SGLT2-inhibitors; more than just glycosuria and diuresis
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SGLT2‑inhibitors; more than just glycosuria and diuresis Amir Fathi1 · Keeran Vickneson2 · Jagdeep S. Singh2,3 Accepted: 5 October 2020 © The Author(s) 2020
Abstract Heart failure (HF) continues to be a serious public health challenge despite significant advancements in therapeutics and is often complicated by multiple other comorbidities. Of particular concern is type 2 diabetes mellitus (T2DM) which not only amplifies the risk, but also limits the treatment options available to patients. The sodium-glucose linked cotransporter subtype 2 (SGLT2)-inhibitor class, which was initially developed as a treatment for T2DM, has shown great promise in reducing cardiovascular risk, particularly around HF outcomes – regardless of diabetes status. There are ongoing efforts to elucidate the true mechanism of action of this novel drug class. Its primary mechanism of inducing glycosuria and diuresis from receptor blockade in the renal nephron seems unlikely to be responsible for the rapid and striking benefits seen in clinical trials. Early mechanistic work around conventional therapeutic targets seem to be inconclusive. There are some emerging theories around its effect on myocardial energetics and calcium balance as well as on renal physiology. In this review, we discuss some of the cutting-edge hypotheses and concepts currently being explored around this drug class in an attempt better understand the molecular mechanics of this novel agent. Keywords SGLT2-inhibitors · Renal disease · Heart failure · Calcium handling · Myocardial energetics · Ventricular remodelling
Introduction Heart failure (HF) is a growing public health concern with 8.5 million people expected to be living with this condition in the year 2030 at a staggering cost of $70 billion in the United States alone [1]. HF not only shortens life, but also reduces its quality. There have been considerable advancements in the management of this disease using a variety of neurohormonal modulators and, more recently, with device therapy. Nevertheless, HF remains a challenge to treat particularly because Amir Fathi and Keeran Vickneson contributed equally to this work. * Jagdeep S. Singh [email protected] 1
Department of Neuroanaesthesia and Critical Care, National Hospital for Neurology and Neurosurgery, University College London, London, UK
2
Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK
3
Department of Cardiology, The Edinburgh Heart Center, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
it is frequently associated with other co-morbidities such as hypertension, type 2 diabetes mellitus (T2DM), ischaemic heart disease and renal impairment. Ischaemic heart disease is the commonest cause of heart failure and T2DM amplifies that risk further. Patients with ischaemic cardiomyopathy and T2DM face a doubling of mortality risk compared to patients without T2DM. Indeed, T2DM increases mortality risk regardless of the underlying aetiology of heart failure [2]. Interest
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