Gastrointestinal tolerability of once‐weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss

Abstract

Aim: We evaluated gastrointestinal (GI) adverse events (AEs) with once-weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL). Materials and methods: AE analyses pooled data from the Semaglutide TreatmentEffect in People With Obesity (STEP) 1-3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run-in.Results: GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), All trials were registered with ClinicalTrials.gov (NCT03548935, NCT03552757, NCT03611582 and NCT03548987).

Once-weekly 2.4 mg Semaglutide for Weight Management in Obesity: A Game Changer?

“…Reducing portions sizes and avoiding fatty foods may also help. 42,[51][52][53][54][59][60][61]66 These GI side effects, along with slow gastric emptying, cannot, however, be considered responsible for the drug's effect on weight loss. 66 Globally, patients treated with 2.4 mg semaglutide in the STEP clinical programme have discontinued the treatment due to adverse events at a higher rate (7%) than those on placebo (3.1%), primarily due to GI adverse events (4.5% versus 0.8%).…”

“…42,[51][52][53][54][59][60][61]66 These GI side effects, along with slow gastric emptying, cannot, however, be considered responsible for the drug's effect on weight loss. 66 Globally, patients treated with 2.4 mg semaglutide in the STEP clinical programme have discontinued the treatment due to adverse events at a higher rate (7%) than those on placebo (3.1%), primarily due to GI adverse events (4.5% versus 0.8%). 42,[51][52][53][54][59][60][61]66 Following on from the theory that molecules acting on two or more different receptors would be expected to generate more weight loss than a single receptor agonist, new molecules have been engineered.…”

“… 42 , 51 – 54 , 59 – 61 , 66 These GI side effects, along with slow gastric emptying, cannot, however, be considered responsible for the drug's effect on weight loss. 66 Like the other GLP-1 RAs, semaglutide has a black box warning for medullary thyroid carcinoma (although thyroid cancers have not been reported in human trials) and should not be used in patients with a personal or family history of medullary carcinoma or multiple endocrine neoplasia syndrome. There are also no concerns about an increased risk of other cancers.…”

Preventing all‐cause hospitalizations in type 2 diabetes with sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: A narrative review and proposed clinical approach

“…GLP‐1RAs are associated with gastrointestinal adverse events such as nausea, diarrhoea, constipation and vomiting, which may lead to dehydration and subsequent hospitalization 74 . The GLP‐1RA regimen should be initiated with a low dose and increased gradually, while paying attention to the possible emergence of adverse events 106,107 …”

“…74 The GLP-1RA regimen should be initiated with a low dose and increased gradually, while paying attention to the possible emergence of adverse events. 106,107 Use of SGLT2 inhibitors reduces eGFR levels by an average of 4 to 6 mL/min/1.73 m 2 immediately upon treatment initiation. 13,15,17 However, a smaller than 30% acute eGFR decrease in patients with diabetic kidney disease was not associated with a higher risk of adverse safety outcomes.…”