Sodium-glucose cotranspor ter 2 (SGLT2) inhibitors in nephrolithiasis: should we "gliflozin" patients with kidney stone disease? / Inibidores de cotransportadores sódio-glicose-2 (SGLT2) na nefrolitíase - devemos "gliflozinar" os litiásicos?

ABSTRACT The prevalence of nephrolithiasis is increasing worldwide. Despite advances in understanding the pathogenesis of lithiasis, few studies have demonstrated that specific clinical interventions reduce the recurrence of nephrolithiasis. The aim of this review is to analyze the current data and potential effects of iSGLT2 in lithogenesis and try to answer the question: Should we also "gliflozin" our patients with kidney stone disease?

RESUMO A prevalência da nefrolitíase está aumentando em todo o mundo. Apesar dos avanços na compreensão da patogênese da doença litiásica, poucos estudos demonstraram que intervenções clínicas específicas diminuem a recorrência da nefrolitíase. O objetivo desta revisão é analisar os dados atuais e efeitos potenciais dos iSGLT2 na doença litiásica e tentar responder à pergunta: devemos também "gliflozinar" os litiásicos?

Control metabólico de pacientes diabéticos tipo 2 tratados con empagliflozina: serie de casos / Metabolic control in type 2 diabetic patients treated with empagliflozin: A case series

Introducción La diabetes mellitus tipo 2 es una enfermedad de alta prevalencia y está asociada a mayor morbimortalidad. Debido al bajo porcentaje de compensación, se han buscado nuevas estrategias de tratamiento farmacológico, como los inhibidores del cotransportador sodio-glucosa tipo 2. Objetivo Describir la evolución de pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor, ubicado en el sector poniente de la Región Metropolitana, Chile. El objetivo primario fue evaluar la eficacia del medicamento respecto a hemoglobina glicosilada A1c. Los objetivos secundarios fueron registrar el logro de hemoglobina glicosilada A1c igual o menor a 7,5% según análisis de supervivencia. Luego, consignar el cambio en la velocidad de filtración glomerular y en la excreción urinaria de albúmina post tratamiento. Métodos Revisión de ficha clínica de todos los pacientes tratados con empagliflozina desde noviembre de 2019 a junio de 2023. Media de seguimiento de 19 (de 16,3 a 40) meses. Para comparación entre valores de hemoglobina glicosilada A1c según rangos de seguimiento, se utilizó prueba T de Student de términos pareados o prueba de Wilcoxon. Resultados Se estudió a 58 pacientes, 15 hombres y 43 mujeres (74,1%). Edad 58,5 ± 9,2 años, rango de 35 a 75 años. Hemoglobina glicosilada A1c basal de 10,3 ± 1,6% y 8,98% ± 2,2 en un rango de seguimiento de 18 a 24 meses post tratamiento, resultando en un descenso de 1,27% (p = 0,002; intervalo de confianza 95%: 0,5 a 2,03). El efecto adverso más frecuente fue infección del tracto urinario. Conclusiones Los pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor lograron un mejor control glicémico con pocos efectos adversos.

Background Type 2 diabetes mellitus is a highly prevalent disease and is associated with increased morbidity and mortality. Due to the low percentage of adequate glycemic control, new strategies for the treatment of type 2 diabetes mellitus have been sought, including sodium-glucose cotransporter type 2 inhibitorss. Objective To describe the evolution of patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital. The primary objective was to evaluate the efficacy of the medication regarding glycosylated hemoglobin A1c (HbA1c). The secondary objectives were: 1) achievement of HbA1c equal to or less than 7.5% according to survival analysis. 2) Change in glomerular filtration rate and urinary albumin excretion post treatment. Methods Review of clinical records of all patients treated with empagliflozin from November 2019 to June 2023. Average follow-up of 19 (16.3 to 40) months. To compare HbA1c values according to follow-up ranges, the paired T test or Wilcoxon test was used. Results We included 58 patients, 15 men and 43 women (74.1%), with an average age of 58.5 ± 9.2 years, ranging from 35 to 75 years. Baseline HbA1c of 10.3 ± 1.6% and 8.98% ± 2.2 in a follow-up of 18 to 24 months post-treatment, resulted in a decrease of 1.27% (p = 0.002; confidence interval 95%: 0.5 to 2.03). The most common adverse effect was urinary tract infection. Conclusions Patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital achieved better glycemic control with few adverse effects.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study / Dapagliflozina em pacientes com doença crítica: justificativa e desenho do estudo DEFENDER

ABSTRACT Background: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. Methods: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. Conclusion: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. ClinicalTrials.gov registry: NCT05558098

RESUMO Antecedentes: A doença crítica é um importante ônus permanente da assistência médica em todo o mundo e está associada a altas taxas de mortalidade. Os inibidores do cotransportador de sódio-glicose do tipo 2 têm demonstrado consistentemente benefícios nos desfechos cardiovasculares e renais. Os efeitos dos inibidores do cotransportador de sódio-glicose do tipo 2 em doenças agudas ainda não foram devidamente investigados. Métodos: O DEFENDER é um estudo de iniciativa do investigador, multicêntrico, randomizado, aberto, desenhado para avaliar a eficácia e a segurança da dapagliflozina em 500 participantes adultos com disfunção orgânica aguda hospitalizados na unidade de terapia intensiva. Os participantes aptos serão randomizados 1:1 para receber 10mg de dapagliflozina e o tratamento padrão por até 14 dias ou apenas o tratamento padrão. O desfecho primário é um composto hierárquico de mortalidade hospitalar, início de terapia renal substitutiva e tempo de internação na unidade de terapia intensiva, até 28 dias. O monitoramento da segurança será rigoroso durante todo o estudo. Conclusão: O DEFENDER é o primeiro estudo desenvolvido para investigar o uso de um inibidor do cotransportador de sódio-glicose do tipo 2 em pacientes de unidade de terapia intensiva geral com disfunção orgânica aguda. O estudo fornecerá informações relevantes sobre o uso de medicamentos dessa classe promissora em pacientes críticos. Registro ClincalTrials.gov: NCT05558098

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.

Effects of sodium-glucose cotransporter-2 inhibitors on nutritional status in heart failure with reduced ejection fraction

SUMMARY OBJECTIVE: This study aimed to evaluate the effects of sodium-glucose cotransporter-2 inhibitors on nutritional status in patients with heart failure with reduced ejection fraction. METHODS: The sodium-glucose cotransporter-2 inhibitor treatment was initiated in 153 patients with heart failure with reduced ejection fraction who were symptomatic despite optimal medical treatment and were followed up for 6 months. The Minnesota Living With Heart Failure Questionnaire scores, New York Heart Association functional class, NT-pro-BNP levels, and nutritional index scores of the patients were evaluated before sodium-glucose cotransporter-2 inhibitor treatment and at the 6-month follow-up. The nutritional status of the patients was evaluated with the COntrolling NUTritional Status score, Geriatric Nutritional Risk Index, and Prognostic Nutritional Index. RESULTS: After sodium-glucose cotransporter-2 inhibitor treatment, significant changes were observed in the mean scores of the three different nutritional indexes: COntrolling NUTritional Status (before: 2.76±2.43 vs. after: 1.12±1.23, p<0.001), Geriatric Nutritional Risk Index (before: 98.2±9.63 vs. after: 104.4±5.83, p<0.001), and Prognostic Nutritional Index (before: 37.9±4.63 vs. after: 42.9±3.83, p<0.001) scores. A significant decrease in the number of patients with malnutrition was observed according to the COntrolling NUTritional Status (before: 46.4% vs. after: 9.7%, p<0.001), Geriatric Nutritional Risk Index (before: 41.8% vs. after: 18.9%, p=0.006), and Prognostic Nutritional Index (before: 36.6% vs. after: 13.7%, p=0.007) scores. A significant functional improvement was observed in patients after sodium-glucose cotransporter-2 treatment: Minnesota Living With Heart Failure Questionnaire scores (before: 39.2±7.2 vs. after: 20.4±7.4, p<0.001), NT-pro-BNP levels (before: 2989±681 vs. after: 1236±760, p<0.001), and New York Heart Association class (before: class II-III: 95.5%; class IV: 4.5% vs. after: class II-III: 78%; class IV: 0%, p<0.001). CONCLUSION: In patients with heart failure with reduced ejection fraction who are symptomatic despite optimal medical treatment, the addition of an sodium-glucose cotransporter-2 inhibitor to treatment can significantly improve both the nutritional and functional statuses.

Efficacy and safety of sodium-glucose transporter 2 inhibitors in the treatment of heart failure: A meta-analysis / 国际生物医学工程杂志

Objective:To evaluate the efficacy and safety of sodium-glucose transporter 2 (SGLT2) inhibitors in the treatment of heart failure (HF).Methods:PubMed, ScienceDirect, EMbase, VIP, CNKI and WanFang Data were searched, randomized controlled trials (RCTs) of SGLT2 inhibitors in the treatment of heart failure were included, and quality evaluation and data extraction were carried out.Results:Ten RCTs (9 544 patients) were included. Meta-analysis showed that there were statistically significant differences between the SGLT2 inhibitor group and the control group in terms of heart failure hospitalization rate or heart failure emergency department visit rate[ RR=0.72, 95% CI(0.65, 0.81), P<0.000 01], all-cause mortality[ RR=0.87, 95% CI(0.78, 0.97), P=0.01], cardiovascular mortality[ RR=0.87, 95% CI(0.77, 0.99), P=0.03], and the reduction of N-terminal pro-brain natriuretic peptide[ RR=-133.76, 95% CI(-229.50, -38.01), P=0.006]. But there was no statistically significant difference in the change of left ventricular ejection fraction (LVEF) after the treatment ( P>0.05). The subgroup analysis showed that there were statistically significant differences between the dapagliflozin group and the heart failure group with reduced ejection fraction (HFrEF) in terms of heart failure hospitalization rate or heart failure emergency department visit rate, all-cause mortality, cardiovascular mortality, and reduced levels of NT-proBNP (all P<0.05). The patients with unknown LVEF and empagliflozin were significantly different from the control group in terms of heart failure hospitalization rate or heart failure emergency department visit rate (all P<0.05). Compared with the control group, the SGLT2 inhibitor group can reduce the risk of adverse renal reactions [ RR=0.82, 95% CI(0.68, 0.99), P=0.03]. Conclusions:SGLT2 inhibitors, especially dapagliflozin, can improve the survival rate of patients with HFrEF and have good safety.

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.

Anti-Inflammatory Effect for Atherosclerosis Progression by Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitor in a Normoglycemic Rabbit Model

BACKGROUND AND OBJECTIVES: We sought to investigate an anti-atherosclerotic and anti-inflammatory effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in normoglycemic atherosclerotic rabbit model.METHODS: Male New Zealand white rabbits (n=26) were fed with a 1% high-cholesterol diet for 7 weeks followed by normal diet for 2 weeks. After balloon catheter injury, the rabbits were administered with the Dapagliflozin (1mg/kg/day) or control-medium for 8 weeks (n=13 for each group). All lesions were assessed with angiography, optical coherence tomography (OCT), and histological assessment.RESULTS: Atheroma burden (38.51±3.16% vs. 21.91±1.22%, p<0.01) and lipid accumulation (18.90±3.63% vs. 10.20±2.03%, p=0.047) was significantly decreased by SGLT-2 inhibitor treatment. The SGLT-2 inhibitor group showed lower macrophage infiltration (20.23±1.89% vs. 12.72±1.95%, p=0.01) as well as tumor necrosis factor (TNF)-α expression (31.17±4.40% vs. 19.47±2.10%, p=0.025). Relative area of inducible nitric oxide synthase+ macrophages was tended to be lower in the SGLT-2 inhibitor-treated group (1.00±0.16% vs. 0.71±0.10%, p=0.13), while relative proportion of Arg1⁺ macrophage was markedly increased (1.00±0.27% vs. 2.43±0.64%, p=0.04). As a result, progression of atherosclerosis was markedly attenuated in SGLT-2 inhibitor treated group (OCT area stenosis, 32.13±1.20% vs. 22.77±0.88%, p<0.01). Mechanistically, SGLT-2 treatment mitigated the inflammatory responses in macrophage. Especially, Toll-like receptor 4/nuclear factor-kappa B signaling pathway, and their downstream effectors such as interleukin-6 and TNF-α were markedly suppressed by SGLT-2 inhibitor treatment.CONCLUSIONS: These results together suggest that SGLT-2 inhibitor exerts an anti-atherosclerotic effect through favorable modulation of inflammatory response as well as macrophage characteristics in non-diabetic situation.

Use of SGLT-2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Abdominal Obesity: An Asian Perspective and Expert Recommendations

The prevalence of obesity in Asia is of epidemic proportions, with an estimated 1 billion overweight/obese individuals in the region. The majority of patients with type 2 diabetes mellitus (T2DM) are overweight/obese, which increases the risk of cardiorenal outcomes in these patients; hence, sustained reductions in body weight and visceral adiposity are important management goals. However, most of the glucose-lowering therapies such as insulin, sulfonylureas, glinides, and thiazolidinediones induce weight gain, which makes the management of overweight/obese T2DM patients challenging. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the only oral glucose-lowering agents that have been shown to reduce body weight and visceral adiposity. In addition, SGLT-2 inhibitors therapy reduces ectopic fat deposition and improves adipose tissue function and weight-related quality of life. In this article, we aim to consolidate the existing literature on the effects of SGLT-2 inhibitors in Asian patients with T2DM and to produce clinical recommendations on their use in overweight or obese patients with T2DM. Recommendations from international and regional guidelines, as well as published data from clinical trials in Asian populations and cardiovascular outcomes trials are reviewed. Based on the available data, SGLT-2 inhibitors represent an evidence-based therapeutic option for the management of overweight/obese patients with T2DM.

Experiencia de uso de inhibidores del cotransportador sodio-glucosa 2 en diabéticos tipo 2 / Use of sodium-glucose cotrasporter 2 inhibitors in type 2 diabetics: experience in 77 patients

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new pharmacological alternative for the treatment of diabetes. Aim: To report our experience with the use of this type of drugs in type 2 diabetics treated in an outpatient clinic. Material and Methods: We selected 77 type 2 diabetic patients aged 59 ± 11 years (45 men) who started SGLT2i, based on the advice of their treating physician. We registered their demographic characteristics and changes in metabolic parameters, weight, blood pressure, albuminuria and adverse effects, during a follow-up of at least three months. Results: We observed a decrease of glycosylated hemoglobin A1c of 0.8 ± 1.14% (p < 0.01) and a weight decrease of 2.5 ± 2.24 kg (p < 0.01). The proportion of patients with a glycosylated hemoglobin A1c of less than 7% increased from 7.2% to 30.9% (p = 0.002). In addition, a relative decrease in albuminuria of 39.9% was observed (p = 0.07). The treatment was well tolerated with a rate of adverse effects of 21%, all of them being categorized as mild. Of these, most of them corresponded to genital mycotic infections. Conclusions: The effects observed in this study are comparable and of similar magnitude to randomized studies of SGLT2i reported in the international literature.

Efectos nefrológicos de los SGLT2. ¿Qué sabemos hasta ahora? / Nephrological effects of SGLT2. What do we know so far?

Resumen: La prevalencia de diabetes mellitus tipo 2 ha crecido de manera significativa, longitudinal y continua a lo largo de los años. Se infiere que el número de adultos con nefropatía diabética también aumentará. Por consiguiente, la nefropatía diabética conserva sustancial importancia en la salud global y existe gran necesidad de minimizar la morbilidad de este padecimiento. Los inhibidores del cotransportador de sodio-glucosa 2 (SGLT2) son la clase farmacológica incorporada más recientemente a los recursos terapéuticos de antidiabéticos orales. Su acción se basa en el bloqueo de los cotransportadores SGLT2 sodio-glucosa que se encuentran en la membrana luminal de las células del túbulo contorneado proximal. Reducen las tasas de hiper-glucemia en pacientes con diabetes mellitus tipo 2 al disminuir la reabsorción renal de glucosa, aumentando así la excreción urinaria de glucosa. Se han demostrado reducciones significativas en hemoglobina glucosilada (HbA1c), junto con disminución de glucosa sérica en ayuno y posprandial en pacientes con diabetes mellitus tipo 2. Aunque la eficacia de los inhibidores de SGLT2 se ve afectada por la función renal, se han realizado subanálisis que evidencian que los inhibidores SGLT2, incluso en el contexto de insuficiencia renal grado 3b o 4, tienen efectos neutros en HbA1c, pero mejoran los parámetros bioquímicos y disminuyen el peso. El objetivo de este artículo es revisar la bibliografía disponible en la actualidad de los efectos renales de los inhibidores de SGLT2.

Abstract Prevalence of type 2 diabetes has increased significantly. It is inferred that the number of adults with diabetic nephropathy will also increase. Therefore, diabetic nephropathy will gain importance in global health and there is a need to minimize morbidity associated to this disease. Sodium-glucose transporter type 2 (SGLT2) inhibitors are the latest pharmacologic class of oral antidiabetics. They act upon the inhibition of SGLT2 co-transporters located in the luminal membrane of cells in the proximal convoluted tubule. Significant reductions in glycated haemoglobin levels, along with lower fasting glucose levels have been associated to SGLT2 inhibitors. Efficacy of SGLT2 inhibitors is affected with kidney failure, nonetheless, a subgroup study showed that SGLT2 inhibitors administered in the context of kidney failure (KDIGO stage 3b or 4) have neutral effects over HbA1C levels, but positive effects over other biochemical parameters and weight loss. The objective of this article is to review literature of renal effects of SGLT2 inhibitors.

Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors

BACKGROUND: We investigated the predictive markers for the therapeutic efficacy and the best combination of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, and ipragliflozin) therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 804 patients with T2DM who had taken SGLT2 inhibitor as monotherapy or an add-on therapy were analyzed. Multivariate regression analyses were performed to identify the predictors of SGLT2 inhibitor response including the classes of baseline anti-diabetic medications. RESULTS: After adjusting for age, sex, baseline body mass index (BMI), diabetes duration, duration of SGLT2 inhibitor use, initial glycosylated hemoglobin (HbA1c) level, estimated glomerular filtration rate (eGFR), and other anti-diabetic agent usage, multivariate analysis revealed that shorter diabetes duration, higher initial HbA1c and eGFR were associated with better glycemic response. However, baseline BMI was inversely correlated with glycemic status; lean subjects with well-controlled diabetes and obese subjects with inadequately controlled diabetes received more benefit from SGLT2 inhibitor treatment. In addition, dipeptidyl peptidase 4 (DPP4) inhibitor use was related to a greater reduction in HbA1c in patients with higher baseline HbA1c ≥7%. Sulfonylurea users experienced a larger change from baseline HbA1c but the significance was lost after adjustment for covariates and metformin and thiazolidinedione use did not affect the glycemic outcome. CONCLUSION: A better response to SGLT2 inhibitors is expected in Korean T2DM patients who have higher baseline HbA1c and eGFR with a shorter diabetes duration. Moreover, the add-on of an SGLT2 inhibitor to a DPP4 inhibitor is likely to show the greatest glycemic response.

Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

BACKGROUND AND OBJECTIVES: Recent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes. METHODS: Cardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects. RESULTS: Mice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor. CONCLUSIONS: SGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.

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.

Sodium-Glucose Cotransporter 2 Inhibitors: Mechanisms of Action and Various Effects / 임상당뇨병

The basic action mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor is to lower the glucose burden by excreting the glucose filtered by the kidney into the urine. Although SGLT2 inhibitors are primarily indicated as glucose-lowering agents, they have a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. That might be why SGLT2 inhibition causes spill-over of sodium and glucose beyond the proximal tubule, triggering dynamic and reversible realignment of energy metabolism, renal filtration, and plasma volume. A better understanding of SGLT2 inhibition in the kidney and the entire body will lead to more benefits in people with and without diabetes.

SGLT2 inhibitors as adjunct therapy to insulin in type 1 diabetes: Meta analysis / 解放军医学杂志

Objective To evaluate the efficacy and safety of sodium glucose co-transporter-2 (SGLT-2) inhibitors as adjunct therapy to insulin in type 1 diabetes (T1DM). Methods The PubMed, The Cochrane Library, EMbase, CENTRRAI, CBM, CNKI, VIP and WangFang database were searched from inception to April 5, 2016 for systematic reviews, references screen was performed manually. The trials of SGLT2 inhibitors versus placebo add to insulin carried out in patients with T1DM were collected, and their bias risk was assessed and meta-analysis was conducted by using RevMan 5.3 software. Results Four randomized control trials (RCTs) were yielded for meta-analysis, including 529 patients. Compared with control group, SGLT2 inhibitors as adjunct therapy to insulin significantly reduced fasting plasma glucose (FPG) [weighted mean difference (WMD)= –0.65mmol/L, 95% confidence interval (CI)=–1.30 to –0.08, P<0.05], glycated hemoglobin A1C (HbA1c) (WMD=–0.37%, 95%CI= –0.54 to –0.20, P<0.00001), body weight (WMD=–2.54kg, 95%CI=–3.48 to –1.60, P<0.0001) and total daily insulin dose (WMD= –6.23IU, 95% CI=–8.05 to –4.40, P<0.0001), but the total adverse events (AEs), hypoglycemia, genital and urinary infections showed no significant difference. Conclusions Based on current studies, SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, may improve glycemic control, reduce body weight and total daily insulin dose without increase of total AEs, hypoglycemia, and genital and urinary infections.

Salutary contributions in addition to hypoglycemic effects of new antidiabetic sodium-glucose transporter 2 inhibitors / 中华内分泌代谢杂志

[Summary] The prevalence of diabetes mellitus in China is increasing significantly in recent decades. According to the results from the diabetes survey of 2010 China Noncommunicable Disease Surveillance Group, the overall prevalence of diabetes was estimated to be 11. 6% ( about 113. 9 millions ) in the Chinese adult population. Despite of the various available treatments, there is still a significant number of diabetes mellitus patients that cannot achieve or maintain their glycemic controls. Additionally, several side effects of these therapies have also been observed, including hypoglycemia, weight gain, fluid retention, and gastrointestinal reactions. Sodium-glucose transporter-2 inhibitors ( SGLT-2is) refer to a new type of antidiabetic drug with its unique mechanism. SGLT-2is inhibit glucose reabsorption in kidney through inhibition of SGLT-2 receptors and thereby reduce plasma glucose by enhancing glucosuria in patients with type 2 diabetes mellitus. In addition to the efficacy in reducing blood glucose, SGLT-2is also show salutary benefits in lowering the body weight, blood pressure, and the risk of cardiovascular events, which have been confirmed recently, providing a promising therapeutic weapon for type 2 diabetes mellitus.