Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits.
GLP-1 receptor agonists lower glucose and body weight while reducing major adverse cardiovascular events and heart failure hospitalisation, and they reduce albuminuria and slow eGFR decline, thereby delaying or preventing kidney failure. Next-generation dual and triple incretin agonists promise greater efficacy, particularly for weight loss, but some programmes carry a high burden of gastrointestinal adverse events.
Background
GLP-1 receptor agonists were originally developed to treat type 2 diabetes and have had a transformative effect on its therapy. They are highly effective for glycaemic control, with the added benefit of bodyweight reduction and a low risk of causing hypoglycaemia. This review summarises their metabolic, cardiovascular and renal benefits alongside the emerging class of next-generation incretin-based medications.
Key findings
GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events — non-fatal myocardial infarction, stroke and cardiovascular death — as well as the risk of admission to or treatment within hospital for heart failure. On the kidney, these drugs reduce albuminuria and slow the decline in estimated glomerular filtration rate over time, therefore delaying or preventing kidney failure. GLP-1 receptor agonists such as liraglutide and semaglutide, together with the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor co-agonist tirzepatide, have also been approved for the treatment of obesity.
Clinical implications
In obesity, clinical trials have established benefits across several obesity-related conditions: prevention of type 2 diabetes; risk of major adverse cardiovascular events; heart failure, especially with preserved ejection fraction; regression of steatosis and prevention of fibrosis in steatotic liver disease; and symptomatic improvement in obstructive sleep apnoea and knee osteoarthritis. Current developments include exploration of novel indications such as neurodegenerative diseases and substance use disorders, where the evidence of efficacy is described as suggestive, and small-molecule GLP-1 receptor agonists for oral treatment to improve convenience. Dual (GLP-1–glucagon and GLP-1–amylin) and triple (GIP–GLP-1–glucagon) receptor agonists activating multiple receptors promise greater efficacy than mono-agonists, especially for weight loss.
Safety
Some clinical development programmes have a high burden of adverse gastrointestinal events, and the authors note that dose-escalation regimens should be optimised to reach acceptable tolerability. The favourable hypoglycaemia profile of the class is retained, with GLP-1 receptor agonists carrying a low risk of causing hypoglycaemia when used for glycaemic control.
Category
Research
Source
Lancet
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