Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors in Heart Failure - Mechanisms and Clinical Applications - A Machine-Generated Literature Overview (Nov 16, 2024)_(9819775671)_(Springer)

Foreword Preface Disclaimer Contents About the Editor Chapter 1: The History of the Development of SGLT2 Inhibitors for the Treatment of Diabetes: From Biology to Chemistry Introduction by the Editor Development of SGLT1 and SGLT2 Inhibitors Introduction Why Target Glucose Handling in the Kidney? Why Target Glucose Handling in the Intestine? Development of SGLT Inhibitors Perspectives Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology Introduction Materials and Methods Results Discussion Conclusion New Oral Antidiabetic Agents Introduction Glitazones Incretin-Based Therapies SGLT2 Inhibitors Glucokinase Activators Pharmacodynamics, Efficacy and Safety of Sodium–Glucose Co-transporter Type 2 (SGLT2) Inhibitors for the Treatment of Type 2 Diabetes Mellitus Introduction Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin Other Sodium–Glucose Co-transporter Type 2 Inhibitors in Development Discussion Conclusion Initiation of the SGLT2 Inhibitor Canagliflozin to Prevent Kidney and Heart Failure Outcomes Guided by HbA1c, Albuminuria, and Predicted Risk of Kidney Failure Introduction Methods Results Discussion Conclusion Insight into the Interaction Mechanism of Human SGLT2 with Its Inhibitors: 3D-QSAR Studies, Homology Modeling, and Molecular Docking and Molecular Dynamics Simulations Introduction Materials and Methods Results and Discussion 3D-QSAR Study Conclusions Development of Sodium Glucose Co-transporter 2 (SGLT2) Inhibitors with Novel Structure by Molecular Docking and Dynamics Simulation Introduction Materials and Methods Results and Discussion Conclusions Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition Introduction Results and Discussions Conclusions Methods Effects of the SGLT2 Inhibitor Dapagliflozin on Cardiac Function Evaluated by Impedance Cardiography in Patients with Type 2 Diabetes. Secondary Analysis of a Randomized Placebo-Controlled Trial Background Materials and Methods Results Discussion Conclusions Bibliography Chapter 2: SGLT2 Inhibitors and Mechanism of Cardiovascular Benefits in Type 2 Diabetes Introduction by the Editor SGLT2 Inhibitors and Mechanisms of Cardiovascular Benefit: A State-of-the-Art Review SGLT2 Inhibitors and Cardiovascular Protection: Setting the Stage Mechanisms of Cardiovascular Protection by SGLT2 Inhibitors Unanswered Mechanistic and Translational Themes Conclusions SGLT2 Inhibitors: A Focus on Cardiac Benefits and Potential Mechanisms Introduction Physiological Action and Pharmacological Inhibition Insights into Cardioprotective Effects of SGLT2i from Clinical Trials SGLT2i: Mechanisms of Cardioprotection Conclusion Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA Introduction Potential Mechanisms of CV Protection with GLP-1RA and SGLT2i Future Perspectives Conclusion SGLT2 Inhibitors: Benefits for CKD and Cardiovascular Disease in Type 2 Diabetes Introduction Conclusion Minireview: Are SGLT2 Inhibitors Heart Savers in Diabetes? Introduction Discussion and Future Perspective Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors Introduction Clinical Trial Evidence Mechanism of Action—Glucose Reduction Mechanism of Action—Cardiovascular Protection Conclusion Addendum Direct Cardiac Effects of SGLT2 Inhibitors Introduction Literature Search Literature Search Results Discussion Conclusion SGLT2 Inhibitors: Cardiovascular Benefits Beyond HbA1c—Translating Evidence into Practice The Role of the Improving Diabetes Steering Committee Taking Type 2 Diabetes Out of Isolation: The Impact of Cardiovascular Disease The Relationship Between Type 2 Diabetes and Cardiovascular Disease: Common Factors Heart Failure: A New Focus for Cardiovascular Disease in Diabetes The Role of Glycaemic Control in Managing Cardiovascular Risk in People with Type 2 Diabetes Why Might SGLT2I Treatments Influence Cardiovascular Outcomes? What Evidence Exists for the Management of CVD Risk in T2DM Treatment with SGLT2i Agents? Broadening the Evidence Base: The Role of Real-World Evidence in Informing Treatment Decisions SGLT2i Treatments in Routine Practice: Real-World Evidence for Cardiovascular Benefits in People with Type 2 Diabetes Primary and Secondary Prevention: When Might Initiation of an SGLT2i Therapy Provide Benefit? How is this Evolving Evidence-Base Being Reflected in Practical Guidelines? Overcoming Treatment Comfort in Type 2 Diabetes Management: And Preparing for New Treatment Approaches Practical Advice: The Use of SGLT2i Treatment in People Receiving Diuretics Maximising Benefits in the Treatment of Type 2 Diabetes: Beyond HbA1c Summary and Practical Considerations Heart Failure in Type 2 Diabetes: Current Perspectives on Screening, Diagnosis and Management Introduction Classification of Heart Failure and Epidemiological Aspects Detection of Heart Failure in Diabetes Diabetes, HF and COVID-19 Conclusions Redox-Driven Cardioprotective Effects of Sodium-Glucose Co-transporter-2 Inhibitors: Comparative Review Introduction Renal Complications Related to Diabetes and Proposed Protective Mechanisms of Gliflozins Cardiovascular Complications Related to Diabetes: Focus on Oxidative Stress Cardioprotective Effects of SGLT-2 Inhibitors from Clinical Trials Potential Cardioprotective Mechanisms of SGLT-2 Inhibitors beyond Systemic Effects SGLT-2 Inhibitors and Oxidative Stress Conclusion Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes Introduction Methods Era Before SGLT2 Inhibitors and GLP-1 Receptor Agonists SGLT2 Inhibitors GLP-1 Receptor Agonists Discussion Conclusion A Bioinformatics Investigation into the Pharmacological Mechanisms of Sodium-Glucose Co-transporter 2 Inhibitors in Diabetes Mellitus and Heart Failure Based on Network Pharmacology Introduction Methods Results Discussion Conclusions Different Effects of SGLT2 Inhibitors According to the Presence and Types of Heart Failure in Type 2 Diabetic Patients Background Methods Results Discussion Conclusion Association of SGLT2 Inhibitors with Lower Incidence of Death in Type 2 Diabetes Mellitus and Causes of Death Analysis Introduction Methods Results Discussion Conclusions Use of Sodium-Glucose Co-transporter-2 Inhibitors in Clinical Practice for Heart Failure Prevention and Treatment: Beyond Type 2 Diabetes. A Narrative Review Introduction Methods SGLT-2i Effects on Cardiovascular Outcomes SGLT-2is and HF Outcomes Knowledge Gaps Regarding the Use of SGLT-2is for HF in Clinical Practice Clinical Ramifications of SGLT-2is for HF Prevention and Treatment Physicians’ Perspectives Regarding the Role of SGLT-2is in Treating HF Conclusions Insights into SGLT2 Inhibitor Treatment of Diabetic Cardiomyopathy: Focus on the Mechanisms Introduction SGLT2i and Improved Heart Function SGLT2i and the Regulation of Heart Metabolism SGLT2i and Myocardial Mitochondria SGLT2i Improve Cardiovascular Disease and Microcirculation SGLT2i Improve Ventricular Compliance and Myocardial Fibrosis SGLT2i Inhibit Oxidative Stress In Diabetes Patients, SGLT2i Rescue Cardiomyocytes from Programmed Cell Death SGLT2i and Autophagy in the Myocardium SGLT2i Reverse ER Stress in Diabetic Cardiomyopathy SGLT2i Improve Diabetic Cardiomyopathy by Regulating the Intestinal Microbiota SGLT2i in Clinical Treatment Current Challenges and Future Therapeutic Strategies Conclusions Improved Erythrocyte Deformability Induced by Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients Introduction Materials and Methods Results Discussion Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure Background Methods Results Discussion Conclusions The Enhanced Cardiac Outcome of Conjugated SGLT2 Inhibitors and GLP-1RA Therapy in Diabetic Patients Introduction SGLT2 Inhibitors Mechanism of Action Conclusion Benefits of SGLT2i for the Treatment of Heart Failure Irrespective of Diabetes Diagnosis: A State-of-the-Art Review Introduction General Mechanisms of Heart Failure (Preserved and Reduced) Heart Failure in Patients With and Without T2DM, Current Understanding and Clinical Practice Consequences Description of the Pathological Mechanisms that Link T2D with Heart Failure: Direct and Indirect Effects of SGLT2i on Myocardial Function SGLT2i in Clinical Trials and Meta-Analyses in Heart Failure New Guidelines: Moving towards an Intensive and Multidimensional Approach for HF Treatment Future Perspectives in the Treatment of HF for Patients with and Without T2D Conclusions Emerging Horizons in Heart Failure with Preserved Ejection Fraction: The Role of SGLT2 Inhibitors Introduction Current Treatment Strategies in HFpEF SGLT2 Inhibitors in HFrEF SGLT2 Inhibitors in HFpEF Potential Mechanisms Improved by SGLT2 Inhibitors on HFpEF Practical Implications Conclusion Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitors Initiation in Patients with Acute Heart Failure, with and Without Type 2 Diabetes: A Systematic Review and Meta-Analysis Background Method Results Discussion Association of Sodium-Glucose Cotransporter 2 Inhibitors with Post-Discharge Outcomes in Patients with Acute Heart Failure with Type 2 Diabetes: A Cohort Study Background Methods Results Discussion Conclusions Potential Impact of SGLT2 Inhibitors on Left Ventricular Diastolic Function in Patients with Diabetes Mellitus Introduction Association of DM with HFpEF DM-Related Cardiac Dysfunction Potential Impact of SGLT2 Inhibitors on LV Diastolic Function in DM Effects of Treatment with SGLT-2 Inhibitors on Arginine-Related Cardiovascular and Renal Biomarkers Background Methods Results Discussion Conclusions Comparison of SGLT2 Inhibitors with DPP-4 Inhibitors Combined with Metformin in Patients with Acute Myocardial Infarction and Diabetes Mellitus Background Methods Results Discussion Conclusions Comparison of SGLT2 Inhibitors with DPP-4 Inhibitors Combined with Metformin in Patients with Acute Myocardial Infarction and Diabetes Mellitus Background Methods Results Discussion Conclusions Effect of SGLT2 Inhibitors on Body Composition, Fluid Status and Renin–Angiotensin–Aldosterone System in Type 2 Diabetes: A Prospective Study Using Bioimpedance Spectroscopy Background Methods Results Discussion Conclusions Observational Study on Unhealthy Eating Behavior and the Effect of Sodium-Glucose Cotransporter 2 Inhibitors: The Luseogliflozin Ehime Diabetes Study Introduction Methods Results Discussion Effects of the SGLT2 Inhibitor Dapagliflozin on Cardiac Function Evaluated by Impedance Cardiography in Patients with Type 2 Diabetes. Secondary Analysis of a Randomized Placebo-Controlled Trial Background Materials and Methods Results Discussion Conclusions Heart Failure in Type 2 Diabetes: Current Perspectives on Screening, Diagnosis and Management Introduction Classification of Heart Failure and Epidemiological Aspects Detection of Heart Failure in Diabetes Diabetes, HF and COVID-19 Conclusions Observational Study on Unhealthy Eating Behavior and the Effect of Sodium-Glucose Cotransporter 2 Inhibitors: The Luseogliflozin Ehime Diabetes Study Introduction Methods Results Discussion Effects of the SGLT2 Inhibitor Dapagliflozin on Cardiac Function Evaluated by Impedance Cardiography in Patients with Type 2 Diabetes. Secondary Analysis of a Randomized Placebo-Controlled Trial Background Materials and Methods Results Discussion Conclusions Effect of SGLT2 Inhibitors on Body Composition, Fluid Status and Renin–Angiotensin–Aldosterone System in Type 2 Diabetes: A Prospective Study Using Bioimpedance Spectroscopy Background Methods Results Discussion Conclusions Bibliography Chapter 3: Cardiovascular and Renal Diseases in Type 2 Diabetes Introduction by the Editor Machine Generated Summaries Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes [2] Introduction Methods Era Before SGLT2 Inhibitors and GLP-1 Receptor Agonists SGLT2 Inhibitors GLP-1 Receptor Agonists Discussion Conclusion SGLT2 Inhibition in Type 1 Diabetes with Diabetic Kidney Disease: Potential Cardiorenal Benefits Can Outweigh Preventable Risk of Diabetic Ketoacidosis [21] Introduction SGLT2 Inhibitors and Diabetic Kidney Disease Kidney Protective Mechanisms of SGLT2 Inhibitors in T1DM Existing Clinical Evidence for SGLT2 Inhibition in T1DM Overall Risks of SGLT2 Inhibitors and Diabetic Ketoacidosis Mitigating Risk of DKA in Patients with T1DM Conclusion Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease [46] Introduction SGLT2 Inhibition Glucose Lowering and Weight Lowering Cardiovascular Effects Diabetic Kidney Disease Kidney Disease and Use of SGLT2 Inhibitors Renal Endpoints Large Randomised Trials in Type 2 Diabetes Trials in People with Impaired Renal Status Additional Evidence from Populations With and Without Diabetes Renal Mechanisms of SGLT2 Inhibitors Acute Kidney Injury Conclusion The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road? [81] Introduction The Biology of the Na/K-ATPase The Biology of SGLTs Protection Effects of SGLT2 Inhibitor on Renal Disease Protection Effects of SGLT2 Inhibitor on Cardiovascular Disease (CVD) Mechanistic Perception of SGLT2 Inhibitor and Na/K-ATPase Conclusion Renal Protection: A Leading Mechanism for Cardiovascular Benefit in Patients Treated with SGLT2 Inhibitors [82] Introduction The Role of SGLTs in the Kidney Direct Renal Benefits Indirect Renal Benefits Renal Outcomes in RCTs on SGLT2 Inhibitors: State of the Art The Credence Trial Conclusions Renoprotection with SGLT2 Inhibitors in Type 2 Diabetes over a Spectrum of Cardiovascular and Renal Risk [105] Introduction Renal Benefits of SGLT2 Inhibitors in People with T2D Renoprotective Effects of SGLT2 Inhibitors According to Baseline Risk Safety of SGLT2 Inhibitors in T2D and Renal Impairment Conclusions Potential Mechanisms Responsible for Cardioprotective Effects of Sodium–Glucose Co-transporter 2 Inhibitors [125] Background Effects of SGLT-2 Inhibitors on Cardiac Structure Effects of SGLT-2 Inhibitors on Cardiac Function Potential Mechanisms of SGLT-2 Inhibitors Responsible for Cardioprotection Conclusions and Perspectives SGLT2i and GLP-1 RA Therapy in Type 1 Diabetes and Reno-Vascular Outcomes: A Real-World Study [140] Introduction Methods Results Discussion SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes [146] Role of the Improving Diabetes Steering Committee Digital Features Introduction The Burden of Kidney Disease in T2DM Evaluation and Classification of DKD Disease Markers Slowing or Preventing DKD Progression SGLT2i Treatments: Renal Outcomes Data Potential Mechanisms Underpinning the Renoprotective Action of SGLT2I Treatments Implications for Clinical Practice Conclusion Renoprotective Effect of SGLT-2 Inhibitors among Type 2 Diabetes Patients with Different Baseline Kidney Function: A Multi-Center Study [167] Background Methods Results Discussion Conclusions Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement [168] Digital Features Introduction Methodology Diagnosis and Prognosis of Chronic Kidney Disease Pathophysiology and Therapeutic Targets of DKD Role of SGLT2i in DKD Clinical Evidence of Renoprotective Effect with SGLT2i Recommendations for Optimal Use of SGLT2 Inhibitors Comparative Efficacy of Five SGLT2i on Cardiorenal Events: A Network Meta-Analysis Based on Ten CVOTs [181] Introduction Methods Results Discussion Conclusion Redox-Driven Cardioprotective Effects of Sodium-Glucose Co-transporter-2 Inhibitors: Comparative Review [223] Introduction Renal Complications Related to Diabetes and Proposed Protective Mechanisms of Gliflozins Cardiovascular Complications Related to Diabetes: Focus on Oxidative Stress Cardioprotective Effects of SGLT-2 Inhibitors from Clinical Trials Potential Cardioprotective Mechanisms of SGLT-2 Inhibitors beyond Systemic Effects SGLT-2 Inhibitors and Oxidative Stress Conclusion Dose-Dependent Renoprotection Efficacy of sglt2 Inhibitors in Type 2 Diabetes: Systematic Review and Network Meta-Analysis [248] Introduction Methods Results Discussion Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D [253] Introduction CKD and T2D: Dance Partners in CV Disease Mechanisms of SGLT2i Effects on Renal Condition Benefits of SGLT2i on Renal Function Beyond Their Glycemic Control Current Recommendations for Treatment of Renal Complications with SGLT2i Changing Paradigm: The Cardiorenal and Metabolic Continuum Conclusions Association of SGLT2 Inhibitors with Cardiovascular, Kidney, and Safety Outcomes Among Patients with Diabetic Kidney Disease: A Meta-Analysis [265] Background Methods Results Discussion Conclusions Sodium–Glucose Transporter-2 Inhibitors for Prevention and Treatment of Cardiorenal Complications of Type 2 Diabetes [271] Introduction Glycemic Control Is Not Enough SGLT-2 Inhibitors Cardiorenal Effects The Effect of Age Class Effect of SGLT-2i Primary vs Secondary Prevention What’s the Road Ahead? Balancing Benefits and Harms Conclusions Cardiorenal and Other Diabetes Related Outcomes with SGLT-2 Inhibitors Compared to GLP-1 Receptor Agonists in Type 2 Diabetes: Nationwide Observational Study [290] Background Materials and Methods Results Discussion Conclusions SGLT2 Inhibitors: Benefits for CKD and Cardiovascular Disease in Type 2 Diabetes [296] Introduction Conclusion Diabetes and Bone Fragility: SGLT2 Inhibitor Use in the Context of Renal and Cardiovascular Benefits [297] Introduction T2DM and Fracture Risk Pathophysiology of T2DM and Bone Fragility Diabetes Medications and Bone Fragility SGLT2 Inhibitors for the Treatment of T2DM SGLT2 Inhibitors and Bone Fracture Pathophysiology of SGLT2 Inhibitors and Bone Fracture Discussion The Actions of SGLT2 Inhibitors on Metabolism, Renal Function and Blood Pressure [333] Introduction SGLT2 Inhibitors and Glucose Control SGLT2 Inhibitors and Weight Control SGLT2 Inhibitors and Renal Function SGLT2 Inhibitors and Blood Pressure Control Conclusions Bibliography Chapter 4: Myocardial Infarction Introduction by the Editor Machine Generated Summaries SGLT2 Inhibitors: New Hope for the Treatment of Acute Myocardial Infarction? [2] Introduction Mechanism of Sodium-Glucose Cotransporter 2 Inhibitors Clinical Trials from 2017 to 2024 Adverse Effect of SGLT2i Conclusion SGLT-2 Inhibitors and In-Stent Restenosis-Related Events After Acute Myocardial Infarction: An Observational Study in Patients with Type 2 Diabetes [13] Background Methods Results Discussion Conclusions The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus [22] [Section 1] Impact of the SGLT2-Inhibitor Empagliflozin on Inflammatory Biomarkers After Acute Myocardial Infarction—A Post-hoc Analysis of the EMMY Trial [25] Introduction Materials and Methods Results Discussion Conclusion Characterization of Left Ventricular Myocardial Sodium-Glucose Cotransporter 1 Expression in Patients with End-Stage Heart Failure [36] Introduction Materials and Methods Results Discussion Conclusions Inhibition of Sodium–Glucose Cotransporter-2 Preserves Cardiac Function During Regional Myocardial Ischemia Independent of Alterations in Myocardial Substrate Utilization [47] Introduction Methods Results Discussion Conclusion SGLT2 Inhibition and Heart Failure—Current Concepts [54] Introduction Conclusions Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors [59] Introduction Clinical Trial Evidence Mechanism of Action: Glucose Reduction Mechanism of Action: Cardiovascular Protection Conclusion Addendum Promising Roles of Sodium–Glucose Cotransporter 2 Inhibitors in Heart Failure Prevention and Treatment [70] Introduction Clinical Relevance of Diabetes and HF Existing HF Prevention Strategies in Diabetes Incretin-Based Drugs and HF Outcomes in Large-Scale Clinical Trials Basic Pharmacological Effects of SGLT2 Inhibitors Summaries of Large-Scale Cardiovascular Outcome Trials Inhibition of Cardiovascular Event and HF Prevention Using SGLT2 Inhibitors What Is the Mechanism of HF Prevention? Future Research Topic and Outlook Conclusions SGLT-2 Inhibitors in Heart Failure: Guide for Prescribing and Future Perspectives [85] Introduction Mechanism of Action Safety of SGLT-2 Inhibitors Evidence from Clinical Trials Guidelines and Approach to SGLT-2 Inhibitors Therapy Future Directions Conclusion Sodium-Glucose Co-transporter 2 Inhibitors in the Failing Heart: A Growing Potential [98] Diabetes and Heart Failure Improving Prognosis: The Clinical Research Arena From Clinical Trials to the Real World Potential Mechanisms Behind the Cardio-renal Benefits Observed with SGLT2i Practical Considerations for SGLT2i Management in T2D Patients with HF Unmet Medical Needs and Conclusions Optimising the Heart Failure Treatment Pathway: The Role of SGLT2 Inhibitors [110] Introduction Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in People with Heart Failure (HF) Safety Profile of SGLT2 Inhibitors The Positioning of SGLT2 Inhibitors Within the HF Treatment Pathway Appropriate Prescribing of an SGLT2 Inhibitor in HF Patients Practical Considerations Future HF Indications for SGLT2 Inhibitors Summary Practical Considerations and Opportunities for SGLT2 Inhibitor Prescription in Heart Failure [118] Introduction SGLT2 Inhibitor Cardiovascular Outcome Trials in Type 2 Diabetes Mellitus: Focus on Heart Failure Evidence for Use of SGLT2 Inhibitor in Heart Failure Without Diabetes Mellitus Practical Considerations for Use of SGLT2 Inhibitors in Clinical Practice Barriers to Prescribing and Using SGLT2 Inhibitors Conclusion Sodium-Glucose Co-transporter 2 Inhibitors and Heart Failure—The Present and the Future [124] Introduction Epidemiology Pathophysiology of Heart Failure in Type 2 Diabetes Mellitus Sodium-Glucose Co-transporter-2 Inhibitors and Cardiovascular Outcome Trials Side Effects and Limitations of Sodium-Glucose Co-transporter-2 Inhibitors Potential Mechanisms of Benefits in Heart Failure Patients Treated with SGLT-2i How Does the Evidence Relate to Day-to-Day Practice? Potential Use of Sodium-Glucose Co-transporter-2 Inhibitors in Patients Without Diabetes Summary Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: The Best Timing for the Right Patient [147] Introduction The Pleiotropic Effects of Sodium-Glucose Cotransporter 2 Inhibitors: Molecular and Pathophysiological Insights Type 2 Diabetes Mellitus and Heart Failure: Role of Sodium-Glucose Cotransporter 2 Inhibitors Heart Failure and Sodium-Glucose Cotransporter 2 Inhibitors: What Is the Best Time of Administration? Conclusions SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled? [154] Introduction: Clinical Background Mechanisms of SGLT2 Inhibitors in HF Conclusion Sodium Glucose Cotransporter 2 Inhibitors: Mechanisms of Action in Heart Failure [155] Introduction Diabetes and CV Risk Diabetes and HF The Target and Mechanisms of Action of SGLT2is SGLT2 Inhibition and Clinical Outcomes The Postulated Mechanisms of the Beneficial Effects of SGLT2is in HF The Importance of SGLT2is as Cardiological Drugs Now and in the Future Conclusions What Makes Sodium-Glucose Co-transporter-2 Inhibitors Stand Out in Heart Failure? [164] Introduction Use of SGLT-2 Inhibitors After Worsening HF Events Use of SGLT-2 Inhibitors in Older Patients with HF SGLT-2 Inhibitor Dosing and Lack of Need for Titration SGLT-2 Inhibitors and Diuretic Activity SGLT-2 Inhibitors and Kidney Function SGLT-2 Inhibitors and Other HF Therapies SGLT-2 Inhibitors and Adjustment of Other Antihyperglycemic Therapies Side Effects of SGLT-2 Inhibitors Unanswered Questions Conclusion Bibliography Chapter 5: Diabetic Cardiomyopathy Introduction by the Editor Machine Generated Summaries Insights into SGLT2 Inhibitor Treatment of Diabetic Cardiomyopathy: Focus on the Mechanisms [2] Introduction SGLT2i and Improved Heart Function SGLT2i and the Regulation of Heart Metabolism SGLT2i and Myocardial Mitochondria SGLT2i Improve Cardiovascular Disease and Microcirculation SGLT2i Improve Ventricular Compliance and Myocardial Fibrosis SGLT2i Inhibit Oxidative Stress In Diabetes Patients, SGLT2i Rescue Cardiomyocytes from Programmed Cell Death SGLT2i and Autophagy in the Myocardium SGLT2i Reverse ER Stress in Diabetic Cardiomyopathy SGLT2i Improve Diabetic Cardiomyopathy by Regulating the Intestinal Microbiota SGLT2i in Clinical Treatment Current Challenges and Future Therapeutic Strategies Conclusions Sodium–Glucose Cotransporter 2 Inhibitor Dapagliflozin Attenuates Diabetic Cardiomyopathy [56] Background Methods Results Discussion Conclusion SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor [ Introduction Methods Results Discussion Limitations Association of Type 2 Diabetes Mellitus with the Development of New-Onset Atrial Fibrillation in Patients with Non-ischemic Dilated Cardiomyopathy: Impact of SGLT2 Inhibitors [76] Introduction Materials and Methods Results Discussion Conclusions Renal Denervation Ameliorates Cardiac Metabolic Remodeling in Diabetic Cardiomyopathy Rats by Suppressing Renal SGLT2 Expression [82] Introduction Materials and Methods Results Discussion Conclusions Mechanisms of Diabetic Cardiomyopathy and Potential Therapeutic Strategies: Preclinical and Clinical Evidence [86] Introduction Cardiomyopathy in T1DM and T2DM Pathophysiology of Diabetic Cardiomyopathy Potential Therapeutic Strategies Future Directions Conclusions Effects of Empagliflozin in Different Phases of Diabetes Mellitus-Related Cardiomyopathy: A Prospective Observational Study [116] Background Methods Results Discussion Conclusions Bibliography Chapter 6: Congestive Heart Failure Introduction by the Editor Machine Generated Summaries SGLT-2 Inhibitors: Potential Novel Strategy to Prevent Congestive Heart Failure in Diabetes? [1] Introduction Discovery of Sodium-Glucose Transporters Genetics of Sodium-Glucose Transporters Renal Glucose Transport in Health and Diabetes Natriuretic Effects of Sodium-Glucose Transporter-2 Inhibitors Rationale for Sodium-Glucose Transport Inhibition in Heart Failure Sodium-Glucose-2 Inhibition as a Novel Target in Heart Failure with Preserved Ejection Fraction? Potential Adverse Effects of Sodium-Glucose Transporter Inhibitors Conclusions Diabetes, Heart Failure and Beyond: Elucidating the Cardioprotective Mechanisms of Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors [26] Introduction Intersection Between Diabetes and Heart Failure: Is SGLT2i the “One Stone for Two Birds” Approach? [27] Introduction HF Patients with or Without DM: Are They Different? HF Patients with or Without DM: Shall Treatment Be Different? HF Patients With or Without DM: Not Different in the Era of SGLT2i? [Section 5] Conclusion Benefits of SGLT2i for the Treatment of Heart Failure Irrespective of Diabetes Diagnosis: A State-of-the-Art Review [46] Introduction General Mechanisms of Heart Failure (Preserved and Reduced) Heart Failure in Patients with and Without T2DM, Current Understanding and Clinical Practice Consequences Description of the Pathological Mechanisms That Link T2D with Heart Failure: Direct and Indirect Effects of SGLT2i on Myocardial Function SGLT2i in Clinical Trials and Meta-Analyses in Heart Failure New Guidelines: Moving Towards an Intensive and Multidimensional Approach for HF Treatment Future Perspectives in the Treatment of HF for Patients with and Without T2D Conclusions Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond [58] Introduction Mechanism of Action of Sodium-Glucose Transporter-2 Inhibitors Glucose-Lowering Drugs in Diabetes and Cardiovascular Risk Glucose-Lowering Drugs in Diabetes and Heart Failure Risk Sodium-Glucose Transporter-2 Inhibitors and Heart Failure Risk Nonglycemic Effects of Sodium-Glucose Transporter-2 Inhibitors Potential Adverse Effects of Sodium-Glucose Transporter-2 Inhibitors The Prospect of Sodium-Glucose Transporter-2 Inhibitors in Heart Failure Different Effects of SGLT2 Inhibitors According to the Presence and Types of Heart Failure in Type 2 Diabetic Patients [75] Background Methods Results Discussion Conclusion Use of Sodium-Glucose Cotransporter-2 Inhibitors in Clinical Practice for Heart Failure Prevention and Treatment: Beyond Type 2 Diabetes. A Narrative Review [79] Introduction Methods SGLT-2i Effects on Cardiovascular Outcomes SGLT-2is and HF Outcomes Knowledge Gaps Regarding the Use of SGLT-2is for HF in Clinical Practice Clinical Ramifications of SGLT-2is for HF Prevention and Treatment Physicians’ Perspectives Regarding the Role of SGLT-2is in Treating HF Conclusions SGLT2 Inhibitors Break the Vicious Circle Between Heart Failure and Insulin Resistance: Targeting Energy Metabolism [100] Introduction The Interaction Between Heart Failure and Insulin Resistance SGLT2 Inhibitor Improve HF and IR by Regulating Energy Metabolism Clinical Evidences of SGLT2 Inhibitors in Heart Failure with Diabetes Conclusion Role of SGLT2 Inhibitors in Patients with Diabetes Mellitus and Heart Failure [111] Introduction Glucose Handling by the Nephron Working Mechanism of Sodium-Glucose Transporter-2 Inhibitors in Diabetes The EMPA-REG Outcome Trial with Empagliflozin Cardiovascular Risk Reduction Through Glycemic Control Comparison of Empagliflozin with Other Glucose-Lowering Medications Adverse Effects with Sodium-Gl