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.

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.

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.

Population diversity of cardiovascular outcome trials and real-world patients with diabetes in a Chinese tertiary hospital / 中华医学杂志(英文版)

BACKGROUND@#Recent cardiovascular outcome trials (CVOTs) changed the therapeutic strategy of guidelines for type 2 diabetes. We compared the characteristics of patients from real-world hospital settings with those of participants in recent pragmatic randomized trials.@*METHODS@#This electronic medical record (EMR)-based retrospective observational study investigated the data of patients with diabetes from inpatient and outpatient settings in West China Hospital of Sichuan University from January 1, 2011, to June 30, 2019. We identified patients meeting the inclusion criteria of a pragmatic randomized trial (EMPA-REG OUTCOME) based on EMRs and compared their baseline characteristics with those of the trial participants. The cutoff for the clinical significance of each characteristic was set as its minimal clinically important difference based on expert consultation.@*RESULTS@#We included 48,257 inpatients and 36,857 outpatients with diabetes and found that 8389 (17.4%) inpatients and 2646 (7.2%) outpatients met the inclusion criteria for the EMPA-REG OUTCOME trial. Compared with the trial population, the real-world inpatients meeting the eligibility criteria of the EMPA-REG OUTCOME had similar age, blood pressure, and lipid profiles but comprised of fewer males, metformin users, anti-hypertensive drug users, and aspirin users, and had a lower body mass index. The group of outpatients meeting the eligibility criteria had fewer males, similar age, fewer metformin users, fewer insulin users, fewer anti-hypertensive drug users, and fewer aspirin users compared with the trial population.@*CONCLUSIONS@#The trial population in EMPA-REG OUTCOME represents only a small portion of patients with diabetes from the inpatient and outpatient departments of a Chinese tertiary medical center. Evidence localization in different clinical settings and validation are essential to enabling extrapolation of the results from CVOTs in patients with diabetes to Chinese clinical practice.

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.

Análise crítica dos estudos que mudaram a prática clínica recente: diabetes mellitus e doenças cardiovasculares / Critical analysis of studies that changed recent clinical practice: diabetes mellitus and cardiovascular disease

Já é bem conhecida a importância da terapêutica para os pacientes com diabetes mellitus (DM) no que diz respeito à redução dos eventos cardiovasculares e, por isso, existe interesse em comprovar a segurança cardiovascular das diferentes terapias anti-hiperglicêmicas disponíveis no mercado. O objetivo desta revisão consiste em discutir três grandes estudos publicados recentemente, LEADER, CANVAS e DECLARE ­ TIME 58, que avaliaram o efeito sobre morbidade e mortalidade cardiovascular das medicações em questão em comparação com placebo

The importance of therapy for patients with diabetes mellitus (DM) in reducing cardiovascular events is well-known and, therefore, there is interest in confirming the cardiovascular safety of the different antihyperglycemic therapies available on the market. The objective of this review is to discuss three large recently-published studies, LEADER, CANVAS and DECLARE ­ TIME 58, which evaluated the effect of the medications in question on morbidity and cardiovascular mortality as compared to a placebo

Prevenção secundária e doenças cardiovascular: onde estamos? / Secondary prevention and cardiovascular disease: where are we?

As doenças cardiovasculares, principalmente as decorrentes de casos de acidente vascular cerebral e infarto agudo do miocárdio, têm importante impacto na mortalidade global e nas internações hospitalares em todo o mundo. A despeito do vasto conhecimento dos diversos fatores de risco implicados na gênese da doença cardiovascular, o número de eventos ainda se mantém elevado e a instituição de medidas de prevenção primária e secundária são essenciais e complementares. Nos últimos anos, importantes avanços no campo do tratamento farmacológico de aterosclerose e insuficiência cardíaca, predominantemente em decorrência de cardiopatia isquêmica, foram publicados e seus principais resultados são destacados no presente artigo

Cardiovascular diseases, particularly those arising from cases of stroke and acute myocardial infarction, have a significant impact on global mortality and hospital admissions around the world. Despite the vast knowledge of the various risk factors involved in the genesis of cardiovascular disease, the number of events remains high and institution of primary and secondary prevention measures is essential and complementary. In recent years, important advances in the field of pharmacological treatment of atherosclerosis and heart failure, particularly those arising from ischemic heart disease, have been published. The main results are highlighted in this article

Use of sodium-glucose cotransporter-2 inhibitors and urinary tract infections in type 2 diabetes patients: a systematic review

SUMMARY Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are drugs that act by maintaining glycosuria. Recent studies have shown promising effects of these in the treatment of type 2 diabetes mellitus (DM2). However, there may be an increased risk of developing urinary tract infections (UTIs) in patients treated with these. Our study aims to analyze the association between the risk of UTI in patients treated with SGLT2i. A systematic review of the literature was carried out by randomized clinical trials, totalizing at the end of the selection 23 articles that were statistically evaluated. The incidence of UTI was generally demonstrated in articles and in different subgroups: patients on SGLT2i monotherapy or on combination therapy; according to specific comorbidities of each sample or according to the drug used. They noticed an increase in the chance of UTI in the SGLT2i groups compared to the control groups on placebo or other oral antidiabetic agents. This increased chance was found predominantly with the use of Dapagliflozin, Canagliflozin, and Tofogliflozin, regardless of the dosing. Lastly, stands out that the dimension of UTI chances for DM2 patients who use SGLT2i remains to be more strictly determined.

RESUMO Os inibidores do cotransportador de sódio-glicose do tipo 2 (SGLT2i) são medicamentos que atuam mantendo a glicosúria. Estudos recentes têm demonstrado efeitos promissores desses no tratamento de diabetes mellitus tipo 2 (DM2). No entanto, pode haver um risco aumentado de desenvolver infecções do trato urinário (UTI) em pacientes tratados com essa classe de medicação. Nosso estudo tem como objetivo analisar a associação entre o risco de desenvolver UTI em pacientes tratados com SGLT2i. Uma revisão sistemática da literatura foi realizada por ensaios clínicos randomizados, totalizando, ao final da seleção, 23 artigos que foram avaliados estatisticamente. A incidência de UTI foi demonstrada genericamente de acordo com os dados dos artigos e em diferentes subgrupos: pacientes em monoterapia com SGLT2i ou em terapia combinada, de acordo com as comorbidades específicas de cada amostra ou de acordo com a droga utilizada. Verificou-se um aumento na chance de UTI nos grupos SGLT2i em comparação com os grupos de controle em placebo ou outros agentes antidiabéticos orais. Essa chance aumentada foi encontrada predominantemente com uso de Dapagliflozina, Canagliflozina e Tofoglifozina, independentemente da dosagem. Por fim, ressaltou-se que as chances de UTI em pacientes com DM2 em uso de SGLT2i ainda precisam ser mais bem determinadas.

The Role of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Reducing Cardiovascular Events in Patients with Type 2 Diabetes

The prevalence of type 2 diabetes mellitus (T2DM), which is associated with cardiovascular morbidity and mortality, is increasing worldwide. Although there have been advances in diabetes treatments that reduce microvascular complications (nephropathy, neuropathy, retinopathy), many clinical studies have found that conventional oral hypoglycemic agents and glucose control alone failed to reduce cardiovascular disease. Thus, incretin-based therapies including glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) represent a new area of research, and may serve as novel therapeutics for treating hyperglycemia and modifying other cardiovascular risk factors. Recently, it has been confirmed that several drugs in these classes, including canagliflozin, empagliflozin, semaglutide, and liraglutide, are safe and possess cardioprotective effects. We review the most recent cardiovascular outcome trials on GLP-1RAs and SGLT-2Is, and discuss their implications for treating patients with T2DM in terms of protective effects against cardiovascular disease.

Safety Issues with Sodium-Glucose Cotransporter 2 Inhibitors: Clinical Considerations / 임상당뇨병

Diabetes mellitus (DM) is linked to poor outcomes after cardiovascular events and renal complications. Recently, novel antidiabetic agents, such as dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists, are available. Among them, studies on SGLT2 inhibitors show favorable results both for cardiovascular and renal outcomes. SGLT2 inhibitors are well-tolerated with few side effects. Urinary tract infection has not been increased in many studies of SGLT2 inhibitors. The most frequent side-effect associated with SGLT2 inhibitors is mycotic infections in the genital area. Fortunately, these are generally mild in severity and easily treated with antibiotics. Hypoglycemia can occur when an SGLT2 inhibitor is added to sulfonylureas or insulin. Volume depletion and hypotension can be minimized by adjusting diuretics or other antihypertensive agents. Of note, acute kidney injury was observed in a few studies with SGLT2 inhibitors. However, in more recent observational studies, acute kidney injury was less frequently observed in conjunction with SGLT2 inhibitor treatment. An increased incidence of lower extremity amputation and fractures was observed in a large study with canagliflozin but not with other SGLT2 inhibitors. In conclusion, it is critical to understand the benefits and risks associated with use of SGLT2 inhibitors.

Prevention of Major Adverse Cardiovascular and Renal Outcomes with Sodium-Glucose Cotransporter 2 Inhibitors / 임상당뇨병

Management of hyperglycemia limits progression of microvascular complications in type 2 diabetes mellitus (T2DM). According to large-scale randomized control studies to demonstrate the cardiovascular safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors, SGLT2 inhibitors showed not only cardiovascular safety, but also cardiovascular benefits. Heart failure is adequately prevented by SGLT2 inhibitors regardless of history of heart failure. Additionally, SGLT inhibitors also showed renal protective benefits in slowing the decline of glomerular filtration rate and reducing proteinuria. SGLT2 inhibitors are beneficial to T2DM patients with established cardiovascular disease, high risk of heart failure, and renal impairment. As oral hypoglycemic agents, SGLT2 inhibitors not only control the serum glucose level, but also reduce the macrovascular complications of T2DM.

Short-term outcomes of patients with Type 2 diabetes mellitus treated with canagliflozin compared with sitagliptin in a real-world setting

<p><b>INTRODUCTION</b>We aimed to evaluate the effectiveness and safety of canagliflozin as compared to sitagliptin in a real-world setting among multiethnic patients with Type 2 diabetes mellitus (T2DM) in Singapore.</p><p><b>METHODS</b>This was a new-user, active-comparator, single-centre retrospective cohort study. Patients aged 18-69 years with T2DM and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m were eligible for inclusion if they were initiated and maintained on a steady daily dose of canagliflozin 300 mg or sitagliptin 100 mg between 1 May and 31 December 2014, and followed up for 24 weeks.</p><p><b>RESULTS</b>In total, 57 patients (canagliflozin 300 mg, n = 22; sitagliptin 100 mg, n = 35) were included. The baseline patient characteristics in the two groups were similar, with overall mean glycated haemoglobin (HbA1c) of 9.4% ± 1.4%. The use of canagliflozin 300 mg was associated with greater reductions in HbA1c (least squares [LS] mean change -1.6% vs. -0.4%; p < 0.001), body weight (LS mean change -3.0 kg vs. 0.2 kg; p < 0.001) and systolic blood pressure (LS mean change: -9.7 mmHg vs. 0.4 mmHg; p < 0.001), as compared with sitagliptin 100 mg. About half of the patients on canagliflozin 300 mg reported mild osmotic diuresis-related side effects that did not lead to drug discontinuation.</p><p><b>CONCLUSION</b>Our findings suggest that canagliflozin was more effective than sitagliptin in reducing HbA1c, body weight and systolic blood pressure in patients with T2DM, although its use was associated with an increased incidence of mild osmotic diuresis-related side effects.</p>

The combination of canagliflozin and omega-3 fatty acid ameliorates insulin resistance and cardiac biomarkers via modulation of inflammatory cytokines in type 2 diabetic rats

The present study was carried out with the hypothesis that combination of canagliflozin and omega-3 fatty acid may have potential effect on insulin level, insulin resistance, cardiac biomarkers, inflammatory cytokines and histological studies in type 2 diabetes mellitus (DM). Type 2 DM was induced by injecting nicotinamide (120 mg/kg, i.p.) 15 min before STZ (60 mg/kg) injection. Canagliflozin (5 and 10 mg/kg) and omega-3 fatty acid (300 mg/kg) were given for 28 days after confirmation of diabetes. Biochemical estimations revealed elevated levels of glucose, insulin, HOMA-R and inflammatory cytokines in diabetic group. Daily dosing of alone canagliflozin and omega-3 fatty acid slightly reduced elevated levels of glucose, insulin, HOMA-R and inflammatory cytokines (IL-1β, IL-2, and TNFα), whereas canagliflozin and omega-3 fatty acid combination has reduced these biochemical parameters significantly when compared with diabetic group. Similarly in diabetic group the levels of cardiac biomarkers such as lipid profile, LDH, CKMB and troponin were significantly increased. Elevated levels of cardiac biomarkers were significantly reduced after daily dosing of alone canagliflozin and omega-3 fatty acid. Canagliflozin and omega-3 fatty acid combination has offered better improvement in cardiac biomarkers compared to alone canagliflozin and omega-3 fatty acid. Histopathological analysis also supported the above hypothesis that combination therapy (canagliflozin and omega-3 fatty acid) offered better protection against degenerative changes in β-cells of pancreas as compared to alone treatment with these drugs. Thus the present study revealed that canagliflozin and omega-3 fatty acid can be used as potential combination therapy in type 2 DM along with cardiac complication.

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus / Uso dos inibidores da SGLT-2 no tratamento do diabetes mellitus tipo 2

Summary Introduction: Diabetes mellitus is one of the most common chronic diseases in the world, with high morbidity and mortality rates, resulting in a greatly negative socioeconomic impact. Although there are several classes of oral antidiabetic agents, most of the patients are outside the therapeutic goal range. Objective: To review the use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus, focusing on their favorable and unfavorable effects, as well as on cardiovascular profile. Method: A literature search on Pubmed database was performed using the following keywords: "SGLT-2 inhibitors," "dapagliflozin," "empagliflozin," "canagliflozin." Results: SGLT-2 inhibitors are a class of oral antidiabetic drugs directed to the kidney. Their mechanism of action is to reduce blood glucose by inducing glycosuria. Extra-glycemic benefits have been described, such as weight loss, decline in blood pressure and levels of triglycerides and uric acid, and they can slow the progression of kidney disease. Genitourinary infections are the main side effects. There is a low risk of hypotension and hypoglycemia. Diabetic ketoacidosis is a serious adverse effect, although rare. Empagliflozin has already had its cardiovascular benefit demonstrated and studies with other drugs are currently being performed. Conclusion: SGLT-2 inhibitors are a new treatment option for type 2 diabetes mellitus, acting independently of insulin. They have potential benefits other than the reduction of blood glucose, but also carry a risk for adverse effects.

Resumo Introdução: O diabetes mellitus é uma das doenças crônicas mais frequentes no mundo, com altas taxas de morbimortalidade, resultando em um grande impacto negativo socioeconômico. Apesar de existirem diversas classes de antidiabéticos orais, a maioria dos pacientes acometidos está fora da meta terapêutica. Objetivo: Revisar o uso dos inibidores da SGLT-2 no tratamento do diabetes mellitus tipo 2, com enfoque nos efeitos favoráveis, desfavoráveis e no perfil cardiovascular. Método: Foi realizada uma pesquisa bibliográfica transversal com artigos científicos obtidos da base de dados Pubmed, utilizando os descritores: "SGLT-2 inhibitors", "dapagliflozin", "empagliflozin", "canagliflozin". Resultados: Os inibidores da SGLT-2 são uma classe de antidiabéticos orais com atuação no rim. O mecanismo de ação é reduzir a glicemia induzindo glicosúria. Benefícios extraglicêmicos já foram descritos, como redução de peso, pressão arterial, triglicerídeos e ácido úrico, além de retardar a progressão da doença renal. O principal efeito colateral é a infecção geniturinária, com baixo risco de hipotensão e hipoglicemia. Cetoacidose diabética é um efeito adverso grave, mas infrequente. A empagliflozina já teve seu benefício cardiovascular demonstrado, e estudos com outras drogas estão em andamento. Conclusão: Os inibidores da SGLT-2 são uma nova opção de tratamento do diabetes mellitus tipo 2, que atua de forma insulino-independente e com potenciais benefícios adicionais, além da redução da glicemia, mas também com risco de efeitos adversos.

Cetoacidosis diabética euglicémica asociada a inhibidor de cotransportador de sodio glucosa Tipo 2 en paciente con diabetes Mellitus Tipo 1 / Diabetic ketoacidosis with mild hyperglycemia associated with the use of canagliflozin. report of one case with type 1 diabetes

Diabetic ketoacidosis with mild hyperglycemia is a major complication of sodium-glucose cotransporter 2 inhibitors. Although its use is not approved for patients with type 1 diabetes mellitus, the drug is often prescribed with the hope of optimizing metabolic control. We report a 20 years old female with hypothyroidism and type 1 diabetes consulting for vomiting and abdominal pain. The patient had used canagliflozin during the two previous months. Laboratory showed a blood glucose of 200 mg/dl, a severe metabolic acidosis (pH 7.1) and ketonemia. The patient was successfully treated in the intensive care unit.

Berberine enhances antidiabetic effects and attenuates untoward effects of canagliflozin in streptozotocin-induced diabetic mice / 中国天然药物

The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFα) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFα in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies.

A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor

Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.