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. 2026 Mar 3;5(5):100912. doi: 10.1016/j.gastha.2026.100912

Impact of Fibrotic Metabolic Dysfunction–Associated Steatohepatitis as a New Indication on Semaglutide Eligibility in the US Adult Population

Laurens A van Kleef 1,∗, Maurice Michel 2,3, Mesut Savas 4,5, Jesse Pustjens 1, Willy Theel 1, Elisabeth FC van Rossum 4,5, James M Paik 6,7, Zobair M Younossi 6,7, Harry LA Janssen 1,8, Christian Labenz 9, Jörn M Schattenberg 2,3, Willem P Brouwer 1
PMCID: PMC13054597  PMID: 41953380

Abstract

Background and Aims

Semaglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of fibrotic (F2-F3) metabolic dysfunction–associated steatohepatitis (MASH) and has recently received accelerated Food and Drug Administration approval. However, the extent to which this new indication expands treatment eligibility beyond existing approvals for type 2 diabetes mellitus (T2DM) and obesity remains unclear.

Methods

We analyzed 6936 community-dwelling adults from the National Health and Nutrition Examination Survey 2017 to 2020 cohort study after excluding individuals with viral hepatitis or excessive alcohol consumption. Semaglutide eligibility was defined according to Food and Drug Administration–approved indications for weight loss, high-risk T2DM, or fibrotic MASH. Findings were validated in the Mainz biopsy cohort (n = 213) with biopsy-proven metabolic dysfunction–associated steatotic liver disease and F2-F3 fibrosis.

Results

In the US general population, 51.5% met indications for semaglutide therapy for weight loss or high-risk T2DM. Among individuals with metabolic dysfunction–associated steatotic liver disease, 80.9% qualified for treatment based on conventional indications, increasing to 95.4% in those with fibrotic MASH. Including fibrotic MASH as an additional indication raised the overall eligibility marginally from 51.5% to 51.8%. Aligning with these findings from the general population, we found that 80.3% of patients with biopsy proven F2-F3 fibrosis were eligible for semaglutide irrespective of fibrotic MASH.

Conclusion

Semaglutide eligibility is high in the US general population and the new fibrotic MASH indication largely overlapped with pre-existing indications. The findings highlight the close overlap between metabolic comorbidities and liver disease and emphasize the need for an integrated, patient-centered approach to semaglutide, alongside policies that improve access and reimbursement.

Keywords: Epidemiology, Fibrosis, Fibrotic MASH, GLP-1, MASH, Pharmaceutical Treatment

Graphical abstract

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Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are increasingly being recognized as an effective treatment for those living with metabolic dysfunction–associated steatotic liver disease (MASLD), particularly in individuals living with metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis, referred to as fibrotic MASH.1 MASLD is present in >30% of the general population and imposes a substantial risk of advanced liver disease, including cirrhosis and hepatocellular carcinoma.2 Reassuringly, the ESSENCE phase III trial on semaglutide, a GLP-1 RA, in 1197 patients living with fibrotic MASH showed compelling evidence that a once-weekly semaglutide dose of 2.4 mg resulted in resolution of MASH in 63%, reduction of fibrosis in 37%, and both in 32.7% after 72 weeks of treatment, leading to accelerated approval by the Food and Drug Administration (FDA).3

Semaglutide has already an established crucial role in the treatment of metabolically complicated obesity and type 2 diabetes mellitus (T2DM) with high cardiovascular risk.4,5 As a result, in 2023, nearly 3 million monthly prescriptions for GLP-1 RAs were dispensed in the United States, representing a 4-fold increase compared to 2021.6,7 Despite broader coverage, prescriptions for obesity alone are often not reimbursed, particularly in programs such as Medicaid, limiting access.8 Nevertheless, further increase of GLP-1 RA use such as semaglutide or dual agonist therapy is expected.9

In light of the FDA’s recent conditional approval of semaglutide for fibrotic MASH and the conventional indications of semaglutide for patients living with T2DM and obesity, we assessed the overlap between these indications and the real-world consequences of expanding semaglutide therapy eligibility to patients living with fibrotic MASH.

Methods

Study Population

This study was a cross-sectional analysis of National Health and Nutrition Examination Survey (NHANES) 2017–2020 data. NHANES is a retrospective ongoing study focusing on the health and nutritional status of the US population. Due to its unique design, the US general population can be simulated based on the survey weights. Data collection included extensive questionnaires, physical examination, blood and urine analysis, and liver health assessment by FibroScan. Further details on the aims, procedures, and design are available elsewhere.10,11 We included participants aged ≥ 18 years who participated in the liver health examination and excluded individuals with hepatitis B or C and/or individuals with excessive alcohol consumption defined as >20 g/day in female and >30 g per day in male. Data are publicly available from the NHANES database (https://www.cdc.gov/nchs/nhanes/index.htm).

Liver Health Assessment

Vibration-controlled transient elastography was performed to obtain data on liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) using the FibroScan model 502 V2 Touch (FibroScan, Echosens, Paris) in individuals who were requested to fast for at least 3 h. At the examination center, both an M-probe and XL-probe were available and used according to the instructions of the device. LSM readings were considered valid if at least 10 measurements were obtained with an interquartile range < 30% in the absence of congestive heart failure (hence, no participants with fibrotic MASH had heart failure).12,13

MASLD was defined as a CAP ≥ 275 dB/m together with metabolic dysfunction as defined in the MASLD consensus statement.14,15 Hypertension was defined as blood pressure ≥ 130/85 mmHg or antihypertensive drug treatment; dyslipidemia as triglycerides ≥ 1.7 mmol/L, high-density lipoprotein cholesterol ≤ 1.0 mmol/L in males or ≤ 1.3 mmol/L in females, and/or lipid-lowering treatment; and T2DM as hemoglobin A1C (HbA1c) ≥ 6.5%, fasting glucose ≥ 7 mmol/L or antidiabetic drug use. Prediabetes was defined as fasting glucose ≥ 5.6 mmol/L or HbA1c ≥ 5.7%.

Fibrotic MASH, the new semaglutide treatment indication, was defined according to the current American Association for the Study of Liver Diseases treatment algorithm in place for Resmetirom, a thyroid hormone receptor β (THR-β) agonist, which has the same indications in the FDA label as semaglutide.16 This algorithm recommends pharmaceutical treatment of fibrotic MASH when MASLD has been established with an LSM between 8 and 15 kPa.

Additional noninvasive assessment of liver health included fibrosis-4 (FIB-4) and metabolic dysfunction–associated fibrosis 5 (MAF-5) based on a recent evaluation.17 They were calculated according to their formula’s available elsewhere.18,19

Conventional Indications for Semaglutide

Semaglutide eligibility was defined according to conventional indications defined as FDA-approved criteria for weight loss and high-risk T2DM as outlined by the American Diabetes Association.

Weight loss

Body mass index > 27 kg/m2 in the presence of at least 1 weight-related comorbidity in addition to diet and physical exercise management.20 Weight-related comorbidity was defined as hypertension, dyslipidemia, (pre)diabetes, obstructive sleep apnea, or cardiovascular disease (CVD) in line with the studies on which semaglutide got approval.21

High-risk T2DM

Semaglutide could be considered in patients with high risk for adverse outcomes defined as (1) having CVD, (2) at high risk of CVD (aged ≥ 55 years with 2 other cardiometabolic risk factors), or (3) chronic kidney disease (estimated glomerular filtration rate < 60 or albumin creatinine ratio > 30 mg/g). The treatment dosage differs from that recommended for weight loss and/or fibrotic MASH compared to T2DM.22

Covariates

Medication use and medical history were based on an interview by trained research assistants. Blood samples were analyzed for various outcomes, including liver enzymes, triglycerides, high-density lipoprotein, and glucose. Urine samples were analyzed for albumin and creatinine. Daily alcohol consumption was obtained through questionnaires and transferred into grams per day using 14 g of ethanol per US standard drink.

Obstructive sleep apnea was defined as 2 out of the following: snoring at least 3 nights a week, snorting or apneas at least 3 nights a week, and feeling sleepy at least 16 days a month, aligning previous studies.23 CVD was defined as congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction, or stroke based on interview data.

Biopsy Cohort

We used the Mainz biopsy cohort to investigate biopsy-proven fibrotic MASH, selecting the individuals with fibrotic MASH defined as the presence of steatosis (>5%) together with F2 or F3 fibrosis according to the Kleiner grading system.24 Semaglutide eligibility was defined identical as in the NHANES cohort, except that data on albuminuria were lacking and therefore not included in the high-risk T2DM definition. Further details regarding the Mainz biopsy cohort are described elsewhere.25

Statistical Analysis

Baseline data were presented using the survey weights to simulate a representative dataset for the US population. First, we stratified the general population based on the presence of a conventional semaglutide indication and provided participant characteristics, a process repeated for individuals living with fibrotic MASH. Second, we made Euler plots (size-proportional Venn diagrams) to visualize the frequency and overlap between the different semaglutide indications in the general population and repeated this for the subgroup living with (1) MASLD and (2) fibrotic MASH. Finally, the assessment of the fibrotic MASH population was repeated in the Mainz biopsy cohort. The analysis was performed according to a prespecified analysis plan. Analyses were performed in R (version 4.0.4; Foundation for Statistical Computing, Vienna, Austria). P values < .05 were considered statistically significant.

Results

Of 7768 adult participants from the NHANES 2017–2020 cycle with data available on liver health, 832 were excluded for excessive alcohol consumption and/or viral hepatitis, leaving 6936 participants for analysis. The weighted median age was 47 years [32–61], and 47.9% were male; MASLD was present in 41.0% (95% confidence interval [CI]: 39.2%–51.3%) and fibrotic MASH in 5.2% (95% CI 4.3%–6.0%). Metabolic dysfunction traits were present in 73.8% T2DM in 14.5% and body mass index ≥ 27 kg/m2 in 59.2%. As a result, 51.5% (95% CI: 49.7%–53.3%) of the US population met the conventional criteria for semaglutide and thus, irrespective of the new fibrotic MASH indication. Extending the semaglutide eligibility with fibrotic MASH, a similar percentage had an indication (51.8% [95% CI: 49.9%–53.6%]). Additional characteristics, stratified for the presence of a semaglutide indication purely for weight loss and/or high-risk T2DM, are shown in Table 1.

Table 1.

Participant Characteristics Stratified for the Presence of a GLP-1 RA Eligibility for Conventional Indications: Weight Loss and/or High-Risk T2DM

Conventional GLP-1 RA treatment indication
No
 Yes
N = 3131 N = 3805
Age 42.8 (41.9–43.7) 51.3 (50.5–52.0)
Sex
 Male 46.0% (43.4%–48.7%) 49.6% (47.2%–52.0%)
Race
 Asian 7.5% (6.7%–8.2%) 3.9% (3.3%–4.4%)
 Black 10.2% (9.2%–11.1%) 11.8% (10.8%–12.7%)
 Hispanic 15.4% (14%–16.8%) 17.8% (16.4%–19.2%)
 White 63.9% (61.7%–66.1%) 61.7% (59.7%–63.8%)
 Other 3.1% (2.3%–3.8%) 4.8% (3.8%–5.8%)
Current smoker 15.8% (13.9%–17.7%) 12.8% (11.4%–14.3%)
BMI ≥ 27 kg/m2 19.9% (17.7%–22.1%) 96.1% (95.2%–97.1%)
High CVD risk 11.1% (9.6%–12.6%) 39.9% (37.5%–42.3%)
Albuminuria 6.7% (5.4%–7.9%) 13.1% (11.6%–14.7%)
Weight-related comorbidity
 Hypertension 23.5% (21.3%–25.6%) 61.6% (59.2%–64%)
 Dyslipidemia 26.8% (24.5%–29.1%) 74.1% (72.0%–76.2%)
 T2DM 1.1% (0.7%–1.5%) 24.5% (22.4%–26.5%)
 Prediabetes 17.7% (15.8%–19.7%) 33.4% (31.2%–35.7%)
 Obstructive sleep apnea 5.7% (4.5%–6.9%) 16.6% (14.8%–18.4%)
CVD 4.6% (3.7%–5.5%) 12.4% (10.8%–14%)
 Congestive heart failure 0.8% (0.4%–1.2%) 2.8% (2.1%–3.4%)
 Coronary heart disease 1.8% (1.2%–2.5%) 5.2% (4.0%–6.3%)
 Angina pectoris 0.9% (0.4%–1.3%) 3.1% (2.2%–4.0%)
 Myocardial infarction 1.5% (1.0%–2.1%) 4.3% (3.4%–5.2%)
 Stroke 1.8% (1.3%–2.3%) 4.7% (3.6%–5.7%)
ALT (U/L) 19.1 (18.4–19.7) 25.0 (24.1–25.8)
Platelets (x 109/L) 242 (239–245) 252 (249–256)
MASLD 16.6% (14.7%–18.5%) 63.9% (61.5%–66.2%)
Increased LSM
 LSM 8–15 kPa 2.7% (1.7%–3.7%) 10.8% (9.3%–12.4%)
CAP (dB/m) 229 (227–231) 293 (290–296)
LSM (kPa) 4.8 (4.7–4.9) 6.5 (6.2–6.7)
Fibrotic MASH 0.5% (0.2%–0.7%) 9.5% (8.0%–11.0%)
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Results were presented as weighted mean or weighted prevalence with 95% CI, based on the provided sample weights to simulate a US representative population.

ALT, alanine aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; CVD, cardiovascular disease; GLP-1 RA, glucagon-like peptide-1, receptor agonist; LSM, liver stiffness measurement; MASLD, metabolic dysfunction–associated steatotic liver disease; MASH, metabolic dysfunction–associated steatohepatitis; T2DM, type 2 diabetes mellitus.

Among the conventional semaglutide indications, weight loss was the main indication, followed by high-risk T2DM and, to a lesser extent, fibrotic MASH, with substantial overlap between the indications (Figure 1A). Among those with a conventional semaglutide indication, all had 1 or more weight-related comorbidities, ranging from dyslipidemia (74%), hypertension (62%), and prediabetes (33%) to obstructive sleep apnea (17%), whereas (required for classification of high-risk T2DM) high CVD risk (40%), albuminuria (13.1%), and CVD (11%) were less common. Among participants living with MASLD, the prevalence of semaglutide indications increased from 80.3% (95% CI: 78.1%–82.5%) for the conventional indications to 80.9% (95% CI: 78.7%–83.1%), when fibrotic MASH was included (Figure 1B).

Figure 1.

Figure 1

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Semaglutide eligibility across the (A) adult US population and (B) MASLD population for each indication in percentages. In the general population, semaglutide was indicated in 51.8%, of which fibrotic MASH was accountable for 0.2%. In the MASLD population, semaglutide was indicated in 80.9%, of which 0.6% was due to fibrotic MASH. Of note, there was a semaglutide indication overlap between fibrotic MASH and T2DM in 0.1% of the general population and 0.2% of the MASLD population, which could not be visualized. Prevalences were calculated using the survey sample weights to simulate a US population.

Further focusing on the recently added treatment indication for fibrotic MASH, it was observed that 95.4% (95% CI: 93.1%–97.7%) of this group already met a conventional treatment indication through weight-related comorbidity (64.5%), high-risk T2DM (1.7%), or both (29.2%) (Figure 2A). Among the remaining 4.6% who would newly qualify under a fibrotic MASH indication, there were lower CAP levels (P < .01) and MAF-5 score (P < .01) but no significant differences in LSM and FIB-4 compared to those with an existing indication (Table 2).

Figure 2.

Figure 2

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Semaglutide eligibility among individuals eligible for treatment due to fibrotic MASH in percentages. In the fibrotic MASH population, the indication of semaglutide other than fibrotic MASH was present in 95.4%. In a German biopsy cohort of patients with F2-F3 fibrosis and MASLD, the indication for semaglutide other than fibrotic MASH was present in 80.3%.

Table 2.

Participant Characteristics Living With Fibrotic MASH Stratified for the Presence of Conventional GLP-1 RA Indications: Weight Loss and/or High-Risk T2DM

Conventional GLP-1 RA treatment indication
No
 Yes
N = 26 N = 369
Age 51.0 (39.3–62.7) 51.1 (48.9–53.4)
Sex
 Male 63.5% (39.9%–87.1%) 57.4% (49.2%–65.7%)
Race
 Asian 18.1% (4.3%–31.9%) 3.3% (1.8%–4.9%)
 Black 12.3% (0%–25%) 8.4% (5.9%–10.8%)
 Hispanic 7.4% (0%–15.5%) 20.3% (15.1%–25.5%)
 White 61% (39.4%–82.6%) 64.9% (58.2%–71.7%)
 Other 1.3% (0%–3.8%) 3.1% (1.1%–5.0%)
Current smoker 9.3% (0%–20%) 11.2% (6.5%–15.8%)
BMI ≥ 27 kg/m2 47.7% (22.4%–73%) 98.2% (96.9%–99.5%)
High CVD risk 14.9% (0%–32.4%) 40.6% (32.7%–48.5%)
Albuminuria 19.2% (0%–46.2%) 22.5% (15.2%–29.8%)
Weight-related comorbidity
 Hypertension 45.7% (21.4%–70%) 72.7% (65.1%–80.3%)
 Dyslipidemia 35% (12.9%–57%) 74.1% (66.4%–81.8%)
 T2DM 12.1% (0%–24.5%) 43.3% (34.9%–51.6%)
 Prediabetes 19.5% (1.2%–37.8%) 28.8% (21.3%–36.3%)
 Obstructive sleep apnea 3.9% (0%–11.6%) 18.5% (13%–24.1%)
CVD 14.9% (0%–32.4%) 10.8% (6.4%–15.1%)
 Coronary heart disease 3.9% (0%–11.6%) 3.8% (1.1%–6.4%)
 Angina pectoris 8.5% (0%–24.2%) 5.1% (1.7%–8.6%)
 Myocardial infarction 3.9% (0%–11.6%) 3.5% (0.8%–6.3%)
 Stroke 10.9% (0%–27.2%) 3.2% (1.4%–5%)
ALT (U/L) 24.1 (16.3–31.9) 34.1 (31.3–37.0)
Platelets (x 109/L) 247 (209–285) 254 (241–267)
CAP (dB/m) 327 (316–338) 340 (334–346)
LSM (kPa) 10.5 (9.8–11.1) 10.2 (9.9–10.5)
FIB-4 1.14 (0.68–1.60) 1.07 (0.85–1.19)
MAF-5 −0.11 (−1.16–0.93) 2.74 (2.41–3.08)
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Results were presented as weighted mean or weighted prevalence with 95% CI, based on the provided sample weights to simulate a US representative population.

ALT, alanine aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; CVD, cardiovascular disease; GLP-1 RA, glucagon-like peptide-1, receptor agonist; LSM, liver stiffness measurement; MAF-5, metabolic dysfunction–associated fibrosis 5; MASLD, metabolic dysfunction–associated steatotic liver disease; MASH, metabolic dysfunction–associated steatohepatitis; T2DM, type 2 diabetes mellitus.

Finally, we investigated the semaglutide indications in a subset of the Mainz biopsy cohort who had MASLD and F2 or F3 on biopsy (n = 213). In this tertiary care population, 80.3% had a conventional treatment indication (Figure 2B). Characteristics stratified for the presence of a conventional semaglutide indication are available in Table 3. Individuals who solely had a semaglutide indication through MASLD-related fibrosis had significantly lower LSM (both continuous [P = .01] and focusing on the 8 kPa threshold [P < .01]) and also lower noninvasive test levels such as MAF-5 (P < .01) and FIB-4 (P < .01).

Table 3.

Patient Characteristics Living With Biopsy Proven Fibrotic MASH Stratified for the Presence of Conventional Indications: Weight Loss and/or High-Risk T2DM

Conventional GLP-1 RA treatment indication
No
 Yes
N = 42 N = 171
Age 43 (16) 53 (13)
Sex
 Male 29 (64%) 109 (50%)
Current smoker 4 (40%) 32 (63%)
BMI ≥ 27 kg/m2 17 (41%) 169 (99%)
High CVD risk 14.9% (−2.7%–32.4%) 40.6% (32.7%–48.5%)
Albuminuria 19.2% (−7.8%–46.2%) 22.5% (15.2%–29.8%)
Weight-related comorbidity
 Hypertension 12 (29%) 134 (78%)
 Dyslipidemia 10 (24%) 94 (55%)
 T2DM 3 (7.1%) 97 (57%)
 Obstructive sleep apnea 2 (5.4%) 32 (21%)
CVD 0 (0%) 6 (3.6%)
ALT (U/L) 118 (72) 93 (76)
Platelets (x 109/L) 243 (61) 228 (76)
Fibrosis
 F2 31 (74%) 99 (58%)
 F3 11 (26%) 72 (42%)
LSM (kPa) 8.4 (3.7) 12.1 (7.3)
LSM ≥ 8 kPa 10 (37%) 66 (65%)
FIB-4 1.57 (1.94) 2.44 (2.10)
MAF-5 2.41 (1.99) 4.94 (2.56)
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Results are presented as mean with SD or n with prevalence.

ALT, alanine aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; CVD, cardiovascular disease; GLP-1 RA, glucagon-like peptide-1, receptor agonist; LSM, liver stiffness measurement; MAF-5, metabolic dysfunction–associated fibrosis 5; MASLD, metabolic dysfunction–associated steatotic liver disease; MASH, metabolic dysfunction–associated steatohepatitis; SD, standard deviation; T2DM, type 2 diabetes mellitus.

Discussion

We demonstrated that semgalutide is already indicated in 51.5% (95% CI: 49.7%–53.3%) of the US adult population with conventional indications (weight loss or high-risk T2DM), irrespective of the new indication fibrotic MASH. As such, 80.3% (95% CI: 78.1%–82.5%) of individuals with MASLD and 95.4% (95% CI: 93.1%–97.7%) of those with fibrotic MASH already had a conventional treatment indication, primarily for weight loss purposes. Weight loss itself is strongly associated with improvements in liver health, even beyond the typically recommended weight loss targets.26 Similar results were observed in our analysis of a German cohort, where 80.3% of patients with biopsy-proven MASLD and F2 or F3 fibrosis already met the criteria for semgalutide at the time of biopsy. Notably, those newly indicated had, in this real-world patient cohort, lower FIB-4, MAF-5, and LSM, making them potentially more challenging to identify. The substantial overlap underscores the intertwined nature of MASLD-related fibrosis and (other) weight-related comorbidities and advocates for a holistic treatment approach rather than a siloed disease management. And although most patients living with fibrotic MASH already had a conventional indication for semaglutide, the new indication for fibrotic MASH is an important tool for the hepatologist and could still facilitate the timely initiation of semaglutide in eligible patients and streamline reimbursement processes, ultimately lowering barriers to access.

While treatment eligibility is high, the optimal dosing of semaglutide varies by indication and warrants careful consideration in clinical practice. The FDA-approved dosage for weight loss (2.4 mg once weekly) aligns with regimens tested in clinical trials such as Essence III and is also recommended for fibrotic MASH.3,21 Lower doses (eg, 1.7 mg weekly) may be considered when tolerability is an issue. The subcutaneous dosage for high-risk T2DM is considerably lower at 1.0 mg once weekly but can be increased to 2.0 mg for additional glycemic control, with oral alternatives also being available.27,28 Hence, despite most individuals in this study with fibrotic MASH already having an indication for semaglutide, this is not necessarily the optimal dosage, particularly when initiated for high risk T2DM. Therefore, from a liver perspective, treatment for patients with fibrotic MASH may be further improved by changing from oral to subcutaneous administration and/or increasing to 2.4 mg semaglutide once weekly. Alternatively, one could consider starting a THR-β agonist alongside semaglutide and lifestyle optimization; however, there is limited information on combining a THR-β agonist with semaglutide since the former was only recently conditionally approved by the FDA (2024) and European Medicine Agency (2025) and no stratified analyses were presented for the MAESTRO NASH trial.29,30

Beyond clinical considerations, initiation and adherence to treatment are highly correlated with reimbursement.31 Despite FDA approval, insurance coverage of these drugs, especially when used for weight loss beyond CVD or T2DM, remains challenging with noncommercial insurance, such as Medicare Part D and Medicaid.8 This is particularly inconvenient since individuals having insurance under the Medicare Part D and Medicaid have more frequent obesity and more weight-related comorbidities.32 Together with limited stock, the insurance issues could explain the relatively poor uptake of semaglutide in light of the overwhelming presence of treatment indications.33, 34, 35 While expanding indications to include fibrotic MASH may not significantly increase treatment eligibility, it could provide a structured clinical rationale for addressing liver disease, initiate case finding, and potentially support broader insurance coverage.

With the approval of multiple agents for fibrotic MASH in the United States, clinical decision-making will increasingly require guidance on sequencing and prioritization. At this point, no head-to-head trials have been performed, and 1 drug cannot be recommended over the other. However, one could consider initiating semaglutide in patients with obesity since a THR-β agonist has no weight loss properties.1,30 On the other hand, when there is primarily dyslipidaemia-related disease, one may prefer a THR-β agonist due to the greater observed LDL cholesterol reduction than semaglutide.3,30 Another factor to take into account is whether it is primarily steatohepatitis with only limited fibrosis that requires treatment or more advanced fibrosis with limited steatohepatitis, since semaglutide seems more effective for MASH resolution and a THR-β agonist for fibrosis regression.3,30 Another aspect to take in mind is treatment costs, which are generally lower with semaglutide, depending on the price agreements, and could therefore end up as the preferred option in local protocols. However, long-term cost-effectiveness data are ultimately required. Despite these pharmacological advances, lifestyle modification remains the cornerstone of treatment for both fibrotic MASH and overweight. Semaglutide, as well as a THR-β agonist, is indicated only as an adjunct to a reduced-calorie diet and increased physical activity, and sustained improvements in diet and exercise remain essential to long-term outcomes.36

Limitations

This policy-oriented study provides an extensive overview of semaglutide indications in a US representative cohort, highlighting that even outside the fibrotic MASH indication, >80% of individuals living with MASLD already have an indication for semaglutide, which was confirmed in patient data. Nevertheless, the following limitations need to be discussed. First, the epidemiologic data originate from the United States and, due to high levels of metabolic dysfunction, may not directly be generalizable to countries where obesity is less prevalent. Second, there might be an alanine aminotransferase threshold in the to-be-developed semaglutide treatment algorithms, similar to some THR-β agonist recommendations.37 However, this would only further reduce the additional semaglutide treatment indications in the general population and would not affect the conclusions of the article. Similarly, data were not fully complete, particularly on CVD risk parameters in the biopsy cohort, and treatment eligibility could be higher than currently reported. Third, there is ongoing discussion about the reliability of LSM readings in individuals with obesity. However, a meta-analysis including more than 11.000 patients indicated that obesity was not a predictor for inflated LSM when using the XL-probe according to the device's instructions; however, it was associated with higher CAP levels.38 Apart from that, there is increasing evidence that up to 30% of LSM ≥ 8 kPa in a screening setting decreases to < 8 kPa without intervention; as such, the reported treatment eligibility for fibrotic MASH reported here is on the high side and may not reflect clinical practice.39 However, if the treatment eligibility in a real-world setting turns out to be even lower than reported here, that would only further support our discussion.

Conclusion

More than 50% of the US general population already meets at least 1 FDA-approved indication for semaglutide, primarily due to weight-related comorbidities. Treatment eligibility increased to over 80% among individuals living with MASLD, and this proportion rises up to 95% in those with fibrotic MASH. Accordingly, the recent FDA label expansion to include fibrotic MASH is unlikely to substantially increase the pool of eligible patients. Instead, the strong overlap between metabolic comorbidities and liver disease highlights the need for an integrated, patient-centered approach, alongside improved access and reimbursement for semaglutide therapy and MASLD care.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

OpenAI’s ChatGPT (GPT-5) was used to improve clarity and readability after the article was completed. All suggestions provided by the AI were reviewed and addressed manually by the authors before including them in the final version of the article.

Acknowledgments

The authors gratefully acknowledge the contribution of the participants of the National Health and Nutrition Examination Survey cohort, research assistants, and facilitating personnel, as well as the research team of the Mainz Cohort.

Authors’ Contributions

Laurens A. van Kleef: Collection of data, study design, data analysis, and writing of the article. Willem P. Brouwer: Collection of data, study design, data analysis, and writing of the article. All authors: Critical review of the article, writing of the article, approval of final version, and approval of submission.

Footnotes

Conflicts of Interest: These authors disclose the following: Christian Labenz: Lecture and consultant fees: Merz Therapeutics, Norgine, Alfasigma, Intercept, Advanz Pharma, Boehringer Ingelheim, Falk Foundation e.V., Ewimed, Abbvie, Gilead Sciences, CSL Behring. Research grants: Merz Therapeutics, Norgine. Elisabeth F.C. van Rossum: Previously been involved in the medical care for patient participating in a clinical trial from Rhythm Pharmaceuticals, Inc (no personal funding) and received personal royalties for the lay book FAT the secret organ. Harry L.A. Janssen: Grants from AbbVie, Arbutus, Gilead Sciences, Janssen and Roche, and is a consultant for Arbutus, Arena, Enyo, Gilead Sciences, GlaxoSmithKline (GSK), Janssen, Merck, Roche, Vir Biotechnology Inc and Viroclinics. Jörn M. Schattenberg: Consultant honorary from Akero, Alentis, Alexion, Altimmune, Astra Zeneca, 89Bio, Bionorica, Boehringer Ingelheim, Gilead Sciences, GSK, HistoIndex, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, Kríya Therapeutics, Lilly, MSD Sharp & Dohme GmbH, Nordic Bioscience, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers, Summit Clinical, and Vantage Biosciences Research; speaker honorarium from AbbVie, Boehringer Ingelheim, Gilead Sciences, Ipsen Novo Nordisk, Madrigal Pharmaceuticals, Worldwide Clinical Trials, Stockholder options: Hepta Bio. Maurice Michel: Consultant honorary from Boehringer Ingelheim and Ipsen; speaker honorarium from AbbVie, Astra Zeneca, Gilead Sciences, GSK, Ipsen, Novo Nordisk. Willem P. Brouwer: Speakers fees for Eli Lilly, is part of the advisory board of Novo Nordisk and participates in trials of 89BIO, Boehringer Ingelheim, Novo Nordisk, and Inventiva Pharma. Willy Theel: Speakers fees for Novo Nordisk and participates in trials of 89BIO, Boehringer Ingelheim, Novo Nordisk, and Inventiva Pharma. Zobair M. Younossi has received research funding and/or serve as consultant/advisor to Intercept, Cymabay, Boehringer Ingelheim, Ipsen, BMS, GSK, NovoNordisk, Siemens, Madrigal, Merck, Aligos, Akero, Sanofi, and Abbott. The remaining authors disclose no conflicts.

Funding: Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. The funding source neither did influence the study design, data collection, and analysis and interpretation of the data nor the writing of the report and decision to submit for publication.

Ethical Statement: NHANES procedures and protocols were approved by the NCHS Research Ethics Review Board. Participants of the NHANES 2017–2020 cycle provided informed consent. Ethical approval was obtained by the local committee for the Mainz cohort under 2018–13269 and 2025–18225. This study was conducted according to the principles as outlined in the Declaration of Helsinki and Istanbul.

Data Transparency Statement: Data are publicly available from the NHANES database (https://www.cdc.gov/nchs/nhanes/index.htm).

Reporting Guidelines: STROBE.

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