Renal and Cardiovascular Metabolic Impact Caused by Ketogenesis of the SGLT2 Inhibitors.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are glycosuric drugs that were originally developed for the treatment of type 2 diabetes mellitus (T2DM). There is a hypothesis that SGLT2i are drugs that are capable of increasing ketone bodies and free fatty acids. The idea is that they could serve as the necessary fuel, instead of glucose, for the purposes of cardiac muscle requirements and could explain antihypertensive effects, which are independent of renal function. The adult heart, under normal conditions, consumes around 60% to 90% of the cardiac energy that is derived from the oxidation of free fatty acids. In addition, a small proportion also comes from other available substrates. In order to meet energy demands with respect to achieving adequate cardiac function, the heart is known to possess metabolic flexibility. This allows it to switch between different available substrates in order to obtain the energy molecule adenosine triphosphate (ATP), thereby rendering it highly adaptive. It must be noted that oxidative phosphorylation in aerobic organisms is the main source of ATP, which is a result of reduced cofactors. These cofactors include nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are the result of electron transfer and are used as the enzymatic cofactors that are involved in the respiratory chain. When there is an excessive increase in energy nutrients-such as glucose and fatty acids-which occur in the absence of a parallel increase in demand, a state of nutrient surplus (which is better known as an excess in supply) is created. The use of SGLT2i at the renal level has also been shown to generate beneficial metabolic alterations, which are obtained by reducing the glucotoxicity that is induced by glycosuria. Together with the reduction in perivisceral fat in various organs, such alterations also lead to the use of free fatty acids in the initial stages of the affected heart. Subsequently, this results in an increase in production with respect to ketoacids, which are a more available energy fuel at the cellular level. In addition, even though their mechanism is not fully understood, their vast benefits render them of incredible importance for the purposes of further research.

Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study.

OBJECTIVES: The goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: Several randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined. METHODS: This study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T1 mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences. RESULTS: Empagliflozin is associated with significant reductions in EAT volume (-5.14 mL; 95% CI: -8.36 to -1.92) compared with placebo (-0.75 mL; 95% CI: -3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (-5.33 cm2 [95% CI: -12.61 to 1.95] vs 9.13 cm2 [95% CI: -2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (-1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (-7.24 mL [95% CI: -11.59 to -2.91] vs 0.70 mL [95% CI: -0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (-11.08 mL [95% CI: -19.62 to -2.55] vs 0.80 mL [95% CI: -1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (-0.58 cm/s [95% CI: -0.92 to -0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers. CONCLUSIONS: Empagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222).

¿Son los inhibidores del receptor SGLT2 fármacos antidiabéticos o cardiovasculares? / Are the antidiabetic SGLT2 inhibitors a cardiovascular treatment?

Los inhibidores del cotransportador de sodio-glucosa tipo 2 (iSGLT2) fueron incialmente desarrollados para el tratamiento de la diabetes por su actividad hipoglucemiante. Sin embargo, a la luz de los estudios clínicos más recientes, están revolucionando el abordaje de la enfermedad cardiovascular (CV) en el paciente diabético. En el año 2015, el ensayo clínico EMPA-REG OUTCOME nos demuestra por primera vez que la empagliflozina -un fármaco considerado «antidiabético»- reduce la mortalidad CV y por cualquier causa, además de eventos CV mayores, hospitalización por IC y progresión de enfermedad renal. Posteriormente, otros estudios clínicos con agentes del mismo grupo farmacológico, CANVAS, con canagliflozina y DECLARE-TIMI-58 con dapagliflozina, corroboran la exitencia de los beneficios CV asociados a la inhibición del receptor SGLT2. Los beneficios observados los sitúan más allá de simples agentes hipoglucemiantes, con un demostrado efecto cardionefroprotector en la enfermedad aterosclerótica, insuficiencia cardiaca, mortalidad total, mortalidad cardiovascular y progresión de insuficiencia renal. Actualmente ya son una realidad en pacientes diabéticos de alto y muy alto riesgo cardiovascular, mientras su evidencia en el paciente no diabético es cada vez mayor. Asistimos, por tanto, a un cambio de paradigma y posiblemente al nacimiento de una nueva especialidad, la cardio-endocrinología, con la implicación de nuevos tratamientos que deben ser considerados más que sólo fármacos antidiabéticos

The sodium-glucose co-transporter 2 inhibitors (SGLT2i) were first conceived to treat type 2 diabetes due to their hypoglycaemic effect. However, due to an increasing number of studies, SGLT2i are changing the way we treat, and understand, diabetes, and cardiovascular risk, in general. The EMPA-REG OUTCOME clinical trial, in 2015, showed for the first time that empagliflozine - a glucose lowering agent - lowers the risk of death from cardiovascular causes and death from any cause. Also, this SGLT2i lowered hospital admission for heart failure and delayed renal function worsening. From then on, other clinical trials with SGLT2i such as CANVAS (canagliflozin) and DECLARE-TIMI-58 (dapagliflozin) confirmed these positive effects. With a proven and non-related glucose-lowering effect on heart failure, overall death, cardiovascular death, and renal function, SGLT2i stands out among the rest of anti-diabetic drugs. Since its role in treating patients with heart failure and type 2 diabetes has been undoubtedly established, new studies are paving the way for non-diabetic patients as well. A potential paradigm shift is being witnessed and, probably, the dawn of a new field, cardio-endocrinology, which involves new and far-reaching pharmacological agents

Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia. OBJECTIVES: The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients. METHODS: In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life. RESULTS: Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. -0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. -145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. -35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001). CONCLUSIONS: Empagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Empagliflozin Ameliorates Diastolic Dysfunction and Left Ventricular Fibrosis/Stiffness in Nondiabetic Heart Failure: A Multimodality Study.

OBJECTIVES: The purpose of this study was to investigate the effect of empagliflozin on diastolic function in a nondiabetic heart failure with reduced ejection fraction (HFrEF) scenario and on the pathways causing diastolic dysfunction. BACKGROUND: This group demonstrated that empagliflozin ameliorates adverse cardiac remodeling, enhances myocardial energetics, and improves left ventricular systolic function in a nondiabetic porcine model of HF. Whether empagliflozin also improves diastolic function remains unknown. Hypothetically, empagliflozin would improve diastolic function in HF mediated both by a reduction in interstitial myocardial fibrosis and an improvement in cardiomyocyte stiffness (titin phosphorylation). METHODS: HF was induced in nondiabetic pigs by 2-h balloon occlusion of proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Cardiac function was evaluated with cardiac magnetic resonance (CMR), 3-dimensional echocardiography, and invasive hemodynamics. In vitro relaxation of cardiomyocytes was studied in primary culture. Myocardial samples were obtained for histological and molecular evaluation. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. RESULTS: Despite similar initial ischemic myocardial injury, the empagliflozin group showed significantly improved diastolic function at 2 months, assessed by conventional echocardiography (higher e' and color M-mode propagation velocity, lower E/e' ratio, myocardial performance Tei index, isovolumic relaxation time, and left atrial size), echocardiography-derived strain imaging (strain imaging diastolic index, strain rate at isovolumic relaxation time and during early diastole, and untwisting), and CMR (higher peak filling rate, larger first filling volume). Invasive hemodynamics confirmed improved diastolic function with empagliflozin (better peak LV pressure rate of decay (-dP/dt), shorter Tau, lower end-diastolic pressure-volume relationship (EDPVR), and reduced filling pressures). Empagliflozin reduced interstitial myocardial fibrosis at the imaging, histological and molecular level. Empagliflozin improved nitric oxide signaling (endothelial nitric oxide synthetase [eNOS] activity, nitric oxide [NO] availability, cyclic guanosine monophosphate (cGMP) content, protein kinase G [PKG] signaling) and enhanced titin phosphorylation (which is responsible for cardiomyocyte stiffness). Indeed, isolated cardiomyocytes exhibited better relaxation in empagliflozin-treated animals. Myocardial consumption of glucose and ketone bodies negatively and positively correlated with diastolic function, respectively. CONCLUSIONS: Empagliflozin ameliorates diastolic function in a nondiabetic HF porcine model, mitigates histological and molecular remodeling, and reduces both left ventricle and cardiomyocyte stiffness.

Correlation between myocardial strain and adverse remodeling in a non-diabetic model of heart failure following empagliflozin therapy.

OBJECTIVES: The sodium-glucose cotransporter type 2 inhibitors reduce mortality and heart failure (HF) hospitalizations. The underlying mechanisms remain unclear but seem to be irrespective of glucose-lowering properties. This study aims to evaluate the impact of empagliflozin on myocardial biomechanics and correlation with markers of adverse remodeling. METHODS: Following myocardial infarct induction to create a model of HF, 14 pigs were randomly assigned in a 1:1 ratio to receive either empagliflozin 10 mg daily or placebo for 2 months. Speckle-tracking echocardiography (STE) and feature-tracking cardiac magnetic resonance (FTCMR) were performed at baseline and at the end of the study to analyze myocardial deformation. The results were correlated with markers of adverse cardiac remodeling. RESULTS: Empagliflozin significantly improved STE indices. These parameters significantly correlated with adverse cardiac remodeling. In contrast, FTCMR indices showed only a trend toward improved myocardial deformation and without significant correlation with adverse cardiac remodeling. The correlation between both techniques to assess myocardial deformation was low. CONCLUSION: Empagliflozin enhances myocardial deformation, assessed by STE techniques, in a non-diabetic porcine model of ischemic HF. This may be related to a mitigation of adverse cardiac remodeling following ischemia reperfusion injury. In contrast, FTCMR technique needs further development and validation.

Direct Oral Anticoagulants and Coronary Artery Disease: The Debacle of the Aspirin Era?

Long-standing aspirin is the cornerstone to prevent recurrence of thrombotic events in patients with ischemic heart disease. However, clopidogrel, a more potent antiplatelet agent, is preferred over aspirin in targeted populations, including those with a high risk of gastrointestinal bleeding. In addition, clopidogrel offers superior oral tolerance, and it may reduce the rates of intracranial hemorrhages compared with aspirin. However, an extensive inhibition of the coagulation cascade seems to be reasonable to minimize thrombotic events in such patients. After several failed exploratory investigations in the past with vitamin K antagonists, the newest direct oral anticoagulants may represent an alternative. To counterbalance bleeding complications, a low dose of these agents should be considered. Few publications have already showed promising results with the combination of clopidogrel and low-dose direct oral anticoagulants. Further investigations should be addressed to elucidate whether this is the downfall of the aspirin era for secondary prevention of atherosclerotic cardiovascular events.

Are the antidiabetic SGLT2 inhibitors a cardiovascular treatment? / ¿Son los inhibidores del receptor SGLT2 fármacos antidiabéticos o cardiovasculares?

The sodium-glucose co-transporter 2 inhibitors (SGLT2i) were first conceived to treat type 2 diabetes due to their hypoglycaemic effect. However, due to an increasing number of studies, SGLT2i are changing the way we treat, and understand, diabetes, and cardiovascular risk, in general. The EMPA-REG OUTCOME clinical trial, in 2015, showed for the first time that empagliflozine - a glucose lowering agent - lowers the risk of death from cardiovascular causes and death from any cause. Also, this SGLT2i lowered hospital admission for heart failure and delayed renal function worsening. From then on, other clinical trials with SGLT2i such as CANVAS (canagliflozin) and DECLARE-TIMI-58 (dapagliflozin) confirmed these positive effects. With a proven and non-related glucose-lowering effect on heart failure, overall death, cardiovascular death, and renal function, SGLT2i stands out among the rest of anti-diabetic drugs. Since its role in treating patients with heart failure and type 2 diabetes has been undoubtedly established, new studies are paving the way for non-diabetic patients as well. A potential paradigm shift is being witnessed and, probably, the dawn of a new field, cardio-endocrinology, which involves new and far-reaching pharmacological agents.

Inhibition of Sodium Glucose Cotransporters Improves Cardiac Performance.

The sodium-glucose cotransporter (SGLT) inhibitors represent a new alternative for treating patients with diabetes mellitus. They act primarily by inhibiting glucose reabsorption in the renal tubule and therefore, decreasing blood glucose levels. While little is yet known about SGLT subtype 1, SGLT2 inhibitors have demonstrated to significantly reduce cardiovascular mortality and heart failure hospitalizations. This cardioprotective benefit seems to be independent of their glucose-lowering properties; however, the underlying mechanism(s) remains still unclear and numerous hypotheses have been postulated to date. Moreover, preclinical research has suggested an important role of SGLT1 receptors on myocardial ischemia. Following acute phase of cardiac injury there is an increased activity of SGLT1 cotransport that ensures adequate energy supply to the cardiac cells. Nonetheless, a long-term upregulation of this receptor may not be that beneficial and whether its inhibition is positive or not should be further addressed. This review aims to present the most cutting-edge insights into SGLT receptors.