Fatty liver: less severe liver complications with SGLT-2 inhibitors?

A study saw less frequent severe liver complications in MASLD patients treated with SGLT-2 inhibitors, compared to glitazones treatments, but not less than GLP-1 receptor agonists treatments.

SGLT-2 inhibitors in MASLD – the key facts in a nutshell

In direct comparison with GLP-1 receptor agonists, there was no significant difference in the risk of severe liver complications and mortality in the overall population.
Compared with glitazones, the risk of hepatic decompensation and liver-related and general mortality was significantly lower with SGLT-2 inhibitors.
Women and patients under 65 years of age benefit particularly from the use of SGLT-2 inhibitors.

A retrospective cohort study included adults with MASLD who were treated for the first time between 2014 and 2022 with an SGLT-2 inhibitor (dapagliflozin, empagliflozin, ipragliflozin or ertugliflozin), a GLP-1 receptor agonist (dulaglutide, lixisenatide, liraglutide, exenatide or albiglutide) or a glitazone (lobeglitazone or pioglitazone) for the first time between 2014 and 2022.

The primary endpoint was a combination of serious liver complications: ascites, oesophageal varices with bleeding, liver failure or liver transplantation. Secondary endpoints included the individual components of this composite endpoint, as well as mortality from liver disease and overall mortality.

A total of 22,550 patients were included in the SGLT-2 vs. GLP-1 comparison and 191,628 in the SGLT-2 vs. glitazone comparison. After an average of 2.1 years, the following results were observed:

SGLT-2 inhibitors vs. GLP-1 receptor agonists: There was no significant difference in the risk of serious liver complications (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.76–1.14). There was also no significant difference between the two groups in terms of secondary endpoints, both for individual complications (e.g. ascites, liver failure) and mortality
SGLT-2 inhibitors vs. glitazones: The risk of hepatic decompensation was significantly lower with SGLT-2 inhibitors than with glitazones (HR 0.77; 95% CI 0.72–0.82). This difference was also evident for the individual components: e.g. ascites (HR 0.75), oesophageal varices with bleeding (HR 0.77) and liver failure (HR 0.77). In addition, both mortality from liver disease (HR 0.61) and overall mortality (HR 0.73) were significantly lower with SGLT-2 inhibitors than with glitazones.

Subgroups: Women and younger patients in particular benefit from SGLT-2 inhibitors

The subgroup analyses revealed an age and gender effect:

In patients under 65 years of age, the risk of liver decompensation was significantly lower with SGLT-2 inhibitors compared to GLP-1 RA (HR 0.68), whereas in older patients (≥ 65 years) an increased risk was observed (HR 1.37).
Compared to glitazones, the risk reduction under SGLT-2 inhibitors was significantly more pronounced in women (HR 0.62) than in men (HR 0.87).

These differences were statistically significant. The results remained stable in sensitivity analyses.

Relevance for everyday practice

The results of this large cohort study support the use of SGLT-2 inhibitors to reduce severe liver complications in patients with MASLD, especially when compared to glitazones. No significant advantage was observed in the overall population compared to GLP-1 receptor agonists, but in the subgroup of patients under 65 years of age, there was a clear benefit in favour of SGLT-2 inhibitors. The data suggest that SGLT-2 inhibitors should be given greater consideration in treatment planning for younger and female patients with metabolic fatty liver disease.

These are real-world data from an observational study; therefore, causal statements are not possible. Further studies, including those with newer GLP-1 agonists, are needed to define the optimal therapy for MASLD.

References

Bea S, Ko HY, Bae JH, Cho YM, Chang Y, Ryu S, Byrne CD, Shin JY. Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease. Gut. 2025 Jan 17;74(2):284-294. doi: 10.1136/gutjnl-2024-332687. PMID: 39242193; PMCID: PMC11874371.