Adverse Effects of GLP-1 Receptor Agonists: From Diabetic Complications to the Risk of Discontinuation - Systematic Analysis and Proposal of A Predictive Model for Personalization of Therapeutics

Abstract This work is a systematic and critical analysis of the safety profile of GLP-1 receptor agonists (GLP-1 RAs), the adverse effects whose incidence and severity are modulated by the presence of chronic complications of type 2 diabetes mellitus (T2DM), and their crucial role in the phenomenon of early therapeutic discontinuation. The primary objective is to construct a clinically usable map of documented adverse effects—gastrointestinal, cardiovascular, renal, thyroid, pancreatic, biliary, skin, and ophthalmological—by analyzing the underlying pathophysiological mechanisms, populations at increased risk, and management implications for each. The secondary objective, which constitutes the original contribution of the work, is to integrate this analysis with the proposal of a predictive discontinuation risk stratification model, intended for both clinical practice and medical affairs strategy. Abbreviations: ADSC: Adipose-Derived Stem Cells; AGEs: Advanced Glycation End Products; AIFA: Italian Medicines Agency; AKI: Acute Kidney Injury; AUC: Area Under the Curve; CKD: Chronic Kidney Disease; CV: Cardiovascular; CVOT: Cardiovascular Outcome Trial; DAN: Diabetic Autonomic Neuropathy; T2DM: Type 2 Diabetes Mellitus 2; DPP-4: Dipeptidyl Peptidase-4; DWAT: Dermal White Adipose Tissue; EA-GI: Gastrointestinal Adverse Events; eGFR: estimated Glomerular Filtration Rate; EMA: European Medicines Agency; GIP: Glucose-dependent Insulinotropic Polypeptide; GLP-1: Glucagon-Like Peptide-1; GLP-1 RA: Glucagon-Like Peptide-1 Receptor Agonists; HbA1c: Glycated hemoglobin; HR: Hazard Ratio; HS: Hidradenitis Suppurativa (Hidradenitis Suppurativa); ICC: Intraclass Correlation Coefficient; MACE: Major Adverse Cardiovascular Events; MASH: Metabolic dysfunction-Associated SteatoHepatitis; MEN2: Multiple Endocrine Neoplasia type 2; TCM: Medullary Thyroid Cancer; NAION: Non-Arteritic Anterior Ischemic Optic Neuropathy; NF-κB: Nuclear Factor kappa-B; PBPK: Physiologically Based Pharmacokinetic; PRAC: Pharmacovigilance Risk Assessment Committee; PSP: Patient Support Program; RAGE: Receptor for Advanced Glycation End Products; RCT: Randomized Controlled Trial; ROS: Reactive Oxygen Species; RWE: Real-World Evidence; SGLT-2i: Sodium-glucose cotransporter 2 inhibitors; SIRT1: Sirtuin 1