summarized in the April ACP Diabetes Monthly. The following commentary by Lorraine L. Lipscombe, MD, MSc, was published in the ACP Journal Club section of the Aug. 20 Annals of Internal Medicine.

Intensive glycemic control targeting HbA1c≤ 7% is recommended for most patients with type 2 diabetes to reduce microvascular complications. It is now easier to achieve with incretin-based agents, such as glucagon-like peptide-1–receptor analogues (GLP-1RAs) and dipeptidyl peptidase 4 (DPP-4) inhibitors, which lower glucose without increasing risk for hypoglycemia or weight gain. Evidence indicates that GLP-1RAs may be superior to DPP-4 inhibitors for glycemic efficacy, weight loss, and cardiovascular outcomes. However, major limitations of GLP-RAs include gastrointestinal (GI) side effects, higher cost, and need for subcutaneous injection.

The PIONEER 3 trial by Rosenstock and colleagues shows that an oral GLP-1RA can reduce HbA1c and weight, and is comparable to subcutaneous formulations. Although these benefits were superior to the oral DPP-4 inhibitor sitagliptin, GI side effects and premature discontinuation were up to 2 times more common with oral semaglutide. Of note, trial participants were relatively young (mean age 58 y) and free of comorbidity. GI tolerability may be more of a barrier to semaglutide use in older patients or those already receiving multiple medications.

The trial supports the choice of oral semaglutide over sitagliptin when an incretin-based agent is being considered for patients who want to avoid injectable medications. However, as with all GLP-1RAs, high cost and GI side effects are important barriers to use. Weekly subcutaneous semaglutide may also be more convenient for some patients, and given that superiority of oral semaglutide for cardiovascular outcomes was not demonstrated in the PIONEER 6 trial, subcutaneous semaglutide or liraglutide may be favored for patients with cardiovascular disease.