Key result
Empagliflozin increases gluconeogenesis ~13% and augments lipolysis, preventing fasting-induced declines in hepatic glucose production.
Why the study?
SGLT2 inhibitors were shown to stimulate endogenous glucose production independent of plasma glucose, insulin, or glucagon changes, prompting investigation into the impact of empagliflozin on fasting hepatic glucose production, gluconeogenic flux, and lipolytic activity in type 2 diabetes.
Does empagliflozin alter hepatic glucose production, gluconeogenesis, and lipolysis in individuals with type 2 diabetes?
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.
Answers are grounded in this paper and cite their sources.
May explain SGLT2i hypoglycemia avoidance; leaves open need for larger prospective validation of hepatic effects.
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 (p<0.01), 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 (p<0.01), in association with increases in plasma glycerol (134 to 157 µmol/L, p<0.01) and FFA (0.51 to 0.71 µmol/L, p<0.01) 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 & Dohme Corp. Speaker's Bureau; Ended; Merck Sharp & Dohme Corp. Other - grant reviewer; 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.
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Merovci et al. (2026) studied 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.
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