‘Highly plausible’ GLP-1s can improve health-related QoL, economic burden of MASH
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Metabolic dysfunction-associated steatotic liver disease affects more than one-third of the world’s population and is associated with significant clinical and economic burden, as well as impairment of health-related quality of life.
MASLD, formerly known as NAFLD, is currently among the top causes of cirrhosis, liver cancer and indication for liver transplantation. Stage of fibrosis — specifically stage 2 or higher — and its noninvasive surrogates are the best predictors of adverse outcomes in patients with MASLD.
Using these tests, risk-stratification algorithms have been developed to identify individuals at risk for adverse outcomes. An important reason to identify these high-risk individuals with MASLD is to optimize their clinical management and potentially reduce their risk for liver-related adverse outcomes.
Effective interventions should ultimately improve not only clinical outcomes but also patients’ health-related quality of life (QoL) and reduce the economic burden of MASLD. Although outcome studies providing this type of evidence are highly desirable, they are impractical. Surrogates of improving long-term liver outcomes have been selected and include improvement of fibrosis or its noninvasive biomarkers. Currently, the liver-targeted drug Rezdiffra (resmetirom, Madrigal Pharmaceuticals) is the only pharmacologic intervention that has met these endpoints in clinical trials.
Nevertheless, given the close association of obesity and type 2 diabetes with MASLD, several other drugs that are approved for treatment of obesity and type 2 diabetes are being tested for treatment of the progressive form of MASLD, or metabolic dysfunction-associated steatohepatitis.
In this Healio Exclusive, two endocrinologists and two hepatologists have provided their perspectives about the role of glucagon-like peptide-1 agonists in managing patients with MASH.
Lifestyle Intervention Alone ‘Not Always Sufficient’
In her perspective, Rita Basu, MD, emphasized the role of lifestyle intervention, primarily through weight loss. Although current evidence suggests that effective weight loss through lifestyle intervention can improve liver histology, programs with dieting rarely show efficacy in maintaining sustainable weight loss.
It is also important to note that lifestyle is not only calorie restriction but also minimizing consumption of ultra-processed food and drink, alcohol use and smoking cessation as well as improving physical activity through exercise. Most of these patients may still require medication to help with sustainable weight loss.
Nevertheless, regardless of the drug regimens used for obesity, type 2 diabetes or MASH, lifestyle intervention should always be the first step in managing these patients. However, as indicated by the experts, for most patients lifestyle alone is not always sufficient.
GLP-1 Use in MASH With Obesity, Diabetes
In his perspective, Scott Isaacs, MD, FACP, FACE, suggests that GLP-1s have been approved for treatment of obesity and type 2 diabetes and should be part of the treatment regimen for patients with MASH who often have these comorbidities.
Although preliminary data from a phase 2 clinical trial of semaglutide (Ozempic, Wegovy; Novo Nordisk) suggest that improvement of steatohepatitis can occur, improvement in fibrosis has not been shown. Nevertheless, GLP-1s do have additional cardiovascular benefit, which could be important for patients with MASLD, for whom cardiovascular disease is the most common cause of death.
Although using GLP-1s for cardiometabolic risks in patients with MASLD with obesity and/or type 2 diabetes should be part of these patients’ management, strong evidence supporting liver benefit with their use is currently lacking. This was noted by Rohit Loomba, MD, MHSc, who emphasized the importance of generating additional data to support the use of these drugs solely for a liver indication.
On the other hand, if patients with MASLD have type 2 diabetes and/or obesity, the use of these medications to manage these comorbidities will be increasingly used in routine clinical practice, as noted by Isaacs.
Arun Sanyal, MD, also highlighted the need for additional evidence for these drugs in treatment of MASH. However, he reflected on the inevitability of these drugs to become a routine part of the clinical practice of hepatology and the comfort for their use in this practice setting must be encouraged.
Managing Comorbidities Can ‘Ultimately Improve’ Outcomes
The burden of MASLD is increasing globally, leading to significant mortality, morbidity and cost. Given the close association of MASLD with obesity and type 2 diabetes, managing these comorbidities — initially though lifestyle intervention and supplemented by anti-obesity and anti-diabetes regimens such as GLP-1s — will be important.
In my experience, a large proportion of our patients with MASH are already on these regimens. Therefore, addition of liver-targeted treatment must be undertaken for patients with noncirrhotic MASLD who continue to show significant fibrosis of stages 2 and 3.
As of now, resmetirom is the only liver-targeted drug approved for MASH and should be used for those who are treatment candidates. Hopefully, managing patients’ cardiometabolic comorbidities and their liver disease can ultimately improve both cardiovascular and liver-related outcomes.
Parallel to these clinical benefits, it is highly plausible that these effective regimens can improve patients’ health-related QoL and reduce the future economic burden of MASLD.
- References:
- Harrison SA, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2309000.
- Younossi ZM, et al. Hepatology. 2023;doi:10.1097/HEP.0000000000000004.
- Younossi ZM, et al. J Hepatol. 2024;doi:10.1016/j.jhep.2024.01.014.
- For more information:
- Zobair M. Younossi, MD, MPH, is chairman of the Global NASH/MASH Council. He can be reached at zobair.younossi@cldq.org.
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