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GLP-1 RAs: Beyond Glycemic Control to Cardiovascular, Renal, and Liver Benefits

Op-Med is a collection of original articles contributed by Doximity members.

When the first GLP-1 RA, exenatide, was released in 2005, the sole indication was for glycemic control, and weight loss was deemed a favorable side effect. The glycemic indication was true for the several GLP-1 RAs that followed. When the FDA mandated CVOTs were performed, several of the GLP-1 RAs also showed a favorable effect on Cardiovascular outcomes. More recently the potent GLP-1 RA, semaglutide, and the dual GLP-1/GIP receptor agonist, Tirzepatide has also been approved for weight loss indications.

Presentations at the most recent ADA scientific sessions in 2024 included discussions of clear benefits to reduce liver fat in MASH (formerly called NAFLD) with tirzepatide (Loomba, NEJM, 2024) and a phase 2 trial with the triagonist (GLP-1/GIP/Glucagon), retatrutide (Sanyal, Nature Medicine, 2024).  Early studies suggesting benefits of GLP-1 RAs on renal function in patients with reduced eGFR were confirmed by the FLOW trial (Perkovic, NEJM, 2024). Data on the benefits of semaglutide on renal function in patients with DM and reduced eGFR were presented at these meetings. Finally, the semaglutide studies on HFPEF in both patients with and without diabetes demonstrated solid data on the use of this GLP-1 RA on heart failure. Thus the benefits of GLP-1 RA (and dual/tri agonists) on reductions in liver fat, favorable effects on renal function and favorable outcomes in HF trials have all been demonstrated in randomized clinical trials presented at these meetings.

Other potential benefits of GLP-1 RAs were presented based on animal studies, small observational studies, and small intervention studies. The potential benefits on asthma, neurodegenerative/neuroinflammatory disorders, including Parkinsons, and possible favorable effects on alcohol use disorders. These reports suggest that we do not yet know all of the potential benefits of GLP-1 RAs. Reports of GLP-1 RA regulation of thirst in animals is of interest, but the clinical relevance is not yet obvious.

Reports on safety concerns included observational data suggesting that GLP-1 RAs, especially the more potent agents are not associated with significantly increased risks for pancreatitis or medullary thyroid carcinoma.  Concerns about whether muscle mass loss in agents associated with significant weight loss are accompanied by loss of muscle function are not yet entirely resolved. Whereas weight loss may be associated with improved physical function as a result of weight reduction, careful analyses of actual muscle function commonly used in sarcopenia evaluations including hand strength, sit to stand, 6 minute walk have not been consistently analyzed or reported. Clinicians who use the agents associated with significant weight loss, should be aware of concerns about associated loss of muscle function.

Dr. Hoogwerf is a former employee and minor stockholder of Eli Lilly who market the GLP-1 RA, dulaglutide, the dual agonist, tirzepatide, and the triagonist, retatrutide.

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