Los inhibidores SGLT2: una mirada al futuro del tratamiento de la insuficiencia cardiaca / Sodium-glucose cotransporter 2 inhibitors for the management of heart failure

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.

Evidencia molecular y clínica del beneficio cardiovascular de los inhibidores SGLT2: estado del arte / Molecular and clinical evidence of the cardiovascular benefit of SGLT2 inhibitors: State of the art / Evidência molecular e clínica do benefício cardiovascular dos inibidores de SGLT2: estado da arte

La diabetes mellitus (dm) es una enfermedad crónica con alta incidencia y prevalencia. La enfermedad es un problema de salud pública que ha impulsado a la continua búsqueda de medidas tanto farmacológicas como no farmacológicas para el control. Gracias a la actual evidencia, se sabe que la dm, además de los niveles elevados de glucosa en sangre, se acompaña de otros problemas metabólicos como lo son la obesidad, alteraciones en el metabolismo de lípidos, entre otros; sumado a lo anterior, los pacientes tienen riesgo de padecer problemas cardiovasculares. El problema radica en que una gran cantidad de pacientes con riesgo cardiovascular (CV) o patología cardiovascular ya establecida, sufren de diabetes mellitus. La relación entre dm y las patologías cardiovasculares es de suma importancia, ya que cada una incrementa el riesgo de padecer la otra y empeora el pronóstico. Entre 1980 y 1990 se identificó el cotransportador de sodio y glucosa tipo 2 (SGLT2) como blanco para el tratamiento de la dm tipo 2. A partir de este hallazgo, se crearon los inhibidores de SGLT2 (i- SGLT2), grupo novedoso de medicamentos que disminuyen los niveles de glucosa. Además, tienen múltiples efectos tanto micro como macrovasculares (empagliflozina, canagliflozina y dapagliflozina). Por lo cual, haremos una revisión sobre la evidencia para los iSGLT2 como tratamiento de la insuficiencia cardiaca crónica y su impacto positivo sobre el sistema renal, reducción de presión arterial, disminución de peso, entre otros beneficios.

Diabetes mellitus (dm) is a chronic disease with high incidence and prevalence. The disease is a public health problem that has prompted the continuous search for both pharmacological and non-pharmacological control measures. Thanks to current evidence, it is known that dm, in addition to high blood glucose levels, is accompanied by other metabolic problems such as obesity, alterations in lipid metabolism, among others, and patients are also at risk of suffering from cardiovascular problems. The problema is that a large number of patients with cardiovascular (CV) risk or already established cardiovascular pathology suffer from diabetes mellitus. The relationship between dm and cardiovascular pathologies is extremely important, since each one increases the risk of suffering from the other and worsens the prognosis. Between 1980 and 1990, the sodium-glucose cotransporter 2 (SGLT2) was identified as a target for the treatment of type 2 dm. Based on this finding, SGLT2 inhibitors (i-SGLT2) were created, a novel group of medications that lower glucose levels. In addition, they have multiple effects, both micro and macrovascular (empagliflozin, canagliflozin and dapagliflozin). Therefore, we will review the evidence for iSGLT2 as a treatment for chronic heart failure and its positive impact on the renal system, blood pressure reduction, weight loss, among other benefits.

O diabetes mellitus (dm) é uma doença crônica com alta incidência e prevalência. A doença é um problema de saúde pública que tem motivado a busca contínua por medidas de controle farmacológico e não farmacológico. Graças às evidências atuais, sabe-se que o dm, além dos níveis elevados de glicose no sangue, é acompanhado por outros problemas metabólicos como obesidade, alterações no metabolismo lipídico, entre outros; Além do exposto, os pacientes estão em risco de problemas cardiovasculares. O problema é que um grande número de pacientes com risco cardiovascular (CV) ou patologia cardiovascular já estabelecida sofre de diabetes mellitus. A relação entre dm e patologias cardiovasculares é de extrema importância, pois cada uma aumenta o risco de sofrer uma da outra e piora o prognóstico. Entre 1980 e 1990, o co-transportador sódio-glicose 2 (SGLT2) foi identificado como alvo para o tratamento do dm tipo 2. Com base nessa descoberta, foram criados os inibidores de SGLT2 (i-SGLT2), um novo grupo de drogas que reduzem a glicose níveis. Além disso, eles têm múltiplos efeitos micro e macrovasculares(empagliflozina, canagliflozina e dapagliflozina). Portanto, re-visaremos as evidências do iSGLT2 como tratamento para insuficiência cardíaca crônica e seu impacto positivo no sistema renal, redução da pressão arterial, perda de peso, entre outros benefícios.

Revisão sobre o uso de inibidores de cotransportador sódio-glicose 2 e agonistas de peptídeo 1 em pessoas com diabetes mellitus tipo 2 e doença cardiovascular / Review on the use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists in people with type 2 diabetes mellitus and cardiovascular disease / Revisión sobre el uso de inhibidores del cotransportador de sodio-glucosa 2 y agonistas de péptido 1 similar al glucagón en personas con diabetes mellitus tipo 2 y enfermedad cardiovascular

Introdução: Introdução: Diabetes mellitus tipo 2 é um importante e crescente problema de saúde para todos os países. Objetivo: Este trabalho visa avaliar a qualidade da evidência disponível sobre os fármacos inibidores de sódio-glicose 2 e agonistas de glucagon 1 em pessoas com diabetes mellitus e doença cardiovascular aterosclerótica Métodos: Realizou-se revisão integrativa utilizando as bases de dados MEDLINE via PubMed, Embase via Cochrane Library, Cochrane Library, LILACS via BVS. A pergunta de pesquisa foi estruturada da seguinte forma: população ­ pessoas com diabetes mellitus tipo 2 e doença cardiovascular estabelecida; intervenção ­ tratamento usual exceto insulina + inibidores de sódio-glicose 2 ou tratamento usual exceto insulina + agonistas de glucagon 1; controle - tratamento usual exceto insulina + placebo; desfecho ­ mortalidade geral, mortalidade por causas cardiovasculares, morbidade, efeitos adversos. Resultados: Selecionaram-se dois estudos sobre empagliflozina. Esse medicamento associado ao tratamento usual foi superior ao placebo associado ao tratamento usual no desfecho primário (HR 0,86; IC95% 0,74­0,99; p=0,04), na redução de hospitalização por insuficiência cardíaca (HR 0,65; IC95% 0,50­0,85; p=0,002), da mortalidade cardiovascular (HR 0,62; IC95% 0,49­0,77) e da mortalidade geral (HR 0,68; IC95% 0,57­0,82; p<0,001). No subgrupo de pessoas com diabetes que não usavam insulina, houve benefício com empagliflozina em relação ao desfecho primário (HR 0,79; IC95% 0,64­0,97; DR 2,5; NNT 40) e a mortes de causa cardiovascular (HR 0,61; IC95% 0,44­0,85; DR 2; NNT 49). Houve heterogeneidade entre os subgrupos com benefício de empagliflozina no desfecho primário apenas para aqueles com idade ³65 anos (p=0,01) e hemoglobina glicada <8,5 (p=0,01). Em relação às mortes por causas cardiovasculares, houve diferença (p=0,05) com o uso de empagliflozina reduzindo o risco somente no subgrupo com índice de massa corporal <30. Não houve diferença significativa em relação ao placebo para acidente vascular encefálico fatal e não fatal, tampouco no desfecho composto de acidente vascular encefálico debilitante não fatal e acidente vascular encefálico fatal (HR 0,81; IC95% 0,43­1,50; p=0,50). Houve mais pessoas acometidas por acidente vascular encefálico no grupo intervenção em que a hemoglobina glicada inicial era ≥8,5%, favorecendo o placebo (p=0,01). Conclusões: Os dados encontrados favorecem o benefício de utilizar esse medicamento no Sistema Único de Saúde em pessoas com doenças cardiovasculares. Entretanto, houve heterogeneidade entre grupos populacionais, o que pode ajudar a delinear estratégias de uso para esses medicamentos. São necessários mais estudos para avaliar qual seria o motivo de não haver benefício em desfechos cerebrovasculares isoladamente.

Introduction: Introduction: Type 2 diabetes mellitus is an important and growing health problem worldwide. Objective: This study aims to evaluate the quality of the evidence available on sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists in people with diabetes mellitus and atherosclerotic cardiovascular disease. Methods: This integrative review was performed using the following databases: MEDLINE via PubMed, Embase via Cochrane Library, Cochrane Library, LILACS via VHL. The research question was structured as follows: population ­ people with type 2 diabetes mellitus and established cardiovascular disease; intervention ­ usual treatment, except insulin + sodium-glucose cotransporter 2 inhibitors or usual treatment, except insulin + and glucagon-like peptide 1 agonists; control ­ usual treatment, except insulin + placebo; outcome ­ overall mortality, mortality from cardiovascular causes, morbidity, adverse effects. Results: Two studies on empagliflozin were selected. This drug associated with the usual treatment was superior to placebo associated with the usual treatment in the primary outcome (hazard ratio ­ HR 0.86; 95% confidence interval ­ 95%CI 0.74­0.99; p=0.04), in reducing heart failure hospitalization (HR 0.65; 95%CI 0.50­0.85; p=0.002), in cardiovascular mortality (HR 0.62; 95%CI 0.49­0.77), and in overall mortality (HR 0.68; 95%CI 0.57­0.82; p<0.001). The subgroup of people with diabetes who were not on insulin benefited from using empagliflozin concerning the primary outcome (HR 0.79; 95%CI 0.64­0.97; risk difference ­ RD 2.5; number needed to treat ­ NNT 40) and cardiovascular mortality (HR 0.61; 95%CI 0.44­0.85; RD 2; NNT 49). The analysis of the subgroups showed heterogeneity. Participants aged 65 years or older (p=0.01) and those with glycated hemoglobin lower than 8.5 benefited from empagliflozin in the primary outcome. A difference (p=0.05) related to cardiovascular mortality was found, with the use of empagliflozin reducing the risk only in the subgroup with body mass index <30. No significant difference was identified with respect to placebo for fatal and nonfatal stroke nor for the composite outcome of nonfatal disabling stroke and fatal stroke (HR 0.81; 95%CI 0.43­1.50; p=0.50). More people had strokes in the intervention group in which the initial glycated hemoglobin was ≥8.5%, favoring placebo (p=0.01). Conclusions: The data found suggest the benefit of the Brazilian public health system using this drug in people with cardiovascular diseases. However, the population groups were heterogeneous, which may help outline strategies for using these medications. Further studies are necessary to assess why isolated cerebrovascular outcomes showed no benefit.

Introducción: Diabetes mellitus tipo 2 es un importante y creciente problema de salud para todos los países. Objetivo: Este trabajo busca evaluar la calidad de la evidencia disponible sobre los fármacos Inhibidores del Cotransportador de Sodio-Glucosa 2 y agonistas de Péptido 1 similar al glucagón en personas con diabetes mellitus y enfermedad cardiovascular aterosclerótica. Métodos: Se realizó revisión integrativa utilizando las bases de datos MEDLINE vía PubMed, Embase vía Cochrane Library, Cochrane Library, LILACS vía BVS. La pregunta de investigación fue estructurada de la siguiente manera: población ­ personas con diabetes mellitus tipo 2 y enfermedad cardiovascular establecida; intervención ­ tratamiento usual excepto insulina + inhibidores de sodium-glucose cotransporter-2 o tratamiento usual excepto insulina + agonistas de Péptido 1 similar al glucagón; control ­ tratamiento habitual excepto insulina + placebo; desenlace ­ mortalidad general, mortalidad por causas cardiovasculares, morbilidad, efectos adversos. Resultados: Se seleccionaron dos estudios sobre empagliflozina. Este medicamento asociado al tratamiento habitual fue superior al placebo asociado al tratamiento usual en el resultado primario (HR 0.86; IC95% 0.74­0.99; p=0,04), en la reducción de hospitalización por insuficiencia cardíaca (HR 0.65; IC95% 0.50­0.85; p=0.002), de la mortalidad cardiovascular (HR 0,62; IC95% 0,49­0,77) y de la mortalidad general (HR 0,68; IC95% 0,57­0,82; p=0,001). En el subgrupo de personas con diabetes que no usaban insulina, hubo beneficio con empagliflozina con relación al desenlace primario (HR 0.79; IC95% 0.64­0.97; DR 2.5; NNT 40) y a muertes de causa cardiovascular (HR 0.61; IC95% 0.44­0.85; DR 2; NNT 49). No hubo diferencia significativa con relación al placebo para accidentes cerebrovasculares fatal y no fatal, tampoco en el resultado compuesto de accidente cerebrovascular debilitante no fatal y fatal (HR 0.81; IC95% 0.43­1.50; p=0.50). Hubo más personas acometidas por accidente cerebrovascular en el grupo intervención en que la hemoglobina glicada inicial era un 8,5%, favoreciendo el placebo (p=0.01). Conclusión: Los datos encontrados favorecen el beneficio de utilizar ese medicamento en el Sistema Único de Salud en personas con enfermedad cardiovascular. Entretanto ha habido heterogeneidad entre los grupos de población, lo que puede ayudar a delinear qué estrategias de uso para estos medicamentos. Son necesarios más estudios para evaluar cuál sería el motivo de no haber beneficio en resultados cerebrovasculares aisladamente.

Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis

ABSTRACT The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI −0.66 to −0.59) and body weight by 0.60 kg (95% CI −0.64 to −0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.

Cardioprotective Effects of Sodium-glucose Cotransporter 2 Inhibitors Regardless of Type 2 Diabetes Mellitus: A Meta-analysis

Abstract Background: Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular impairment, increasing the rates of atherosclerotic and non-atherosclerotic events. Additionally, adverse kidney events are directly linked with T2DM and cardiovascular diseases. In this context, the sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated both cardioprotective and renoprotective effects in patients with or without T2DM. Therefore, the present meta-analysis aims to evaluate cardiovascular outcomes involving SGLT2i as monotherapy or other add-on antidiabetic agents (ADA) in patients with or without T2DM. Objetive: The present meta-analysis aims to evaluate cardiovascular outcomes involving SGLT2i as monotherapy or add-on other ADA in patients with or without T2DM. Methods: The entrance criteria to SGLT2i studies were: describing any data regarding cardiovascular effects; enrolling more than 1,000 participants; being approved by either the FDA or the EU, and having available access to the supplementary data. The trial had to exhibit at least one of the following results: major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure, cardiovascular death, hospitalization for heart failure, renal or cardiovascular adverse events, or non-cardiovascular death. The significance level of 0.05 was adopted in the statistical analysis. Results: Nine trials with a total of 76,285 participants were included in the meta-analysis. SGLT2i reduced MACE (RR 0.75, 95% CI [0.55-1.01]), cardiovascular death or hospitalization for heart failure (RR 0.72, 95% CI [0.55-0.93]), cardiovascular death (RR 0.66, 95% CI [0.48-0.91]), hospitalization for heart failure (RR 0.58, 95% CI [0.46-0.73]), renal or cardiovascular adverse events (RR 0.55, 95% CI [0.39-0.78]), and non-cardiovascular death (RR 0.88, 95% CI [0.60-1.00]). Conclusions: Conjunction overall data suggests that these drugs can minimize the risk of cardiovascular events, thus decreasing mortality in patients, regardless of the presence of T2DM.

Canagliflozin reduces the contractile response of isolated heart of normal adult rats / Canagliflozin reduce la respuesta contráctil del corazón aislado de ratas adultas normales

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.

Ação dos isglt2 no hipertenso diabético, quando indicar? / Effect of sglt-2 inhibitor in diabetic hypertensive patients, when to indicate?

A doença cardiovascular (DCV) representa um fardo individual e social em pacientes com diabetes mellitus tipo 2 (DM2). A diabetes é uma doença crônica onerosa do ponto de vista social e econômico. O seu tratamento inclui medidas não farmacológicas, como dieta e exercício físico, bem como a adição de medicamentos em pacientes que não atingem controle glicêmico satisfatório através de medidas comportamentais. Medicamentos da classe inibidores de SGLT2 (iSGLT2), objeto deste manuscrito, têm sido associados com a redução de eventos cardiovasculares e mortalidade, além de redução da pressão arterial e peso, sem conferir aumento de risco de hipoglicemia

Cardiovascular disease (CVD) represents an individual and social burden in patients with type 2 diabetes mellitus (T2DM). Diabetes is a chronic, socially and economically costly disease. Its treatment includes non-pharmacological measures, such as diet and exercise, as well as the addition of medication in patients who do not achieve satisfactory glycemic control through behavioral approach. Drugs as SGLT2 inhibitor (SGLT2i), object of this manuscript, have been associated with a reduction in cardiovascular events and mortality, in addition to a reduction in blood pressure and weight, without increasing the risk of hypoglycemia.

Gliflozinas: más que antidiabéticos orales: una breve revisión de la literatura / Gliflozins: more than oral antidiabetics: a brief review of the literature / Gliflozinas: mais do que antidiabéticos orais: uma breve revisão da literatura

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.

Inhibidores del cotransportador de sodio-glucosa tipo 2: Efecto de los mecanismos moleculares en el miocardio / Sodium-glucose cotransporter 2 inhibitors: Effect of molecular mechanisms on the myocardium

Resumen Los receptores del cotransportador de sodio-glucosa han demostrado una gran relevancia en la función miocárdica. Los receptores tipo 1 se encuentran en el miocardio en valores bajos, sin embargo, se elevan en patologías cardiacas por medio de distintos mecanismos moleculares. Por otra parte, los receptores tipo 2 están ausentes en el miocardio. Los fármacos que inhiben este receptor tienen beneficio cardiovascular evidente en estudios clínicos y experimentales, principalmente en pacientes con diabetes mellitus tipo 2 e insuficiencia cardiaca, en los que se ha demostrado una reducción de la mortalidad por causas cardiovasculares y reducción en hospitalización por insuficiencia cardiaca. Existen interrogantes sobre el mecanismo de acción directo de este grupo antihiperglicemiantes sobre el cardiomiocito y se han desarrollado hipótesis y teorías para explicar este efecto. El objetivo de este artículo es revisar y analizar los diferentes mecanismos metabólicos, estructurales, funcionales y mitocondriales en un contexto molecular de los inhibidores del cotransportador sodio-glucosa tipo 2. La acción fisiopatológica del receptor tipo 1 en el miocardio también es importante y se encuentran en desarrollo estudios clínicos para establecer el efecto de su inhibición a nivel cardíaco.

Abstract Sodium-glucose cotransporter receptors have demonstrated relevance in myocardial function. Type 1 receptors are found in the myocardium in low values, however, they are elevated in cardiac pathologies by means of different molecular mechanisms. On the other hand, type 2 receptors are absent in the myocardium. The drugs that inhibit this receptor have been shown to have a cardiovascular benefit demonstrated in clinical and experimental studies, mainly in patients with type 2 diabetes mellitus and heart failure, presenting a reduction in mortality due to cardiovascular causes and a reduction in hospitalization due to heart failure. Due to the above, many questions arise about the mechanism of direct action of this antihyperglycemic group on cardiomyocyte, which is why they have been developed from hypotheses and theories to clarify this action by medicines. The objective of this article is to analyze the different metabolic, structural, functional and mitochondrial mechanisms in a molecular context of the inhibitors of the sodium-glucose cotransporter type 2. On the other hand, to analyze the pathophysiological action of the type 1 receptor in the myocardium, since that future clinical studies will be developed to establish the effect with its inhibition at the cardiac level.

Nuevos hipoglucemiantes en el cuidado de las personas con diabetes tipo 2: por fin hay un avance / New hypoglycemic agents in the care of people with diabetes: finally, there is a breakthrough

En este artículo, la autora jerarquiza la relevancia de la eficacia documentada de los agonistas del péptido similar alglucagón-1 y los inhibidores del cotransportador sodio-glucosa tipo 2, que ha conducido a recientes modificaciones en el paradigma del cuidado en los pacientes con diabetes tipo 2. (AU)

In this article, the author highlights the relevance of the documented efficacy of glucagon-like peptide-1 agonists and type 2 sodium-glucose cotransporter inhibitors, which has led to recent changes in the paradigm of care in patients with type 2diabetes. (AU)

Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection / Argumentando a favor do uso combinado de inibidores de SGLT2 e agonistas do receptor GLP1 para proteção cardiorrenal

ABSTRACT Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.

RESUMO Inibidores do cotransporter-2 de glicose sódica (SGLT2) e agonistas do receptor peptídeo-1 do tipo glucagon (GLP-1RA) foram inicialmente aprovados para melhorar o controle glicêmico no tratamento da diabetes tipo 2. Os ensaios clínicos também demonstraram efeitos benéficos em relação aos parâmetros cardiovasculares e renais. Além de melhorar o controle glicêmico, essas terapias promovem perda de peso e redução da pressão arterial quando usadas individualmente, e de forma aditiva quando usadas em conjunto. Consequentemente, tirar proveito de mecanismos de ação complementares com o uso combinado dessas duas classes de agentes para melhorar ainda mais os resultados cardiorrenais é conceitualmente atraente, mas ainda precisa ser explorado em detalhes em ensaios clínicos. Nesta revisão, discutimos os mecanismos propostos para proteção renal, benefícios clínicos e eventos adversos associados ao uso individual e combinado de inibidores de SGLT2 e GLP-1RA. O tratamento do diabetes tipo 2 mudou significativamente nos últimos anos, passando do controle exclusivamente glicêmico para o tratamento simultâneo de comorbidades associadas em uma população de pacientes com risco significativo de doença cardiovascular e progressão da doença renal crônica. É nessa perspectiva que procuramos delinear a justificativa para o uso sequencial e/ou combinado de inibidores de SGLT2 e GLP-1RA em pacientes com diabetes tipo 2.

Los inhibidores del cotransportador sodio-glucosa tipo 2 en el tratamiento de la diabetes mellitus / Type 2 sodium-glucose co-transporter inhibitors in the treatment of diabetes mellitus

Introducción: Los medicamentos inhibidores del cotransportador sodio-glucosa actúan inhibiéndose de forma selectiva y reversible a nivel renal. A través de este mecanismo, reducen la reabsorción de glucosa, la cual pasa a excretarse por la orina y de esta forma, contribuyen a normalizar la glucemia. Objetivo: Describir la función de los inhibidores del cotransportador sodio-glucosa tipo 2 en el tratamiento de la diabetes mellitus. Métodos: Se utilizó como buscador de información científica a Google Académico, Google, Pubmed y SciELO. Se evaluaron artículos de revisión, de investigación y páginas Web, que en general, tenían menos de 10 años de publicados, en idioma español, portugués o inglés. Fueron excluidos los artículos que no cumplieron con estos requisitos. Esto permitió el estudio de 98 artículos, de los cuales 75 fueron referenciados. Conclusiones: La administración de los inhibidores del cotransportador sodio-glucosa induce cambios favorables en la hemoglobina glucosilada, el peso corporal y la presión arterial, además de presentar un bajo riesgo de hipoglucemia. Aunque constituyen un grupo farmacológico que puede ser utilizado como monoterapia, con mayor frecuencia son usados como coadyuvantes en el tratamiento de los pacientes con diabetes mellitus, que reciben tratamiento farmacológico con otros medicamentos normo o hipoglucemiantes y que no han alcanzado las metas de control. Se debe estar alerta ante la aparición de posibles efectos secundarios o reacciones adversas, para descontinuar el tratamiento y tomar las medidas correspondientes(AU)

Introduction: Sodium-glucose co-transporter inhibitors´ drugs (SGLT) work by selectively and reversiblely inhibiting at the renal level. Through this mechanism, they reduce glucose reabsorption, which is excreted through urine and thus contribute to normalizing blood glucose. Objective: Describe the role of sodium-glucose co-transporter inhibitors 2 in the treatment of diabetes mellitus. Methods: There were used as search engines for scientific information : Google Scholar, Google, Pubmed and SciELO. The keywords used were: Glyphozines, sodium-glucose co-transporter inhibitors, diabetes mellitus, treatment and weight loss. Review articles, research articles and web pages were assessed, which generally had less than 10 years of publication, and were in Spanish, Portuguese or English language. Items that did not meet these requirements were excluded. This allowed the study of 98 articles, of which 75 were referenced. Conclusions: Administration of sodium-glucose co-transporter inhibitors induces favorable changes in glycosylated haemoglobin, body weight and blood pressure, as well as a low risk of hypoglycaemia. Although they are a pharmacological group that can be used as monotherapy, they are mostly used as adjuvants in the treatment of patients with diabetes mellitus who receive drug treatment with other normo or hypoglycemic medications and who have not met control goals. It is important to be alert to possible side effects or adverse reactions to discontinue treatment and take appropriate action(AU)

Pharmacological therapy and cardiovascular risk reduction for type 2 diabetes

SUMMARY The pharmacological therapy for type 2 diabetes mellitus has presented important advances in recent years, which has impacted the treatment of patients with established cardiovascular disease or with high cardiovascular risk. In this scenario, two drug classes have emerged and demonstrated clear clinical benefits: SGLT-2 inhibitors and GLP-1 agonists. The present review discusses the pharmacology, adverse effects, and clinical trials that have demonstrated the benefits of these medications in reducing cardiovascular risk.

RESUMO A terapia farmacológica do diabetes mellitus tipo 2 apresentou avanços importantes nos últimos anos, impactando principalmente o tratamento dos pacientes com doença cardiovascular estabelecida ou com alto risco cardiovascular. Nesse cenário, surgiram duas classes de fármacos com claros benefícios clínicos; os inibidores da SGLT-2 e os agonistas do GLP-1. Na presente revisão os autores discutem desde a farmacologia, efeitos adversos e também os estudos clínicos que demonstraram os benefícios dessas medicações na redução de risco cardiovascular.

Vertebral fractures in adult women with type 2 diabetes mellitus / Fracturas vertebrales en mujeres adultas con diabetes mellitus tipo 2

Introduction. Diabetes is a chronic disease associated with important comorbidities. Type 2 diabetes (T2DM) is associated with a three times increased risk of hip fracture but reports describing potential associations with vertebral fractures (VF) are contradictory. Our objective was to evaluate the factors involved in the prevalent VF in women with and without T2DM. Materials and methods. A cross-sectional design was used and the relationship between morphometric VF and T2DM in adult women was evaluated. The cases were adult women with morphometric VF and the controls were adult women without VF. Thoracic and spinal radiographs in lateral and antero-posterior projections were obtained. Bone mineral density (BMD) values of the lumbar spine (L-BMD) were measured by DXA. Results. A greater number of women with T2DM were found in the VF group (61% vs 31.5%). Non-T2DM women with VF were significantly older and with lower L-BMD than non-T2DM without VF. We observed a negative correlation between age and L-BMD (r=-0.463) in non-T2DM women, but not in the T2DM with FV group. T2DM was a risk factor for prevalent VF with OR of 3.540 (IC95% 1.750-7.160). Conclusion. Our study showed a higher prevalence of T2DM in the VF group. T2DM women with VF were younger and had higher L-BMD than non-T2DM women, L-BMD did not correlate with age and VF were not distributed according to BMD-L and age. (AU)

Introducción. La diabetes es una enfermedad crónica asociada con comorbilidades importantes. La diabetes tipo 2 (DM2) se asocia con un riesgo tres veces mayor de fractura de cadera pero la asociación con fracturas vertebrales (FV) es contradictoria. Nuestro objetivo fue evaluar los factores involucrados en las FV prevalentes en mujeres adultas con y sin DM2. Materiales y métodos. Se realizó un diseño transversal y se evaluó la relación entre FV morfométrica y DM2 en mujeres adultas. Los casos fueron mujeres adultas con FV morfométricas y los controles fueron mujeres adultas sin FV. Se obtuvieron radiografías torácicas y espinales en proyecciones lateral y anteroposterior. Los valores de densidad mineral ósea (DMO) de la columna lumbar (DMO-L) se midieron por DXA. Resultados. Se observó un mayor número de mujeres con DM2 en el grupo de FV (61% frente a 31.5%). Las mujeres sin DM2 con FV eran significativamente mayores y con una DMO-L más baja que las mujeres sin DM2 sin FV. Observamos una correlación negativa entre la edad y la DMO-L (r= -0.463) en mujeres sin DM2 y FV, pero no en DM2 con FV. La DM2 fue un factor de riesgo para FV prevalente con un OR 3.540 (IC95% 1.750-7.160). Conclusión. Nuestro estudio demostró una mayor prevalencia de DM2 en el grupo de FV. Las mujeres con DM2 y FV eran más jóvenes y tenían mayor DMO-L que las mujeres sin DM2, la DMO-L no correlacionó con la edad y las FV no se distribuyeron de acuerdo a la DMO-L y edad. (AU)

El efecto de los antihiperglicemiantes en los parámetros ecocardiográficos diastólicos y sistólicos / The effect of antihyperglycemic agents on diastolic and systolic echocardiographic parameters

Resumen La enfermedad metabólica diabetes mellitus tipo 2 ocasiona alteraciones en la estructura y en la funcionalidad miocárdica por diferentes mecanismos bioquímicos los cuales pueden ocasionar disfunción diastólica y sistólica, por lo cual el uso de los antihiperglicemiantes aparte de su efecto en la reducción de la hiperglicemia y la hemoglobina glicosilada, algunos han demostrado reducción en la mortalidad cardiovascular y de las hospitalizaciones por insuficiencia cardiaca, basado en estudios clínicos sobre este impacto en el miocardio. También se ha evaluado el efecto de estos fármacos por medio del ecocardiograma transtorácico. El objetivo de este articulo es analizar los valores de los parámetros ecocardiográficos sistólicos y diastólicos en pacientes diabéticos tipo 2 o alguna cardiopatía de base como antecedente de infarto al miocardio e insuficiencia cardiaca con el uso de metformina, sulfonilureas, los inhibidores de la dipeptidilpeptidasa 4 (sitagliptina, alogliptina y linagliptina, vildagliptina), los análogos de GLP1 (liraglutide, albiglutide y exenatide).

Abstract Metabolic disease type 2 diabetes mellitus causes alterations in both structure and myocardial functionality by different biochemical mechanisms which can cause diastolic and systolic dysfunction, which is why the use of antihyperglycemic agents apart from its effect in the reduction of hyperglycemia and glycosylated hemoglobin, some groups have shown reduction in cardiovascular mortality and hospitalizations for heart failure this based on clinical studies, by hypothesis, theories and pleiotropic mechanisms on this impact on the myocardium. On the other hand, the effect of these drugs on the myocardium has also been evaluated by transthoracic echocardiography. Therefore, the aim of this article is to analyze the values of systolic and diastolic echocardiographic parameters in type 2 diabetic patients or some underlying heart disease as a history of myocardial infarction and heart failure with the use of metformin, sulfonylureas, inhibitors of the dipeptidylpeptidase 4 (sitagliptin, alogliptin and linagliptin, vildagliptin), GLP1 analogues (liraglutide, albiglutide and exenatide).

SGLT-2 inhibitors in diabetes: a focus on renoprotection

SUMMARY 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.