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Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus

Published:September 24, 2019DOI:https://doi.org/10.1016/j.jcjd.2019.09.003

      Abstract

      The growing global burden of type 2 diabetes mellitus confers significant morbidity and mortality in addition to significant cost to local health-care systems. In recent years, 2 classes of therapies have shown some promise in reducing the risk of adverse cardiovascular (CV) events: 1) glucagon-like-peptide-1 (GLP-1) receptor agonists and 2) sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The mechanisms whereby these therapies reduce the risk of adverse CV outcomes are emerging. Both classes of therapies have overlapping yet distinct mechanisms of action. GLP-1 receptor agonists appear to target the incretin axis, inhibit gastric mobility pathways, modify CV risk factors through weight reduction, induce protection of ischemia/reperfusion injury and improve endothelial dysfunction. In comparison, SGLT-2 inhibitors appear to improve ventricular loading conditions, reduce sympathetic nervous system activation, reduce cardiac fibrosis, reduce renal hypoxia and renal-cardiac signalling, reduce left ventricular mass and improve cardiac energetics. In this review, we summarize the potential mechanisms whereby GLP-1 receptor agonists and SGLT-2 inhibitors improve CV outcomes in patients with type 2 diabetes and highlight evidence for their use in populations without diabetes.

      Résumé

      Outre les coûts importants liés aux systèmes de soins de santé locaux, l’accroissement du fardeau mondial du diabète sucré de type 2 entraîne une morbidité et une mortalité importantes. Au cours des dernières années, 2 classes thérapeutiques se sont révélées prometteuses pour réduire le risque d’événements cardiovasculaires (CV) indésirables : 1) les agonistes des récepteurs du GLP-1 (de l’anglais glucagon-like-peptide-1); 2) les inhibiteurs du SGLT-2 (de l’anglais sodium-glucose cotransporter-2). Les mécanismes par lesquels ces traitements réduisent le risque d’événements CV indésirables se profilent. Les 2 classes thérapeutiques ont des mécanismes d’action qui se recoupent, mais qui sont distincts. Les agonistes des récepteurs du GLP-1 semblent cibler la voie de l’incrétine, inhiber les voies de la motilité gastrique, modifier les facteurs de risque CV en réduisant le poids, conférer une protection contre les lésions d’ischémie-reperfusion et corriger le dysfonctionnement endothélial. En comparaison aux agonistes des récepteurs du GLP-1, les inhibiteurs du SGLT-2 semblent améliorer les conditions de charge ventriculaire, réduire l’activation du système nerveux sympathique, réduire la fibrose cardiaque, réduire l’hypoxie rénale et la signalisation rénale-cardiaque, réduire la masse ventriculaire gauche et améliorer l’énergétique cardiaque. Dans la présente revue, nous résumons les mécanismes potentiels par lesquels les agonistes des récepteurs du GLP-1 et les inhibiteurs du SGLT-2 améliorent les résultats CV chez les patients atteints du diabète de type 2, et présentons les données scientifiques sur leur utilisation dans les populations non diabétiques.

      Keywords

      Mots clés

      • Some glucagon-like-peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated efficacy in reducing the risk of cardiovascular outcomes.
      • There are extensive overlapping and distinct mechanisms of action for each class of drugs.
      • GLP-1 receptor agonists mechanisms of action appear to reduce atherothrombotic outcomes, whereas SGLT-2 inhibitors mechanisms of action preferentially target heart failure outcomes.

      Introduction

      The prevalence of type 2 diabetes mellitus (T2DM) continues to increase, with >12% of the adult United States population and 8.5% of the adult population globally affected (
      • Benjamin E.J.
      • Muntner P.
      • Alonso A.
      • et al.
      Heart Disease and Stroke Statistics—2019 update: A report from the American Heart Association.
      ,
      American Diabetes Association.
      ,
      Diabetes Canada Clinical Practice Guidelines Expert Committee
      Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada.
      ). This growing burden of disease has had massive public health consequences because T2DM imposes significant complications, such as coronary and cerebrovascular disease, peripheral arterial disease (including lower limb amputation), heart failure (HF), atrial fibrillation, kidney disease, vision loss and impaired quality of life (
      • Chan M.
      Global report on diabetes.
      ). T2DM is also 1 of the most prevalent comorbidities among patients with established cardiovascular (CV) disease and HF (
      • Rawshani A.
      • Rawshani A.
      • Franzén S.
      • et al.
      Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Sharma A.
      • Zhao X.
      • Hammill B.G.
      • et al.
      Trends in noncardiovascular comorbidities among patients hospitalized for heart failure.
      ). Based on accumulated data up to 2007, questions were raised around the CV safety of thiazolidinedione rosiglitazone. A meta-analysis of 43 small short-term trials with relatively low numbers of events suggested a 43% increased risk of myocardial infarction (MI) with the drug (p=0.03) (
      • Nissen S.E.
      • Wolski K.
      Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
      ). These analyses instigated a congressional investigation, in which concern was expressed about the role of the Food and Drug Administration in protecting public health related to T2DM glucose-lowering therapies. In response to this, and safety issues related to the use of some other glucose-lowering therapies, the Food and Drug Administration (
      U.S. Food and Drug Administration
      Guidance for industry diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.
      ) issued new guidance in 2008 regarding evaluating the CV safety of glucose-lowering therapies. This resulted in a significant increase in the size, duration and cost of trials. To date, there are 2 classes of glucose-lowering therapies that have convincingly demonstrated a reduction in the risk of adverse CV outcomes, including glucagon-like-peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial.
      ,
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • Sharma A.
      • Cooper L.B.
      • Fiuzat M.
      • et al.
      Antihyperglycemic therapies to treat patients with heart failure and diabetes mellitus.
      ,
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • et al.
      SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials.
      ).
      Although the identification of an improvement in CV outcomes with these therapies has ushered a new era in the use of glucose-lowering therapies, the evidence for the mechanisms driving these results is emerging. Here we present a comprehensive review of the potential mechanisms whereby GLP-1 receptor agonists and SGLT-2 inhibitors reduce the risk of CV outcomes.

      GLP-1 Receptor Agonists: Clinical Evidence and Mechanisms of Benefit

      Summary of the clinical evidence

      For GLP-1 receptor agonists, the trials that examined these therapies included the following: lixisenatide in the Evaluation of Lixisenatide in Acute Coronary Syndrome trial (
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ), liraglutide in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ), semaglutide in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ), oral semaglutide in the Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (
      • Bain S.C.
      • Mosenzon O.
      • Arechavaleta R.
      • et al.
      Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.
      ), once-weekly exenatide in the Exenatide Study of Cardiovascular Event Lowering trial (
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ), continuous subcutaneous delivery of exenatide in the Study to Evaluate Cardiovascular Outcomes with ITCA 650 in Patients Treated with Standard of Care for Type 2 Diabetes (
      Intarcia
      Intarcia announces successful cardiovascular safety results in phase 3 FREEDOM-CVO trial for ITCA 650, an investigational therapy for type 2 diabetes.
      ), albiglutide in the Harmony Outcomes trial (
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial.
      ) and dulaglutide in the Researching Cardiovascular Events With a Weekly Incretin in Diabetes trial (
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial.
      ).
      The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial evaluated the CV safety of the GLP-1 receptor antagonist liraglutide in 9,340 subjects with established CV disease or CV risk factors. Liraglutide reduced the risk of the primary major adverse cardiovascular events (MACE) outcome of CV death, nonfatal MI and nonfatal stroke by 23% (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.78 to 0.97; p<0.001 for noninferiority; p=0.01 for superiority). CV mortality was reduced by 22% (HR, 0.78; 95% CI, 0.66 to 0.93). The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes randomized 3,297 patients with T2DM and established CV disease, chronic HF or chronic kidney disease (stage 3 or higher) with CV risk factors to semaglutide (GLP-1 receptor antagonist) or placebo. The trial showed that semaglutide reduced the primary 3-point MACE outcome by 26% (HR, 0.74; 95% CI, 0.58 to 0.95; p<0.001 for noninferiority; p=0.02 for superiority) (
      • Verma S.
      • Bain S.C.
      • Buse J.B.
      • et al.
      Frequency of first and recurrent major adverse cardiovascular events with liraglutide treatment among patients with type 2 diabetes and high risk of cardiovascular events. A post hoc analysis of a randomized trial.
      ). The Harmony Outcomes trial randomized 9,463 participants with established atherosclerotic vascular disease to albiglutide, a GLP-1 receptor agonist, vs placebo and followed them for a median of 1.6 years (
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial.
      ). The primary composite outcome of CV death, MI or stroke occurred in 7.1% in the albiglutide group and in 9.0% in the placebo group (HR, 0.78; 95% CI, 0.68 to 0.90). MI occurred in 3.8% of the patients receiving albiglutide and in 5.1% of those receiving placebo (HR, 0.75; 95% CI, 0.61 to 0.90); stroke occurred in 2.0% and 2.3%, respectively (HR, 0.86; 95% CI, 0.66 to 1.14). Rates of death from CV causes were 2.6% and 2.7%, respectively (HR, 0.93; 95% CI, 0.73 to 1.19). The Researching Cardiovascular Events With a Weekly Incretin in Diabetes trial randomized 9,901 participants with a prior CV event or CV risk factors to dulaglutide or placebo (
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial.
      ). After a median follow up of 5.4 years, the primary composite endpoint of 3-point MACE was reduced with dulaglutide compared with placebo (HR, 0.88, 95% CI, 0.79 to 0.99). CV death was not reduced with dulaglutide compared with placebo.

      Glucose-dependent and -independent mechanisms for reduction in CV outcomes

      The reduction in the risk of CV outcomes associated with GLP-1 receptor agonists likely occurs through a variety of complex and interdependent mechanisms which include potentiation of the incretin axis, targeting gastric mobility pathways, CV risk factor modification, direct cardiac contractile impact, optimization of cardiac energy consumption, protection of ischemia/reperfusion injury and improvement in endothelial dysfunction (Figure 1 and Table 1).
      Figure thumbnail gr1
      Figure 1Mechanisms whereby glucagon-like-peptide-1 receptor agonists modify the risk of cardiovascular outcomes. A1C, glycated hemoglobin; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1.
      Table 1Suggested mechanisms of GLP-1 receptor agonists and SGLT-2 inhibition benefits
      GLP-1 receptor agonistsSGLT-2 inhibitors
      • 1.
        Potentiation of the incretin axis
      • 2.
        Targeting gastric mobility pathway
      • 3.
        Reducing gastric emptying through central CNS effect
      • 4.
        CV risk factor modification through weight reduction
      • 5.
        Direct cardiac contractile improvement
      • 6.
        Optimization of cardiac energy consumption
      • 7.
        Protection of ischemia/reperfusion injury
      • 8.
        Improvement in endothelial dysfunction
      • 1.
        Improved ventricular loading conditions
      • 2.
        Reduced preload and afterload
      • 3.
        Reduction in LV wall stress
      • 4.
        Reduction in sympathetic nervous system activation
      • 5.
        Reduction in cardiac fibrosis
      • 6.
        Direct effects on ion channels in the heart
      • 7.
        Modulation of autophagy and mitophagy
      • 8.
        Increased reparative vascular progenitor cells
      • 9.
        Reduction in renal hypoxia and renal-cardiac signalling
      • 10.
        Improved endothelial function
      • 11.
        Reduction in LV mass
      • 12.
        Improved cardiac energetics
      • 13.
        Modulation of myocardial CamKII
      CNS, central nervous system; CV, cardiovascular; GLP-1, glucagon-like-peptide-1; LV, left ventricular; SGLT-2, sodium-glucose cotransporter-2.

      Targeting the incretin axis and gastric motility pathways

      Peptides known as incretins are secreted by gastrointestinal cells in response to the ingestion of oral nutrients. In normal homeostatic conditions, the role of these peptides is to promote pancreatic beta-cell insulin production. The blunted efficacy of incretins may play a pivotal role in the pathogenesis of T2DM. GLP-1 and glucose-dependent insulinotropic polypeptide account for most of the so-called incretin effect, whereby an oral glucose load promotes greater insulin release than the equivalent parenteral load (
      • Elrick H.
      • Stimmler L.
      • Hlad C.J.
      • et al.
      Plasma insulin response to oral and intravenous glucose administration.
      ). GLP-1 is a 30-amino-acid peptide secreted in the distal small intestine by L cells in response to luminal stimulation through oral intake. Upon systemic release, circulating GLP-1 is rapidly degraded by dipeptidyl-dipeptidase-4 (
      • Scheen A.J.
      Cardiovascular effects of gliptins.
      ); this results in an extremely shortened half-life of 1 to 2 min. After an oral glucose load, released GLP-1 will bind onto receptors in the endocrine pancreas, resulting in glucose-dependent insulin secretion from the pancreatic β cells, an inhibition of glucagon secretion and enhanced insulin gene transcription (
      • Gautier J.F.
      • Choukem S.P.
      • Girard J.
      Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes.
      ). In people with T2DM, the function of the incretin axis appears to be disrupted through both a reduction in GLP-1 secretion and GLP-1 resistance.
      In addition to the direct pancreatic β-cells interaction, GLP-1 delays gastric emptying by reducing gastrointestinal secretions and gastric mobility (
      • Umapathysivam M.M.
      • Lee M.Y.
      • Jones K.L.
      • et al.
      The effect of prolonged glucagon-like peptide-1 receptor stimulation on gastric emptying and glycemia.
      ,
      • Umapathysivam M.M.
      • Lee M.Y.
      • Jones K.L.
      • et al.
      Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia.
      ). The mechanisms whereby GLP-1 reduces gastrointestinal secretion and motility is not fully understood. There is limited evidence to support direct actions on gastric GLP-1 receptors; however, some studies of GLP-1 receptor distribution have identified expression in gastric mucosa, suggesting a direct role in regulating gastric secretion (
      • Broide E.
      • Bloch O.
      • Ben-Yehudah G.
      • Cantrell D.
      • Shirin H.
      • Rapoport M.J.
      GLP-1 receptor is expressed in human stomach mucosa: Analysis of its cellular association and distribution within gastric glands.
      ). Growing evidence suggests that the impact of GLP-1 on gastric motility is neurally mediated. GLP-1 can inhibit central parasympathetic outflow, resulting in reduction in gastropancreatic function (
      • Holmes G.M.
      • Browning K.N.
      • Tong M.
      • Qualls-Creekmore E.
      • Travagli R.A.
      Vagally mediated effects of glucagon-like peptide 1: In vitro and in vivo gastric actions.
      ). In addition, plasma concentrations of pancreatic polypeptide, a surrogate measure of vagal nervous activity, was suppressed by GLP-1 during a first meal, with less suppression after the second test meal, suggesting that the autonomic nervous system adapts to GLP-1 signalling (
      • Nauck M.A.
      • Kemmeries G.
      • Holst J.J.
      • Meier J.J.
      Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans.
      ).
      GLP-1 secretion has been demonstrated to be reduced in people with diabetes, and there was an associated reduction in incretin-mediated glucose-dependent insulin secretion (
      • Toft-Nielsen M.B.
      • Damholt M.B.
      • Madsbad S.
      • et al.
      Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.
      ,
      • Nauck M.A.
      • Vardarli I.
      • Deacon C.F.
      • Holst J.J.
      • Meier J.J.
      Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: What is up, what is down?.
      ). Subsequent data have suggested GLP-1 resistance also contributes to the deterioration of the incretin effect in people with T2DM and highlights that clinical factors, such as age and plasma glucagon level, also play a role in determining incretin axis activity (
      • Calanna S.
      • Christensen M.
      • Holst J.J.
      • et al.
      Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: Systematic review and meta-analyses of clinical studies.
      ). The use of synthetic GLP-1 receptor agonists resistant to dipeptidyl peptidase 4 (DPP-4) breakdown results in targeted activation of the incretin and gastric modulating pathways of GLP-1. In animal models, GLP-1 can reduce cellular apoptosis in the pancreatic β cells and promote β-cell proliferation and neogenesis (
      • Farilla L.
      • Hongxiang H.
      • Bertolotto C.
      • et al.
      Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats.
      ); this impact may be potentiated through the clinical use of GLP-1 receptor agonists, thereby ameliorating the impact of T2DM on the incretin pathway. The impact of GLP-1 receptor agonists on weight reduction has been seen across the spectrum of people with CV disease (
      • Sharma A.
      • Ambrosy A.P.
      • DeVore A.D.
      • et al.
      Liraglutide and weight loss among patients with advanced heart failure and a reduced ejection fraction: Insights from the FIGHT trial.
      ,
      • Pi-Sunyer X.
      • Astrup A.
      • Fujioka K.
      • et al.
      A randomized, controlled trial of 3.0 mg of liraglutide in weight management.
      ). A reduction of gastric emptying may result in early satiety, which can promote reduced caloric intake, weight loss, a delay in the need for exogeneous insulin and subsequent improvement in CV risk factors (
      • Smilowitz N.R.
      • Donnino R.
      • Schwartzbard A.
      Glucagon-like peptide-1 receptor agonists for diabetes mellitus: A role in cardiovascular disease.
      ). This improvement in CV risk factors is likely a major driver of the CV benefit seen in the cardiovascular outcome trials (CVOTs) of GLP-1 receptor agonists.

      Direct Myocardial and Vascular Effects of GLP-1 and GLP-1 Receptor Agonists

      Prior studies have demonstrated the presence of GLP-1 receptors in human and animal cardiac and vascular tissue models, specifically in cardiomyocytes, the endothelium and vascular smooth muscle cells (
      • Wei Y.
      • Mojsov S.
      Tissue-specific expression of the human receptor for glucagon-like peptide-I: Brain, heart and pancreatic forms have the same deduced amino acid sequences.
      ,
      • Bullock B.P.
      • Heller R.S.
      • Habener J.F.
      Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor.
      ,
      • Green B.D.
      • Hand K.V.
      • Dougan J.E.
      • McDonnell B.M.
      • Cassidy R.S.
      • Grieve D.J.
      GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP.
      ). The presence of receptors directly in cardiac and vascular tissues suggests that GLP-1 receptor agonists may modify CV outcomes through direct cardiac benefit in addition to targeting the incretin axis and gastric motility.

      Cardiac output and heart rate

      GLP-1 receptor agonists appear to play a direct role in the electrophysiologic pathway in the heart because clinical trials have consistently described an increase in heart rate associated with GLP-1 receptor agonists (
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Pi-Sunyer X.
      • Astrup A.
      • Fujioka K.
      • et al.
      A randomized, controlled trial of 3.0 mg of liraglutide in weight management.
      ,
      • Margulies K.B.
      • Hernandez A.F.
      • Redfield M.M.
      • et al.
      Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial.
      ,
      • Jorsal A.
      • Kistorp C.
      • Holmager P.
      • et al.
      Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
      ). Although the results are varied, GLP-1 infusions in murine models appear to cause a dose-dependent inotropic and chronotropic effect (
      • Barragán J.M.
      • Rodríguez R.E.
      • Eng J.
      • Blázquez E.
      Interactions of exendin-(9-39) with the effects of glucagon-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats.
      ). Murine infusion of GLP-1-(7-36) amide induced the increases in both heart rate and blood pressure compared with glucagon. In addition, rats pretreated with reserpine, propranolol or phentolamine still experienced GLP-1-(7-36) amide-mediated increases in mean arterial blood pressure and heart rate to the same level or even greater than that observed in non-pretreated rats. These findings implicate GLP-1 in arterial blood pressure and heart rate modulation independent of catecholamines (
      • Barragan J.M.
      • Rodriguez R.E.
      • Blazquez E.
      Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats.
      ). These findings were supported by demonstration of a diminished basal heart rate after insulin administration in GLP-1R knockout mice (
      • Gros R.
      • You X.
      • Baggio L.L.
      • et al.
      Cardiac function in mice lacking the glucagon-like peptide-1 receptor.
      ). Exenatide and liraglutide do not impact on QT interval in trials compared with moxifloxacin as a positive control (
      • Chatterjee D.J.
      • Khutoryansky N.
      • Zdravkovic M.
      • Sprenger C.R.
      • Litwin J.S.
      Absence of QTc prolongation in a thorough qt study with subcutaneous liraglutide, a once-daily human GLP-1 analog for treatment of type 2 diabetes.
      ). Despite these results, how this catecholamine-independent modification of heart rate impacts the CV benefit of GLP-1 receptor agonists is unclear.

      Microcirculatory pathway

      GLP-1 potentially impacts directly on the microcirculatory pathway, which may be modified by GLP-1 receptor agonists. Ventricular fibrillation was induced electrically in 20 anesthetized domestic swine (30 to 35 kg). Animals were resuscitated with aggressive advanced cardiac life support and blindly randomized to receive a continuous infusion of either GLP-1 or equal volume saline as placebo for 4 h, beginning 1 min after return of spontaneous circulation. Coronary flow reserve as measured by intracoronary Doppler flow measurements were significantly increased in GLP-1-treated animals at 1 h (1.79±0.13 in control animals vs 2.05±0.12 in GLP-1-treated animals, p≤0.05). There was no improvement in echocardiographic left ventricular parameters (
      • Dokken B.B.
      • Hilwig W.R.
      • Teachey M.K.
      • et al.
      Glucagon-like peptide-1 (GLP-1) attenuates post-resuscitation myocardial microcirculatory dysfunction.
      ). These results demonstrate the potential microcirculatory modification that can occur with GLP-1, which may be potentiated by GLP-1 receptor agonists.

      Ischemia/preconditioning and antiapoptosis

      Several antiapoptotic mechanisms in the setting of ischemia and reperfusion have been described, which may explain the CV benefits observed in the CVOTs. After induction of MI, 120 mice were treated twice daily for 7 days with liraglutide vs saline; survival was significantly higher in liraglutide-treated mice, and liraglutide significantly reduced cardiac rupture (12 of 60 vs 46 of 60; p=0.0001) in addition to infarct size (21%±2% vs 29%±3%, p=0.02) and improved cardiac output (12.4±0.6 vs 9.7±0.6 mL/min; p=0.002) (
      • Noyan-Ashraf M.H.
      • Abdul Momen M.
      • Ban K.
      • et al.
      GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.
      ). Compared with saline-infused mice, liraglutide also modulated the expression and activity of cardioprotective genes in the mouse heart, such as AKT, GSK3β, PPARβ, NRF-2 and HO-1. The effects of liraglutide on survival were independent of weight loss. The cardioprotective benefit of liraglutide appeared to be greater than metformin, despite glycemic equivalence. Furthermore, the liraglutide-mediated cardioprotective effects were present 4 days after therapy cessation potentially because of increased cyclic adenosine monophosphate (cAMP) formation and reduced the extent of caspase-3 activation in cardiomyocytes. These findings have been suggested by other animal model studies (
      • Sonne D.P.
      • Engstrøm T.
      • Treiman M.
      Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart.
      ,
      • Bose A.K.
      • Mocanu M.M.
      • Carr R.D.
      • Brand C.L.
      • Yellon D.M.
      Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury.
      ).
      GLP-1 receptor agonists also directly reduced infarct size in swine models. In a randomized pig study, exenatide vs phosphate-buffered saline treatment was given after 75 min of coronary artery ligation and subsequent reperfusion. Exenatide reduced myocardial infarct size (32.7%±6.4% vs 53.6%±3.9%, p=0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3%±6.3% vs 8.1%±1.9%, p<0.001; myocardial stiffness: 0.12±0.06 vs 0.22±0.07 mmHg/mL, p=0.004). Furthermore, after exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with phosphate-buffered saline treatment. In addition, active caspase-3 expression was lower in exenatide-treated pigs. In addition, nuclear oxidative stress as measured with 8-hydroxydeoxyguanosine staining was reduced with exenatide treatment, whereas superoxide dismutase activity and catalase activity were increased. These results provide significant evidence toward the hypothesis of ischemia-reperfusion and antiapoptosis-mediated mechanism of GLP-1 receptor agonists after an acute MI (
      • Timmers L.
      • Henriques J.P.S.
      • de Kleijn D.P.V.
      • et al.
      Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury.
      ).

      Postprandial lipids

      Other than the expected impact of weight loss, GLP-1 receptor agonists do not appear to have specific effects on fasting lipids. However, there is evidence of improvements in postprandial lipid levels. Both liraglutide and semaglutide, with randomized, placebo-controlled trials, have demonstrated a lowering of both apolipoprotein B48 (ApoB48) and triglycerides after a fat-enriched breakfast (
      • Hermansen K.
      • Bækdal T.A.
      • Düring M.
      • et al.
      Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, cross-over trial.
      ,
      • Hjerpsted J.B.
      • Flint A.
      • Brooks A.
      • Axelsen M.B.
      • Kvist T.
      • Blundell J.
      Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity.
      ). Potential mechanisms for reduction in postprandial lipids with GLP-1 receptor agonists have been demonstrated from hamsters and rat models, suggesting that GLP-1 may decrease intestinal lipoprotein biosynthesis and secretion (
      • Hsieh J.
      • Longuet C.
      • Baker C.L.
      • et al.
      The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice.
      ). Furthermore, a clinical study with liraglutide showed a reduction in ApoB48 production and an increase in ApoB48 catabolism (
      • Vergès B.
      • Duvillard L.
      • Pais De Barros J.P.
      • et al.
      Liraglutide reduces postprandial hyperlipidemia by increasing ApoB48 (apolipoprotein B48) catabolism and by reducing ApoB48 production in patients with type 2 diabetes mellitus.
      ). Importantly, the clinical benefits of liraglutide appear to occur independently of baseline low-density lipoprotein cholesterol (
      • Verma S.
      • Poulter N.R.
      • Bhatt D.L.
      • et al.
      Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke: Post hoc analysis from the leader trial.
      ).

      Atherosclerosis

      Both animal and human studies have demonstrated a reduction in the burden of atherosclerosis as potential mechanisms explaining the CV benefit of GLP-1 receptor agonists. Using apolipoprotein E-deficient mice, liraglutide attenuated the development of atherosclerosis and improved plaque stability, as measured by a change in plaque composition, reflected by an increase in collagen content and alpha-smooth muscle action (
      • Gaspari T.
      • Welungoda I.
      • Widdop R.E.
      • Simpson R.W.
      • Dear A.E.
      The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE-/- mouse model.
      ). There was also GLP-1 receptor-independent reduction in plaque size with liraglutide. In another in vitro and apolipoprotein E-deficient mice study, treatment with liraglutide suppressed foam cell formation through a reduced uptake of oxidized low-density lipoprotein cholesterol, potentially caused by a downregulation of scavenger receptor cluster of differentiation 36 (
      • Tashiro Y.
      • Sato K.
      • Watanabe T.
      • et al.
      A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis.
      ). Subsequent studies of liraglutide and semaglutide on low-density lipoprotein receptor and apolipoprotein E knockout mice attenuated aortic atherosclerotic plaque lesion size independent of their effects on glycemic control, body weight and lipid profile (
      • Rakipovski G.
      • Rolin B.
      • Nøhr J.
      • et al.
      The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE −/− and LDLr −/− mice by a mechanism that includes inflammatory pathways.
      ). These studies have suggested the potential role for liraglutide in prevention and atherosclerosis stabilization in addition to possible protection against future CV events.

      Inflammation

      Several basic and clinical studies have demonstrated the role of GLP-1 receptor agonists in reducing markers of inflammation. Liraglutide decreased levels of tumor necrosis factor-alpha (TNF-α)-induced secretion of intracellular adhesion molecule, vascular cell adhesion molecule and plasminogen activator inhibitor-1 (PAI-1) in human umbilical vein endothelial cells (
      • Liu H.
      • Dear A.E.
      • Knudsen L.B.
      • Simpson R.W.
      A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules.
      ). These findings were supported by a randomized, placebo-controlled study of liraglutide in people with T2DM; liraglutide significantly reduced reduction in PAI-1 (−25%, from a baseline of 31.4±28.4 U/mL) and C-reactive protein (−20%, from a baseline of 4.2±4.2 mg/L), without a change in TNF-α or interleukin-6 (
      • Courrèges J.P.
      • Vilsbøll T.
      • Zdravkovic M.
      • et al.
      Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with type 2 diabetes.
      ). In the SCALE-Obesity randomized, placebo-controlled trial, liraglutide reduced C-reactive protein by 35% (from a baseline of approximately 3.5 mg/dL) in subjects with obesity; this result may have been driven by a reduction in weight also seen in the study (
      • Pi-Sunyer X.
      • Astrup A.
      • Fujioka K.
      • et al.
      A randomized, controlled trial of 3.0 mg of liraglutide in weight management.
      ). In a noncontrolled study, liraglutide lowered levels of markers of inflammation including sCD163 (
      • Hogan A.E.
      • Gaoatswe G.
      • Lynch L.
      • et al.
      Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus.
      ), selectin E and PAI-1 (
      • Rakipovski G.
      • Rolin B.
      • Nøhr J.
      • et al.
      The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE −/− and LDLr −/− mice by a mechanism that includes inflammatory pathways.
      ,
      • Forst T.
      • Michelson G.
      • Ratter F.
      • et al.
      Addition of liraglutide in patients with type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function.
      ).

      SGLT-2 Inhibitors: Summary of Clinical Evidence and Mechanisms of CV Benefit

      Summary of clinical evidence

      For SGLT-2 inhibitors, there are 3 completed CVOTs as follows: empagliflozin in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) (
      • Holmes G.M.
      • Browning K.N.
      • Tong M.
      • Qualls-Creekmore E.
      • Travagli R.A.
      Vagally mediated effects of glucagon-like peptide 1: In vitro and in vivo gastric actions.
      ), canagliflozin in the Canagliflozin Cardiovascular Assessment Study Program (
      • Nauck M.A.
      • Kemmeries G.
      • Holst J.J.
      • Meier J.J.
      Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans.
      ) and dapagliflozin in the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 trial (
      • Toft-Nielsen M.B.
      • Damholt M.B.
      • Madsbad S.
      • et al.
      Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.
      ). EMPA-REG OUTCOME was a CV safety trial of the SGLT-2 inhibitor empagliflozin. The trial randomized 7,020 patients with T2DM and established CV disease to receive 10 or 25 mg of empagliflozin or placebo. Empagliflozin reduced the risk of the primary MACE endpoint compared with placebo (10.5% vs 12.1%, respectively; HR, 0.86; 95% CI, 0.74 to 0.99; p=0.04 for superiority). EMPA-REG OUTCOME also demonstrated that empagliflozin reduced the risk of HF admissions compared with placebo (4.1% vs 2.7%, respectively; HR, 0.65; 95% CI, 0.50 to 0.85) (
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ). Among the patients with a baseline history of HF, empagliflozin therapy was associated with a numerically lower rate of HF hospitalization (10.4% vs 12.3%, respectively; HR, 0.75; 95% CI, 0.48 to 1.19) and CV mortality (8.2% vs 11.1%, respectively; HR, 0.71; 95% CI, 0.43 to 1.16) (
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME® trial.
      ). The first trial of an SGLT-2 inhibitor dapagliflozin has reported positive top-line results in a population of patients with reduced ejection fraction.
      The Canagliflozin Cardiovascular Assessment Study Program included 2 clinical trials, which enrolled a total of 10,142 patients with T2DM and high CV risk (both with established CV disease or with CV risk factors). Patients were randomized to receive canagliflozin or placebo, and the trial demonstrated a significant reduction in the 3-point MACE risk of CV death, nonfatal MI or nonfatal stroke (26.9 vs 31.5, respectively, per 1,000 patient-years; HR, 0.86; 95% CI, 0.75 to 0.97; p=0.02 for superiority) (
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ). However, despite the evidence of CV benefit, an unexpected finding of an increased risk of toe or metatarsal amputation was identified (6.3 vs 3.4, respectively, per 1,000 patient-years; HR, 1.97; 95% CI, 1.41 to 2.75). Compared with placebo, canagliflozin reduced the risk of HF hospitalization by 335 (HR, 0.67; 95% CI, 0.52 to 0.87) (
      • Figtree G.A.
      • Rådholm K.
      • Barrett T.D.
      • et al.
      Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes: Results from the CANVAS Program.
      ).
      The Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 trial randomized 17,160 people with T2DM with either atherosclerotic CV disease or CV risk factors to dapagliflozin or placebo (
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ). Dapagliflozin reduced the coprimary endpoint of the composite of CV death or HF hospitalization (HR, 0.83; 95% CI, 0.73 to 0.95) but not the 3-point MACEs (HR, 0.93; 95% CI, 0.84 to 1.03). The reduction in CV death or HF hospitalization was driven by a reduction in the risk of HF hospitalization (HR, 0.73; 95% CI, 0.61 to 0.88) (
      • Kato E.T.
      • Silverman M.G.
      • Mosenzon O.
      • et al.
      Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
      ).

      Mechanisms of CV Benefit Associated With SGLT-2 Inhibitors

      Compared with GLP-1 receptor agonists, where the mechanism of benefit appears to be in the reduction of atherothrombotic events, the benefit of SGLT-2 inhibitors appears to primarily derive from prevention and possible treatment of fatal and nonfatal HF events (
      • Verma S.
      • Jüni P.
      • Mazer C.D.
      Pump, pipes, and filter: Do SGLT2 inhibitors cover it all?.
      ,
      • Verma S.
      • McMurray J.J.V.
      SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review.
      ). Although traditionally ignored, these results re-emphasized the burden of HF among people with T2DM (
      • Sharma A.
      • Cooper L.B.
      • Fiuzat M.
      • et al.
      Antihyperglycemic therapies to treat patients with heart failure and diabetes mellitus.
      ,
      • McMurray J.J.V.
      • Gerstein H.C.
      • Holman R.R.
      • Pfeffer M.A.
      Heart failure: A cardiovascular outcome in diabetes that can no longer be ignored.
      ,
      • Ferreira J.P.
      • Girerd N.
      • Gregson J.
      • et al.
      Stroke risk in patients with reduced ejection fraction after myocardial infarction without atrial fibrillation.
      ,
      • Sharma A.
      • Bhatt D.L.
      • Calvo G.
      • Brown N.J.
      • Zannad F.
      • Mentz R.J.
      Heart failure event definitions in drug trials in patients with type 2 diabetes.
      ). Although atherothrombotic complications of T2DM, namely fatal and nonfatal stroke and MI, are well recognized, HF outcomes are just as common compared with the rates of ischemic events. Clinically, because routine markers can stratify for patients at high risk of future HF events (
      • Verma S.
      • Sharma A.
      • Kanumilli N.
      • Butler J.
      Predictors of heart failure development in type 2 diabetes.
      ), questions remain on the mechanism of benefit of SGLT-2 inhibitors and whether these therapies reduce the risk of events across the spectrum of CV diseases, including HF with preserved and reduced ejection fraction. To date, there are several overlapping mechanisms thought to be driving the clinical CV benefits seen in the CVOTs: reduction in myocardial Na+/H+ exchange inhibition, improvement in cardiac metabolism and bioenergetics, improvement in ventricular loading conditions secondary to natriuresis, afterload reduction secondary to reduction in blood pressure and improvement in vascular function, modulation of the cardiac extracellular matrix and reduction in cardiac fibrosis (Table 1).

      Reduction in myocardial Na+/H+ exchange inhibition

      SGLT-2 inhibitors impart CV benefit through direct inhibition of the Na+/H+ exchanger (NHE)-1 isoform in the myocardium (
      • Packer M.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • Zannad F.
      Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure - proposal of a novel mechanism of action.
      ,
      • Uthman L.
      • Baartscheer A.
      • Bleijlevens B.
      • et al.
      Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
      ). Activation of NHE-1 results in increased cytosolic sodium and calcium, a finding which has been shown in experimental models of HF (
      • Uthman L.
      • Baartscheer A.
      • Bleijlevens B.
      • et al.
      Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
      ). In mouse models, empagliflozin, dapagliflozin and canagliflozin directly inhibit NHE flux and reduce cardiac cytosolic Na+, potentially through binding of the Na+ binding site of NHE-1 (
      • Uthman L.
      • Baartscheer A.
      • Bleijlevens B.
      • et al.
      Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
      ). Empagliflozin and canagliflozin also have been shown to induce vasodilation in a normal mouse heart but did not alter oxygen consumption and energetics as measured by the phosphocreatine/adenosine triphosphate (ATP) ratio (
      • Uthman L.
      • Baartscheer A.
      • Bleijlevens B.
      • et al.
      Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
      ). This has been supported by prior studies, which have demonstrated that empagliflozin inhibits cardiomyocyte NHE to increase mitochondrial calcium while reducing cytoplasmic sodium and calcium levels (
      • Baartscheer A.
      • Schumacher C.A.
      • Wüst R.C.I.
      • et al.
      Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits.
      ). A similar exchanger NHE-3 is known to mediate tubular sodium reuptake, and expression is increased in HF (
      • Gallo L.A.
      • Wright E.M.
      • Vallon V.
      Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences.
      ); inhibiting NHE-3 may result in strategies to restore whole-body sodium homeostasis (
      • Packer M.
      Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure.
      ). In addition to the binding of the HNE-1 site, downregulation of HNE-3 may represent 1 target of SGLT-2 inhibition to promote diuresis given the absence of SGLT-2 receptors in the myocardium (
      • Verma S.
      • McMurray J.J.V.
      SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review.
      ,
      • Gallo L.A.
      • Wright E.M.
      • Vallon V.
      Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences.
      ,
      • Packer M.
      Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure.
      ). As previously postulated, either direct or indirect inhibition of NHE-1 and NHE-3 may represent the common renal mechanism through which these agents prevent and/or treat HF (
      • Zile M.R.
      • Claggett B.L.
      • Prescott M.F.
      • et al.
      Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure.
      ).

      Improvements in cardiac energetics with SGLT-2 inhibitors

      Another possible mechanism whereby SGLT-2 inhibitors improve CV outcomes is through optimizing cardiac energy metabolism; this may result in improvements in myocardial energetics and substrate efficiency that can ultimately result in enhanced cardiac output (
      • Ferrannini E.
      • Mark M.
      • Mayoux E.
      CV protection in the EMPA-REG OUTCOME trial: A thrifty substrate hypothesis.
      ,
      • Lopaschuk G.D.
      • Verma S.
      Empagliflozin’s fuel hypothesis: Not so soon.
      ,
      • Verma S.
      • Rawat S.
      • Ho K.L.
      • et al.
      Empagliflozin increases cardiac energy production in diabetes: Novel translational insights into the heart failure benefits of SGLT2 inhibitors.
      ).
      To meet the significant metabolic demands of the heart, the myocardium relies on metabolic flexibility, whereby heterogenous sources of energy, such as glucose, fatty acid, ketone bodies and amino acids, are used to generate ATP (
      • Stanley W.C.
      • Recchia F.A.
      • Lopaschuk G.D.
      Myocardial substrate metabolism in the normal and failing heart.
      ,
      • Lopaschuk G.D.
      • Ussher J.R.
      • Folmes C.D.L.
      • Jaswal J.S.
      • Stanley W.C.
      Myocardial fatty acid metabolism in health and disease.
      ,
      • Lopaschuk G.D.
      • Verma S.
      Empagliflozin’s fuel hypothesis: Not so soon.
      ). As the heart begins to fail, it loses this metabolic flexibility. Accordingly, an over-reliance on nonesterified fatty acid as a substrate for ATP generation results in accumulation of toxic intermediates that promote lipotoxicity, impair sarcoplasmic reticulum calcium uptake and initiate the development of diastolic dysfunction (
      • Stanley W.C.
      • Recchia F.A.
      • Lopaschuk G.D.
      Myocardial substrate metabolism in the normal and failing heart.
      ,
      • Lopaschuk G.D.
      • Ussher J.R.
      • Folmes C.D.L.
      • Jaswal J.S.
      • Stanley W.C.
      Myocardial fatty acid metabolism in health and disease.
      ).
      Marked and aberrant changes in metabolic flexibility and substrate use may contribute to the development and perpetuation of HF.
      The ketone body β-hydroxybutyrate is an energy source oxidised by the heart in preference to nonesterified fatty acid and glucose; ketones may not only improve cardiac function in the failing heart, but also increase mechanical efficiency and prevent the development of HF (
      • Kolwicz S.C.
      • Airhart S.
      • Tian R.
      Ketones step to the plate: A game changer for metabolic remodeling in heart failure?.
      ). SGLT-2 inhibitors may increase ketone body β-hydroxybutyrate production; potentially, this may be a more acceptable myocardial ATP source in hearts with T2DM (
      • Kolwicz S.C.
      • Airhart S.
      • Tian R.
      Ketones step to the plate: A game changer for metabolic remodeling in heart failure?.
      ,
      • Mizuno Y.
      • Harada E.
      • Nakagawa H.
      • et al.
      The diabetic heart utilizes ketone bodies as an energy source.
      ). In pig studies, it has been demonstrated that empagliflozin increases myocardial ketone consumption while reducing glucose consumption and lactate production (
      • Santos-Gallego C.G.
      • Ibanez J.A.R.
      • Antonio R.S.
      • et al.
      Empagliflozin induces a myocardial metabolic shift from glucose consumption to ketone metabolism that mitigates adverse cardiac remodeling and improves myocardial contractility.
      ). In addition to ketone production, branched-chain amino acid degradation is impaired in HF and may contribute to aberrant myocardial energy optimization (
      • Kappel B.A.
      • Lehrke M.
      • Schütt K.
      • et al.
      Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease.
      ). In 25 patients with T2DM and CV disease, plasma was taken at baseline and after 1 month of empagliflozin use. Using an untargeted metabolomic approach, empagliflozin appeared to promote branched-chain amino acid degradation, thereby providing an alternative energy substrate (
      • Lopaschuk G.D.
      • Verma S.
      Empagliflozin’s fuel hypothesis: Not so soon.
      ).
      Further evidence for the benefit of SGLT-2 inhibitors on cardiac energetics arises from several experimental models. In db/db mice with diabetes, empagliflozin prevented the development of cardiac dysfunction (
      • Verma S.
      • Rawat S.
      • Ho K.L.
      • et al.
      Empagliflozin increases cardiac energy production in diabetes: Novel translational insights into the heart failure benefits of SGLT2 inhibitors.
      ). Among these mice, in vehicle-treated db/db mice, cardiac glucose oxidation rates were decreased by 61%, compared with control mice, but only by 43% in empagliflozin-treated mice with diabetes, implying an increase in myocardial energetic efficiency. Overall db/db vehicle-treated hearts (compared with control mice) had 36% reduction in ATP production rates; however, empagliflozin-treated db/db mice increased cardiac ATP production by 31% compared to db/db vehicle-treated mice. In vehicle-treated db/db mice hearts, ATP generation was as follows: 42% from fatty acid oxidation, 26% from glucose oxidation, 10% from ketone oxidation and 22% from glycolysis. In empagliflozin-treated db/db mice, there was a 61% increase in the contribution of glucose oxidation to energy production. These results confirm an earlier hypothesis of the role of SGLT-2 inhibitors in increasing ATP production to optimize cardiac myocardial energetics.

      SGLT-2 inhibitors and improvements in ventricular loading conditions

      It has been proposed that one of the primary drivers of the improvement of CV outcomes with SGLT-2 inhibitors occurs through improvement of ventricular loading conditions through the following 2 mechanisms: 1) secondary to a reduction in preload because of the natriuretic and diuretic effects and 2) improvement in ventricular afterload (
      • Verma S.
      • McMurray J.J.V.
      • Cherney D.Z.I.
      The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: The search for the sweet spot in heart failure.
      ,
      • Sattar N.
      • McLaren J.
      • Kristensen S.L.
      • Preiss D.
      • McMurray J.J.
      SGLT2 Inhibition and cardiovascular events: Why did EMPA-REG Outcomes surprise and what were the likely mechanisms?.
      ). Clinical evidence for this arises from the Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes (EMPA-HEART) Cardio-Link-6 randomized trial (
      • Verma S.
      • Mazer C.D.
      • Yan A.T.
      • et al.
      Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: The EMPA-HEART CardioLink-6 randomized clinical trial.
      ). In this study, 97 individuals with T2DM and coronary artery disease were randomized to empagliflozin (10 mg/d, n=49) or placebo (n=48) for 6 months. The primary outcome was the 6-month change in left ventricular mass index (LVMi) to body surface area from baseline as measured by cardiac magnetic resonance imaging. Mean LVMi regression over 6 months was 2.6 g/m2 and 0.01 g/m2 for those assigned empagliflozin and placebo, respectively (adjusted difference, −3.35 g/m2; 95% CI, −5.9 to −0.81 g/m2; p=0.01). In patients randomized to empagliflozin, there was also a significant lowering of overall ambulatory systolic blood pressure (adjusted difference, −6.8 mmHg; 95% CI, −11.2 to −2.3 mmHg; p=0.003) and diastolic blood pressure (adjusted difference, −3.2 mmHg; 95% CI, −5.8 to −0.6 mmHg; p=0.02), and an elevation of hematocrit (p=0.0003). This was the first randomized controlled trial that demonstrated a reduction in LVMi associated with an SGLT-2 inhibitor (
      • Verma S.
      • Mazer C.D.
      • Yan A.T.
      • et al.
      Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: The EMPA-HEART CardioLink-6 randomized clinical trial.
      ). These results highlight that the clinical benefit seen by empagliflozin may be in part because of a reduction in LVMi.
      The mechanisms whereby this reduction in LVMi occurs may be multifold. SGLT-2 inhibition in the proximal tubule results in natriuresis and glucosuria, with a resulting osmotic diuresis. This may be favourable in preventing HF development in patients at risk (i.e. all patients with T2DM) and those with both diastolic or systolic cardiac dysfunction. SGLT-2 inhibitors and the resulting natriuresis induce afferent arteriolar vasoconstriction with resultant reductions in intraglomerular hypertension, which may account for the initial drop in the estimated glomerular filtration rate observed in patients. This is followed by a plateau over time, even among patients with HF (
      • Butler J.
      • Zannad F.
      • Fitchett D.
      • et al.
      Empagliflozin improves kidney outcomes in patients with or without heart failure.
      ). Similar mechanisms are seen with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
      A mediation analyses from EMPA-REG OUTCOME demonstrated that a hematocrit increase, as reflective of increased hemoconcentration, is a key feature contributing to the HF benefit seen in the trial (
      • Inzucchi S.E.
      • Zinman B.
      • Fitchett D.
      • et al.
      How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial.
      ). This is further explored in a study where dapagliflozin reduced total tissue sodium content in people with T2DM; furthermore, because people with diabetes are known to have an increase in whole-body sodium content, this may account for the prevention of HF as seen in the CVOTs of SGLT-2 inhibitors (
      • Karg M.V.
      • Bosch A.
      • Kannenkeril D.
      • et al.
      SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: A randomised controlled trial.
      ). The ability to selectively reduce interstitial fluid may be a unique feature of SGLT-2 inhibitors vs other diuretics, which limits neurohumoral reflexive stimulation that occurs with intravascular volume contraction associated with traditional diuretics.

      Improvements in ventricular afterload with SGLT-2 inhibition

      Extending from the potential mechanisms relating to volume changes, SGLT-2 inhibitors can optimize ventricular loading conditions by reducing blood pressure and altering vascular endothelial function. Aortic vasodilation is induced by dapagliflozin in a dose-dependent manner. This may occur via activation of Kv channels and protein kinase G. This finding was independent of other K+ channels, Ca2+ channels, intracellular Ca2+ and the endothelium (
      • Li H.
      • Shin S.E.
      • Seo M.S.
      • et al.
      The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels.
      ). In 16 patients with T2DM, dapagliflozin also decreased systolic blood pressure and induced an increase in 24-h diuresis (
      • Solini A.
      • Giannini L.
      • Seghieri M.
      • et al.
      Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: A pilot study.
      ); furthermore, brachial artery flow-mediated dilation was significantly increased and pulse-wave velocity was reduced. Empagliflozin reduced central and 24-h systolic and diastolic blood pressure, central pulse pressure and forward wave amplitude in individuals with T2DM (
      • Striepe K.
      • Jumar A.
      • Ott C.
      • et al.
      Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus.
      ). Aligning with the results of the EMPA-HEART Cardio-Link-6 trial, improvements in ventricular afterload may also contribute to the improvement in LVMi and clinical CV outcomes.

      Alteration in ventricular structure through extracellular matrix remodelling

      In addition to ventricular afterload reduction and improvements in loading conditions, empagliflozin, via cardiac fibroblasts, may exert a cardioprotective effect through modulation of the extracellular matrix. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodelling in HF by regulating extracellular matrix (ECM) homeostasis. Alterations in ECM molecules have been noted in network analyses of biomarkers in patients with diabetes and acute HF (
      • Sharma A.
      • Demissei B.G.
      • Tromp J.
      • et al.
      A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure.
      ). In 11 patients undergoing open heart surgery, cardiac fibroblasts were isolated via explant culture. Empagliflozin significantly attenuated cell-mediated ECM remodelling as measured by the collagen fiber alignment index (
      • Kang S.
      • Verma S.
      • Hassenabad A.F.
      • et al.
      Direct effects of empagliflozin on extracellular matrix remodeling in human cardiac myofibroblasts: Novel translational clues to EMPA-REG OUTCOME.
      ). Empagliflozin also significantly attenuated transforming growth factor (TGF)-β1-induced fibroblast activation. Morphologic assessment showed smaller myofibroblasts with fewer extension in those that were exposed to empagliflozin. Gene expression profiling demonstrated a suppression of profibrotic markers by empagliflozin including COL1A1, ACTA2, CTGF, FN1 and MMP-2. These data provide a novel hypothesis of the mechanisms of SGLT-2 inhibitor benefit in ventricular remodelling.

      Reduction in cardiac fibrosis with SGLT-2 inhibitors

      Extending from the potential benefit on ECM remodelling, SGLT-2 inhibition may also prevent the development of cardiac fibrosis. In human cardiac fibroblasts, empagliflozin attenuates TGF-β1-induced fibroblast activation while reducing cell-mediated ECM remodelling (
      • Kang S.
      • Verma S.
      • Teng G.
      • et al.
      Abstract 15925: empagliflozin attenuates extracellular matrix remodeling by human cardiac fibroblasts: Novel translational clues to EMPA-REG OUTCOME.
      ). In addition, empagliflozin suppressed expression of type I collagen, α-smooth muscle actin, connective tissue growth factor and matrix metalloproteinase-2, which are key profibrotic markers. The post-MI setting is high risk for patients with T2DM for recurrent HF and vascular events (
      • Sharma A.
      • Cannon C.P.
      • White W.B.
      • et al.
      Early and chronic dipeptidyl-peptidase-IV inhibition and cardiovascular events in patients with type 2 diabetes mellitus after an acute coronary syndrome: A landmark analysis of the EXAMINE trial.
      ). In post-MI rat models, dapagliflozin suppressed collagen synthesis by activation of M2 macrophages and inhibiting myofibroblast differentiation, thereby resulting in cardiac antifibrotic effects (
      • Lee T.M.
      • Chang N.C.
      • Lin S.Z.
      Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.
      ). In totality, these results suggest, independent of hyperglycemia, SGLT-2 inhibition may directly impact cardiac fibroblast function, resulting in a decrease in cardiac fibrosis and subsequent development or worsening of HF.

      SGLT-2 inhibitors and sympathetic overactivity

      Another novel hypothesis of the mechanism of SGLT-2 inhibition benefit is a reduction in sympathetic overactivity (Figure 2). SGLT-2 inhibitors promote a reduction in the renal sympathetic tone to the kidneys, which produces a subsequent reduction in central nervous system sympathetic outflow to vessels and the heart (
      • Sano M.
      A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity.
      ). The result is a decrease in left ventricular afterload, decreased myocardial wall stress and improved myocardial contraction.
      Figure thumbnail gr2
      Figure 2Exploratory central nervous system mechanisms of sodium-glucose cotransporter-2 inhibitors’ benefit in preventing and treating heart failure. SNS, sympathetic nervous system; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

      Improvement in vascular progenitor cells

      Because blood vessel repair is impaired during diabetes, we recently hypothesized that the SGLT-2 inhibitor empagliflozin would increase circulating provascular progenitor cell content in people with diabetes and established coronary artery disease. In a substudy of the randomized EMPA-HEART Cardio-Link-6 trial, multiparametric flow cytometry was used to quantify circulating cells with high aldehyde dehydrogenase activity (ALDHhi), a conserved function that protects progenitor cells from oxidative stress. Although the placebo-assigned group showed equal ALDHhi cell distribution at baseline and 6 months postintervention, SGLT-2 inhibitor treatment strikingly increased circulating proangiogenic cluster of differentiation 133+ progenitor cells, decreased proinflammatory ALDHhi granulocyte precursors and increased ALDHhi monocytes with M2 polarization. This highlights a novel mechanism of SGLT-2 inhibitors to improve T2DM-associated regenerative cell depletion, which may contribute to the MACE benefit observed in clinical trials (
      • Hess D.
      • Terenzi D.C.
      • Trac J.Z.
      • et al.
      SGLT2 inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus.
      ).

      Experimental studies show benefit on HF without diabetes

      An important question is whether the mechanisms of cardioprotection are observed even in the absence of diabetes (Figure 3). In rats without diabetes, although empagliflozin did not modify molecular markers of metabolism or hypertrophy, there was a reduced left ventricular and cardiomyocyte hypertrophy and reduced wall stress, which improved markers of diastolic dysfunction (
      • Connelly K.A.
      • Zhang Y.
      • Visram A.
      • et al.
      Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction.
      ). Furthermore, empagliflozin improved indices of cardiac function in rat models with HF and without diabetes (
      • Byrne N.J.
      • Parajuli N.
      • Levasseur J.L.
      • et al.
      Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure.
      ). In a porcine model without diabetes, empagliflozin switched myocardial energy utilization from glucose toward ketone body, free-fatty acid and branched-chain amino acids, thereby improving myocardial energetics (
      • Santos-Gallego C.G.
      • Requena-Ibanez J.A.
      • San Antonio R.
      • et al.
      Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics.
      ). In a post-MI rat model without diabetes, empagliflozin resulted in an improvement in cardiac function, remodelling and ATP production (
      • Yurista S.R.
      • Silljé H.H.W.
      • Oberdorf-Maass S.U.
      • et al.
      Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction.
      ).
      Figure thumbnail gr3
      Figure 3Rationale for use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients without diabetes. HF, heart failure; HHF, hospitalization for heart failure; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

      Summary

      GLP-1 receptor agonists and SGLT-2 inhibitors have demonstrated a reduction in the risk of CV endpoints in various CVOTs. The benefits appear to emerge across levels of CV risk, and experimental models suggest this benefit occurs independent of the glucose-lowering impact of these therapies. We have reviewed the extensive number of mechanisms whereby these classes of glucose-lowering therapies can reduce the risk of CV outcomes in patients with T2DM. Key future directions are establishing the safety and efficacy of these therapies in reducing the risk of CV events in patients without T2DM, demonstrating benefit in patients with both HF and preserved and reduced ejection fractions, use of therapies in higher-risk populations (e.g. end-stage HF) and exploring potential benefit in clinically challenging populations, such as resistant hypertension. Although more studies are eventually needed, GLP-1 receptor agonists and SGLT-2 inhibitors have fundamentally changed the way T2DM will be managed to reduce the burden of morbidity and mortality.

      Addendum

      The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial demonstrated that dapagliflozin, versus placebo, reduced the risk of CV death or worsening HF in patients with chronic symptomatic HF with reduced ejection fraction (left ventricular ejection fraction of 40% or less) (
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ). The overall events were 16.3% in the dapagliflozin group and in 21.2% in the placebo group (HR 0.74; 95% CI, 0.65 to 0.85). The benefit was consistent in patients both with and without diabetes. These results suggest that the mechanism of action of SGLT-2 inhibitors are independent of the potential mitigation of glycemia-related cardiotoxicity. Dapagliflozin did not produce a meaningful decline in natriuretic peptides in a smaller mechanistic study in patients with HF with reduced ejection fraction (
      • Nassif M.E.
      • Sindsor S.L.
      • Tang F.
      • et al.
      Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: The DEFINE-HF trial.
      ) suggesting that enhanced diuresis and decongestion may not be a primary driver of the reduced risk of outcomes seen in DAPA-HF. Further research will be needed to identify the mechanisms of action of dapagliflozin and other SGLT-2 inhibitors in patients with HF and reduced ejection fraction.

      Author Disclosures

      Dr Sharma reports grants from FRSQ Junior-1 clinician scientist program, personal fees from Akcea, personal fees from PharmaSolutions, grants from Alberta Innovates Health Solutions, personal fees from Bayer-Canadian Cardiovascular Society, personal fees from Boehringer-Ingelheim, personal fees from Roche Diagnostics, personal fees from Takeda; all outside the submitted work. Dr Sharma is supported by the Fonds de la recherche en sante du Quebec (FRSQ) Junior -1 clinician scientist award. Dr Verma reports grants and personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Bayer, grants and personal fees from Boehringer-Ingelheim, grants from Bristol-Myers Squibb, personal fees from Eli Lilly, from Janssen, personal fees from Merck, personal fees from Novartis, personal fees from Novo Nordisk, personal fees from Sanofi; all outside the submitted work.

      Author Contributions

      Drs Sharma and Verma equally contributed to the writing, critical review, and revisions of the article.

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