Effects of canagliflozin on amino acid metabolism in atherosclerotic mice / 中华心血管病杂志

Objective: To explore the possible anti-atherosclerotic mechanisms of glucose co-transporter-2 inhibitor canagliflozin. Methods: ApoE-/-mice fed on Western diet were randomly assigned into the model group (n=10) and the canagliflozin group (n=10). C57BL/6J mice fed on normal diet were chosen as the control group (n=10). Mice in the canagliflozin group were gavaged with canagliflozin for 14 weeks. The presence and severity of atherosclerosis were evaluated with HE and oil red O stainings in aortic root section slices. PCR assay was performed to determine the mRNA expression levels of nitric oxide synthase. Hepatic transcriptome analysis and hepatic amino acid detection were conducted using RNA-seq and targeted LC-MS, respectively. Results: HE staining and oil red O staining of the aortic root showed that AS models were successfully established in ApoE-/-mice fed on Western diet for 14 weeks. Canagliflozin alleviated the severity of atherosclerosis in pathology. Hepatic transcriptome analysis indicated that canagliflozin impacted on amino acid metabolism, especially arginine synthesis in ApoE-/-mice. Targeted metabolomics analysis of amino acids showed that canagliflozin reduced hepatic levels of L-serine, L-aspartic acid, tyrosine, L-hydroxyproline, and L-citrulline, but raised the hepatic level of L-arginine. Compared to the model group, the canagliflozin group exhibited higher serum arginine and nitric oxide levels as well as elevated nitric oxide mRNA expression in aortic tissues (P<0.05). Conclusion: Canagliflozin regulated the amino acid metabolism, reduced the levels of glucogenic amino acids,and promoted the synthesis of arginine in atherosclerotic mice.

Effects of canagliflozin on amino acid metabolism in atherosclerotic mice / 中华心血管病杂志

Objective: To explore the possible anti-atherosclerotic mechanisms of glucose co-transporter-2 inhibitor canagliflozin. Methods: ApoE-/-mice fed on Western diet were randomly assigned into the model group (n=10) and the canagliflozin group (n=10). C57BL/6J mice fed on normal diet were chosen as the control group (n=10). Mice in the canagliflozin group were gavaged with canagliflozin for 14 weeks. The presence and severity of atherosclerosis were evaluated with HE and oil red O stainings in aortic root section slices. PCR assay was performed to determine the mRNA expression levels of nitric oxide synthase. Hepatic transcriptome analysis and hepatic amino acid detection were conducted using RNA-seq and targeted LC-MS, respectively. Results: HE staining and oil red O staining of the aortic root showed that AS models were successfully established in ApoE-/-mice fed on Western diet for 14 weeks. Canagliflozin alleviated the severity of atherosclerosis in pathology. Hepatic transcriptome analysis indicated that canagliflozin impacted on amino acid metabolism, especially arginine synthesis in ApoE-/-mice. Targeted metabolomics analysis of amino acids showed that canagliflozin reduced hepatic levels of L-serine, L-aspartic acid, tyrosine, L-hydroxyproline, and L-citrulline, but raised the hepatic level of L-arginine. Compared to the model group, the canagliflozin group exhibited higher serum arginine and nitric oxide levels as well as elevated nitric oxide mRNA expression in aortic tissues (P<0.05). Conclusion: Canagliflozin regulated the amino acid metabolism, reduced the levels of glucogenic amino acids,and promoted the synthesis of arginine in atherosclerotic mice.

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.

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.

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.