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.

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.

[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.

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.

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.

Cetoacidosis diabética euglucémica asociada al uso de inhibidores del cotransportador de sodio-glucosa 2

RESUMEN Mujer de 48 años con antecedentes de diabetes mellitus tipo 2 tratada con empaglifozina acudió a consulta después de 8 horas de dolor abdominal, náuseas, vómitos y falta de aliento. Tras el examen físico, la paciente estaba alerta, álgica, pálida, con mucosas secas, taquipneica, taquicárdica y con dolor abdominal difuso sin signos de irritación peritoneal. Los resultados de su laboratorio mostraron una glucemia sérica de 115 mg/dL (70-100 mg/dL), gasometría arterial con acidosis metabólica con anión gap elevado 20 mmol/L. El análisis de orina reportó cetonuria (cuerpos cetónicos 150) y la HbA1C fue 12,4% (4,8%-6%). Se descartó una causa quirúrgica de dolor abdominal y finalmente fue diagnosticada con cetoacidosis diabética euglucémica secundaria al uso de Inhibidores del cotransportador de sodio-glucosa 2.

ABSTRACT A 48-year-old woman with a history of type 2 diabetes mellitus treated with empaglifozine came to consultation after 8 hours of abdominal pain, nausea, vomiting, and shortness of breath. After the physical examination, the patient was alert, allergic, pale, with dry mucosa, tachypnea, tachycardia, and with diffuse abdominal pain without signs of peritoneal irritation. The results of his laboratory showed a serum glucose of 115 mg/dL (70-100 mg/dL), arterial blood gasometry with metabolic acidosis with an elevated gap anion of 20 mmol/L. Urine analysis reported ketonuria (150 ketone bodies) and HbA1C was 12.4% (4.8% -6%). A surgical cause of abdominal pain was ruled out and she was finally diagnosed with euglycemic diabetic ketoacidosis secondary to the use of sodium-glucose cotransporter inhibitors 2.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors and microvascular outcomes in patients with type 2 diabetes: systematic review and meta-analysis.

PURPOSE: The effect of the sodium-glucose 2 (SGLT-2) inhibitors on microvascular complications remains uncertain. We performed a systematic review to determine the efficacy of the SGLT-2 inhibitors on microvascular outcomes in patients with type 2 diabetes. METHODS: A comprehensive search was performed using Ovid, MEDLINE, EMBASE, Web of Science, and Scopus from inception to May 2019. Randomized trials comparing SGLT-2 inhibitors with placebo or other medication for type 2 diabetes for ≥ 4 weeks were included. Diabetes-related microvascular complications such as nephropathy, retinopathy, neuropathy, and peripheral vascular disease were evaluated. A random-effect model using mean differences for continuous outcomes and risk ratio for dichotomous outcomes was used to synthesize data. PROSPERO (CRD 42017076460). RESULTS: A total of 40 RCTs with overall moderate quality of evidence were included. SGLT-2 inhibitors reduced the risk of renal-replacement therapy (0.65; 95% CI 0.54-0.79), renal death (0.57; 95% CI 0.49-0.65), and progression of albuminuria (0.69; 95% CI 0.66-0.73). Conversely, they appeared ineffective in maintaining eGFR (0.33; 95% CI - 0.74 to 1.41) or reducing serum creatinine (- 0.07; 95% CI - 0.26 to 0.11), whereas urine albumin-creatinine ratio (- 23.4; 95% CI - 44.6 to - 2.2) was reduced. Risk of amputation was non-significant (1.30; 95% CI 0.93-1.83). No available data were found regarding neuropathy and retinopathy to perform a quantitative analysis. CONCLUSION: SGLT-2 inhibitors may reduce the risk of renal patient-important outcomes but fail to improve surrogate outcomes. Apparently, no increased risk of amputations was observed with these medications. No data were available regarding other microvascular complications.

Uso de la dapagliflozina en el tratamiento de la diabetes mellitus tipo 2 / Use of dapagliflozin in the treatment of type 2 diabetes mellitus

Introducción: la dapagliflozina es un inhibidor del cotransportador sodio-glucosa tipo 2, un nuevo grupo de fármacos que disminuyen la glucemia, con bajo riesgo de hipoglucemia y con discreta pérdida de peso. Objetivo: describir algunos aspectos de interés sobre el uso de la dapagliflozina en el tratamiento de los pacientes con diabetes mellitus tipo 2, para lo cual, se realizó una revisión de varios artículos publicados sobre el tema, a través de algunas bases de datos y de los buscadores habituales (PubMed, Cochrane, Google, y otros), teniendo en cuenta su calidad y actualidad, según criterio de los autores. Desarrollo: la dapagliflozina es administrada por vía oral, e inhibe la reabsorción de glucosa en el túbulo proximal renal y aumenta la excreción urinaria de glucosa (efecto glucosúrico). Se utiliza a una dosis de 10 mg diarios, sola o asociada a otros medicamentos normo o hipoglucemiantes. En ambos casos es capaz de disminuir los niveles de la hemoglobina glucosilada. Su efectividad es similar a las sulfonilureas. Los efectos adversos más frecuentes se relacionan con un incremento de las infecciones genitourinarias, cetoacidosis con glucemias no tan elevadas, y cáncer. Conclusiones: la dapagliflozina es efectiva en reducir los niveles de la hemoglobina glucosilada, el peso corporal y de la presión arterial en pacientes con diabetes mellitus tipo 2, sobre todo, cuando se adiciona a otros medicamentos como la metformina. Su uso debe ser considerado como un tratamiento coadyuvante, aunque su indicación se debe individualizar, debido a su costo y sus posibles efectos adversos(AU)

Introduction: dapagliflozin is a sodium-glucose cotransporter 2 inhibitor, a new group of pharmaceuticals that reduce glycemia, with low risk of hypoglycemia and modest loss of weight. Objective: to describe some aspects of interest on the use of dapagliflozin in the treatment of patients with type 2 diabetes mellitus for which several articles published on this topic were reviewed through some databases and the regular searchers (PubMed, Cochrane, Google and others), taking into account their quality and topicality, according to the authors' criteria. Development: dapagliflozin is orally administered and inhibits the re-absorption of glucose in the renal proximal tubule and increases the urinary glucose excretion (glycosuric effect). The dose is 10 mg daily, single or combined with other normoglycemic and hypoglycemic drugs. In both cases, it is able to diminish the levels of glycosylate hemoglobin. The effectiveness of this new drug is similar to that of the sulfonylureas. The most frequent effects are related to increase in genitourinary infections, ketoacidosis with not so high glycemia values and cancer. Conclusions: dapagliflozin is effective for the reduction of levels of glycosylate hemoglobin, body weight and blood pressure in patients with type 2 diabetes mellitus, mainly when added to other drugs like metformin. It should be considered as a coadjuvant treatment, although it should be prescribed on an individual footing due to its cost and possible adverse effects(AU)