Therapeutic Potential of Sotagliflozin in Animal Models of
                    Non-alcoholic Fatty Liver Disease with and without Diabetes

Nitin J. Deshmukh; M. S. Kalshetti; Mohan Patil; Manohar Nandanwar; Ganesh V. Sangle

doi:10.1055/a-2557-8927

Drug Research, Table of Contents

Drug Res (Stuttg) 2025; 75(05): 129-139
DOI: 10.1055/a-2557-8927

Original Article

Therapeutic Potential of Sotagliflozin in Animal Models of Non-alcoholic Fatty Liver Disease with and without Diabetes

Nitin J. Deshmukh

¹D.S.T.S. Mandal’s Collage of Pharmacy, Solapur, Maharashtra, India

²Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India

,

M. S. Kalshetti

¹D.S.T.S. Mandal’s Collage of Pharmacy, Solapur, Maharashtra, India

,

Mohan Patil

²Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India

³Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia

,

Manohar Nandanwar

²Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India

,

Ganesh V. Sangle

²Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India

⁴Kashiv BioSciences Private Limited, Ahmedabad, Gujarat

› Author Affiliations

Abstract

Purpose

Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.

Methods

Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.

Results

In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.

Conclusion

Study underscores sotagliflozinʼs potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.

Keywords

antidiabetic drugs - endocrine pharmacology - metabolic disorders - lipidlowering drugs - insulin/glucagons

Full Text

References

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