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The management of heart failure (HF) in patients with type 2 diabetes has significantly evolved with the introduction of sodium-glucose cotransporter 2 (SGLT2) inhibitors. This article aims to consolidate existing knowledge on the efficacy of these inhibitors in managing HF in this patient population. Major medical databases, including PubMed, Scopus, and Web of Science, were reviewed, prioritizing research from the last decade. The results of this review highlight the mechanisms of action of SGLT2 inhibitors, their clinical benefits, challenges in patient management, and outcomes associated with their use. These medications were found to not only improve glycemic control but also offer significant cardiovascular and renal benefits, reducing cardiovascular mortality and major adverse cardiovascular events. However, challenges and knowledge gaps persist, particularly regarding long-term effects and safety in diverse populations. The conclusions of this review underscore the importance of updating clinical guidelines to incorporate these findings and propose the need for future research to address existing gaps and optimize the use of SGLT2 inhibitors in clinical practice.
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Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5'-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia-reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.
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BACKGROUND AND OBJECTIVES: The efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) may depend on renal function, and this raises theoretical concern over its effects on cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS: This systematic review and updated meta-analysis of randomized controlled trials (RCTs) compared cardiovascular outcomes of patients with T2DM and CKD treated with SGLT2i to placebo. PubMed, Embase, and Cochrane were systematically searched. Prespecified subgroup analyses were performed in strata of estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73 m² and 45 to 59 mL/min/1.73 m². RESULTS: Nine RCTs comprising 29,146 patients were selected. Average follow-up ranged from 0.75 to 4.2 years. SGLT2i were shown to reduce the risk of all-cause mortality (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.79-0.97; p=0.01), the composite of cardiovascular mortality or hospitalizations for heart failure (HHF: HR, 0.71; 95% CI, 0.65-0.78; p<0.001), cardiovascular mortality (HR, 0.86; 95% CI, 0.76-0.98; p=0.02), HHF (HR, 0.62; 95% CI, 0.55-0.71; p<0.001), major adverse cardiovascular events (HR, 0.85; 95% CI, 0.77-0.94; p=0.002), stroke (HR, 0.76; 95% CI, 0.59-0.97; p=0.03), and myocardial infarction (HR, 0.78; 95% CI, 0.67-0.91; p=0.001). These findings were consistent over strata of eGFR, albeit with a lower incidence of stroke in patients treated with SGLT2i with eGFR <45 mL/min/1.73 m² (p-value for interaction=0.04). CONCLUSIONS: Compared with a placebo, patients with T2DM and CKD treated with SGLT2i experience a reduction in all-cause mortality, cardiovascular mortality, and HHF. TRIAL REGISTRATION: PROSPERO Identifier: CRD42023401081.
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Glicemia , Controle Glicêmico , Hipoglicemiantes , Humanos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismoRESUMO
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC α and γ subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension.NEW & NOTEWORTHY This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least in part, for the BP-lowering effect of SGLT2 inhibitors in the setting of hypertension. It also demonstrates that chronic treatment with SGLT2 inhibitors upregulates NCC activity, phosphorylation, and expression in the distal tubule of normotensive but not hypertensive rats. SGLT2 inhibitor-mediated upregulation of NCC seems crucial to counteract proximal tubule natriuresis in subjects with normal BP.
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Compostos Benzidrílicos , Glucosídeos , Hipertensão , Ratos Endogâmicos SHR , Ratos Wistar , Inibidores do Transportador 2 de Sódio-Glicose , Trocador 3 de Sódio-Hidrogênio , Regulação para Cima , Animais , Masculino , Trocador 3 de Sódio-Hidrogênio/metabolismo , Trocador 3 de Sódio-Hidrogênio/genética , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Glucosídeos/farmacologia , Compostos Benzidrílicos/farmacologia , Regulação para Cima/efeitos dos fármacos , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/genética , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Rim/metabolismo , Rim/efeitos dos fármacosRESUMO
BACKGROUND: Sodium-glucose cotransporter (SGLT)2 inhibitors have displayed beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, their effects in Type 1 DM have not been established. OBJECTIVE: To evaluate the influence of long-term treatment with SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, energy metabolism, and metabolomics in rats with Type 1 DM. METHODS: Male Wistar rats were divided into groups: Control (C, n = 15); DM (n = 15); and DM treated with dapagliflozin (DM + DAPA, n = 15) for 30 weeks. DM was induced by streptozotocin. Dapagliflozin 5 mg/kg/day was added to chow. STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn. RESULTS: DM + DAPA presented lower glycemia and higher body weight than DM. Echocardiogram showed DM with left atrium dilation and left ventricular (LV) hypertrophy, dilation, and systolic and diastolic dysfunction. In LV isolated papillary muscles, DM had reduced developed tension, +dT/dt and -dT/dt in basal condition and after inotropic stimulation. All functional changes were attenuated by dapagliflozin. Hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) activity was lower in DM than C, and PFK and PK activity higher in DM + DAPA than DM. Metabolomics revealed 21 and 5 metabolites positively regulated in DM vs. C and DM + DAPA vs. DM, respectively; 6 and 3 metabolites were negatively regulated in DM vs. C and DM + DAPA vs. DM, respectively. Five metabolites that participate in cell membrane ultrastructure were higher in DM than C. Metabolites levels of N-oleoyl glutamic acid, chlorocresol and N-oleoyl-L-serine were lower and phosphatidylethanolamine and ceramide higher in DM + DAPA than DM. CONCLUSION: Long-term treatment with dapagliflozin attenuates cardiac remodeling, myocardial dysfunction, and contractile reserve impairment in Type 1 diabetic rats. The functional improvement is combined with restored pyruvate kinase and phosphofructokinase activity and attenuated metabolomics changes.
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SGLT2 inhibitors (SGLT2i) are now the mainstay therapy for both diabetes and heart failure. Post-hoc publications, meta-analysis, and conference presentations of the eight SGLT2i Cardiovascular Outcomes trials (CVOTS) done in diabetic patients constantly echo that this class of drug decreases mortality, reduces cardiovascular events, and prevents heart failure and kidney disease. This review of medical agencies' SGLT2i analysis (FDA and EMA) helps to understand the reality of SGLT2i results in those trials, avoiding to consider observational and statistically undemonstrated endpoints as validated. They also confirmed the unique diuretic mode of action of SGLT2i, promoting osmotic diuresis, and its potential adverse events secondary to hypovolemia and hematocrit increase. They also support the understanding that the beliefs in SGLT2i morbi-mortality benefits are largely overstated mostly based on undemonstrated endpoints. Finally, it is clear that SGLT2i's antidiabetic action, secondary to its renal mode of action, plateaued after a few months and decreased strongly over time, questioning its long-term goal of maintaining diabetic patients' HbA1c below 7%. Also, this effect in patients with renal impairment is quasi null. We think that this review would be very helpful to every physician treating diabetic patients to better balance belief and reality of SGLT2i prescription effects.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/complicações , Estudos Observacionais como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.
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BACKGROUND: Percutaneous coronary intervention (PCI) is one of the most performed well-succeeded therapeutic procedures worldwide, reducing symptoms and improving quality of life. Neutrophil Gelatinase-associated Lipocalin (NGAL) is a biomarker of acute kidney injury (AKI) produced early after an ischemic renal insult. Osmotic diuresis and the vasoconstriction of the afferent arteriole promoted by Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) generate a concern regarding the possibility of dehydration and consequent AKI. There is no consensus on the maintenance or discontinuation of SGTL2i in patients who will undergo PCI. This study aimed to evaluate the safety of empagliflozin in diabetic patients submitted to elective PCI regarding kidney function. METHODS: SAFE-PCI trial is a prospective, open-label, randomized (1:1), single-center pilot study and a follow-up of 30 days. The SGLT2i empagliflozin 25 mg daily was initiated at least 15 days before PCI in the intervention group and maintained until the end of the follow-up period. Serum NGAL was collected 6 h after PCI and creatinine before PCI, 24 h, and 48 h after the procedure. As per protocol, both groups received optimal medical treatment and standard protocol of nephroprotection. RESULTS: A total of 42 patients were randomized (22 patients in the iSGLT-2 group and 20 patients in the control group). There was no difference between-group baseline data. The primary outcome (NGAL and creatinine values post PCI) did not differ in both groups: the mean NGAL value was 199 ng/dL in the empagliflozin group and 150 ng/dL in the control group (p = 0.249). Although there was an initial increase in creatinine in the SGLT-2i group compared to the control group between baseline creatinine and pre-PCI and 24 h post-PCI creatinine, no difference was detected in creatinine 48 h post-PCI (p = 0.065). The incidence of CI-AKI, determined by KDIGO criteria, in the iSGLT2-group was 13.6% and 10.0% in the control group without statistical difference. CONCLUSION: The present study showed that the use of empagliflozin is safe regarding kidney function during elective PCI in patients with T2D when compared with no use of SGLT2i. Trial registration Our clinical study is registered on ClinicalTrials.gov with the following number: NCT05037695.
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PURPOSE OF REVIEW: To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes. RECENT FINDINGS: Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1ß (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.
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Doenças Cardiovasculares , Diabetes Mellitus , Hipertensão , Síndrome Metabólica , Sirtuínas , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Sirtuínas/metabolismo , Sirtuínas/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Remodelação Ventricular , Hipertensão/tratamento farmacológico , Estresse Oxidativo/fisiologia , Angiotensina II/metabolismo , FibroseRESUMO
BACKGROUND: We sought to compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for acute heart failure (AHF) with or without the addition of SGLT2i. METHODS AND RESULTS: Systematic search of three electronic databases identified nine eligible randomized controlled trials involving 2,824 patients. The addition of SGLT2i to conventional therapy for AHF reduced all-cause death (odds ratio [OR] 0.75; 95% CI 0.56-0.99; p = 0.049), readmissions for heart failure (HF) (OR 0.54; 95% CI 0.44-0.66; p < 0.001), and the composite of cardiovascular death and readmissions for HF (hazard ratio 0.71; 95% CI 0.60-0.84; p < 0.001). Furthermore, SGLT2i increased mean daily urinary output in liters (mean difference [MD] 0.45; 95% CI 0.03-0.87; p = 0.035) and decreased mean daily doses of loop diuretics in mg of furosemide equivalent (MD -34.90; 95% CI [- 52.58, - 17.21]; p < 0.001) without increasing the incidence worsening renal function (OR 0.75; 95% CI 0.43-1.29; p = 0.290). CONCLUSION: SGLT2i addition to conventional diuretic therapy reduced all-cause death, readmissions for HF, and the composite of cardiovascular death or readmissions for HF. Moreover, SGLT2i was associated with a higher volume of diuresis with a lower dose of loop diuretics.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diuréticos/efeitos adversos , Diuréticos/farmacologia , Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Rim/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Simportadores de Cloreto de Sódio e Potássio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50-60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation. The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars. To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results. It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied. We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.
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Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Criança , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Carcinoma Hepatocelular/complicações , Controle Glicêmico , Neoplasias Hepáticas/complicações , Cirrose Hepática/complicações , Redução de PesoRESUMO
Introduction: SGLT2 inhibitors (SGLT2Is) have demonstrated cardioprotective and nephroprotective effects in patients with and without diabetes. Recent studies suggest that SGLT2Is may reduce the risk of contrast-induced nephropathy (CIN) in patients with diabetes undergoing coronary arteriography (CAG) or percutaneous coronary interventions (PCI). However, the evidence is still inconclusive. We aimed to systematically review the evidence regarding the potential nephroprotective role of SGLT2Is in preventing CIN in this population. Methods: We searched for studies in six databases published up to September 30, 2023, following a PECO/PICO strategy. Initially, we meta-analyzed five studies, but due to several reasons, mainly methodological concerns, we excluded one RCT. In our final meta-analysis, we included four observational studies. Results: This meta-analysis comprised 2,572 patients with diabetes undergoing CAG or PCI, 512 patients treated with SGLT2Is, and 289 events of CIN. This is the first meta-analysis demonstrating that SGLT2Is may reduce the risk of developing CIN by up to 63% (RR 0.37; 95% CI 0.24-0.58) in patients with diabetes undergoing CAG or PCI, compared to not using SGLT2Is. Statistical heterogeneity was not significant (I2 = 0%, p = 0.91). We assessed the certainty of the evidence of this systematic review and meta-analysis, according to the GRADE criteria, as moderate. Conclusion: SGLT2Is significantly reduce the risk of CIN by up to 63% in patients with diabetes undergoing CAG or PCI. Clinical trials are needed; several are already underway, which could confirm our findings and investigate other unresolved issues, such as the optimal dose, type, and duration of SGLT2 inhibitor therapy to prevent CIN. Systematic Review: PROSPERO, identifier CRD42023412892.
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Injúria Renal Aguda , Diabetes Mellitus , Intervenção Coronária Percutânea , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Injúria Renal Aguda/induzido quimicamente , Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Diabetes Mellitus/etiologia , Estudos Observacionais como Assunto , Intervenção Coronária Percutânea/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
La insuficiencia cardíaca (IC) es un problema de salud mundial. En la actualidad existe una clara asociación entre la IC y la diabetes mellitus tipo 2 (DM2), con una prevalencia cada vez mayor de pacientes que presentan concomitantemente ambas patologías. Los inhibidores del cotransportador 2 de sodio-glucosa (ISGLT2) han demostrado disminuir los eventos cardiovasculares, incluida la muerte de origen cardiovascular, por lo que se han instalado como uno de los pilares en su tratamiento. En el presente artículo se describen los principales mecanismos de acción de los ISGLT2 y sus efectos: mejora de condiciones de carga ventricular, metabolismo cardíaco, bioenergética, remodelado ventricular y sus efectos cardioprotectores directos y posiblemente antiarrítmicos.
Heart failure (HF) is a global health problem. Currently there is a clear association between HF and type 2 diabetes mellitus (DM2), with an increasing prevalence of patients presenting with both pathologies concomitantly. Sodium-glucose cotransporter 2 inhibitors (ISGLT2) have shown to significantly reduce cardiovascular events, including cardiovascular death. These results have placed ISGLT2 as one of the main pillars in the treatment of HF. This article will focus on the mechanisms of action, and their effects: improved ventricular loading conditions, cardiac metabolism, bioenergetics, ventricular remodeling, direct cardioprotective and possibly antiarrhythmic effects.
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Humanos , Cardiotônicos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Cardiotônicos/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
The development of essential hypertension involves several factors. Vascular dysfunction, characterized by endothelial dysfunction, low-grade inflammation and structural remodeling, plays an important role in the initiation and maintenance of essential hypertension. Although the mechanistic pathways by which essential hypertension develops are poorly understood, several pharmacological classes available on the clinical settings improve blood pressure by interfering in the cardiac output and/or vascular function. This review is divided in two major sections. The first section depicts the major molecular pathways as renin angiotensin aldosterone system (RAAS), endothelin, nitric oxide signalling pathway and oxidative stress in the development of vascular dysfunction. The second section describes the role of some pharmacological classes such as i) RAAS inhibitors, ii) dual angiotensin receptor-neprilysin inhibitors, iii) endothelin-1 receptor antagonists, iv) soluble guanylate cyclase modulators, v) phosphodiesterase type 5 inhibitors and vi) sodium-glucose cotransporter 2 inhibitors in the context of hypertension. Some classes are already approved in the treatment of hypertension, but others are not yet approved. However, due to their potential benefits these classes were included.
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Anti-Hipertensivos , Hipertensão , Humanos , Anti-Hipertensivos/farmacologia , Músculo Liso Vascular/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Neprilisina/metabolismo , Óxido Nítrico/metabolismo , Hipertensão Essencial/tratamento farmacológico , Hipertensão Essencial/metabolismo , Inibidores da Fosfodiesterase 5/uso terapêutico , Receptor de Endotelina A/metabolismo , Hipertensão/metabolismo , Sistema Renina-Angiotensina , Endotelinas/metabolismo , Endotelinas/farmacologia , Endotelinas/uso terapêutico , Antagonistas dos Receptores de Endotelina/farmacologia , Receptores de Angiotensina/metabolismo , Receptores de Angiotensina/uso terapêutico , Glucose/metabolismo , Sódio/metabolismo , Sódio/farmacologia , Sódio/uso terapêuticoRESUMO
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.
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Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Glicemia , Peso Corporal , Brasil , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
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.
Assuntos
Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hipoglicemiantes/uso terapêutico , Sangue , Peso Corporal , Brasil , Hemoglobinas Glicadas/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Canagliflozina/uso terapêuticoRESUMO
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.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Hipertensão/tratamento farmacológicoRESUMO
Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.