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#NephMadness 2024: From Poison to Remedy – The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists in the Management of Chronic Kidney Disease

Stephen Sammons

Steve Sammons is a nephrology fellow at the University of Utah in Salt Lake City, Utah. His academic interests include glomerulonephritis, evidence-based medicine, and medical education.

Jamie Dwyer @jamie_dwyer

Jamie P. Dwyer, MD is Associate Dean for Clinical Research, Professor of Medicine, and Director of the Utah Data Coordinating Center at the University of Utah Health in Salt Lake City, Utah.  He is a clinical trialist dedicated to the design, conduct, analysis, and reporting of large multi-center clinical trials.

Sarah Gilligan

Sarah Gilligan, MD is an Assistant Professor of Medicine and the Nephrology Fellowship Program Director at University of Utah Health in Salt Lake City, Utah.

The remaining competitors, our Left and Right Kidneys:

Team Gila Monster vs Team Simultaneous Pancreas-Kidney Transplantation

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising drugs that have shown benefit in the management of diabetes and cardiovascular disease and, more recently, they are gaining evidence for a role in managing chronic kidney disease (CKD). The discovery and development of GLP-1RAs from the venom of Gila Monsters is a fascinating zoonotic story that has been covered in this year’s Animal House NephMadness blog post.

GLP-1RAs have been used in clinical practice since exenatide was first approved for use in Type 2 Diabetes Mellitus (T2DM) in 2005, though hints of a renal role emerged in 2015 with the publication of the ELIXA trial in which lixisenatide was compared to placebo in subjects with T2DM and recent Acute Coronary Syndrome events. While there was no difference in the primary composite cardiovascular outcome between the treatment and placebo groups, it was noted that those treated with lixisenatide had a modest benefit on albuminuria, though this difference was attenuated by adjusting for glycemic control.

The year 2016 brought sweeping changes to the GLP-1RA world with publication of two major trials, LEADER and SUSTAIN. In LEADER, liraglutide was compared to placebo in subjects with T2DM at high cardiovascular risk and was found to confer a lower risk of the primary composite cardiovascular outcome. In SUSTAIN, SQ semaglutide was compared to placebo in subjects with T2DM and was similarly found to confer a lower risk of the primary composite cardiovascular outcome. While neither LEADER nor SUSTAIN were designed to be kidney trials, both trials included composite renal outcomes among the secondary outcomes and showed that GLP-1RAs provided renal benefit, which in both cases was driven primarily by improvement in albuminuria.  More recent trials such as 2023’s SELECT, which found that SQ semaglutide provided superior cardiovascular outcomes when compared to placebo in a population of overweight or obese subjects, suggested a renal benefit of semaglutide in this population.

While LEADER, SUSTAIN, and SELECT established that GLP-1RAs provide a clear cardiovascular benefit, the design of these trials as cardiovascular outcome trials limits the conclusions surrounding renal outcomes. This is an area in which the FLOW trial should shed some light. FLOW was designed to evaluate the effect of weekly SQ semaglutide on CKD progression in participants with T2DM and CKD, with a primary composite renal outcome composed of onset of persistent ≥ 50% reduction in eGFR compared with baseline, onset of persistent eGFR < 15 mL/min, initiation of renal replacement therapy, death from kidney disease, or death from cardiovascular disease. This composite outcome is a standard renal outcome in contemporary clinical trials of CKD progression. The study began in 2019 and had enrolled 3534 subjects by October 2023 when the trial’s sponsor announced that the Independent Data Monitoring Committee recommended stopping the trial early for efficacy based on pre-specified criteria.  We’ll learn more at an upcoming scientific meeting when these data are presented fully and are peer-reviewed.

Importantly, ongoing trials with drugs acting on different components of nutrient hormone pathways are in development and should broaden our understanding into how this pathway can be targeted to affect outcomes such as weight loss and CKD progression. For example, the SURMOUNT-1 trial published in 2022 studied tirzepatide, a dual agonist of the GLP-1R and the Glucose-dependent insulinotropic polypeptide (GIP) receptor, in overweight or obese adults and found substantial weight loss in treatment groups that suggests an additive benefit in targeting both the GLP-1 and GIP receptors. Expanding the agonist pool even larger, the drug retatrutide has agonist activity against GLP-1, GIP, and glucagon receptors, and showed dose-dependent weight loss in a trial published in 2023. Both tirzepatide and retatrutide are currently being studied in Phase II trials currently in recruitment that are assessing these drugs in overweight and obese participants with CKD.

Don’t let GLP-1RAs humble zoonotic origin fool you. GLP-1RAs may not have made it out of the first round of #NephMadness 2017 (in spite of Dr. Katherine Tuttle’s prediction that they would win all of NephMadness that year), but we have so much more data to support their use now. While we anxiously await the results of the FLOW trial, it is clear that of all the teams in this years NephMadness that Team Gila Monster (AKA Team GLP-1RA) is likely to cause the most practice change in nephrology over the next 5 years and therefore should be crowned NephMadness 2024 Champion.

<img loading="lazy" decoding="async" aria-describedby="caption-attachment-41466" data-attachment-id="41466" data-permalink="" data-orig-file="" data-orig-size="4571,3047" data-comments-opened="1" data-image-meta="{"aperture":"0","credit":"Shutterstock","camera":"","caption":"","created_timestamp":"0","copyright":"Copyright (c) 2020 Erin Donalson/Shutterstock. No use without permission.","focal_length":"0","iso":"0","shutter_speed":"0","title":"Close,Up,Low,Angle,Venomous,Gila,Monster,Lizard,Standing,On","orientation":"1"}" data-image-title="NM24 Animal House Gila Monster" data-image-description data-image-caption="

Copyright: Erin Donalson / Shutterstock

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Copyright: Erin Donalson / Shutterstock

– Guest Post written by Stephen Sammons, Jamie Dwyer, and Sarah Gilligan

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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