Objective: In patients with diabetes, the beneficial effects of empagliflozin on glucose metabolism, body adiposity, and liver fat content are well established. As the mode of action of SGLT2 inhibitors partly depends on elevated blood glucose, we investigated if these effects also occur in prediabetes.

Methods: Forty participants with prediabetes (mean±SD: age: 60±9 years; BMI: 31.5±3.8 kg/m²; FG: 5.98±0.57 mmol/l) were randomized to receive 25 mg empagliflozin qd or placebo for 8 weeks. Before and after treatment, all participants underwent a 75 g oral glucose tolerance test to evaluate glucose tolerance, peripheral insulin sensitivity and insulin secretion. Body fat was assessed by whole-body MRI and intrahepatic fat by localized MR-spectroscopy. Resting energy expenditure and respiratory quotient (RQ) were assessed by indirect calorimetry at fast.“Per protocol” analysis using ANCOVA was performed.

Results: Fasting glucose, glucose tolerance, peripheral insulin sensitivity, and insulin secretion were not significantly changed by treatment. Though, after 8 weeks of treatment, total adipose tissue (mean difference between groups at the end of study±SEM: 3.1±2.3 liters; p= 0.034) and intrahepatic fat (2.1±2.3%; p= 0.029) were lower in patients who received empagliflozin, compared to placebo. Empagliflozin treatment resulted in a lower RQ compared to placebo (p= 0.022) without differences in resting energy expenditure (p= 0.2), indicating preferential lipid oxidation upon treatment.

Conclusion: In prediabetes, treatment with empagliflozin for 8 weeks has no major effects on glucose metabolism. However, this SGLT2 inhibitor reduced body adiposity and liver fat content, presumably by shifting energy metabolism towards lipid oxidation. Therefore, empagliflozin might represent a treatment option for obesity and hepatic steatosis in prediabetes, independent of drug effects on blood glucose.