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Role of GLP-1 Receptor Agonists in Metabolic Dysfunction–Associated Steatohepatitis
abstract
This abstract is available on the publisher's site.
Access this abstract nowDespite its considerable and growing burden, there are currently no Food and Drug Administration-approved treatments for metabolic dysfunction-associated steatotic liver disease or its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all-cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction-associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP-1RAs are Food and Drug Administration-approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP-1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP-1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP-1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta-analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP-1RAs. Large-scale, phase 3 trials, which will provide definitive data on GLP-1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH.
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The role of glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatohepatitis
Diabetes Obes Metab 2024 Mar 21;[EPub Ahead of Print], MF Abdelmalek, SA Harrison, AJ SanyalFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
GLP-1 agonists for steatotic liver disease
This industry sponsored–paper written by authors strongly tied to the sponsor makes a case for using GLP-1 agonists for steatotic liver disease. There are currently no pharmaceutical drugs approved for treating this condition, but it seems that it is just a matter of time before GLP-1 agonists are the first. It is helpful to understand this by looking at how these drugs work.
Glugacon-like peptide is an incretin. The word “incretin” means “to increase.” In this case, it increases beta-cell production of insulin. However, it was discovered that this increase only happens when sugar is given orally and not intravenously. This led to the development of these incretin drugs that fool the body into thinking it just ate. GLP-1 agonists and other incretins are the “I am full” hormones of the upper gastrointestinal tract. In metabolic dysfunction with type 2 diabetes, the body becomes less sensitive to the effects of incretins, which is part of insulin resistance. It can become resensitized through lifestyle changes including nutrition, exercise, and weight loss. Or we can simply give more incretins to overpower the resistance, pushing the beta cells to produce insulin, reducing gluconeogenesis in the liver, and delaying gastric emptying.
This mechanism of action helps understand the most common side effects. If we are fooling the body into thinking it just ate a big meal, nausea and vomiting (the most common side effects) would be expected. When the upper gastrointestinal tract delays emptying to digest food, it often stimulates the lower gastrointestinal tract to evacuate, which is why diarrhea is another common side effect. The long-term concerns arise when we trick the pancreas into secreting digestive enzymes when there is nothing to digest. This may help explain the risk of pancreatitis. We also often see more gallstone development with rapid weight loss. This may explain why we see more cholecystitis with these drugs, or maybe it is related to gallbladder relaxation associated with incretins and lack of stimulation from fatty foods.
The mechanism of how incretins treat steatosis is most likely multifactorial, but their effect on weight loss is likely dominant. Previous studies have shown that steatosis without fibrosis can be reversed with 10% weight loss. The ethical dilemma will come in how easy it will be to manage this disease with a drug. It is easy to prescribe medications, but it is hard to change lifestyles, which can reverse and cure the disease. Humans don’t resist change as much as they resist being changed. Lifestyle support to reverse this condition as early as possible should be our goal in primary care. However, the draw of this easy intervention encourages deeper reflection…
Should we promote pharmaceutical management when there is a lifestyle cure?