[Geriatric Care 2020; 6:9079] [page 67] Glyphozines and treatment of cardiac disease Francesco Ferrara, 1 Giovanni Granata, 2 Chiara Pelliccia, 3 Raffaele La Porta, 4 Antonio Vitiello 1 1 Usl Umbria 1, Perugia; 2 Asl Salerno, Salerno; 3 Usl Umbria 2, Terni; 4 Asur Marche, Ancona, Italy Abstract Glyphozines also called SGLT2 inhibitors, are a new class of agents that inhibit reabsorption of glucose in the kidney, in proximal tubules, and therefore lower blood sugar. They act by inhibiting sodium- glucose transport protein 2 (SGLT2). Glyphozines are used in the treatment of type II diabetes mellitus. In studies with canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure. In addition to regulate blood glucose, recent studies have shown that glyphozines have important positive cardiovascular benefits, such as weight loss, decreased volaemia and PA, reduced triglycerides, natriuresis and improved endothelial wall dysfunction. Clinical studies have shown reduction in deaths from cardiovascular events among diabetic patients treated with glyphozines. At the moment these drugs are being studied for an extension of the therapeutic indication also for cardiovascular diseases such as heart failure. In this review, we discuss the class of SGLT2 inhibitors in the treatment of dia- betes, and studies focused on their possible role in the treatment of cardiac disease. Introduction The prevalence of type II diabetes melli- tus (T2DM) is on the increase worldwide, tightly linked to the expanding number of individuals who are overweight and obese. T2DM is a metabolic disease commonly characterized by an increase in blood glucose levels and characterized by tissue insulin resistance and insulin reduction production. 1- 4 It is important that all forms of diabetes are diagnosed and managed in advance to pre- vent or slow down its potential complica- tions other organs such as nephropathy, retinopathy, neuropathy, cardiovascular dam- ages, diabetic foot disease and ulcer. T2DM is also a socio-economic problem consider- ing the high incidence of the disease, there- fore, this has contributed to the creation and development of numerous drug treatments. Today, a number of new classes of drugs used to treat T2D have been developed. T2DM is strongly associated with cardio- vascular disease (CVD). Several studies have shown that a significant proportion of diabet- ic patients are at risk of experiencing acute coronary syndrome and/or heart failure (HF). This is due to abnormal cardiac management of glucose and free fatty acids (FFAs) and the effect of metabolic changes in diabetes on the cardiovascular system (CV). Furthermore, studies have reported that the incidence of HF in diabetic patients is significantly correlated with HbA1c levels. 5-7 Hyperglycemia is an independent risk factor for ischemic heart dis- ease (IHD) as several mechanisms lead to vascular damage due to long-term hyper- glycemia. 8,9 To clarify the mechanisms responsible for decreased myocardial con- tractility in the diabetic population, several explanations have been proposed. 10,11 In patients with diabetes, altered metabolism has been associated with increased myocardial oxygen consumption and increased serum free fatty acid (FFA) concentrations. 10 Abnormalities in contractile and regulatory protein expression and cardiomyocyte sensi- tivity Ca2+ are also found in DM. In diabetes, reduced activity of the sarcoplasmic reticular calcium pump (SRCP) and the rate of removal of Ca2+ from the cytoplasm in the diastole may be responsible for diastolic dys- function. 10,11 The main pathogenetic mecha- nism in HF and DM leading to structural alteration is hyperglycemia. Hyperglycemia leads to the glycation of several macromole- cules that result in a decrease in the elasticity of the vessel walls and in myocardial dys- function. 10,11 Hyperglycemia also induces dia- betes-specific changes in the microvascular architecture, such as reduced nitric oxide pro- duction resulting in endothelial dysfunction. The rennin-angiotensin-aldosterone (RAAS) system is activated at the beginning of T2DM. As HF progresses, the activation of the sympathetic nervous system (SNS) and RAAS increases, leading to a worsening of CV and renal function. 10-12 Current therapy For the treatment of T2DM there are sev- eral pharmacological treatment options available. Among the medications used rou- tinely there is insulin replacement therapy. Insulin replacement therapy when used cor- rectly at the appropriate doses and times has shown a significant reduction in mortality in patients with T2DM due to cardiovascular causes, however, some studies show that insulin has not provided benefits for cardio- vascular diseases in patients with diabetes that are more severe compared to the stan- dard of care with oral therapies. In this regard, several studies have shown that met- formin and glucagon-like peptide 1 agonists (GLP-1) provide greater benefits for cardio- vascular disease in diabetic patients. In addi- tion, dipeptidil peptidase-4 inhibitors (DPP4) are associated with increased HF hospitaliza- tions and in 2016 the Food and Drug Administration (FDA) issued an alert for increased HF risk associated with both saxagliptin but not sitagliptin. 13 Therefore, a positive strategy is needed to address the risk of heart failure in diabetes. The first-line drug to manage hyperglycemia in type 2 DM is metformin. The diabetic patient with HF represents a particular challenge in the phar- macological treatment of diabetes. Current management strategies focus on known modifiable risk factors such as glucose, lipids and blood pressure (BP) which pro- duce modest effects. Although these are important risk markers, none of these inter- ventions substantially prevent HF or improve its outcome. 14,15 SGLT-2 inhibitors: an overview Glyphozines are oral antidiabetic agents that inhibit the SGLT-2 protein in the prox- imal renal tubules and expel glucose in the Geriatric Care 2020; volume 6:9079 Correspondence: Francesco Ferrara, Usl Umbria 1, P.le Gambuli, 06132 Perugia, Italy. E-mail: francesco.ferrara@uslumbria1.it Key words: Cardiology; diabetes; glyphozine; SGLT2; T2DM. Conflict of interests: the authors declare no potential conflict of interests. Ethical approval and consent: the authors declare that: there are no sensitive data and no patients were recruited for this study; the document does not conflict with ethical legis- lation. Received for publication: 4 May 2020. Revision received: 23 June 2020. Accepted for publication: 7 July 2020. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). © Copyright: the Author(s), 2020 Licensee PAGEPress, Italy Geriatric Care 2020; 6:9079 doi:10.4081/gc.2020.9079 Non-commercial use only