Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies.

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence.

Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.

Sodium-Glucose Cotransporter Inhibitors: Cellular Mechanisms Involved in the Lipid Metabolism and the Treatment of Chronic Kidney Disease Associated with Metabolic Syndrome.

Metabolic syndrome (MetS) is a multifactorial condition that significantly increases the risk of cardiovascular disease and chronic kidney disease (CKD). Recent studies have emphasized the role of lipid dysregulation in activating cellular mechanisms that contribute to CKD progression in the context of MetS. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated efficacy in improving various components of MetS, including obesity, dyslipidemia, and insulin resistance. While SGLT2i have shown cardioprotective benefits, the underlying cellular mechanisms in MetS and CKD remain poorly studied. Therefore, this review aims to elucidate the cellular mechanisms by which SGLT2i modulate lipid metabolism and their impact on insulin resistance, mitochondrial dysfunction, oxidative stress, and CKD progression. We also explore the potential benefits of combining SGLT2i with other antidiabetic drugs. By examining the beneficial effects, molecular targets, and cytoprotective mechanisms of both natural and synthetic SGLT2i, this review provides a comprehensive understanding of their therapeutic potential in managing MetS-induced CKD. The information presented here highlights the significance of SGLT2i in addressing the complex interplay between metabolic dysregulation, lipid metabolism dysfunction, and renal impairment, offering clinicians and researchers a valuable resource for developing improved treatment strategies and personalized approaches for patients with MetS and CKD.

Importance of genetic sequencing studies in managing chronic neonatal diarrhea: a case report of a novel variant in the glucose-galactose transporter SLC5A1.

Introduction: Congenital glucose-galactose malabsorption (CGGM) is a rare autosomal recessive disorder that primarily causes chronic intractable diarrhea. This study aims to describe the clinical history, laboratory profile, diagnostic workflow, and management of the first patient reported with CGGM in Mexico. Methods: The case involves a Mexican female infant with recurrent admissions to the emergency room since birth due to chronic diarrhea. Results: The infant was born at term by C-section with a birth weight of 3.120 kg and height of 48 cm for consanguineous parents. She had been breastfed until day 5 of her life when she presented lethargy, diarrhea, abdominal discomfort, and jaundice. During the first evaluation at the emergency room, the significant laboratory finding was blood tyrosine elevation; afterward, amino acid and succinylacetone determinations were obtained, discarding tyrosinemia. When admitted to the hospital, an abdominal ultrasound detected a duplex collecting system. At this time, rice formula was introduced to the patient. She was discharged with jaundice improvement, but diarrhea persisted. Several formula changes had been made from rice to extensively hydrolyzed casein protein to whey-based, with no clinical improvement; the patient still had 10-12 excretions daily. In the second hospitalization, the patient presented anemia, severe dehydration, hyperammonemia, and renal tubular acidosis. A next-generation sequencing panel for inborn errors of metabolism and congenital diarrhea was performed, identifying a homozygous variant in SLC5A1 (c.1667T > C). The diagnosis of CGGM was made at 3 months of age. The infant was initially treated with a modular galactose-glucose-free formula with oil, fructose, casein, minerals, and vitamins until a commercial fructose-based formula was introduced. This led to a complete resolution of diarrhea and improved nutritional status. Discussion: Diagnosing CGGM is challenging for clinicians, and next-generation sequencing is a valuable tool for providing appropriate treatment. More detailed information on patients with this condition might lead to possible phenotype-genotype correlations. This case's primary clinical and biochemical findings were chronic diarrhea, anemia, jaundice, renal tubular acidosis, hyperammonemia, and initial hypertyrosinemia. Symptoms were resolved entirely with the fructose-based formula.

A cross-sectional study on the prevalence of cardiovascular disease in elderly patients with long-term type 2 diabetes mellitus mainly attended in private clinics in Mexico. The CAPTURE study.

BACKGROUND: To estimate the contemporary prevalence of established cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) in Mexico. METHODS: CAPTURE was a multinational, non-interventional, cross-sectional study across 13 countries from five continents. Standardized demographic and clinical data were collected from adults with T2D attending a single routine healthcare visit in primary or specialized care between December 2018 and September 2019. Data from Mexico are analyzed in this study. RESULTS: Of the 9,823 patients included in the CAPTURE study, 820 (8.3%) participants were from Mexico, mainly attended in private centers (29.3% in 6 specialized diabetes treatment centers and 70.7% in 26 primary care centers). The median age was 63.0 years, 52.6% were women, the duration of diabetes was 11.8 years and the average HbA1c 7.5%. The weighted prevalence [95% CI] of CVD and atherosclerotic CVD was 36.9% [34.1-39.6] and 29.5% [26.7-32.3], respectively. Additionally, the prevalence of coronary heart disease, heart failure, peripheral arterial disease and cerebrovascular disease was 23.1% [20.6-25-7], 8.4% [6.8-10.0], 5.0% [3.5-6.5] and 3.9% [2.6-5.2], respectively. Glucose lowering drugs were used in 88.5% of patients, being metformin the most commonly drug used (79.4%), followed by sulfonylureas (26.3%). SGLT-2 inhibitors and GLP1 receptor agonists were used in 15.5% and 3.9%, respectively. CONCLUSIONS: In Mexico, nearly four out of ten patients with T2D mainly attended in private centers have CVD, particularly atherosclerotic CVD. Most patients were not taking glucose lowering drugs with proven CV benefit.

[Real-world evidence on pharmacological appropriateness in type 2 diabetes mellitus and cardiovascular disease]. / Evidencia de mundo real sobre adecuación farmacológica en diabetes tipo 2 y enfermedad cardiovascular.

Objective: To estimate the proportion of individuals with established Type 2 Diabetes Mellitus (T2DM) and Cardiovascular Disease (CVD) who are receiving pharmacological anti-diabetic treatment with evidence of cardiovascular benefit at a hospital in Argentina. Materials and Methods: Cross-sectional study conducted at the Italian Hospital of Buenos Aires. A consecutive sample of adult patients affiliated with the institutional prepaid health plan active in March 2020, diagnosed with T2DM and established CVD, was included. Data were collected from the Electronic Health Record. The proportion of pharmacological adequacy (combined use of metformin plus sodium-glucose co-transporter 2 inhibitors and/or glucagon-like peptide 1 receptor agonists) was reported along with its respective 95% confidence interval (CI). Results: A total of 1539 patients were included, with a mean age of 76.2 years; 65.3% were male, and 81.6% were overweight or obese. Hemoglobin A1c levels were recorded in the past year for 74.9% of patients, with an average value of 6.9% (SD 1.2). The most prescribed drugs were metformin (61.3%), insulin (26.7%), and gliptins (11%). Out of the total included patients, 82 exhibited pharmacotherapeutic adequacy for diabetes treatment, with a prevalence of 5.3% (95% CI 4.2-6.5). Conclusions: The prevalence of prescribing anti-diabetic drugs with evidence of cardiovascular benefit was 5.3% (95% CI 4.2-6.5). This real-world evidence highlights the low frequency of prescribing this type of medication at the time of the study in a high cardiovascular risk population.

Objetivo: Estimar la proporción de personas con Diabetes Mellitus tipo 2 (DM2) y Enfermedad Cardiovascular (ECV) establecida que reciben tratamiento farmacológico anti-diabético con evidencia de beneficio cardiovascular en un hospital en Argentina. Materiales y Métodos: Estudio de corte transversal realizado en el Hospital Italiano de Buenos Aires. Se incluyó una muestra consecutiva de pacientes adultos afiliados a prepaga institucional activos a Marzo 2020, con diagnóstico de DM2 y ECV establecida. Los datos se tomaron de la Historia Clínica Electrónica. Se informó la proporción de adecuación farmacológica (uso combinado de metformina más inhibidores del cotransportador de sodio glucosa tipo 2 y/o agonistas del Péptido Similar al Glucagón tipo 1) con su respectivo IC95%. Resultados: Se incluyeron 1539 pacientes, con una media de edad 76,2 años, 65,3% eran de sexo masculino, 81,6% con sobrepeso u obesidad. Un 74,9% de los pacientes tenían registro de hemoglobina glicosilada en el último año, con un valor promedio de 6,9% (DE 1,2). Las drogas más prescritas fueron: metformina (61,3%), insulina (26,7%), y gliptinas (11%). Del total de pacientes incluidos, 82 presentaron adecuación fármaco-terapéutica antidiabética, con una prevalencia de 5,3% (IC95% 4,2-6,5). Conclusiones: La prevalencia de prescripción de drogas antidiabéticas con evidencia de beneficio cardiovascular fue de 5,3% (IC95% 4,2-6,5). Esta información extraída de evidencia del mundo real identifica la baja frecuencia de prescripción de este tipo de fármacos al momento del estudio en una población de alto riesgo cardiovascular.

Cardiovascular Risk Related to Glomerular Hyperfiltration in Nondiabetic Individuals: Increasing Visibility is Crucial.

Glomerular hyperfiltration (GHF), defined by different estimation formulas, has been widely studied as a predictor of proteinuria and progression to chronic kidney disease (CKD) in diabetic patients. GHF is also an important cardiovascular (CV) risk factor and is related to allcause mortality in non-diabetic populations; however, the upper limit of glomerular filtration rate (GFR) above which it indicates the presence of GHF is weakly defined. This higher risk is as high as in the intermediate stages of CKD and is greater than the presence of diabetes or smoking and is still present in non-albuminuria patients. The original Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimation GFR formula showed lower error at higher glomerular filtration (GF) values, was the most used in population studies, and behaved as a better risk predictor. In our review (including approximately 3.6 million individuals), higher GFR values related to increased mortality risk varied from 106.6 to 113.7 ml/min, which are usually not considered risk values for standard guidelines in non-albuminuric patients. However, the lack of consensus on a GF cutoff value, as well as its variability due to sex and progressive reduction with age, affect the knowledge of this serious phenomenon in clinical practice. Although the elderly population is not exempted from the effects of GHF, the search for this phenomenon should be intensified in middle-aged populations because of their lower disease burden, where this situation may be more evident, and the possibility of reversing the consequences is greater. A population group often considered healthy includes obese people, essential hypertensives, smokers, and carriers of fatty liver, where the GHF phenomenon is frequent and is associated with CV disease, kidney disease, and higher mortality. Increasing its visibility by the medical community is essential to reduce the effects of GHF, emphasizing more frequent controls and implementing general measures that include strict control of hypertension, Na restriction, rich in vegetables diets and increased physical activity. Initiatives to confirm the beneficial effects of sodium-glucose cotransporter-2 inhibitors to treat isolated GHF would be an important breakthrough in reducing the severe consequences of this phenomenon.

Cardiovascular and renal effects of SGLT2 inhibitor initiation in acute heart failure: a meta-analysis of randomized controlled trials.

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.

Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease.

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.

Reacciones adversas de los inhibidores del cotransportador sodio-glucosa tipo 2 en personas con diabetes mellitus / Adverse reactions of sodium-glucose cotransporter type 2 inhibitors in people suffering from diabetes mellitus

Introducción: Las bondades que ofrece el uso de los inhibidores del cotransportador sodio-glucosa tipo 2 en el tratamiento de la diabetes mellitus, se reportan preocupantes eventos y reacciones adversas por el empleo de este grupo de medicamentos. De ahí, la necesidad de su conocimiento por parte de los facultativos. Objetivo: Mencionar las reacciones adversas a medicamentos más frecuentes de los inhibidores del cotransportador sodio-glucosa tipo 2 en personas con diabetes mellitus. y describir aquellas de mayor interés clínico por su gravedad. Métodos: La información se obtuvo en el trimestre octubre-diciembre de 2020. Se evaluaron diferentes artículos de revisión, de investigación y páginas Web, en general tenían menos de 10 años de publicados, en idioma español, portugués o inglés. Se utilizó como motores de búsqueda de información científica a Google Académico, Pubmed y SciElo. Fueron utilizadas como palabras claves: inhibidores del cotransportador sodio-glucosa tipo 2; tratamiento; reacciones adversas; y diabetes mellitus. Fueron excluidos los artículos que no reunían las condiciones señaladas. Esto permitió el estudio de 88 artículos, de los cuales 50 fueron referenciados. Conclusiones: Los inhibidores del cotransportador sodio-glucosa tipo 2, pueden producir variadas reacciones adversas -descritas en el texto-, que de manera potencial pueden aumentar la morbilidad y mortalidad. Su uso ofrece la posibilidad de reacciones adversas graves de interés clínico, entre las que se describen: cetoacidosis diabética euglucémica, insuficiencia renal aguda, riesgo de amputaciones de los pies y fascitis necrosante del perineo(AU)

Introduction: The benefits offered by the use of sodium-glucose cotransporter type 2 inhibitors in the treatment of diabetes mellitus, worrisome adverse events and reactions are reported for the use of this group of drugs. Hence, the need for physicians to be aware of them. Objective: To describe the most frequent adverse drug reactions of sodium-glucose cotransporter type 2 inhibitors in people with diabetes mellitus and those of greatest clinical interest due to their severity. Methods: The information was obtained in the October-December 2020 quarter. Different review articles, research articles and Web pages were evaluated, generally less than 10 years old, in Spanish, Portuguese or English. Google Scholar, Pubmed and SciElo were used as search engines for scientific information. The following keywords were used: sodium-glucose cotransporter type 2 inhibitors; treatment; adverse reactions; and diabetes mellitus. Articles that did not meet the indicated conditions were excluded. This allowed the study of 88 articles, of which 50 were referenced. Conclusions: Type 2 sodium-glucose cotransporter inhibitors can produce various adverse reactions -described in the text-, which can potentially increase morbidity and mortality. Their use offers the possibility of serious adverse reactions of clinical interest, among which the following are described: euglycemic diabetic ketoacidosis, acute renal failure, risk of foot amputations and necrotizing fasciitis of the perineum(AU)

Patients' Preference Between DPP4i and SGLT2i for Type 2 Diabetes Treatment: A Cross-Sectional Evaluation.

Purpose: Despite newer type 2 diabetes (T2D) medications, patients do not always achieve metabolic targets, remaining at risk for cardiorenal complications. Therapeutic decisions are generally made by the healthcare team without considering patients' preferences. We aimed to evaluate patients' T2D treatment preference in two Latin-American countries between two different oral medication profiles, one resembling dipeptidyl peptidase-4 inhibitors (DPP4i) and another resembling sodium-glucose cotransporter-2 inhibitors (SGLT2i). Patients and Methods: In this cross-sectional, multicenter study from June to September 2020, patients with T2D from Argentina and Mexico (n = 390) completed a discrete choice experiment questionnaire to identify preferences between DPP4i (medication profile A) and SGLT2i (medication profile B). The reason behind patients' choice, and the association between their baseline characteristics and their preference were evaluated using logistic regression methods. Results: Most participants (88.2%) preferred SGLT2i's profile. Participants with older age (p = 0.0346), overweight or obesity (p < 0.0001), high blood pressure (BP; p < 0.0001), high total cholesterol (p = 0.0360), and glycosylated hemoglobin (HbA1c) <7% (p = 0.0001) were more likely to choose SGLT2i compared with DPP4i's profile. The most and least important reasons to choose either drug profile were HbA1c reduction and genital infection risk, respectively. The likelihood of selecting the SGLT2i's profile significantly increased in participants with increased body mass index (BMI; odds ratio [OR] = 8.9, 95% confidence interval [CI]: 3.5-22.5, p < 0.05), high BP (OR = 4.9, 95% CI: 1.9-12.4, p < 0.05), and lower education level (OR = 3.6, 95% CI: 1.0-12.6, p < 0.05). Conclusion: Latin-American patients with T2D preferred medication with a profile resembling SGLT2i over one resembling DPP4i as a treatment option. A patient-centered approach may aid the healthcare team in decision-making for improved outcomes.

Uso de empagliflozina en pacientes diabéticos tipo 2 con insuficiencia cardíaca

Resumen: Introducción: La insuficiencia cardíaca es una patología con alta prevalencia y morbimortalidad. Entre las estrategias terapéuticas se debe considerar el abordaje de las comorbilidades, entre ellas la diabetes mellitus tipo 2. Los pacientes con insuficiencia cardíaca que la asocian, tienen 75% más riesgo de hospitalización y mortalidad. La Food and Drug Administration ha enfatizado desde 2008 que todo nuevo hipoglucemiante debe tener un efecto beneficioso o al menos neutro a nivel cardiovascular. Varios estudios han demostrado que los inhibidores del cotransportador sodio glucosa tipo 2 (empagliflozina, canagliflozina y dapagliflozina) cumplen con estos requerimientos. El objetivo de este trabajo es describir la experiencia en "vida real" de la empagliflozina en pacientes con diabetes mellitus 2 e insuficiencia cardíaca con fracción de eyección reducida. Metodología: Se realizó un estudio prospectivo, longitudinal, entre julio 2019 - abril 2021 en una Unidad Multidisciplinaria de Insuficiencia Cardíaca. Resultados: Se incluyeron 25 pacientes Se incluyeron 25 pacientes (13 hombres) con edad media 61 años. La dosis objetivo de empagliflozina se alcanzó en el 95% de los pacientes. Se observó un descenso de peso, hemoglobina glicosilada y glicemia de ayunas. Conclusiones: La empagliflozina presentó buena tolerabilidad, con efectos beneficiosos a nivel cardiovascular y mínimos efectos adversos.

Abstract: Introduction: Heart failure is a pathology with high prevalence and morbidity and mortality. Among the therapeutic strategies, addressing comorbidities should be considered, including type 2 diabetes mellitus. Patients with associated heart failure have a 75% higher risk of hospitalization and mortality. The Food and Drug Administration has emphasized since 2008 that all new hypoglycemic agents must have a beneficial or at least neutral effect at the cardiovascular level. Several studies have shown that sodium-glucose cotransporter 2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) meet these requirements. The objective of this work is to describe the "real life" experience of empagliflozin in patients with type 2 diabetes mellitus and heart failure with reduced ejection fraction. Methodology: A prospective, longitudinal study was carried out between July 2019 and April 2021 in a Multidisciplinary Heart Failure Unit. Results: Twenty-five patients (13 men) with a mean age of 61 years were included. The target dose of empagliflozin was achieved in 95% of patients. A decrease in weight, glycosylated hemoglobin and fasting blood glucose was observed. Conclusions: Empagliflozin presented good tolerability, with beneficial effects at the cardiovascular level and minimal adverse effects.

Resumo: Introdução: A insuficiência cardíaca é uma patologia com alta prevalência e morbidade e mortalidade. Dentre as estratégias terapêuticas, deve-se considerar a abordagem de comorbidades, incluindo diabetes mellitus tipo 2. Pacientes com insuficiência cardíaca associada apresentam risco 75% maior de hospitalização e mortalidade. A Food and Drug Administration tem enfatizado desde 2008 que todos os novos agentes hipoglicemiantes devem ter um efeito benéfico ou pelo menos neutro no nível cardiovascular. Vários estudos mostraram que os inibidores do cotransportador 2 de sódio-glicose (empagliflozina, canagliflozina e dapagliflozina) atendem a esses requisitos. O objetivo deste trabalho é descrever a experiência da "vida real" da empagliflozina em pacientes com diabetes mellitus tipo 2 e insuficiência cardíaca com fração de ejeção reduzida. Metodologia: Foi realizado um estudo prospectivo, longitudinal, entre julho de 2019 e abril de 2021 em uma Unidade Multidisciplinar de Insuficiência Cardíaca. Resultados: Vinte e cinco pacientes (13 homens) com idade média de 61 anos foram incluídos. A dose alvo de empagliflozina foi alcançada em 95% dos pacientes. Observou-se diminuição do peso, da hemoglobina glicosilada e da glicemia de jejum. Conclusões: A empagliflozina apresentou boa tolerabilidade, com efeitos benéficos a nível cardiovascular e efeitos adversos mínimos.

The Effect of Dapagliflozin on Platelet Function Testing Profiles in Diabetic Patients: The EDGE Pilot Study.

INTRODUCTION: This prospective pharmacodynamic (PD) study assessed the effect of the sodium-glucose co-transporter-2 inhibitor (SGLT2i), dapagliflozin, on platelet reactivity. METHODS: Patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) (n = 27) who were on maintenance dual antiplatelet therapy (DAPT) of aspirin 81 mg daily, and clopidogrel 75 mg daily were recruited. Platelet function was evaluated with the VerifyNow™ P2Y12 assay (Werfen, Bedford, MA, USA) and assessed prior to initiation of and after 10 days of treatment with dapagliflozin 10 mg once-daily dose regimen. Results were compared with a paired t test. RESULTS: Treatment with dapagliflozin significantly decreased P2Y12 reaction units (PRU) by 20%, (95% confidence interval (CI) 8.5-32.6%, p value 0.002). The mean difference in PRU was 36.70 (95% CI 16.66-56.75). No patients experienced any serious adverse events (SAEs). CONCLUSIONS: Significantly diminished platelet reactivity was observed on dapagliflozin as compared to without dapagliflozin. This dedicated pharmacodynamic study could be potentially informative and applicable for Trinidadian stable CAD patients with T2DM on DAPT. Further studies are required to confirm these exploratory findings. CLINICAL TRIAL REGISTRATION: EDGE ClinicalTrials.gov number NCT04400760.

Use of a Sodium-Glucose Cotransporter 2 Inhibitor, Empagliflozin, in a Patient with Rabson-Mendenhall Syndrome.

INTRODUCTION: Among the insulin resistance syndromes that lead to diabetes mellitus in young people, Rabson-Mendenhall syndrome (RMS; OMIM # 262190) is an autosomal recessive inherited disease caused by an insulin receptor mutation (INSR; 147,670). Due to the rarity and complexity of the disease, we have few therapeutic alternatives other than insulin with clinical studies with robust evidence. Some reports suggest the adjunct use of metreleptin, metformin, and pioglitazone with improved glycemic control, however, with results still unsatisfactory for the desirable glycemic targets for this age group. CASE PRESENTATION: We report a case of an 11-year-old patient who was diagnosed with RMS at 6 years of age, confirmed through genetic sequencing, with unsatisfactory glycemic control despite the use of >5 IU/kg/day of insulin, pioglitazone, and metformin. To optimize therapy, we used empagliflozin (SGLT2i) to correct hyperglycemia. With the use of the drug, we obtained a decrease of almost 3% in the value of glycated hemoglobin (HbA1c) and about 30% reduction in the total daily dose of insulin. DISCUSSION/CONCLUSION: In this specific case, considering the glycosuric effects independent of the functionality of insulin receptors (which in this case had partial activity due to the INSR gene mutation), an improvement in glycemic control was obtained, with optimization of HbA1c without documented or reported adverse effects. From this isolated case and understanding the pharmacokinetics of this drug class, the question remains whether it would be possible to use this treatment in other situations of SIR where we also have few therapeutic perspectives.

Effect of SGLT2-Inhibitors on Epicardial Adipose Tissue: A Meta-Analysis.

(1) Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) reduce adipose tissue and cardiovascular events in patients with type 2 diabetes (T2D). Accumulation of epicardial adipose tissue (EAT) is associated with increased cardio-metabolic risks and obstructive coronary disease events in patients with T2D. (2) We performed a systematic review and meta-analysis of SGLT2-i therapy on T2D patients, reporting data on changes in EAT after searching the PubMed/MEDLINE, Embase, Science Direct, Scopus, Google Scholar, and Cochrane databases. A random effects or fixed effects model meta-analysis was then applied. (3) Results: A total of three studies (n = 64 patients with SGLT2-i, n = 62 with standard therapy) were included in the final analysis. SGLT2 inhibitors reduced EAT (SMD: -0.82 (-1.49; -0.15); p < 0.0001). An exploratory analysis showed that HbA1c was significantly reduced with SGLT2-i use, while body mass index was not significantly reduced with this drug. (4) Conclusions: This meta-analysis suggests that the amount of EAT is significantly reduced in T2D patients with SGLT2-i treatment.

Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure.

BACKGROUND: SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. METHODS: Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. RESULTS: EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. CONCLUSIONS: Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

Novel antidiabetic drugs and risk of cardiovascular events in patients without baseline metformin use: a meta-analysis.

AIMS: To evaluate the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major cardiovascular events (MACE) in metformin-naïve patients with type 2 diabetes (T2D). METHODS AND RESULTS: A meta-analysis was performed of randomized controlled clinical trials of GLP-1RAs and SGLT-2 inhibitors on T2D populations, after searching the PubMed/MEDLINE, Embase, and Cochrane Controlled Trials databases. The primary endpoint was MACE. The secondary endpoint, explored in the subgroup of SGLT-2 inhibitors studies, was cardiovascular death or hospitalization for heart failure. A random-effects meta-analysis model was applied. Six eligible trials (three studies of SGLT-2 inhibitors and three trials of GLP-1RAs), including 13 049 patients, were identified and considered eligible for the analyses. The new antidiabetic drugs were associated with a significant reduction in MACE [odds ratio (OR): 0.80, 95% confidence interval: 0.70-0.93; I2: 53%]. The subgroup analysis showed the following findings: GLP-1RAs group, OR: 0.77 (95% confidence interval 0.67-0.88); SGLT-2 inhibitors, OR: 0.85 (95% confidence interval 0.63-1.15). SGLT-2 inhibitors were associated with a significant reduction in hospitalization for heart failure or cardiovascular mortality incidence (OR: 0.67, 95% confidence interval: 0.47-0.95; I2: 78%). CONCLUSION: In this meta-analysis, new antidiabetic drugs reduced the incidence of MACE in metformin-naïve T2D patients. The beneficial effect was especially observed in the GLP-1RAs subgroup. The use of SGLT-2 inhibitors was associated with a reduction in cardiovascular death or hospitalization for heart failure. These results support the fact that metformin would not be indispensable to obtain positive cardiovascular effects when new antidiabetic drugs are administered.

The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure, Regardless of Diabetes Status: Focus on Cardiovascular Disease.

OBJECTIVE: To provide clinical guidance and an overview of the available data on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence of type 2 diabetes mellitus (T2DM). DATA SOURCES: We searched the MEDLINE database via PubMed (from January 2015 to November 2020) for the following key terms: SGLT2 inhibitors, sodium-glucose co-transporter-2 inhibitors, SGLT2i, heart failure, and heart failure with reduced ejection fraction. STUDY SELECTION AND DATA EXTRACTION: To be included in the review, the articles needed to assess the effects of SGLT2 inhibitors in the heart failure (HF) scenario. DATA SYNTHESIS: There is consistent evidence that SGLT2 inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization in patients with HFrEF, even in the absence of T2DM. On May 5, 2020, the U.S. Food and Drug Administration approved dapagliflozin for adults with HFrEF, regardless of the presence of T2DM, even in those patients on standard therapy, including an angiotensin receptor/neprilysin inhibitor. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The SGLT2 inhibitors are well tolerated, and their once-daily dosing without the need for adjustments is convenient. These drugs can be considered a major breakthrough in pharmacotherapy for HF, providing physicians with a new treatment approach to reduce major clinical outcomes. CONCLUSIONS: SGLT2 inhibitor therapy reduces CV death and hospitalizations in HFrEF patients regardless of T2DM. The decision to prescribe this class of drugs should not be determined by glycemic status.

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review.

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.

The Effect of Empagliflozin on Platelet Function Profiles in Patients with Stable Coronary Artery Disease in Trinidad: The EFFECT Pilot Study.

INTRODUCTION: This prospective pharmacodynamic (PD) study aimed to assess the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin on platelet reactivity. METHODS: Patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) (n = 20) who were actively treated with dual antiplatelet therapy (DAPT) of aspirin 81 mg daily and clopidogrel 75 mg daily were recruited. Platelet function was measured with the VerifyNow™ P2Y12 assay (Instrumentation Laboratory, Massachusetts, USA) and assessed before the initiation of and after 10 days of treatment with empagliflozin 25 mg once daily maintenance dose regimen. Results were compared with a paired t test. RESULTS: The mean P2Y12 reaction units (PRU) on empagliflozin was significantly less than without empagliflozin at baseline (187.35, 95% confidence interval (CI) 155.38-219.32 vs. 217.25, CI 180.60-253.90; p < 0.030). The mean difference in PRU was 29.90 (95% CI 3.17-56.63). No patients experienced any serious adverse events (SAEs). CONCLUSIONS: Significantly attenuated platelet reactivity was observed on empagliflozin as compared to without empagliflozin. This dedicated pharmacodynamic study could be clinically pertinent for Trinidadian patients with stable CAD and T2DM on DAPT. Further studies are required to confirm these exploratory findings. (Funded by the University of the West Indies, St. Augustine; EFFECT). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT04342819.