Introduction
The association between type 2 diabetes (T2D) and overweight/obesity is well established,1 2 with more than 90% of people with T2D being overweight.3 Individuals with T2D and overweight/obesity are at increased risk of developing T2D complications compared with people who are not overweight/obese.4 Body weight (BW) reductions of ≥5% improve glycemic control, lipid levels and blood pressure.5 BW control is an important component of an individualized, multifactorial approach to T2D management, as recommended in current treatment guidelines.6 7
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended as second-line therapy (add-on to metformin) where minimizing weight gain, promoting weight loss or when hypoglycemia and cardiovascular risk reduction are considerations.7–9 All available GLP-1RAs (dulaglutide, exenatide, liraglutide and lixisenatide) have demonstrated weight loss in people with T2D.10–12 Semaglutide (Novo Nordisk, Denmark) is a GLP-1RA approved for the treatment of T2D as once-weekly (OW) subcutaneous13 and once-daily oral formulations.14 The efficacy and safety of OW semaglutide have been established in the global phase 3 SUSTAIN clinical trial program, encompassing subjects from across the continuum of T2D care.15–24 In addition to significantly greater reductions in glycated hemoglobin (HbA1c), semaglutide demonstrated superior reductions in BW versus all comparators across all SUSTAIN trials.15–24
The SUSTAIN 3, 7 and 10 trials compared semaglutide with the GLP-1RAs OW exenatide extended release (exenatide ER), OW dulaglutide and once-daily liraglutide, respectively. In these trials, mean BW loss was significantly greater with semaglutide versus comparators at end of treatment (EOT: weeks 56, 40 and 30 for SUSTAIN 3, 7 and 10, respectively): SUSTAIN 3: –5.6 kg vs –1.9 kg with semaglutide 1.0 mg vs exenatide ER 2.0 mg; SUSTAIN 7: –4.6 kg vs –2.3 kg with semaglutide 0.5 mg vs dulaglutide 0.75 mg and –6.5 kg vs –3.0 kg with semaglutide 1.0 mg vs dulaglutide 1.5 mg; SUSTAIN 10: –5.8 kg vs –1.9 kg with semaglutide 1.0 mg vs liraglutide 1.2 mg; all p<0.0001.17 21 24
Consistent with the GLP-1RA class,25–27 gastrointestinal (GI) adverse events (AEs) were the most frequently reported AEs in the SUSTAIN 3, 7 and 10 trials: 42% with semaglutide 1.0 mg vs 33% with exenatide ER 2.0 mg in SUSTAIN 3; 43% with semaglutide 0.5 mg vs 33% with dulaglutide 0.75 mg and 44% with semaglutide 1.0 mg vs 48% with dulaglutide 1.5 mg in SUSTAIN 7; 44% with semaglutide 1.0 mg vs 38% with liraglutide 1.2 mg in SUSTAIN 10.17 21 24 The five most commonly reported GI AEs in SUSTAIN 3, 7 and 10 were: nausea (23% with semaglutide 0.5 mg, 21%–22% with semaglutide 1.0 mg and 12%–20% with comparators); vomiting (10% with semaglutide 0.5 mg, 7%–10% with semaglutide 1.0 mg and 4%–10% with comparators); diarrhea (14% with semaglutide 0.5 mg, 11%–16% with semaglutide 1.0 mg and 8%–18% with comparators); dyspepsia (3% with semaglutide 0.5 mg, 4%–7% with semaglutide 1.0 mg and 3%–5% with comparators) and constipation (5% with semaglutide 0.5 mg, 5%–6% with semaglutide 1.0 mg and 3%–5% with comparators).17 21 24 28
Given the clinical significance of weight loss in T2D management, it is important to understand the mechanism by which semaglutide provides greater weight loss versus class comparators and, in particular, whether it is mediated by GI AEs. A previous mediation analysis examining superior weight loss with semaglutide versus mixed class comparators by GI AEs in the SUSTAIN 1–5 trials showed that only 0.07 kg of 2.3 kg (semaglutide 0.5 mg) and 0.5 kg of 6.3 kg (semaglutide 1.0 mg) of the treatment difference in weight loss was mediated by nausea/vomiting.29
To further determine if GI AEs of nausea/vomiting and others are associated with weight loss, we performed a post hoc mediation analysis to examine the extent to which the treatment difference with semaglutide versus the other GLP-1RAs in the SUSTAIN 3, 7 and 10 trials might be driven by a difference in GI AEs (indirect effects) or treatment (direct effect). Data on nausea and/or vomiting were pooled and data on nausea, vomiting, diarrhea, constipation and dyspepsia were analyzed individually.