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When given orally in a tablet together with an absorption enhancer, semaglutide undergoes transcellular absorption in the stomach. Although associated with low bioavailability, semaglutide delivered in this way provides systemic effects similar to those when given as injections. Beyond intrinsic factors such as absorbability, extrinsic factors may also affect how well orally administered semaglutide is absorbed or functions. Accordingly, Meier and co-workers investigated if the presence of upper GI disease impacts the pharmacokinetics of oral semaglutide in people with type 2 diabetes. There were no significant differences in the pharmacokinetics or safety and tolerability between participants with mild-to-moderate upper GI disease (chronic gastritis or gastroesophageal reflux disease) and those without. As noted by the authors, this reassuringly allows for the use of the orally administered semaglutide regardless of presence of such diseases, which are relatively common amongst people living with diabetes.

Whilst dose escalation regimens have been designed for GLP-1 RAs to improve tolerability, GI side effects such as nausea, vomiting and diarrhoea represent barriers that may limit the real-world usage of the drug class. Efforts to mitigate this situation would arguably allow for greater use of and better adherence to GLP-1 RA treatment. In this paper, which is accompanied by a narrated video, Wharton and colleagues provide their evidence-based and personal recommendations on how to best manage the GI side effects of GLP-1 RAs in weight management. 

To evaluate if people with type 2 diabetes can achieve better glycaemic control with GLP-1 RA treatment whilst avoiding unacceptable gastrointestinal and other side effects, De Vries and colleagues analysed data from five of the phase 3 trials in the clinical development programme for once-weekly s.c. semaglutide in T2D (SUSTAIN 1-5). In this post hoc analysis, with semaglutide 0.5 or 1.0 mg (vs. placebo and active comparators) more participants were able to achieve better glycaemia control (HbA1c <7.0%) without experiencing moderate or severe GI adverse events, weight gain and severe or symptomatic hypoglycaemia. 

GLP-1 RA treatment is associated with weight loss but also with GI side effects such as nausea and vomiting. To what extent do these side effects contribute to the weight loss? Analysing data from five of the phase 3 trials in the clinical development programme for once-weekly s.c. semaglutide in T2D (SUSTAIN 1-5), Ahrén and co-workers examined this aspect and found that only a minor fraction of the observed weight loss was mediated by nausea and vomiting. Similar results were reported by Lingvay and colleagues, who found that the nausea and vomiting occurring during the dose-escalation phase of SUTAIN 3, 7 and 10 only had very little impact on the weight loss achieved by the participants at end-of-trial. 

The effectiveness of GLP-1 RAs is a complex matter, governed by various factors including how well recipients are satisfied with and tolerate the treatment regimen. In a paper analysing various aspects of the effects of once-weekly s.c. semaglutide in SUSTAIN 2-5 and 7, Jendle et al. , evaluated the extent to which GI adverse events affected treatment satisfaction as assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ), a patient-reported outcome. Although the picture was slightly more complex in SUSTAIN 7, the common finding was that treatment with semaglutide consistently improved treatment satisfaction (vs. active comparators or placebo) regardless of whether trial participants had experienced GI adverse events during treatment.