title: Empagliflozin, via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels Through Reduced LDL Catabolism.
abstract: In clinical trials, a small increase in LDL cholesterol has been reported with sodium-glucose cotransporter 2 (SGLT2) inhibitors. The mechanisms by which the SGLT2 inhibitor empagliflozin increases LDL cholesterol levels were investigated in hamsters with diet-induced dyslipidemia. Compared with vehicle, empagliflozin 30 mg/kg/day for 2 weeks significantly reduced fasting blood glucose by 18%, with significant increase in fasting plasma LDL cholesterol, free fatty acids, and total ketone bodies by 25, 49, and 116%, respectively. In fasting conditions, glycogen hepatic levels were further reduced by 84% with empagliflozin, while 3-hydroxy-3-methylglutaryl-CoA reductase activity and total cholesterol hepatic levels were 31 and 10% higher, respectively (both P < 0.05 vs. vehicle). A significant 20% reduction in hepatic LDL receptor protein expression was also observed with empagliflozin. Importantly, none of these parameters were changed by empagliflozin in fed conditions. Empagliflozin significantly reduced the catabolism of (3)H-cholesteryl oleate-labeled LDL injected intravenously by 20%, indicating that empagliflozin raises LDL levels through reduced catabolism. Unexpectedly, empagliflozin also reduced intestinal cholesterol absorption in vivo, which led to a significant increase in LDL- and macrophage-derived cholesterol fecal excretion (both P < 0.05 vs. vehicle). These data suggest that empagliflozin, by switching energy metabolism from carbohydrate to lipid utilization, moderately increases ketone production and LDL cholesterol levels. Interestingly, empagliflozin also reduces intestinal cholesterol absorption, which in turn promotes LDL- and macrophage-derived cholesterol fecal excretion.
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France f.briand@physiogenex.com.
authors.forename: François
authors.initials: F
authors.lastname: Briand
authors.affiliation: Cardiometabolic Diseases Research, Boehringer Ingelheim, Biberach an der Riss, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Mayoux
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brousseau
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Burr
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Urbain
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Costard
authors.affiliation: Cardiometabolic Diseases Research, Boehringer Ingelheim, Biberach an der Riss, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D008078:Cholesterol, LDL; D005960:Glucosides; D007004:Hypoglycemic Agents; C570240:empagliflozin