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Resumen: Los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) han demostrado su beneficio cardiovascular y renal en pacientes con diabetes mellitus tipo 2, insuficiencia cardiaca (IC) o enfermedad renal crónica (ERC). Desde los primeros estudios, con estos fármacos se objetivó un incremento inicial de los niveles de hemoglobina/hematocrito que se atribuyó a un aumento de la hemoconcentración asociados a su efecto diurético, aunque pronto se constató que aumentaban los niveles de eritropoyetina (EPO) y eritropoyesis, mejorando el metabolismo férrico. Los estudios de mediación objetivaron que el incremento de hemoglobina se asociaba estrechamente con los beneficios cardiorrenales de estas sustancias. En la presente revisión se discuten los mecanismos de mejora de la eritropoyesis y la implicación del aumento de hemoglobina sobre el beneficio pronóstico cardiorrenal de estos medicamentos. Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was soon seen that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs.

Heart failure (HF), which has a high morbidity and mortality rate, is nevertheless a common and crippling ailment, especially in older populations. The complicated pathophysiology of heart failure (HF), which includes oxidative stress, endothelial dysfunction, fibrosis, and inflammation, is frequently not sufficiently treated despite advances in medication. Inhibitors of the sodium-glucose co-transporter 2 (SGLT2) have become a key treatment for HF in patients with varying left ventricular ejection fractions (LVEF). SGLT2 inhibitors have been shown in recent clinical trials to considerably lower hospitalization rates for heart failure, cardiovascular mortality, and all-cause mortality. The mechanisms of SGLT2 inhibitors, such as better ventricular loading, increased heart metabolic efficiency, and decreased inflammation and necrosis, are covered in this review. Additionally, we provide an overview of four important clinical trials—DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER—highlighting their effectiveness in lowering unfavourable cardiovascular outcomes for patients with heart failure who have preserved (HFpEF), slightly reduced (HFmrEF), or reduced (HFrEF). The results validate the need for SGLT2 inhibitors in all-inclusive HF treatment plans by highlighting their adaptability and safety in a range of clinical contexts.

Background:Dementia is a progressive and irreversible disease entity that affects memory, verbal fluency, thinking and the performance of daily activities.The most common type of dementia is alzheimer's disease(AD).Currently, there are no specific therapies with established efficacy against cognitive decline or AD. Objective:The aim of this study is to summarize the current knowledge about the effectiveness of SGLT2 inhibitors(SGLT2i) in the treatment of cognitive disorders. Method and material:The article was created based on the PubMed database and the Polish Journal of Endocrinology.Articles were searched in English using the following keywords: SGLT2ihibitors;dementia;Alzheimer type 3 diabetes mellitus. State of knowledge:Patients with type 2 diabetes (TD2) are 1.5-2 times more likely to develop dementia than the general population.Dementia among diabetic patients is characterized by an earlier age of onset, slightly worse overall cognitive status and a higher prevalence of cognitive impairment in male patients.Diabetes and pre-diabetes shorten the time from the onset of mild cognitive impairment (MCI) to the development of full-blown dementia. Conclusions:The use of SGLT2i is associated with reduced mortality from dementia, in contrast to insulin and sulfonylurea derivatives.SGLT2 inihibitors prevent cognitive impairment more potently than dipeptidylpeptidase-4 inhibitors. Taking empagliflozin for one month, is associated with improved cognitive function and increased scores on the Montreal Cognitive Assessment scale.

Introduction and aim of the study. Currently only minimal information is available regarding ketoacidosis without significant hyperglycemia. Some study describe that the sodium –glucose cotransporters (SGLT) may alter the normal balance between gluconeogenesis and ketogenesis.Aim of the study is to present the problem of the occurrence of ketoacidosis without hyperglycemia. Results. Phlorizen, the sodium –glucose cotransporters SGLT inhibitor was recognized to increase acetoacetate reabsorption and to induce hyperketonemia to an extent comparable to that seen with insulin deficiency. SGLT2 is expressed on the α -cells of the pancreatic islets, functioning in their glucose-sensing mechanism, so that earlier reports of SGLT2 inhibition-induced hyperglucagonemia. Episodes of diabetic ketoacidosis with SGLT2 inhibitors use were characterized by lower blood glucose levels. Drugs as ipragliflozin, dapagliflozin and tofogliflozin (SGLT inhibitors) may increase ketogenesis. Ipragliflozin increases lipolysis and both fatty acid oxidation and ketogenesis. In trials of tofogliflozin hyperketonemia and ketonuria were reported, with dose-related increases both in β-hydroxybutyrate and acetoacetate. Conclusions. Ketoacidosis may cause by phlorizen – SGLT inhibitor with slightly / moderately elevated levels of blood glucose.

The publication of the EMPEROR-Preserved trial and data on the benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF)> 40% represent a significant step forward in the treatment of HF with preserved EF. Given these results, in February 2022 the US Food and Drug Administration approved the use of empaglifozin in adults with HF with reduced or preserved EF. However, more detailed analysis of the EMPEROR-Preserved trial led to doubts about the effect of empagliflozin in patients with an EF of> 60% this patient group is widely heterogeneous and, probably, a single phenotype cannot be considered in treatment goals or the clinical approach. Moreover, EF occurs on a continuum and classifications of HF according to arbitrary cut-points in EF do not appear consistent with recent evidence, which points to a gradual shift and considerable overlap in underlying mechanisms, phenotypes and treatment response over the spectrum of EF. Enhanced knowledge of pathophysiological mechanisms is essential to establish new therapeutic targets, interpret the results of clinical trials, and develop targeted and effective therapies., (Copyright © 2022 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aim: To identify existing controversies in the routine management of patients with T2D and to contrast them with the latest scientific evidence and clinical guidelines, in order to help optimize and homogenize the treatment of patients with T2D in Primary Care (PC) in Spain., Material and Methods: 240 family doctors responded to an online questionnaire about the management of 6 patient profiles with T2D of increasing complexity., Results: The main drivers for the antihyperglycemic treatment choice are an HbA1c>10% and the presence of cardiovascular disease (CVD), although in evolved patients, the estimated glomerular filtration rate and the risk of hypoglycemia become more relevant. In newly diagnosed patients with an HbA1c>9%, treatment is still initiated with monotherapy (24%). In patients not controlled with metformin, dipeptidyl peptidase 4 inhibitors (DPP4-I, 54%) or sodium-glucose cotransporter 2 inhibitors (SGLT2-I, 39%) are usually added. On the other hand, type1 glucagon-like peptide receptor agonists (GLP1-RA) are mainly associated with obese patients with T2D. In patients not controlled with metformin+sulfonylurea (SU), SU replacement is preferred to adding a third antihyperglycemic agent to background therapy (77% vs. 23%)., Conclusions: T2D treatment in PC is still focused on HbA1c reduction and treatment safety. Thus, DPP4-I are widely used. SGLT2-I are usually preferred for patients with T2D and CVD and GLP1-RA for patients with T2D and obesity, although their use in PC is low., (Copyright © 2021 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

Sodium-glucose transport protein 2 (SGLT2) inhibitors are a new class of oral hypoglycemic agents that increase urinary glucose excretion independently of insulin secretion, although an apparently simple mechanism, but with multiple metabolic effects. Dapagliflozin was the first SGLT2 inhibitor marketed in Europe in 2012 for the treatment of patients with type 2 diabetes, and consequently, with the greatest clinical experience. The results of different clinical trials and real-life studies have demonstrated its effectiveness in glycemic control, as they reduce glycosylated hemoglobin, while achieving a decrease in body weight and blood pressure, among others, providing a comprehensive metabolic protection., (Copyright © 2021 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

In the last five years, the medical community was astonishingly surprised by the sequential large outcome trials that displayed the renal effects of sodium glucose co-transporter inhibitors (SGLT2Is) in type 2 diabetes mellitus (T2DM) patients with or without chronic kidney disease (CKD). This favorable effect was later disclosed in non-diabetic CKD patients. The EMPA-REG OUTCOME trial was the first trial that showed a reduction for the need for dialysis in patients suffering diabetic kidney disease (DKD) by 55%. This figure is double the score achieved by the angiotensin receptor blocker, Losartan, in RENAAL trial. The need for dialysis in DAPA-CKD trial was reduced in diabetic and non-diabetic CKD patients by 33%. The renal-specific composite outcome was reduced by 39% in EMPA-REG trial, 40% in CANVAS study, 47% in DECLARE-TIMI 58 study, 34% in CREDENCE trial, and 44% in DAPA-CKD trial. The greater surprise is the significant favorable effect of SGLT2Is on overall mortality in CKD patients with or without T2DM. Similar survival benefit was not previously encountered with any of the medications used in CKD patients with or without diabetes. In this review, we disclose the results of the DAPA-CKD trial, the CREDENCE trial and those of several cardiovascular outcome trials (CVOT) that used different SGLT2Is and showed that patients with lower eGFR levels may have greater benefit with respect to cardiovascular morbidity than patients with normal kidney function. In addition, we discuss the different mechanisms of action that explain the renal beneficial effects of SGLT2Is., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

There is a bidirectional association between heart failure (HF) and type 2 diabetes mellitus (DM2), which has resulted in an exponential increase in the combination of the 2 diseases in a single patient. This combination is one of many common causes that lead to the pathophysiological pathways resulting in the deleterious effect of DM2 on HF. The inevitable clinical consequence is that, when faced with this situation, patients present worse symptoms and a poorer prognosis than patients with HF but without DM2. We should therefore consider how to treat DM2 in patients with HF and how to treat HF in patients with DM2. In this review, we highlight the latest published data on this issue., (Copyright © 2019 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Aim: To compare the efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors and metformin in adults with type1 diabetes mellitus (T1DM)., Methods: Randomized clinical trials until February 2019, designed to assess the efficacy and safety of SGLT2 inhibitors/metformin in adults with T1DM, were searched on PubMed, EMBASE, the Cochrane Library, and Web of Science. Safety and efficacy data were synthesized using Bayesian network meta-analyses., Results: Twenty eligible studies with 5868 participants were included in network meta-analysis. SGLT2 inhibitors provided greater reductions in HbA1c than placebo (weighted mean difference [WMD] -0.40; 95% confidence interval [CI] -0.47, -0.32) and metformin (WMD: -0.32; 95%CI: -0.47, -0.14). Both SGLT2 inhibitors and metformin promoted greater reductions in body weight than placebo. SGLT2 inhibitors caused greater reductions in body weight than metformin (WMD: -1.54; 95%CI: -2.93, -0.09). Both SGLT2 inhibitors and metformin provided greater reductions in total insulin dose than placebo, while no difference between metformin and SGLT2 inhibitors was found. No difference in severe hypoglycemia was found between SGLT2 inhibitors and metformin. SGLT2 inhibitors induced a higher risk for diabetic ketoacidosis (DKA) than metformin/placebo., Conclusion: SGLT2 inhibitors provided greater reductions in HbA1c and body weight than metformin/placebo. Both SGLT2 inhibitors and metformin induced greater reductions in total insulin dosage than placebo, with no significant differences observed between SGLT2 inhibitors and metformin. SGLT2 inhibitors induced a higher risk for DKA than metformin/placebo., (Copyright © 2019 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

DeFronzo spoke of the "ominous octet", in which he referred to the existence of distinct pathways and organs related to the physiopathology of type 2 diabetes mellitus (DM2). One of these key organs is the kidney, which plays an important role in regulating glucose metabolism through gluconeogenesis and through glomerular filtration and glucose reabsorption in the proximal convoluted tubules. Approximately 180 g of glucose are filtered to the renal tubule from the blood stream through the glomerulus. The filtrate is subsequently reabsorbed from the tubules to the peritubular capillaries through the action of sodium glucose cotransporters (SGLT). There are 2 main cotransporters in the kidney, SGLT1 and SGLT2, which reabsorb the glucose (10% and 90%, respectively) and return it to the blood. In persons with DM2, SGLT2 is increased, leading to greater renal absorption of glucose, which has adverse effects as it contributes to the maintenance of hyperglycemia. Selective pharmacological SGLT2 inhibition increases renal glucose excretion and secondarily reduces its plasma values. SGLT2 inhibitors act exclusively on the kidney, reduce glycosylated hemoglobin (HbA1c) by about 0.66%, decrease blood pressure, and induce a weight loss of approximately 1.8 kg. These drugs have a low risk of hypoglycemia but carry an increased risk of genitourinary infections. Several clinical trials have shown that dapagliflozin (10mg/day), the first SGLT2 inhibitor commercialized in Spain, produces a statistically significant reduction in HbA1c of 0.82-0.97%, both in monotherapy and in combination with metformin, glimepiride, pioglitazone, or insulin. Its use produces a weight loss of between 2 and 3 kg and reduces both systolic and diastolic blood pressure, while the risk of hypoglycemias is low., (Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.)

Diabetes increases the risk of both microvascular and macrovascular complications. Although reducing plasma glucose levels to recommended targets decreases the risk of microvascular outcomes, the effects of anti-diabetic drugs on macrovascular complications and cardiovascular death are of concern. In fact, it has been suggested that some anti-diabetic agents could even be harmful for cardiovascular outcomes. In this context, several health care regulatory agencies have established the need for performing clinical trials specifically designed to assess the cardiovascular safety of anti-diabetic drugs. The results of 2 clinical trials have recently been published that provide important information on the cardiovascular safety of dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this document was to review the available evidence on the cardiovascular safety of non-insulin anti-diabetic drugs and provide practical recommendations on their use in this context., (Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.)

Dapagliflozin is the first novel sodium-glucose co-transporter-2 (SGLT2) inhibitor approved by the European Medicines Agency (EMA) for the treatment of type 2 diabetes. By inhibiting SGLT2, dapagliflozin blocks reabsorption of filtered glucose in the kidney, increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of pancreatic β cell function and modulation of insulin sensitivity. The results of phase III clinical trials showed that dapagliflozin, at a dose of 5 or 10mg/day for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both HbA1c and fasting plasma glucose levels compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. In most clinical trials, dapagliflozin reduced body weight. The combination of both effects (improved glycemic control and weight loss) is achieved to a greater extent in treatments that include dapaglifozin. Longer-term extension studies indicated that the efficacy of dapagliflozin on the glycemic control and weight reducción is maintained for up to 2 and 4 years. Dapagliflozin was well tolerated. Genital infections and urinary tract infections were more frequent in patients who received dapagliflozin than in placebo recipients. Hypoglycemic episodes were scarce with dapagliflozin. In conclusion, dapagliflozin is a novel option for the management of type 2 diabetes, particularly when used as add-on therapy., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)