SGLT2i Outperforms DPP4i in Improving Hepatic Fibrosis Indices in MASLD

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) proved more effective than dipeptidyl peptidase 4 inhibitors (DPP4i) in ameliorating hepatic inflammation and fibrosis indices in patients with type 2 diabetes (T2D) and suspected metabolic dysfunction-associated steatotic liver disease (MASLD).¹

This retrospective study, utilizing a Japanese medical claims database, found patients with suspected MASLD treated with SGLT2i also experienced a reduction in the incidence of both esophageal varices and extrahepatic cancer, compared with DPP4i.

“These findings suggest that SGLT2i may be more beneficial than DPP4i in suppressing life-threatening events in patients with T2D and suspected MASLD,” wrote the investigative team, led by Takumi Kawaguchi, MD, PhD, division of gastroenterology, department of medicine, Kurume University School of Medicine.

Hepatic steatosis is prevalent in T2D, with the American Diabetes Association (ADA) updating clinical practice recommendations to propose screening for non-alcoholic fatty liver disease (NAFLD) in patients with T2D.² MASLD recently replaced NAFLD after a consensus statement was released by 3 large pan-national liver associations.³

SGLT2i, a widely utilized anti-diabetic medication, has demonstrated improvements in glucose and lipid metabolisms, as well as serum hepatic enzyme levels, including alanine aminotransferase (ALT), in patients with MASLD. SGLT2i has also exhibited anti-tumor effects, but these results are conflicting and a consensus has not been achieved.

Given the need for a large-scale, real-world database study, Kawaguchi and colleagues set out to explore the preventive effect of SGLT2i on the incidence of liver-related events and extrahepatic cancer, compared with DPP4i in patients with T2D and suspected MASLD using the Japanese medical claims database.

All patients with T2D prescribed either SGLT2i or DPP4i between April 2014 and October 2022 (n = 1,628,656) were enrolled in the study. Eligible individuals were classified into SGLT2i or DPP4i cohorts, according to the the initial prescription on the index date. All patients underwent 1:1 propensity score matching, to create a population analysis using 67 covariates.

Outcomes for the analysis included changes in hemoglobin A1c (HbA1c) and ALT after 6 months of treatment, changes in hepatic fibrosis indexes, and the incidence of newly diagnosed liver-related events over 12 months. Eligible patients were separated into the SGLT2i (n = 4790) or DPP4i (n = 17,037) groups and propensity score matching left 4204 patients in each group for the analysis.

After 6 months of treatment, SGLT2i and DPP4i lowered HbA1c levels by 0.95% and 1.15%, respectively. These data showed DPP4i significantly decreased HbA1c levels compared with SGLT2i, while SGLT2i significantly decreased ALT levels.

Each treatment cohort demonstrated no significant differences in platelet counts over 12 months, while SGLT2i significantly lowered the FIB-4 index, Forns index, and AST/ALT ratio versus DPP4i over 12 months.

Analyses revealed no significant differences in the overall incidence of liver-related events between the SGLT2i and DPP4i cohorts. However, the data showed SGLT2i significantly lowered the incidence of esophageal varices (hazard ratio [HR], 0.12; 95% CI, 0.01–0.95; P = .044).

Further analysis showed no notable difference in cardiovascular events between the SGLT2i and DPP4i. However, SGLT2i significantly reduced the incidence of extrahepatic cancer (HR, 0.50; 95% CI, 0.30–0.84; P = .009), compared with DPP4i.

In their summary, Kawaguchi and colleagues noted these beneficial effects observed in the SGLT2i cohort were apparent in patients at high risk of cancer, including the elderly, hepatitis, hepatic fibrosis, chronic kidney disease (CKD), and hypertriglyceridemia.

“We have to be cautious about the interpretation of the results,” they wrote, “Because the Medical Data Vision (MDV) database does not include the details of medical history, there is a possible bias in the duration of T2D history between the DPP4i and SGLT2i groups.”

References

1. _{Kawaguchi, T., Fujishima, Y., Wakasugi, D. et al. Effects of SGLT2 inhibitors on the onset of esophageal varices and extrahepatic cancer in type 2 diabetic patients with suspected MASLD: a nationwide database study in Japan. J Gastroenterol (2024). https://doi.org/10.1007/s00535-024-02158-z}
2. _{ElSayed NA, Aleppo G, Aroda VR, et al. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2023 [published correction appears in Diabetes Care. 2023 Sep 1;46(9):1722. doi: 10.2337/dc23-er09a] [published correction appears in Diabetes Care. 2023 Sep 01;46(9):1718-1720. doi: 10.2337/dc23-ad09]. Diabetes Care. 2023;46(Suppl 1):S49-S67. doi:10.2337/dc23-S004}
3. _{Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79(6):1542-1556. doi:10.1016/j.jhep.2023.06.003}
4. _{He K, Li J, Xi W, Ge J, Sun J, Jing Z. Dapagliflozin for nonalcoholic fatty liver disease: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2022;185:109791. doi:10.1016/j.diabres.2022.109791}