Empagliflozin increased gluconeogenesis from 1.57 to 1.77 mg/kg/min (p<0.01) and augmented lipolysis, preventing the normal fasting-induced decline in hepatic glucose production.
Does empagliflozin alter hepatic glucose production, gluconeogenesis, and lipolysis in individuals with type 2 diabetes?
Empagliflozin stimulates gluconeogenesis and augments lipolysis in type 2 diabetes, providing a mechanistic explanation for why SGLT2 inhibitors do not cause hypoglycemia.
Absolute Event Rate: 1.77% vs 1.57%
p-value: p=<0.01
Introduction and Objective: We previously showed that SGLT2 inhibitors stimulate endogenous glucose production, offsetting their glucosuria-induced glucose lowering action, and that this effect is not explained by changes in plasma glucose, insulin, or glucagon concentration using a pancreatic clamp. To investigate the impact of Empagliflozin (an SGLT2 inhibitor) on fasting hepatic glucose production (HGP), gluconeogenic flux, and lipolytic activity in type 2 diabetes individuals. Methods: 15 individuals with type 2 diabetes (Age 57 ± 2 yrs, HbA1c = 9.0 ± 1.0%; BMI 31 ± 1.5 kg/m²) underwent a tracer-based metabolic study with 6, 6-²H2-Glucose (to measure HGP) and ²H5-Glycerol (to measure lipolysis). Tracers were infused continuously from -180 min to 300 min (total 480 min). D2O (to measure gluconeogenesis) was ingested on the night prior to study. Empagliflozin 25 mg was ingested at time 0 min. This design allowed quantitation of baseline (following overnight fast) and hepatic and adipocyte responses to SGLT2 inhibition over a 5-hour treatment period. Results: Baseline (following overnight fast) HGP and gluconeogenesis were 2.33 and 1.57 mg/kg/min, respectively. Following Empagliflozin gluconeogenesis (GNG) increased to 1.77 mg/kg/min (p0.01), while HGP remained unchanged (2.43 mg/kg/min). Baseline glycerol Ra was 3.57 µmol/kg/min and following empagliflozin increased to 4.02 µmol/kg/min (p0.01), in association with increases in plasma glycerol (134 to 157 µmol/L, p0.01) and FFA (0.51 to 0.71 µmol/L, p0.01) concentrations. Conclusion: SGLT2 Inhibition with empagliflozin: (i) stimulates gluconeogenesis, preventing the normal fasting - induced decline in HGP and (ii) augments lipolysis, providing glycerol as a substrate to drive gluconeogenesis. This explains why SGLT2i do not cause hypoglycemia. Disclosure A. Merovci: None. A. Gastaldelli: Consultant; Current; Boehringer Ingelheim International GmbH. Speaker's Bureau; Current; Boehringer Ingelheim International GmbH. Other - educational grant; Ended; Boehringer Ingelheim International GmbH. Other - educational grant; Current; Eli Lilly and Company. Consultant; Ended; Merck Sharp Ended; Merck Sharp Ended; Pfizer Inc. Advisory Panel; Ended; Novo Nordisk Global Business Services. Speaker's Bureau; Ended; Novo Nordisk Global Business Services. Advisory Panel; Ended; Regeneron Pharmaceuticals Inc. Other - educational grant; Current; Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. S. Pezzica: None. J.M. Adams: None. A.O. Chavez-Velazquez: Advisory Panel; Ended; Crinetics Pharmaceuticals, Inc. A.A. Hansis-Diarte: None. M. Lalovich: None. H. Zaitoon: None. E.Y. Feigin: None. R. Belfort DeAguiar: None. M. Abdul-Ghani: None. R.A. DeFronzo: Advisory Panel; Ended; AstraZeneca. Research Support; Current; AstraZeneca. Advisory Panel; Current; Novo Nordisk. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Corcept Therapeutics. Speaker's Bureau; Current; Corcept Therapeutics. Consultant; Current; Alnylam Pharmaceuticals, Inc. Advisory Panel; Current; Regeneron Pharmaceuticals Inc., Aardvark. Funding NIH NIDDK (5 RO1 DK024092-40)
Merovci et al. (Sun,) conducted a other in type 2 diabetes (n=15). Empagliflozin vs. Baseline (following overnight fast) was evaluated on gluconeogenesis (GNG) (p=<0.01). Empagliflozin increased gluconeogenesis from 1.57 to 1.77 mg/kg/min (p<0.01) and augmented lipolysis, preventing the normal fasting-induced decline in hepatic glucose production.