Basal insulin secretion capacity predicts the initial response and maximum levels of beta‐hydroxybutyrate during therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin, in relation to weight loss

Abstract

Aims To investigate predictors of the initial response of beta‐hydroxybutyrate (BHB) and maximum BHB (max‐BHB) values during long‐term therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus. Methods We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max‐BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model. Results Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m2 and 83.9 mL/min/1.73 m2, respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* μmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max‐BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C‐peptide levels compared with the lower three quartiles. Conclusions Lower basal insulin secretion capacity might predict greater initial BHB elevations and max‐BHB levels during long‐term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations.

Potential Safety Issues with Use of Sodium-Glucose Cotransporter 2 Inhibitors, Particularly in People with Type 2 Diabetes and Chronic Kidney Disease

“…This decrease in the insulin-to-glucagon ratio and increase in free fatty acids promotes ketogenesis [52,72]. SGLT2 inhibitor treatment increases plasma ketone levels, and an elevated ketone level does not necessarily indicate DKA [72][73][74][75]. SGLT2 inhibitor-associated DKA most frequently occurs in patients with one or more additional risk factor(s) for insulin deficiency and/or ketogenesis (Table 3) [67][68][69][70][71].…”