Hepatic Benefits of GLP-1 RAs Are Independent of Weight Loss in MASLD, Diabetes

Findings from a recent study are providing clinicians with an overview of the impact of treatment with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on weight loss and hepatic fat reduction in patients with diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD).¹

The retrospective study examined a real-life cohort of patients with diabetes and MASLD and found treatment with GLP-1RAs was associated with greater weight loss, improvement in liver function tests, and reduction of hepatic fat. Of note, the beneficial effect on liver parameters was independent of weight loss.¹

“MASLD is expected to pose a significant burden on healthcare systems over the next few years, driven by the epidemics of obesity and T2DM,” Roberta Forlano, MD, PhD, a clinical research fellow and hepatologist at Imperial College London/Imperial college Healthcare NHS Trust, and colleagues wrote.¹ “Despite significant progress in risk-stratification of patients at high risk of progression, there are still limited options to treat the condition. Among others, GLP-1RAs are in late-stage trials for treating MASLD given their beneficial effects on weight loss and cardio-metabolic health.”

On March 14, 2024, the US Food and Drug Administration granted accelerated approval to resmetirom (Rezdiffra) for the treatment of noncirrhotic nonalcoholic steatohepatitis (NASH), also known as metabolic dysfunction-associated steatohepatitis (MASH), making it the first and only treatment to receive approval for the progressive liver disease.² Of note, the approval was only for patients with MASH and moderate to advanced (stage 2 and 3) fibrosis. Currently, resmetirom’s use in patients who do not meet those criteria is not recommended, as emphasized in a recent expert panel recommendation reviewing the intended treatment population for resmetirom.³

For patients in whom resmetirom cannot be used, lifestyle modifications and weight loss are the cornerstones of disease management. Although GLP-1RAs are not currently approved for MASLD, their approval for type 2 diabetes and obesity, both of which are common in patients with MASLD, presents a pathway for their use in this patient population.¹

To assess the effect of long-term GLP-1 therapy on liver disease severity in patients with type 2 diabetes and MASLD, investigators conducted a retrospective, observational study including consecutive patients with type 2 diabetes with a clinical or histological diagnosis of MASLD followed up between January 2010 and May 2023 in the specialist joint metabolic liver clinic at St Mary's Hospital in London. Patients with evidence of other chronic liver disease, use of steatogenic drugs, and excessive alcohol consumption (defined as alcohol consumption ≥14 units/week) were excluded.¹

Clinical outcomes were major acute cardiovascular events, including acute coronary syndrome; transient ischaemic attack; stroke; and cardiovascular death, as well as hepatic decompensation, including ascites; encephalopathy; and/or variceal bleeding.¹

Overall, among 335 patients diagnosed with type 2 diabetes, 94 (28%) were prescribed a GLP-1RA, and the median treatment period was 42 (8–171) months. Among those who were on GLP-1RAs, 47 (50%) patients were on dulaglutide, 31 (32%) were on semaglutide, 14 (15%) were on liraglutide, and 2 (2%) were on exenatide. Regarding liver disease severity, the median liver stiffness measurement (LSM) was 11.2 (7.1–18) kPa, with 61 (65%) patients having LSM >8 kPa.¹

At the end of a median 60 months of follow-up, patients on GLP-1RAs experienced a significant improvement in BMI (33.1 vs 34.9 kg/m2; P = .005), alanine aminotransferase (ALT) (37 vs 58 IU/L; P = .009), HbA1c (58 vs 61 mmol/lL; P = .006) and controlled attenuation parameter (CAP) score (331 vs 354 dB/m; P = .0001). However, there was no difference in LSM (7.9 vs 11.8 kPa; P = .15).¹

The 72 patients with diabetes treated with GLP-1RAs were age-, gender- and HbA1c-matched to patients with diabetes who were not receiving GLP-1RAs. At baseline, those who were prescribed a GLP-1RA had a greater BMI (34.8 vs 30.4 kg/m2; P = .002) and greater CAP scores (354 vs 328 dB/m; P = .0001) compared to matched controls who were not on GLP-1RAs.¹

At the time of their most recent clinic review, there was a significantly greater reduction in BMI (−1.4 vs −0.4 kg/m2; P <.05), ALT (−16 vs −6 IU/L; P <.05), AST (−6.5 vs −1 IU/L; P <.05), and GGT levels (−31 vs −5 IU/L; P <.01) in those treated with GLP-1RAs compared to matched controls. Investigators also noted a significant reduction in CAP score (−33 vs −9.5 dB/m; P = .0001) but pointed out there was no difference in key clinical outcomes for major adverse cardiovascular events, decompensation events, or all-cause mortality between the 2 groups.¹

Among those who were treated with GLP-1RAs, 37 patients had <5% weight loss over a median of 38 (10–134) months while 50 patients reported >5% weight loss. Among those with <5% weight loss, investigators observed a significant reduction in ALT (32 vs 58 IU/L; P = .0001), AST (30 vs 36 IU/L; P = .004), and CAP score (329 vs 349 dB/m; P = .05) compared with those who lost >5% weight. However, there was no statistically significant difference in terms of pre- and post-treatment LSM (8.9 vs 10.2 kPa; P = .056).¹

“In this cohort of patients with diabetes and MASLD, treatment with GLP-1RAs was associated with greater weight loss, greater improvement in liver function tests and hepatic fat reduction. A beneficial effect on liver parameters was independent of weight loss,” investigators concluded.¹ “Nevertheless, longer prospective studies are required to assess the effect of GLP-1RA therapy on hepatic fibrosis, which is the main predictor of outcomes in this population.”

References

1. ^{Forlano R, Malik H, Mullish BH, et al. The beneficial hepatic effects of glucagon-like peptide 1 receptor agonists in patients with diabetes and metabolic dysfunction-associated steatotic liver disease are independent of weight loss. Liver International Communications. https://doi.org/10.1002/lci2.86}
2. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed August 7, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}
3. ^{Brooks, A. Considerations for Resmetirom Use, Monitoring in Patients with MASH, Fibrosis. HCPLive. August 5, 2024. Accessed August 7, 2024. https://www.hcplive.com/view/considerations-resmetirom-use-monitoring-patients-mash-fibrosis}