Abstract
"Nonalcoholic fatty liver disease" (NAFLD) is a comprehensive term encompassing a range of liver diseases that occur in individuals who do not consume excessive amounts of alcohol. 1 NAFLD ranges from nonalcoholic steatosis, a benign accumulation of fat in liver cells; to nonalcoholic steatohepatitis (NASH), a more serious condition characterized by inflammation and liver cell damage to fibrosis, scarring of liver and nearby blood vessels (ranges from stage F0: no scarring to stage F4: severe scarring); to cirrhosis, increasing risk for developing liver failure and hepatocellular carcinoma (HCC). 2
Due to the nomenclature not accurately reflecting the etiology of the disease and to the associated stigma with the term "fatty," the American Association for the Study of Liver Disease (AASLD) announced NAFLD and NASH terminologies were updated and changed as of June 2023. 3 "Steatotic liver disease" (SLD) is the comprehensive term for all etiologies of steatosis. NAFLD has been replaced by metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, the definition has been updated to include presentation of at least 1 of 5 cardiometabolic risk factors. NASH is now replaced by metabolic dysfunction-associated steatohepatitis (MASH). 3
The prevalence of steatosis is over 70% in individuals with type 2 diabetes mellitus (T2DM). 4 T2DM is considered a risk factor for the development and progression of MASLD due to similar pathophysiological features of metabolic syndrome (increase insulin resistance, weight gain, obesity).1,2,5
The American Diabetes Association (ADA) recently updated its "Standards of Care in Diabetes-2023," recommending to screen patients for MASH and fibrosis using the Fibrosis-4 (F1B-4) calculator when they present with T2DM or prediabetes with cardiometabolic risk factors and either increased alanine transaminase or fatty liver detected on imaging or ultrasound. 1 Early screening aims at identifying patients who are at risk of cirrhosis, HCC, and liver-related death. 1
Currently, there is an absence of Food and Drug Administration (FDA) approved medication therapy for both MASLD and its more severe form, MASH. There is credible evidence supporting that accumulation of excessive adipose tissue in individuals who are overweight or obese contributes to the development or worsening of MASLD. 1 Similarly, with T2DM, obesity exacerbates insulin resistance and steatohepatitis, thereby increasing the likelihood of developing cirrhosis. 1 Based on these factors, in individuals with MASLD and T2DM, it is imperative to focus on lifestyle modifications consisting of dietary changes, exercise, and addition of obesity pharmacotherapy to promote weight loss of at least 5%, preferably >10%. 1 Bariatric surgery may be considered in special cases to improve MASH and reduce the risk of HCC.1,2,5
Screening
F1B-4 index has been reported by the ADA as a cost-effective initial screening strategy for determining extent of liver scarring and need for biopsy in patients with prediabetes, T2DM, and cardiometabolic risk factors.1,2,5 The calculator estimates risk of hepatic cirrhosis utilizing age, plasma aminotransferases, and platelet count through noninvasive means.1,2,5 A F1B-4 value below 1.3 is considered low risk for having advanced fibrosis (F3-F4) and developing adverse liver outcomes, a F1B-4 value of 1.3 to 2.67 is considered intermediate risk, and higher than 2.67 is high risk.1,2,5
Of note, F1B-4 has reasonable specificity but low sensitivity, therefore confirmatory testing is recommended for a positive result. 1 When patients have low risk, they can be followed up with primary care every 2 to 3 years. For patients with intermediate to high risk (>1.3), additional testing with liver stiffness measurement using transient elastography or enhanced liver fibrosis test is needed. Following adequate risk stratification, patients with diabetes and intermediate or high risk should be referred to a gastroenterologist or hepatologist.1,2,5
T2DM is considered a risk factor for the development and progression of MASLD due to similar pathophysiological features of metabolic syndrome (increase insulin resistance, weight gain, obesity).
Potential Therapeutic Agents
According to the ADA, American Association of Clinical Endocrinology (AACE), and AASLD, the medications discussed in this section, although approved for other indications, have shown some benefit for MASH in clinical trials and should be considered based on patient-specific factors.1,2,5
In terms of medication therapy for MASH (>F2), the approach is like any patient beyond glycemic control. The focus is more cardiometabolic and patient centered.1,2,5 Consequently, the use of metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin for the treatment of steatohepatitis is not recommended at this time due to lack of benefit on hepatocyte necrosis or inflammation. However, their use may be continued as needed for the treatment of hyperglycemia in persons with T2DM and MASLD or MASH 2
Currently, there is an absence of Food and Drug Administration (FDA) approved medication therapy for both MASLD and its more severe form, MASH.
Although pioglitazone does not cause weight loss, it is well studied with evidence in people with and without diabetes. The glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) all have varying degrees of success to date with studies ongoing. Although not indicated for MASLD, those with some evidence should be favored. See Table 1.
Preferred Therapies
Abbreviations: MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; SGLT2, sodium glucose cotransporter 2; SGLT2-I, sodium-glucose cotransporter 2 inhibitors; T2DM, type 2 diabetes mellitus.
Pioglitazone
FDA approved for T2DM and belonging to the thiazolidinedione class of hypoglycemic agents, pioglitazone increases insulin-dependent glucose disposal and decreases hepatic glucose output by decreasing insulin resistance in the periphery and in the liver 6 Pioglitazone may be used in MASLD due to its known efficacy in MASH with or without prediabetes or T2DM because it may improve fibrosis and slows disease progression.2,4
From various studies, pioglitazone use improves insulin resistance, glucose and lipid metabolism, and resolution of MASH.1,2,7 A study utilizing combination therapy of pioglitazone with vitamin E for individuals with T2DM noted other histologic improvements in steatosis, ballooning necrosis, and inflammation. 7 It has been reported that the long-term use of pioglitazone can lead to the reversal of MASH and continued histological improvements, such as reduction in fibrosis score. 8
When selecting pioglitazone as a potential agent, keep in mind the associated clinical benefits in cardiovascular risk reduction and stroke prevention. Potential side effects include moderate dose-dependent weight gain and minimal cases of bone fractures.2,5 Additionally, there has been a debated risk for bladder cancer as a potential side effect, but with minimal prevalence.2,5 Lastly, an important side effect to be aware of is the potential risk of heart failure exacerbation for patients with history of cardiac disease. 5
GLP-1 RAs and Dual GLP-1/GIP RAs
GLP-1 RAs are FDA approved for the treatment of T2DM. GLP-1 RAs work by stimulating glucose-dependent insulin release from the pancreatic islets, slow gastric emptying, inhibit inappropriate postmeal glucagon release, and reduction in appetite resulting in decreased food intake leading to weight loss. 5 Due to the promising biological effects on lipids, glucose metabolism, weight loss, and cardiovascular outcomes, GLP-1 RAs liraglutide and semaglutide and the dual GLP-1/ GIP RA tirzepatide are compelling agents for the treatment of MASLD.1,2,5 Dulaglutide and exenatide have limited evidence and were not included as recommendations by the ADA, AASLD, or AACE .
Liraglutide and semaglutide are injectable GLP-1 RAs with dual FDA-approved indications: T2DM and obesity. 5 Both agents are recommended by the ADA, AASLD, and AACE to be used in MASH without cirrhosis because they confer cardiovascular benefit, weight loss, aminotransferase levels normalization, and improvement in steatosis but no proven impact on fibrosis.1,2,5 Semaglutide is preferred because it may offer potential benefit in slowing down fibrosis progression and MASH resolution and stroke prevention. 5 Side effects are notable for gastrointestinal effects, weight-loss-related gallstones, and pancreatitis. 5
Tirzepatide, an injectable combination of GLP-1 RA and GIP RA, is FDA approved for T2DM and has been submitted to the FDA for an obesity indication. Like the GLP-1 RAs, tirzepatide also suppresses appetite, which enhances weight loss. Tirzepatide works by enhancing insulin secretion and reducing glucagon levels in glucose-dependent manner. 9 GIP receptors are concentrated in the central nervous system and adipose tissue, thus playing a role in carbohydrate and lipid metabolism. 7
Tirzepatide's mechanism of action makes it an attractive candidate for MASLD. 5 Its association with cardiovascular outcomes requires further evaluation; however, benefits of use in MASLD include reduction in steatosis on imaging, significant weight loss, and improvement in insulin sensitivity. 5 Although there is reduction in hepatic steatosis, there is no report of the effect on steatohepatitis. 1 There are ongoing studies with tirzepatide and MASLD. The adverse effects associated with tirzepatide are similar to GLP-1 RAs. 5
SGLT2-Is
SGLT2-Is is a class of antidiabetic agents with FDA approval for T2DM, and their mechanism of action involves the inhibition of the SGLT2 receptor, preventing renal reabsorption of glucose. 10 SGLT2-Is are recommended in patients with T2DM and MASLD given the modest weight loss, renal, and cardiovascular benefit.1,2,5 Although improvements in liver steatosis (observed on imaging) have been documented, its impact on MASH has not been reported yet. 1 Adverse effects associated with this class include risk of genitourinary yeast infections, volume depletion, and bone loss. 5
Given the close association between MASLD, obesity, insulin resistance, and T2DM, health care providers can effectively identify and screen individuals at risk early on to prevent the progression of disease.
Conclusions
Given the close association between MASLD, obesity, insulin resistance, and T2DM, health care providers can effectively identify and screen individuals at risk early on to prevent the progression of disease. Despite it being the most prevalent form of liver disease, there are currently no FDA-approved therapies specifically designed for the treatment of MASLD. There are many therapies being developed for treatment, but challenges remain.
The current therapeutic approach focuses on inducing weight loss by lifestyle modifications and obesity pharmacotherapy and treating comorbid conditions (T2DM, hypertension, dyslipidemia) and preventing macrovascular and microvascular complications.
The current therapeutic approach focuses on inducing weight loss by lifestyle modifications and obesity pharmacotherapy and treating comorbid conditions (T2DM, hypertension, dyslipidemia) and preventing macrovascular and microvascular complications. The antidiabetic agent pioglitazone is recommended for use in MASH with or without T2DM. Liraglutide and semaglutide are recommended for use in T2DM/obesity for MASH without cirrhosis, but semaglutide use is preferred due to better evidence. Tirzepatide can be used in patients with T2DM or obesity with MASLD, and SGLT-21 use is recommended for T2DM and MASLD. There are currently no therapies for prevention, but lifestyle changes would certainly be prudent for those patients at risk.
When selecting a medication option, clinicians should consider those with cardiovascular and renal benefits in addition to weight loss and glycemic control. Additionally, clinicians should prefer agents with reported benefit, hence it is not recommended to use agents such as metformin, acarbose, dipeptidyl peptidase 1V inhibitors, and insulin for the treatment of steatohepatitis. However, it is crucial to involve the patient in the decision-making process, considering their preferences, concerns, and access.
Note that the ADA Standards of Care in Diabetes 2024 will not be released until January 2024, and any updates made to the guidelines are not reflected in this article. ■
Footnotes
Duality of Interest
Allison Zhang and Rita El Hachem declare having no professional or financial association or interest in an entity, product, or service related to the content or development of this article. Jennifer D. Goldman declares she serves on speaker's bureaus for Bayer, Boheringer 1ngelheim, Lilly, NovoNordisk, Xeris, and Abbott Diabetes.
Funding
The authors declare having received no specific grant from a funding agency in the public, commercial, or not-for-profit sectors related to the content or development of this article.
Allison Zhang, PharmD Candidate 2024; Rita El Hachem, PharmD; and Jennifer Goldman, PharmD, CDCES, BC-ADM, FCCP, are with the Massachusetts College of Pharmacy and Health Sciences in Boston, MA.