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

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.