875-P: Different Effects of SGLT-2 Inhibitors on Subcutaneous and Epicardial Adipose Tissue Metabolome in Heart Failure Subjects

Abstract

The exact mechanisms behind favorable metabolic and cardioprotective effects of SGLT-2 inhibitors (SGLT-2i) are still not fully understood. We performed a complex metabolomic analysis of subcutaneous (SAT) and epicardial (EAT) adipose tissue of heart failure subjects treated with SGLT-2i in order to assess their impact on different fat depots and identify potential cardioprotective factors. Nine subjects with severe heart failure with reduced ejection fraction (NYHA class III-IV) treated with SGLT-2i and 8 age-, BMI- and left ventricular ejection fraction-matched control subjects scheduled for heart transplantation or mechanical support implantation were included into the study. Eight SGLT-2i subjects and 5 control subjects had type 2 diabetes mellitus. A complex metabolomic analysis of SAT and EAT obtained during surgery was performed using liquid chromatography and mass spectrometry. SAT of SGLT-2i subjects showed marked increase in ketone bodies and a corresponding decrease of ketogenic triacylglycerols with medium-chain fatty acids suggesting enhanced ketogenesis typical for SGLT-2i use. In contrast, no such change was seen in EAT which, conversely, contained increased amount of long-chain triacylglycerols indicating significant differences in response to SGLT-2i treatment between these depots and a tendency to preserve EAT lipid content. Compared with control group, both SAT and EAT of SGLT-2i subjects consistently exerted surprisingly high levels of sphingolipids, especially sphingomyelins and ceramides, and ether-linked lipid species. In conclusion, SGLT-2i treatment leads to different metabolic responses in SAT and EAT with SAT showing mainly accented ketogenesis, while the preservation of EAT suggests other functions including potential cardioprotection. The exact role of increased sphingolipids and ether-linked lipids in both adipose tissue depots remains to be elucidated. Disclosure B.Kasperova: None. I.Pleyerova: None. K.Rosolová: None. P.Svoboda: None. J.Trnovska: None. P.Novodvorsky: Advisory Panel; Novo Nordisk, Sanofi, Other Relationship; Eli Lilly and Company, Sanofi, Research Support; Dexcom, Inc., Speaker's Bureau; Eli Lilly and Company, KRKA, Mundipharma, Novo Nordisk, Sanofi. P.Ivak: Consultant; Abbott, CARMAT SA. V.Melenovsky: Consultant; Bayer AG, Merck Sharp & Dohme Corp., Novo Nordisk, Research Support; Regeneron Pharmaceuticals Inc. I.Netuka: Board Member; LeviticusCardio Ltd., Consultant; Abbott, CARMAT SA. M.Haluzik: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novartis AG. M.Mraz: None. O.Kuda: None. T.Cajka: None. D.Hlavácek: None. J.Mahrík: None. L.Tomanová: None. I.Lankova: n/a. S.Stemberkova hubackova: None. Funding Ministry of Health, Czech Republic - conceptual development of research organization („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“) NV19-02-00118