From insulin resistance to incretin receptor agonism in the prevention of type 2 diabetes mellitus in obese individuals.

Abstract

Type 2 diabetes mellitus (T2DM) represents one of the most significant metabolic challenges of the modern era, with more than 828 million people worldwide living with diabetes. Obesity and insulin resistance are major modifiable contributors to T2DM risk and progression, although the disease is heterogeneous and arises from complex interactions among β-cell dysfunction, hepatic glucose dysregulation, adipose-tissue dysfunction, altered incretin biology, chronic low-grade inflammation, and genetic susceptibility. In individuals with obesity and insulin resistance, progression through prediabetes to overt hyperglycaemia represents an important, although not universal, disease trajectory and provides a clinically relevant window for preventive intervention. This review examines pharmacological strategies relevant to T2DM prevention in individuals without established diabetes who have prediabetes and/or obesity associated with a high risk of progression to T2DM, with particular emphasis on incretin-based obesity pharmacotherapy. Metformin remains the glucose-lowering agent with the most established long-term evidence for diabetes prevention in selected high-risk individuals with prediabetes, acting through multiple hepatic and intestinal mechanisms involving both AMPK-dependent and AMPK-independent pathways. Other established antihyperglycaemic drug classes are discussed primarily to distinguish therapies with evidence for delaying progression to diabetes from agents whose principal role remains the treatment of established T2DM. SGLT2 inhibitors provide substantial cardiovascular and renal protection, although current evidence is insufficient to support their routine use solely for T2DM prevention. GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide have substantially advanced obesity pharmacotherapy, producing clinically meaningful weight loss and broader cardiometabolic benefits that may reduce progression to T2DM in high-risk individuals.Next-generation incretin-based therapies, including triple receptor agonists, may further expand therapeutic options but remain an evolving area of investigation. Lifestyle intervention and sustained weight management remain the foundation of T2DM prevention, with pharmacological strategies selected according to individual metabolic risk, obesity-related treatment indications, comorbidities, and the strength of evidence supporting diabetes prevention.