‘Future of treating MASH’ will combine GLP-1 drugs, liver-specific medications
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Metabolic dysfunction-associated steatotic liver disease is a public health threat, affecting 30% to 38% of the adult population globally. The prevalence has risen in parallel with epidemics of obesity and type 2 diabetes.
One in five patients with type 2 diabetes has undiagnosed metabolic dysfunction-associated steatohepatitis with liver fibrosis. MASLD is associated with double the rate of significant adverse cardiovascular events, including acute coronary syndrome and ischemic stroke, as well as mortality related to these events. MASLD is sometimes referred to as diabetic hepatopathy because it is thought of as a complication of type 2 diabetes and the metabolic syndrome.
Screen High-Risk Population for MASH
There are many shared risk factors and a common metabolic milieu in MASLD, type 2 diabetes, obesity, dyslipidemia and cardiovascular disease. These are interconnected through common pathophysiology of insulin resistance and lipotoxicity, an accumulation of toxic fat metabolites in cells that cause liver dysfunction and inflammation, which then worsens insulin resistance.
The best way to screen patients for MASH is to identify high-risk populations, such as those with type 2 diabetes, obesity or other features of the metabolic syndrome. Patients with elevated aspartate transaminase or alanine transaminase greater than 30 for 6 months or incidentally discovered steatosis on imaging should also be screened.
The first step is to calculate the fibrosis-4 using an online calculator. Patients with a FIB-4 score less than 1.3 are considered low risk for advanced liver fibrosis and can be managed by the primary care physician or endocrinologist. Patients with a FIB-4 greater than 1.3 should be referred to a hepatologist or liver specialist for further evaluation. Noninvasive testing, such as transient elastography or blood-based biomarkers, can also be used to further risk-stratify patients for advanced liver fibrosis.
Combination Therapy: GLP-1s, Liver-Specific Medications
Glucagon-like peptide-1 agonist drugs and pioglitazone have proven benefit in reducing liver fat and improving MASH. sodium-glucose transport protein 2 (SGLT2) inhibitors and tirzepatide (Mounjaro, Zepbound; Lilly), a glucose-dependent insulinotropic polypeptide/ GLP-1, reduce liver fat seen with noninvasive tests, but we don’t yet have histologic data on these agents. These medications are recommended for treating type 2 diabetes and obesity, but they’re recommended especially for patients who have MASH.
The No. 1 cause of death for people with MASH is CVD and pioglitazone, GLP-1 receptor agonists and SGLT2 inhibitors reduce this risk. Many people with MASH are already on these medications for diabetes or obesity.
The future of treating MASH will be combination therapy that includes diabetes and anti-obesity medications with proven benefits in MASLD and MASH in addition to liver-specific medications such as Rezdiffra (resmetirom, Madrigal). Medications that address multiple cardiometabolic issues — liver fat, liver enzymes, hepatic de novo lipogenesis, MASH, dyslipidemia glucose and body weight — are ideal therapies.
Because so many patients have MASH and MASLD, this is a disease of primary care and endocrinology. Guidelines categorize patients into low risk, intermediate risk and high risk for advanced liver disease. Low-risk patients are still at high risk for metabolic complications, so they are managed by endocrinology, primary care and cardiology. The intermediate- and especially high-risk patients must be managed by a multidisciplinary team including a hepatologist.
- References:
- Cusi K, et al. Endocr Pract. 2022;doi:10.1016/j.eprac.2022.03.010.
- Lomonaco R, et al. Diabetes Care. 2021;doi:10.2337/dc20-1997.
- For more information:
- Scott Isaacs, MD, FACP, FACE, is adjunct associate professor of medicine at Emory University School of Medicine and president-elect of the American Association of Clinical Endocrinology. He can be reached at sisaacs@aace.com; X (Twitter): @scottisaacsmd.
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