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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.
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Compuestos de Bencidrilo , Canagliflozina , Cardiotónicos , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/uso terapéutico , Glucósidos/farmacología , Animales , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/farmacología , Humanos , Cardiotónicos/uso terapéutico , Cardiotónicos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Canagliflozina/uso terapéutico , Canagliflozina/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Evaluación Preclínica de MedicamentosRESUMEN
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.
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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.
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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.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Metformina , Humanos , Argentina/epidemiología , GlucosaRESUMEN
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.
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Enfermedades Cardiovasculares , Hipertensión , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Persona de Mediana Edad , Humanos , Anciano , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo , Factores de Riesgo de Enfermedad Cardiaca , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
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 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diuréticos/efectos adversos , Diuréticos/farmacología , Diuréticos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Riñón/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
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.
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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.
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Compuestos de Bencidrilo/uso terapéutico , Síndrome de Donohue/genética , Glucósidos/uso terapéutico , Receptor de Insulina/genética , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Antígenos CD/genética , Niño , Humanos , Resistencia a la Insulina/genética , Masculino , Mutación/genéticaRESUMEN
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.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Metformina , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Receptor del Péptido 1 Similar al Glucagón , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Humanos , Hipoglucemiantes/efectos adversos , Metformina/efectos adversosRESUMEN
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.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Sodio , Volumen SistólicoRESUMEN
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.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) in postmenopausal women is associated with a high incidence of urogenital infections, which negatively impact the quality of life and increase morbidity, mortality, and health-care costs. Glucosuria is a known risk factor for these infections; therefore, it is of interest to determine if increased glucosuria secondary to sodium-glucose cotransporter-2 inhibitors (SGLT2in) impacts the incidence and severity of urogenital infections in postmenopausal women with T2DM. METHODS: The study was conducted at Gaffrée Guinle University Hospital on two groups of postmenopausal women with T2DM: with and without SGLT2in therapy (n = 80 in each group). Medical records and laboratory parameters (urinary dipstick test and culture; blood glucose, glycosylated hemoglobin, and creatinine; cervical cytologic study) of all subjects were carefully assessed at baseline and thrice during the 12-month study period. RESULTS: We observed a significant incidence of vulvovaginitis (relative risk [RR], 2.37; 95% confidence interval [CI], 1.10-5.10; P = 0.03) and asymptomatic bacteriuria (RR, 2.47; 95% CI, 1.09-5.60; P = 0.03), but not of urinary tract infections (RR, 2.08; 95% CI, 0.74-5.81; P = 0.16), secondary to SGLT2in therapy. Genital infection was severe enough to warrant treatment discontinuation in 57.89% of patients in group 1. All urinary tract infections were of mild intensity with a good response to antibiotic therapy. CONCLUSION: Glucosuria induced by SGLT2in therapy may lead to a high incidence of urogenital infections in postmenopausal women with T2DM and can be considered a risk factor for these infections.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosuria/inducido químicamente , Glucosuria/complicaciones , Posmenopausia , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Infecciones Urinarias/etiología , Anciano , Antibacterianos/uso terapéutico , Bacteriuria/etiología , Glucemia , Estudios de Casos y Controles , Creatinina/sangre , Femenino , Hemoglobina Glucada , Humanos , Incidencia , Estudios Longitudinales , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Infecciones Urinarias/tratamiento farmacológico , Vulvovaginitis/etiologíaRESUMEN
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.
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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.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Humanos , Resultado del TratamientoRESUMEN
Monitoring the plasma concentrations of metformin and sodium-glucose cotransporter-2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) is essential for pharmacokinetic and bioequivalence studies and therapeutic monitoring. The present work therefore aimed to develop and validate a high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous quantification of these drugs in human plasma. The analyses were performed using an Agilent 1200 HPLC system coupled to an Applied Biosystems API 3200 triple quadrupole MS/MS with electrospray ionization in positive ion mode. After one-step protein precipitation of plasma with acetonitrile containing 0.1% formic acid, chromatographic separation was achieved on an Xbridge C18 column, with a mobile phase consisting of a gradient of water and acetonitrile, both containing 1 mm ammonium formate and 0.1% formic acid. Quantification was performed in multiple reaction monitoring mode using m/z 130.1 â 71.1 for metformin, m/z 462.0 â 191.2 for canagliflozin, m/z 426.1 â 167.1 for dapagliflozin and m/z 468.0 â 354.9 for empagliflozin. The proposed method was validated and demonstrated to be adequate for the quantification of metformin, canagliflozin, dapagliflozin and empagliflozin for clinical monitoring, pharmacokinetics and bioequivalence studies.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Metformina/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/sangre , Espectrometría de Masas en Tándem/métodos , Compuestos de Bencidrilo/sangre , Canagliflozina/sangre , Glucósidos/sangre , Humanos , Modelos Lineales , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
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)
Asunto(s)
Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Transportador 2 de Sodio-Glucosa/uso terapéutico , Materiales Bibliográficos , Hemoglobina Glucada/uso terapéuticoRESUMEN
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)
Asunto(s)
Humanos , Terapia Combinada/métodos , Diabetes Mellitus Tipo 2/diagnóstico , Hemoglobina Glucada/uso terapéutico , Materiales Bibliográficos/estadística & datos numéricos , Transportador 2 de Sodio-Glucosa/uso terapéuticoRESUMEN
Los riñones contribuyen a la homeostasis de la glucosa a través de varios mecanismos, incluyendo la gluconeogénesis, utilización y reabsorción de la glucosa a partir del filtrado glomerular. Bajo condiciones fisiológicas normales, la glucosa filtrada es casi totalmente reabsorbida en el epitelio de las células tubulares; en consecuencia, no aparece glucosa en la orina. El transporte de glucosa dentro de las células epiteliales del túbulo se cumple gracias a cotransportadores activos glucosa-sodio (SGLT), una familia de proteínas dependientes de adenosin trifosfato (ATP) involucradas en el transporte de glucosa contra un gradiente de concentración con carga simultánea de sodio, igualmente en contra gradiente. La mayoría de la glucosa filtrada es reabsorbida por medio del SGLT2, un transportador de baja afinidad pero elevada capacidad localizado, predominantemente, en el segmento S1 del tubo contorneado proximal. Por largo tiempo la inhibición del SGLT2 ha sido considerada como un abordaje terapéutico potencial de la hiperglucemia en la diabetes mellitus tipo 2 (DM2), ya que al prevenir la reabsorción de glucosa por los túbulos renales promueven su excreción renal y descienden los valores de la glucemia. Los datos en humanos indican que los inhibidores de SGLT2 representan una estrategia novedosa y efectiva para controlar las cifras de glucemia en los pacientes con DM2. El recién publicado estudio EMPA-REG OUTCOME diseñado para examinar los desenlaces cardiovasculares con empagliflozina en sujetos con DM2 y enfermedad ardiovascular coexistente mostró beneficios tempranos, los cuales se mantuvieron durante el período de observación(AU)
The kidneys contribute to glucose homeostasis through several mechanisms, including gluconeogenesis, glucose use, and glucose reabsorption from the glomerular filtrate. Under normal physiological conditions, this filtered glucose is almost completely reabsorbed by renal tubular epithelial cells; thus, there is no glucose in urine. The transport of glucose into renal tubular epithelial cells is mediated by active cotransporters, the SGLT, a family of ATP-dependent proteins involved in the transport of glucose against a concentration gradient with simultaneous transport of Na+ down a concentration gradient. Most of the filtered glucose is reabsorbed through SGLT2, a low-affinity high-capacity transporter located predominantly in the S1 segment of the renal proximal tubule. Inhibition of SGLT2 has long been regarded as a potential treatment approach for hyperglycemia during T2DM, as they prevent glucose reabsorption from renal tubules, thereby promoting urinary glucose excretion and decreasing plasma glucose levels. Current data in humans indicate that SGLT2 inhibitors represent an effective and novel strategy to control the plasma glucose concentration in patients with T2DM. The recently published EMPA-REG OUTCOME trial, which assessed cardiovascular outcomes with empagliflozin therapy in persons with type 2 diabetes mellitus and coexisting cardiovascular disease showed that the benefits were noted early and continued throughout the study(AU)