GLP-1 Therapies Show Antiinflammatory and Cardiovascular Benefits Beyond Metabolic Effects
Recent reviews highlight expanding clinical benefits of GLP-1-based therapies, including antiinflammatory actions across multiple organs and cardiovascular risk reduction, with combination approaches emerging for obesity treatment.
Therapies based on glucagon-like peptide-1 (GLP-1) reduce rates of cardiovascular and chronic kidney disease in people with type 2 diabetes and/or obesity. Acute and chronic activation of GLP-1 receptor signaling also reduces systemic and tissue inflammation in mice and humans.
Ongoing clinical trials are investigating their effects in people with metabolic liver disease, arthritis, and both substance use and neurodegenerative disorders. The mechanisms are both weight loss–dependent and –independent and these actions may contribute to the expanding spectrum of clinical benefits ascribed to GLP-1 medicines.
The incretin hormone glucagon-like peptide-1 (GLP-1) exerts potent effects on glucose metabolism, prompting the development of therapeutic strategies that enhance activity of the GLP-1 receptor (GLP-1R) pathway. Inhibitors of dipeptidyl peptidase 4 (DPP-4) prolong the half-life of endogenous GLP-1 and typically achieve reductions in HbA1c of 0.5%–0.8%. However, large-scale cardiovascular (CV) outcomes trials (CVOTs) with DPP-4 inhibitors demonstrated CV safety but did not show a reduction in CV events.
Various GLP-1RAs, including liraglutide, semaglutide, and dulaglutide, demonstrated a reduction in CV outcomes in large CVOTs. Initially, these medications were only available as injectable agents for subcutaneous administration, but recent technological advancements have enabled the development of orally available GLP-1RAs.
A third incretin-based approach is tirzepatide, a dual agonist of GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR), which achieves greater HbA1c reduction and weight loss compared with GLP-1RAs alone. MACE occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P=0.003 for noninferiority; P=0.09 for superiority).
Bariatric surgery remains the most efficacious treatment for obesity, despite improved pharmacotherapies. However, its low acceptability and accessibility render it an underutilized treatment. The real-world effectiveness of GLP1RA is hindered by issues including cost and tolerability.
Many patients after bariatric surgery will eventually start regaining weight and the use of GLP-1-based therapies is an excellent option how to prevent weight regain. Furthermore, despite numerous positive effects of bariatric surgery on CV risk factors, addition of GLP-1-based therapies has a strong potential for further improvement of metabolic and CV health beyond weight loss. At the same time, exercise and proper diet is still needed to preserve muscle and overall fitness.