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. 2025 Dec 9.
doi: 10.1007/s00125-025-06616-y. Online ahead of print.

Empagliflozin improves beta cell function independently of relief of glucotoxicity in patients with type 2 diabetes: results from a randomised cross-over study with insulin as comparator

Roopameera Thirumathyam  1 , Erik A Richter  2 , Gerrit van Hall  3 , Nicoline R Andersen  2 , Per L Madsen  2   4   5 , Jens J Holst  6   7 , Sten Madsbad  1   5 , Nils B Jørgensen  8   9
Affiliations

Empagliflozin improves beta cell function independently of relief of glucotoxicity in patients with type 2 diabetes: results from a randomised cross-over study with insulin as comparator

Roopameera Thirumathyam et al. Diabetologia. .

Abstract

Aims/hypothesis: Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve beta cell function in individuals with type 2 diabetes. It has been suggested this is due to relief of glucotoxicity, but the mechanism is unknown. The objective of the present study was to evaluate the effect of the SGLT2 inhibitor empagliflozin, compared with NPH insulin treatment, on beta cell function, and, secondarily, on insulin sensitivity.

Methods: In this open-label, randomised, cross-over study, 17 individuals with non-insulin-treated type 2 diabetes were randomised to receive 5 weeks of treatment with either empagliflozin or insulin titrated to a similar level of glycaemic control as with empagliflozin before crossing over to the other treatment. Key inclusion criteria included age ≥18 years, BMI ≥ 28 kg/m2, and a diabetes duration of more than 3 months. Treatments were preceded by a 3 week washout. Fasting and post-OGTT (5 h) metabolism were studied before and during treatments. Beta cell glucose sensitivity (bGS) was calculated as the slope of the linear relationship between the pre-hepatic insulin secretion rate and the corresponding plasma glucose value, and insulin sensitivity was calculated as glucose clearance relative to insulin concentrations. Endogenous glucose production, tissue glucose disposal and lipolysis were measured using stable isotopes. The disposition index was calculated as bGS × insulin sensitivity to assess beta cell function. Data for the present study were collected at the Department of Endocrinology, Hvidovre Hospital, Denmark.

Results: All participants who completed the study were included in the analyses. With equipoised glycaemic control, insulin concentrations were higher during insulin treatment than during empagliflozin treatment. bGS and insulin sensitivity were higher during empagliflozin treatment than during insulin treatment. The disposition index thus improved during empagliflozin treatment compared with insulin treatment.

Conclusions/interpretation: With similar glycaemic control, insulin sensitivity was higher and beta cell function improved during empagliflozin compared with insulin treatment, possibly due to a disinhibitory effect of lower insulin concentrations.

Trial registration: EudraCT 2017-002101-35.

Funding: This study was supported by Boehringer Ingelheim. Additional funding was provided by the Grosserer L.F. Foghts Fond, Charlottenlund, Denmark.

Keywords: Beta cell function; Glucotoxicity; Hyperinsulinaemia; Insulin; Sodium–glucose co-transporter 2 inhibition; Type 2 diabetes.

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Conflict of interest statement

Acknowledgements: The authors would like to thank A. Andersen (Department of Endocrinology, Hvidovre Hospital, Denmark) for technical support during the conduct of the study, and M.S. Svane, K. Bojsen-Møller, M. Hindsøe and N. Hedbäck (Department of Endocrinology, Hvidovre Hospital, Denmark) for helpful discussions and support during the conduct of the study, for which they did not receive any financial support. Data have been presented previously at the ADA’s 82nd Scientific Sessions, 2022, at the EASD 58th Annual Meeting, 2022, and at the annual meeting of the Danish Endocrine Society, 2022. Data availability: The datasets generated during and/or analysed in the current study are available from the corresponding author upon reasonable request. Funding: This study was kindly supported by a grant from Boehringer Ingelheim. Boehringer Ingelheim had no influence on the study conduct, analysis or interpretation, but were given the opportunity to review the manuscript for medical and scientific consistency as it relates to Boehringer Ingelheim substances, as well as intellectual property considerations. Additional funding was provided by the Grosserer L.F. Foghts Fond, Charlottenlund, Denmark (grant number not applicable). Authors’ relationships and activities: NBJ reports having received lecture fees from Novo Nordisk Denmark A/S and Boehringer Ingelheim, having received support for conference participation from Novo Nordisk Denmark A/S, and having taken a position in Novo Nordisk A/S, Søborg, Denmark after finalisation of the present study. SM reports having received fees for serving on advisory boards from AstraZeneca, Boehringer Ingelheim, Intarcia Therapeutics, Novo Nordisk, Sanofi, Abbott Lab, Bayer and Amgen. He also reports having received lecture fees from AstraZeneca, Novo Nordisk and MSD. He has received research grants from Novo Nordisk, the Novo Nordisk Foundation and Boehringer Ingelheim, and has received support for conference participation from Novo Nordisk, Boehringer Ingelheim and Bayer. JJH reports having received a grant from Novo Nordisk Foundation Center for Metabolic Research. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: RT collected data, performed data analyses, and drafted the manuscript. SM and PLM helped to design the study, supervised its conduct, analysed and interpreted data, and critically revised the manuscript. EAR, GvH, NRA and JJH provided input to study design, produced data, and critically revised the manuscript. NBJ conceived the study, wrote the protocol, supervised the conduct of experiments, analysed and interpreted data, and critically revised the manuscript. All authors approved the final manuscript. NBJ is the guarantor of this work, and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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