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Mishina et al

Clinical Study Data: PIONEER Trials (Oral Semaglutide): PIONEER 1 (Oral Semaglutide vs Placebo): 14 mg oral semaglutide: 4.2 kg (9.3 pounds) average weight loss Placebo: 0.8 kg (1.8 pounds) average weight loss Duration: 26 weeks Conclusion: Modest weight loss, far below injectable results PIONEER 4 (Oral vs Injectable Semaglutide Direct Comparison): 14 mg oral semaglutide daily: 3.7 kg (8.2 pounds) 1.0 mg injectable semaglutide weekly: 5.0 kg (11 pounds) Even at lower injectable dose, injections produced 35% more weight loss Duration: 26 weeks Real-World Effectiveness: Doctors report that real-world results with Rybelsus are often worse than clinical trials because: Adherence Challenges: Must take on empty stomach first thing in morning 30-minute wait before eating or drinking anything else Patients frequently forget or break the rules Each missed or improperly taken dose reduces effectiveness Food Interference: Coffee with oral medication: Dramatically reduces absorption Taking with food: Almost completely prevents absorption Taking with other medications: May interfere with absorption Patient Expectations: Many patients expect oral semaglutide to work as well as injections, leading to disappointment and discontinuation

Lets take a closer look at the biological mechanisms that make this possible

Cannabis use and reduced risk of insulin resistance in HIV-HCV infected patients: a longitudinal analysis (ANRS CO13 HEPAVIH)

3 GLP-1R localization and mechanistic pathways in metabolic and behavioral regulation GLP-1 Rs exhibit high expression in pancreatic -cells in both rodents and humans, where they play a pivotal role in mediating glucose-dependent insulin secretion (Nauck et al., 1993