Sodium-Glucose Cotransporter Type 2 (SGLT-2) Inhibitors and Ketogenesis: the Good and the Bad
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PHARMACOLOGIC TREATMENT OF TYPE 2 DIABETES (HE LEBOVITZ AND G BAHTIYAR, SECTION EDITORS)
Sodium-Glucose Cotransporter Type 2 (SGLT-2) Inhibitors and Ketogenesis: the Good and the Bad Preethika Ekanayake 1,2 & Christopher Hupfeld 1,2 & Sunder Mudaliar 1,2,3 Accepted: 28 October 2020 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020
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/antioxidative 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. Summary 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. Keywords Sodium-glucose cotransporter 2 (SGLT-2) inhibitors . Ketogenesis . Beta-hydroxy butyrate . Diabetic ketoacidosis . Euglycemic ketoacidosis . Fuel metabolism
Introduction Type 2 diabetes mellitus (T2DM) causes significant morbidity and premature cardiovascular (CV) mortality. Until recently, the mainstay of T2DM treatment involved a glucocentric approach [1]. Tight glucose control improves microvascular complications but has neutral/harmful effects on the macrovascular complications [2]. The SGLT2 inhibitors This article is part of the Topical Collection on Pharmacologic Treatment of Type 2 Diabetes * Sunder Mudaliar [email protected] 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
Diabetes/Metabolism Section, VA San Diego HealthCare System, 3350 La Jolla Village Drive (Mail Code: 111G), San Diego, CA 92161, USA
(SGLT2i) are the first T2DM medications to demonstrate significant cardiorenal benefits, including reduction of major adverse cardiovascular events (MACE), CV death, heart failure (HF) hospitalization, and progression to end-stage renal disease (ESRD) [3–5, 6••, 7–10] (Table 1). A unique feature in the SGLT2i CVOTs
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