RESUMEN
Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) worldwide. The pathogenesis of DKD is influenced by functional, histopathological, and immune mechanisms, including NLRP3 inflammasome activity and oxidative stress. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown metabolic benefits and the ability to slow the progression of DKD in several clinical studies over the years. Recent studies suggest that the antidiabetic activity also extends to inhibition of the inflammatory response, including modulation of the NLRP3 inflammasome, reduction of pro-inflammatory markers and reduction of oxidative stress. Here we review the efficacy of SGLT2i in the treatment of CKD and discuss the role of the inflammatory response in the development of DKD, including its relationship to the NLRP3 inflammasome and oxidative stress.
Asunto(s)
Nefropatías Diabéticas , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Inflamasomas/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacosRESUMEN
Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.
Asunto(s)
Compuestos de Bencidrilo , Canagliflozina , Cardiotónicos , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/uso terapéutico , Glucósidos/farmacología , Animales , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/farmacología , Humanos , Cardiotónicos/uso terapéutico , Cardiotónicos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Canagliflozina/uso terapéutico , Canagliflozina/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Evaluación Preclínica de MedicamentosRESUMEN
Type 2 diabetes mellitus (T2DM) is associated with a heightened risk of cardiovascular and renal complications. While glycemic control remains essential, newer therapeutic options, such as SGLT2 inhibitors, offer additional benefits beyond glucose reduction. This review delves into the mechanisms underlying the cardio-renal protective effects of SGLT2 inhibitors. By inducing relative hypoglycemia, these agents promote ketogenesis, optimize myocardial energy metabolism, and reduce lipotoxicity. Additionally, SGLT2 inhibitors exert renoprotective actions by enhancing renal perfusion, attenuating inflammation, and improving iron metabolism. These pleiotropic effects, including modulation of blood pressure, reduction of uric acid, and improved endothelial function, collectively contribute to the cardiovascular and renal benefits observed with SGLT2 inhibitor therapy. This review will provide clinicians with essential knowledge, understanding, and a clear recollection of this pharmacological group's mechanism of action.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Hipoglucemiantes/efectos adversos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , AnimalesRESUMEN
Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: 1) the impact on renal hemodynamics and tubuloglomerular feedback; 2) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; 3) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; 4) the impact on erythropoiesis, not only in the context of local hypoxia but also systemic inflammation and iron regulation; 5) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; 6) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance, and stimulation of lipolysis and ketogenesis; 7) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and 8) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscores the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermore, this review sets the stage for future research to evaluate the individual contributions of these mechanisms in diverse clinical settings.
Asunto(s)
Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Animales , Riñón/efectos de los fármacos , Riñón/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidoresRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC α and γ subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension.NEW & NOTEWORTHY This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least in part, for the BP-lowering effect of SGLT2 inhibitors in the setting of hypertension. It also demonstrates that chronic treatment with SGLT2 inhibitors upregulates NCC activity, phosphorylation, and expression in the distal tubule of normotensive but not hypertensive rats. SGLT2 inhibitor-mediated upregulation of NCC seems crucial to counteract proximal tubule natriuresis in subjects with normal BP.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Hipertensión , Ratas Endogámicas SHR , Ratas Wistar , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Intercambiador 3 de Sodio-Hidrógeno , Regulación hacia Arriba , Animales , Masculino , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/genética , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Glucósidos/farmacología , Compuestos de Bencidrilo/farmacología , Regulación hacia Arriba/efectos de los fármacos , Ratas , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Presión Sanguínea/efectos de los fármacos , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Riñón/metabolismo , Riñón/efectos de los fármacosRESUMEN
Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly assigned to Sham surgery, bilateral ischemia for 30 minutes (abbreviated as IR), and IR + Dapa groups. Daily treatment with Dapa was initiated just 24 hours after IR and maintained for only 10 days. Initially, rats were euthanized at this point to study early renal repair. After severe AKI, Dapa promptly restored creatinine clearance (CrCl) and significantly reduced renal vascular resistance compared with the IR group. Furthermore, Dapa effectively reversed the mitochondrial abnormalities, including increased fission, altered mitophagy, metabolic dysfunction, and proapoptotic signaling. To study this earlier, another set of rats was studied just 5 days after AKI. Despite persistent renal dysfunction, our data reveal a degree of mitochondrial protection. Remarkably, a 10-day treatment with Dapa demonstrated effectiveness in preventing CKD transition in an independent cohort monitored for 5 months after AKI. This was evidenced by improvements in proteinuria, CrCl, glomerulosclerosis, and fibrosis. Our findings underscore the potential of Dapa in preventing maladaptive repair following AKI, emphasizing the crucial role of early intervention in mitigating AKI long-term consequences.
Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Animales , Humanos , Masculino , Ratas , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Glucosa , Ratas Wistar , Insuficiencia Renal Crónica/tratamiento farmacológico , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , Sodio/metabolismo , Transportador 2 de Sodio-Glucosa/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéuticoRESUMEN
In metabolic syndrome and diabetes, compromised mitochondrial function emerges as a critical driver of cardiovascular disease, fueling its development and persistence, culminating in cardiac remodeling and adverse events. In this context, angiotensin II - the main interlocutor of the renin-angiotensin-aldosterone system - promotes local and systemic oxidative inflammatory processes. To highlight, the low activity/expression of proteins called sirtuins negatively participates in these processes, allowing more significant oxidative imbalance, which impacts cellular and tissue responses, causing tissue damage, inflammation, and cardiac and vascular remodeling. The reduction in energy production of mitochondria has been widely described as a significant element in all types of metabolic disorders. Additionally, high sirtuin levels and AMPK signaling stimulate hypoxia- inducible factor 1 beta and promote ketonemia. Consequently, enhanced autophagy and mitophagy advance through cardiac cells, sweeping away debris and silencing the orchestra of oxidative stress and inflammation, ultimately protecting vulnerable tissue from damage. To highlight and of particular interest, SGLT2 inhibitors (SGLT2i) profoundly influence all these mechanisms. Randomized clinical trials have evidenced a compelling picture of SGLT2i emerging as game-changers, wielding their power to demonstrably improve cardiac function and slash the rates of cardiovascular and renal events. Furthermore, driven by recent evidence, SGLT2i emerge as cellular supermolecules, exerting their beneficial actions to increase mitochondrial efficiency, alleviate oxidative stress, and curb severe inflammation. Its actions strengthen tissues and create a resilient defense against disease. In conclusion, like a treasure chest brimming with untold riches, the influence of SGLT2i on mitochondrial function holds untold potential for cardiovascular health. Unlocking these secrets, like a map guiding adventurers to hidden riches, promises to pave the way for even more potent therapeutic strategies.
Asunto(s)
Mitocondrias , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & controlRESUMEN
The antidiabetic agent class of sodium-glucose cotransporter 2 (SGLT2) inhibitors confer unprecedented cardiovascular benefits beyond glycemic control, including reducing the risk of fatal ventricular arrhythmias. However, the impact of SGLT2 inhibitors on the electrophysiological properties of cardiomyocytes exposed to stimuli other than hyperglycemia remains elusive. This investigation tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) affects cardiomyocyte electrical activity under hypoxic conditions. Rat neonatal and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes incubated or not with the hypoxia-mimetic agent CoCl2 were treated with EMPA (1 µM) or vehicle for 24 h. Action potential records obtained using intracellular microelectrodes demonstrated that EMPA reduced the action potential duration at 30%, 50%, and 90% repolarization and arrhythmogenic events in rat and human cardiomyocytes under normoxia and hypoxia. Analysis of Ca2+ transients using Fura-2-AM and contractility kinetics showed that EMPA increased Ca2+ transient amplitude and decreased the half-time to recover Ca2+ transients and relaxation time in rat neonatal cardiomyocytes. We also observed that the combination of EMPA with the Na+/H+ exchanger isoform 1 (NHE1) inhibitor cariporide (10 µM) exerted a more pronounced effect on Ca2+ transients and contractility than either EMPA or cariporide alone. Besides, EMPA, but not cariporide, increased phospholamban phosphorylation at serine 16. Collectively, our data reveal that EMPA reduces arrhythmogenic events, decreases the action potential duration in rat neonatal and human cardiomyocytes under normoxic or hypoxic conditions, and improves cytosolic calcium handling at least partially independent of NHE1. Moreover, we provided further evidence that SGLT2 inhibitor-mediated cardioprotection may be partly attributed to its cardiomyocyte electrophysiological effects.
Asunto(s)
Compuestos de Bencidrilo , Calcio , Células Madre Pluripotentes Inducidas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Humanos , Ratas , Arritmias Cardíacas , Compuestos de Bencidrilo/farmacología , Calcio/metabolismo , Miocitos Cardíacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
BACKGROUND: We sought to compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for acute heart failure (AHF) with or without the addition of SGLT2i. METHODS AND RESULTS: Systematic search of three electronic databases identified nine eligible randomized controlled trials involving 2,824 patients. The addition of SGLT2i to conventional therapy for AHF reduced all-cause death (odds ratio [OR] 0.75; 95% CI 0.56-0.99; p = 0.049), readmissions for heart failure (HF) (OR 0.54; 95% CI 0.44-0.66; p < 0.001), and the composite of cardiovascular death and readmissions for HF (hazard ratio 0.71; 95% CI 0.60-0.84; p < 0.001). Furthermore, SGLT2i increased mean daily urinary output in liters (mean difference [MD] 0.45; 95% CI 0.03-0.87; p = 0.035) and decreased mean daily doses of loop diuretics in mg of furosemide equivalent (MD -34.90; 95% CI [- 52.58, - 17.21]; p < 0.001) without increasing the incidence worsening renal function (OR 0.75; 95% CI 0.43-1.29; p = 0.290). CONCLUSION: SGLT2i addition to conventional diuretic therapy reduced all-cause death, readmissions for HF, and the composite of cardiovascular death or readmissions for HF. Moreover, SGLT2i was associated with a higher volume of diuresis with a lower dose of loop diuretics.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diuréticos/efectos adversos , Diuréticos/farmacología , Diuréticos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Riñón/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
Heart failure (HF) is a global health problem. There is a strong association h between HF and type 2 diabetes mellitus (DM2), with an increasing prevalence of patients having both conditions concomitantly. Sodium-glucose cotransporter 2 inhibitors (ISGLT2) significantly reduce cardiovascular events, including cardiovascular death. In this article we will focus on the current evidence about the effectiveness of these medications in adults with heart failure with reduced or preserved ejection fraction.
Asunto(s)
Humanos , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Sodio/metabolismo , Volumen Sistólico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , GlucosaRESUMEN
La insuficiencia cardíaca (IC) es un problema de salud mundial. En la actualidad existe una clara asociación entre la IC y la diabetes mellitus tipo 2 (DM2), con una prevalencia cada vez mayor de pacientes que presentan concomitantemente ambas patologías. Los inhibidores del cotransportador 2 de sodio-glucosa (ISGLT2) han demostrado disminuir los eventos cardiovasculares, incluida la muerte de origen cardiovascular, por lo que se han instalado como uno de los pilares en su tratamiento. En el presente artículo se describen los principales mecanismos de acción de los ISGLT2 y sus efectos: mejora de condiciones de carga ventricular, metabolismo cardíaco, bioenergética, remodelado ventricular y sus efectos cardioprotectores directos y posiblemente antiarrítmicos.
Heart failure (HF) is a global health problem. Currently there is a clear association between HF and type 2 diabetes mellitus (DM2), with an increasing prevalence of patients presenting with both pathologies concomitantly. Sodium-glucose cotransporter 2 inhibitors (ISGLT2) have shown to significantly reduce cardiovascular events, including cardiovascular death. These results have placed ISGLT2 as one of the main pillars in the treatment of HF. This article will focus on the mechanisms of action, and their effects: improved ventricular loading conditions, cardiac metabolism, bioenergetics, ventricular remodeling, direct cardioprotective and possibly antiarrhythmic effects.
Asunto(s)
Humanos , Cardiotónicos/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Cardiotónicos/farmacología , Remodelación Ventricular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
Random-walk models are frequently used to model distinct natural phenomena such as diffusion processes, stock-market fluctuations, and biological systems. Here, we present a random-walk model to describe the dynamics of glucose uptake by the sodium-glucose transporter of type 2, SGLT2. Our starting point is the canonical alternating-access model, which suggests the existence of six states for the transport cycle. We propose the inclusion of two new states to this canonical model. The first state is added to implement the recent discovery that the Na+ion can exit before the sugar is released into the proximal tubule epithelial cells. The resulting model is a seven-state mechanism with stochastic steps. Then we determined the transition probabilities between these seven states and used them to write a set of master equations to describe the time evolution of the system. We showed that our model converges to the expected equilibrium configuration and that the binding of Na+and glucose to SGLT2 in the inward-facing conformation must be necessarily unordered. After that, we added another state to implement inhibition in the model. Our results reproduce the experimental dependence of glucose uptake on the inhibitor concentration and they reveal that the inhibitors act by decreasing the number of available SGLT2s, which increases the chances of glucose escaping reabsorption.
Asunto(s)
Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa , Sodio/metabolismo , Proteínas de Transporte de Sodio-Glucosa , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
Heart failure (HF) is a global health problem. There is a strong association h between HF and type 2 diabetes mellitus (DM2), with an increasing prevalence of patients having both conditions concomitantly. Sodium-glucose cotransporter 2 inhibitors (ISGLT2) significantly reduce cardiovascular events, including cardiovascular death. In this article we will focus on the current evidence about the effectiveness of these medications in adults with heart failure with reduced or preserved ejection fraction.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Adulto , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa , Insuficiencia Cardíaca/tratamiento farmacológico , Sodio/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Volumen SistólicoRESUMEN
SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.
RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.
Asunto(s)
Animales , Masculino , Ratas , Canagliflozina/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Ratas Wistar , NG-Nitroarginina Metil ÉsterRESUMEN
La diabetes mellitus, la insuficiencia cardíaca y la enfermedad renal crónica tienen alta prevalencia en la población. Asimismo, estas patologías están comprendidas en un "círculo vicioso" porque comparten mecanismos fisiopatológicos que predisponen a su coexistencia en un mismo paciente, incrementando significativamente el riesgo de eventos cardiovasculares. Recientemente se han agregado al arsenal terapéutico las gliflozinas, un grupo de fármacos con beneficios en las tres enfermedades mencionadas. Saber cómo se desarrolló la investigación con estos fármacos y sus mecanismos de acción es fundamental para optimizar el tratamiento de los pacientes.
Diabetes mellitus, heart failure, and chronic kidney disease are highly prevalent in the population. Likewise, these pathologies are included in a "vicious circle" because they share pathophysiological mechanisms that predispose to their coexistence in the same patient, significantly increasing the risk of cardiovascular events. Gliflozins, a group of drugs with benefits in the three mentioned pathologies, have recently been added to the therapeutic arsenal. Knowing how research with these drugs and its mechanisms of action is essential to optimize the treatment of patients.
Diabetes mellitus, insuficiência cardíaca e doença renal crônica são altamente prevalentes na população. Estas patologias fazem parte de um "círculo vicioso", compartilhando mecanismos fisiopatológicos que predispõem à coexistência no mesmo paciente, e aumentando significativamente o risco de eventos cardiovasculares. As gliflozinas, são un grupo de drogas com benefícios das três patologias citadas, foram adicionadas recentemente ao arsenal terapêutico. Saber como foram desenvolvidas as pesquisas com esses medicamentos e seus mecanismos de ação é essencial para otimizar o tratamento dos pacientes.
Asunto(s)
Humanos , Diabetes Mellitus/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Hipoglucemiantes/farmacología , Resultado del TratamientoRESUMEN
In this report, we aim to provide an updated meta-analysis of the sodium-glucose cotransporter 2 (SGLT2) inhibitors trial data with the new trial data on sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor. We searched Medline, Cochrane library, and Embase databases for randomized clinical trials comparing cardiovascular and kidney outcomes between SGLT2 and dual SGLT1/2 inhibitors and placebo. Nine randomized clinical trials with a total of 60,914 patients with type 2 diabetes were included. In patients with type 2 diabetes, the use of SGLT2 and dual SGLT1/2 inhibitors improves the cardiovascular and kidney outcome.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicósidos/farmacología , Riñón/efectos de los fármacos , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Compuestos de Bencidrilo/farmacología , Causas de Muerte , Tasa de Filtración Glomerular/efectos de los fármacos , Glucósidos/farmacología , Hospitalización , Humanos , Enfermedades Renales/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Type 2 diabetes mellitus (DM2) is a chronic condition that affects more than 400 million individuals worldwide. In DM2 patients, an appropriate glycemic control slows the onset and delays the progression of all its micro and macrovascular complications. Even though there are several glucose-lowering drugs, only approximately half of patients achieve glycemic control, while undesirable adverse effects (e.g., low serum glucose) normally affect treatment. Therefore, there is a need for new types of treatments. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have just been developed for treating DM2. Renal hyperfiltration as a marker of increased intraglomerular pressure in diabetic patients, and the role of renin-angiotensin-aldosterone system (RAAS) in this phenomenon have been studied. Nevertheless, RAAS blockade does not completely reduce hyperfiltration or diabetic renal damage. In this sense, the contribution of renal tubular factors to the hyperfiltration state, including sodium-glucose cotransporter (SGLT), has been currently studied. SGLT2i reduce proximal tubular sodium reabsorption, therefore increasing distal sodium delivery to the macula densa, causing tubule-glomerular feedback activation, afferent vasoconstriction, and reduced hyperfiltration in animal models. In humans, SGLT2i was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients suffering from type 1 diabetes mellitus. In DM2 clinical trials, SGLT2 is associated with significant hyperfiltration and albuminuria reduction. The aim of this article is to compile the information regarding SGLT2i drugs, emphasizing its mechanism of renal repercussion.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Riñón/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Humanos , Riñón/fisiopatologíaRESUMEN
Previous studies have suggested that sodium-glucose co-transporter-2 (SGLT2) inhibitors may improve hepatic function; however, the evidence is scarce. Hence, we performed a meta-analysis of randomized controlled trials to evaluate the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on hepatic parameters. PubMed, Web of Science, Scopus, and Google Scholar databases were searched to identify randomized controlled trials examining the effect of SGLT2 inhibitors on hepatic parameters. Meta-analysis was performed using a random-effects model and sensitivity analysis. Meta-analysis revealed that SGLT2 inhibitors therapy significantly lowered alanine aminotransferase (ALT) (WMD: -4.79 U/L, 95 % CI: -6.10, -3.47, I2 = 62 %, p < 0.00001), aspartate aminotransferase (AST) (WMD: -2.49 U/L, 95 % CI: -3.30, -1.68, I2 = 54 %, p < 0.00001), alkaline phosphatase (AP) (WMD: -1.13 U/L, 95 % CI: -2.03, -0.22, I2 = 23 %, p = 0.02), and gamma-glutamyl transferase (GGT) (WMD: -7.77 U/L, 95 % CI: -9.33, -6.21, I2 = 5 %, p < 0.00001). Additionally, SGLT2 inhibitors showed a significant increase in bilirubin levels (WMD: 0.64 U/L, 95 % CI: 0.27, 1.00, I2 = 53 %, p < 0.0006. Finally, no significant changes were found on albumin levels (WMD: 0.13 U/L, 95 % CI: -0.06, 0.32, I2 = 53 %, p < 0.0006) after SGLT2 inhibitors treatment. In conclusion, our results suggest that treatment with SGLT2 inhibitors exerts a beneficial effect on liver function tests through decreased ALT, AST, AP, and GGT concentrations.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Hígado/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Aspartato Aminotransferasas/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hígado/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , gamma-Glutamiltransferasa/sangreRESUMEN
Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Enfermedades Renales/prevención & control , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/farmacología , Compuestos de Bencidrilo/uso terapéutico , Canagliflozina/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/prevención & control , Tasa de Filtración Glomerular , Glucosa/metabolismo , Glucósidos/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Transportador 2 de Sodio-Glucosa/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins, improve glycemia by suppressing glucose reuptake in the renal proximal tubule. Currently, SGLT2 inhibitors are primarily indicated as antidiabetic agents; however, their benefits extend far beyond glucose control. Cardiovascular outcome trials indicated that all studied SGLT2 inhibitors remarkably and consistently reduce cardiovascular mortality and hospitalization for heart failure (HF) in type 2 diabetes (T2D) patients. Nevertheless, the mechanisms underlying the unprecedented cardiovascular benefits of gliflozins remain elusive. Multiple processes that directly or indirectly improve myocardial performance may be involved, including the amelioration of proximal tubular dysfunction. Therefore, this paper provides a perspective on the potential cellular and molecular mechanisms of the proximal tubule that may, at least in part, mediate the cardioprotection conferred by SGLT2 inhibitors. Specifically, we focus on the effects of SGLT2 on extracellular volume homeostasis, including its plausible functional and physical association with the apical Na+/H+ exchanger isoform 3 as well as its complex and its possible bidirectional interactions with the intrarenal angiotensin system and renal sympathetic nervous system. We also discuss evidence supporting a potential benefit of gliflozins in reducing cardiovascular risk, attributable to their effect on proximal tubule handling of uric acid and albumin as well as in erythropoietin production. Unraveling the mechanisms behind the beneficial actions of SGLT2 inhibitors may not only contribute to a better understanding of the pathophysiology of cardiovascular diseases but also enable repurposing of gliflozins to improve the routine management of HF patients with or without T2D.