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2 After 18 months, the WL, WL + AT, and WL + RT groups achieved weight reductions of 5.7 kg, 9.9 kg, and 10.1 kg, respectively

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Mechanisms of Action-Mediated DDIs Furthermore, assessing DDIs for GLP-1 RAs and a dual GLP-1/GIP RA requires additional considerations, including the possible occurrence of DDIs mediated by mechanisms of action that remain poorly understood (Figure 3).120 Long-acting GLP-1 RAs remain in the body for an extended period (eg, with a mean residence time [MRT] of 224 hours at a steady state after administering 14 mg of oral semaglutide).141 This prolonged duration may be driven by albumin binding to the fatty acid residues of GLP-1 RAs and their ability to escape protease metabolism due to amino acid substitutions (Figure 1).141 They remain in the body, interacting with GLP-1 receptors in various organs, which could lead to DDIs through mechanisms of action such as slowing gastric emptying, reducing fat mass and inflammation, and increasing glomerular filtration rate (GFR) and renal plasma flow, consequently altering the pharmacokinetics of the victim drug (Figure 3).124,142 Investigations into mechanism of action-mediated pharmacokinetic DDIs are currently limited to those mediated by the slowing of gastric emptying, with examples summarized in other reviews.124,143 The pharmacokinetic DDI are commonly expressed in terms of victim drug and perpetrator drug