Comprehensive review covering GLP-1 RA and next-generation incretin-based therapy mechanisms, cardiovascular trial evidence (MACE reduction, HF outcomes), renal benefits (albuminuria reduction, eGFR preservation), and the emerging dual and triple agonist landscape. Synthesizes SUSTAIN, LEADER, FLOW, SELECT, and STEP trial data with mechanistic explanations. Provides the most current clinical and mechanistic synthesis for incretin-based pharmacotherapy—serving as a comprehensive reference for clinicians and researchers navigating the expanding GLP-1 RA evidence base from T2DM through obesity, CKD, and heart failure.
Abstract
GLP-1 receptor agonists were initially developed to treat type 2 diabetes and have had a transformative effect on its therapy, and are highly effective for glycaemic control, with the added benefit of bodyweight reduction and a low risk of causing hypoglycaemia. GLP-1 receptor agonists reduce risks for major adverse cardiovascular events (eg, non-fatal myocardial infarction, stroke, and cardiovascular death), and the risk of admission to or treatment within hospital for heart failure. These drugs reduce albuminuria and slow the decline in estimated glomerular filtration rate over time, therefore delaying or preventing kidney failure. Furthermore, GLP-1 receptor agonists (eg, liraglutide and semaglutide) and the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor co-agonist tirzepatide have been approved for treatment of obesity, with clinical trials establishing benefits for various obesity-related conditions: prevention of type 2 diabetes; risk for major adverse cardiovascular events; heart failure, especially with preserved ejection fraction; regression of steatosis and prevention of fibrosis in steatotic liver disease; and symptomatic improvements in obstructive sleep apnoea and knee osteoarthritis. Current developments include the exploration of novel indications (eg, neurodegenerative diseases and substance use disorders) with suggestive evidence of efficacy, and the development of small-molecule GLP-1 receptor agonists for oral treatment to improve convenience. Dual (ie, GLP-1-glucagon and GLP-1-amylin) and triple (ie, GIP-GLP-1-glucagon) receptor agonists activating multiple receptors promise greater efficacy than mono-agonists, especially for weight loss. However, some clinical development programmes have a high burden of adverse gastrointestinal events, and dose-escalation regimens should be optimised to reach acceptable tolerability.