Preethika Ekanayake1,2, Christopher Hupfeld1,2, Sunder Mudaliar3,4,5. 1. Veterans Affairs Medical Center, San Diego, CA, USA. 2. Department of Medicine, University of California at San Diego, San Diego School of Medicine, San Diego, USA. 3. Veterans Affairs Medical Center, San Diego, CA, USA. smudaliar@vapop.ucsd.edu. 4. Department of Medicine, University of California at San Diego, San Diego School of Medicine, San Diego, USA. smudaliar@vapop.ucsd.edu. 5. Diabetes/Metabolism Section, VA San Diego HealthCare System, 3350 La Jolla Village Drive (Mail Code: 111G), San Diego, CA, 92161, USA. smudaliar@vapop.ucsd.edu.
Abstract
PURPOSE OF REVIEW: The micro/macrovascular complications of diabetes cause considerable morbidity and premature mortality. The SGLT2 inhibitors are the first diabetes medications with significant benefits on microvascular disease (nephropathy) and macrovascular cardiovascular disease. In this review, we evaluate one of the potential mechanisms for these cardiorenal benefits-the production of ketones, their benefits, and risks. RECENT FINDINGS: In recent cardiovascular outcome trials (CVOTs), the SGLT2 inhibitors demonstrated significant cardiorenal benefits and they are now approved to reduce CV events/death, heart failure hospitalization, and progression to end-stage renal disease. Glucosuria induced by the SGLT2 inhibitors leads to increased ketone production. Ketones are an efficient fuel source and can improve myocardial and renal function. Further, the ketone body beta-hydroxybutyrate exhibits anti-inflammatory/anti-oxidative actions, which favorably impact myocardial and renal remodeling/fibrosis. Uncontrolled ketogenesis leads to ketoacidosis, especially during conditions of acute illness and excessive insulin dose reductions. The SGLT2 inhibitors have demonstrated significant cardiorenal benefits in large CVOTs. Studies are in progress to elucidate whether SGLT2 inhibitor-induced low-grade hyperketonemia contributes to these benefits.
PURPOSE OF REVIEW: The micro/macrovascular complications of diabetes cause considerable morbidity and premature mortality. The SGLT2 inhibitors are the first diabetes medications with significant benefits on microvascular disease (nephropathy) and macrovascular cardiovascular disease. In this review, we evaluate one of the potential mechanisms for these cardiorenal benefits-the production of ketones, their benefits, and risks. RECENT FINDINGS: In recent cardiovascular outcome trials (CVOTs), the SGLT2 inhibitors demonstrated significant cardiorenal benefits and they are now approved to reduce CV events/death, heart failure hospitalization, and progression to end-stage renal disease. Glucosuria induced by the SGLT2 inhibitors leads to increased ketone production. Ketones are an efficient fuel source and can improve myocardial and renal function. Further, the ketone body beta-hydroxybutyrate exhibits anti-inflammatory/anti-oxidative actions, which favorably impact myocardial and renal remodeling/fibrosis. Uncontrolled ketogenesis leads to ketoacidosis, especially during conditions of acute illness and excessive insulin dose reductions. The SGLT2 inhibitors have demonstrated significant cardiorenal benefits in large CVOTs. Studies are in progress to elucidate whether SGLT2 inhibitor-induced low-grade hyperketonemia contributes to these benefits.
Authors: Vincenzo Mollace; Giuseppe M C Rosano; Stefan D Anker; Andrew J S Coats; Petar Seferovic; Rocco Mollace; Annamaria Tavernese; Micaela Gliozzi; Vincenzo Musolino; Cristina Carresi; Jessica Maiuolo; Roberta Macrì; Francesca Bosco; Marcello Chiocchi; Francesco Romeo; Marco Metra; Maurizio Volterrani Journal: Nutrients Date: 2021-01-17 Impact factor: 5.717
Authors: James P Curtain; Kieran F Docherty; Pardeep S Jhund; Mark C Petrie; Silvio E Inzucchi; Lars Køber; Mikhail N Kosiborod; Felipe A Martinez; Piotr Ponikowski; Marc S Sabatine; Olof Bengtsson; Anna Maria Langkilde; Mikaela Sjöstrand; Scott D Solomon; John J V McMurray Journal: Eur Heart J Date: 2021-09-21 Impact factor: 29.983
Authors: Prawej Ansari; Samara T Choudhury; Veronique Seidel; Akib Bin Rahman; Md Abdul Aziz; Anika E Richi; Ayesha Rahman; Umme H Jafrin; J M A Hannan; Yasser H A Abdel-Wahab Journal: Life (Basel) Date: 2022-07-28
Authors: Huitzilihuitl Saucedo-Orozco; Suzanne N Voorrips; Salva R Yurista; Rudolf A de Boer; B Daan Westenbrink Journal: J Lipid Atheroscler Date: 2022-01-13