Abstract Obesity is the leading risk factor for prediabetes, a highly prevalent and insidious condition that markedly increases the likelihood of developing cardiovascular disease and type 2 diabetes. While lifestyle modifications remain the foundation of prevention, pharmacological strategies targeting the incretin axis have emerged as powerful tools. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and, more recently, dual GLP-1/GIP agonists have shown robust efficacy in promoting weight loss and improving glycemic outcomes in individuals with obesity and prediabetes. This manuscript reviews the clinical evidence for three key molecules. Liraglutide was first tested in the SCALE Obesity and Prediabetes trial, showing a 79% reduction in diabetes incidence over three years. Semaglutide demonstrated consistent benefits across the STEP 1, 3, 4, and 10 trials and in the large cardiovascular outcomes trial SELECT, with significant reversion to normoglycaemia and reduced progression to diabetes. Tirzepatide, evaluated in SURMOUNT-1 and in the phase 3 Tirzepatide for Obesity Treatment and Diabetes Prevention trial, achieved profound and durable weight loss with an unprecedented reduction in diabetes onset. Recent real-world data further suggest a superior effect of tirzepatide compared to semaglutide in preventing type 2 diabetes. By synthesizing these findings, we aim to highlight the pivotal role of anti-obesity pharmacotherapy in modifying the natural history of prediabetes and preventing type 2 diabetes in patients with obesity. Indeed, the title recalls the concept of an ‘insurmountable problem,’ highlighting how advances in obesity pharmacotherapy are making diabetes prevention a realistic and achievable goal.
Ponziani et al. (Sat,) studied this question.