Optimizing Reporting and Outreach for Surveillance and Risk-Reducing Surgeries for Cancer Genetic Predisposition: Findings of a Workshop Organized by the International Cascade Consortium.

Obesity, a chronic, multifactorial disease estimated to affect more than a billion people worldwide, is associated with numerous adverse health sequelae including metabolic disease, several cancers and mental health disorders []. Semaglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA), is now approved for the treatment of obesity and Type 2 diabetes (T2D) as both a once‐weekly subcutaneous injection and a once‐daily oral formulation []. In the OASIS 4 trial including adults with obesity (or overweight with ≥ 1 obesity‐related comorbidity), treatment with oral semaglutide 25 mg was shown to reduce body weight by 13.6% (estimated 11.4% placebo‐subtracted difference) for the treatment policy estimand (effect regardless of treatment discontinuation or use of rescue medication, such as other obesity medications), and 16.6% for the trial product estimand (assuming that the drug or placebo was taken without discontinuation or use of rescue medication) []. Several other GLP‐1 RA‐based therapies are also available or in development for the treatment of obesity and/or T2D including liraglutide [], tirzepatide [] and orforglipron []. Missing doses of prescribed medications is common in real‐world settings, and may result from both personal and healthcare/insurance‐related causes []. The recommended dosing regimen for GLP‐1 RAs is important [] as disruptions to the prescribed dosing regimen may alter treatment efficacy and tolerability []. Indeed, inconsistent use of GLP‐1 RA‐based therapies can be challenging because tolerance is commonly developed to their known gastrointestinal side effects with regular use. This is also why all GLP‐1 RA‐based therapies, including oral semaglutide, have guidance on resumption of therapy after missed doses []. With the array of injectable and oral medication options available, each with unique dosing regimens, it is important to understand the differences between how missed doses affect the drug concentrations achieved via once‐daily and once‐weekly dosing schedules. As deviating from optimal dosing conditions can result in decreased exposure [], obesity medications that do not substantially vary in efficacy or safety following a missed dose may be preferred by patients and healthcare providers compared with medications that are more sensitive to missed doses. Here, we compare the pharmacokinetic (PK) profile of oral semaglutide 25 mg with subcutaneous semaglutide 2.4 mg, liraglutide 3 mg and tirzepatide 15 mg, and with oral orforglipron 36 mg, all following missed doses. We also indirectly compare previously published efficacy and safety data to determine whether the efficacy and the low rates of adverse event‐related discontinuations seen in oral semaglutide trials are due to a low sensitivity to missed doses.