Diuretic treatment of the patient with diabetes and heart failure. Role of SGLT2 inhibitors and similarities with carbonic anhydrase inhibitors

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El papel de los inhibidores de la SGLT2 y semejanzas con los inhibidores de la anhidrasa carbónica" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "208" "paginaFinal" => "217" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Diuretic treatment of the patient with diabetes and heart failure. 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AC: anhidrasa carbónica; iSGLT2: sodium-glucose cotransporter-2 inhibitors («inhibidores del cotransportador sodio-glucosa tipo 2»); Na+/K+ATPasa: transportador activo sodio-potasio adenosín trifosfato; NHE3: intercambiador de Na+/H+ tipo 3; SGLT2: sodium-glucose cotransporter-2 («cotransportador sodio-glucosa tipo 2»)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D. León Jiménez, R. Gómez Huelgas, A.J. Fernández Romero, J.M. López Chozas, L. Pérez de Isla, J.P. Miramontes González" "autores" => array:6 [ 0 => array:2 [ "nombre" => "D." "apellidos" => "León Jiménez" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Gómez Huelgas" ] 2 => array:2 [ "nombre" => "A.J." "apellidos" => "Fernández Romero" ] 3 => array:2 [ "nombre" => "J.M." "apellidos" => "López Chozas" ] 4 => array:2 [ "nombre" => "L." "apellidos" => "Pérez de Isla" ] 5 => array:2 [ "nombre" => "J.P." 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"apellidos" => "Miramontes González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Unidad de Riesgo Vascular, Medicina Interna, Hospital Universitario Virgen Macarena, Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Gestión Clínica de Medicina Interna, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Cardiología, Hospital Universitario Virgen Macarena, Sevilla, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Gestión Clínica de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Cardiología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IDISSC), Universidad Complutense, Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Medicina Interna, Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento diurético del paciente con diabetes e insuficiencia cardiaca. El papel de los inhibidores de la SGLT2 y semejanzas con los inhibidores de la anhidrasa carbónica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1539 "Ancho" => 2084 "Tamanyo" => 122371 ] ] "descripcion" => array:1 [ "en" => "Bar graph representing the hazard ratios of cardiovascular studies with SGLT2-i. The p-value is in the upper part of each bar. EMPAREG (orange), CANVAS (green) and CVD-REAL (gray). Abbreviations: HHF, hospitalization for heart failure; ACD, all-cause death; CVD, cardiovascular death." ] ] ] "textoCompleto" => "BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2-i) are a new family of drugs that have recently been incorporated into the therapeutic arsenal for treating diabetes mellitus (DM). These drugs exert their activity in the kidneys in the proximal convoluted tubule (PCT) by blocking SGLT2, the main agent responsible for renal glucose reabsorption, which is accompanied by sodium (Na+) reabsorption. Thus, the blocking of this cotransporter causes natriuresis and glycosuria, which in turn triggers systemic and renal effects, including reduced blood pressure without an increase in heart rate (due to the nonactivation of the sympathetic system), weight loss at the expense of fat and visceral mass, albuminuria and uric acid excretion. All these effects are related to a low probability of hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0360">1</a>Therefore, we have reasons to believe that these drugs develop a double effect, both antidiabetic and diuretic, both of which are relevant. This diuretic effect occurs in the PCT, and its action is very similar to that of carbonic anhydrase (CA) inhibitor diuretics, such as acetazolamide, and unlike that of loop diuretics, as has been postulated by other authors.<a class="elsevierStyleCrossRef" href="#bib0365">2</a>Diabetes mellitus and heart failureThe prevalence of DM is increasing and is considered a global problem. Worldwide, it is estimated that the number of adults with diabetes will increase from 135 million in 1995–300 million in 2025.<a class="elsevierStyleCrossRef" href="#bib0370">3</a> Patients with DM have up to a 2-fold greater likelihood of experiencing cardiovascular diseases, both coronary and cerebrovascular.<a class="elsevierStyleCrossRef" href="#bib0375">4</a> Cardiovascular diseases represent approximately 80% of deaths among patients with diabetes.<a class="elsevierStyleCrossRef" href="#bib0380">5</a>DM also considerably increases the risk of developing HF and negatively affects the progression of HF.<a class="elsevierStyleCrossRef" href="#bib0385">6</a> The prevalence of HF in patients without diabetes is 1–2% and increases drastically after the age of 70 years to more than 10%.<a class="elsevierStyleCrossRef" href="#bib0390">7</a> In patients with diabetes, the prevalence of HF is 2.5-fold higher, ranging from 9.5% to 22.3%.<a class="elsevierStyleCrossRef" href="#bib0380">5</a> The combination of type 2 DM (DM2) and HF is expected to increase. In patients with DM2, HF is associated with 40% mortality at 3 years, a rate 10 times higher than for individuals with diabetes but without HF.<a class="elsevierStyleCrossRef" href="#bib0395">8</a>DM contributes to the onset of several cardiovascular complications, many of which arise from effusions in small blood vessels, a condition known as microangiopathy. In the absence of other disorders, DM can also affect the cardiac structure and function and the development of coronary artery disease, a condition known as diabetic cardiomyopathy.<a class="elsevierStyleCrossRef" href="#bib0400">9</a> This condition can be described, although not exclusively, by diastolic dysfunction, which is more apparent in the presence of hypertension or myocardial ischemia.<a class="elsevierStyleCrossRef" href="#bib0405">10</a> Hyperinsulinemia and hyperglycemia are associated in DM with metabolic disorders such as the formation of advanced glycosylation end products and the activation of reactive oxygen species. All these changes lead to endothelial dysfunction: the impairment of myocytes and their contractility.<a class="elsevierStyleCrossRef" href="#bib0410">11</a>Despite the presence of numerous treatments for HF and DM, the morbidity and mortality of these patients remains high. As a result, new drugs are needed to improve symptoms, which would improve quality of life and in turn reduce morbidity and mortality.Antidiabetic drugs and heart failureIn terms of the results of HF, the classical antidiabetic drugs have shown no benefit in patients with DM2. It is interesting that intensive glycemic control has not shown a reduction in the incidence of HF in patients with DM2. The beneficial effect consists of controlling blood glucose, and this cannot be attributed to any compound or family of drugs. This lack of results was observed in the meta-analysis by Turnbull et al., published in 2009.<a class="elsevierStyleCrossRef" href="#bib0415">12</a>Since no drug has shown a benefit and considering that some of them are contraindicated for patients with HF, the selection process for antidiabetic drugs gains importance. Due to its ability to trigger lactic acidosis, metformin is contraindicated for patients with acute HF but is considered safe for patients with stable HF (a number of observational studies have related the use of metformin with increased survival for patients with DM and HF, when compared with controls).<a class="elsevierStyleCrossRefs" href="#bib0420">13,14</a> In contrast, the use of sulfonylureas has been questioned due to the high mortality found by observational studies when comparing with metformin.<a class="elsevierStyleCrossRef" href="#bib0430">15</a> However, the ADVANCE study observed that intensive diabetes treatment, in which gliclazide is included, was safe for patients with HF and showed cardiovascular benefits.<a class="elsevierStyleCrossRef" href="#bib0435">16</a>Insulin induces sodium retention, and therefore its use could theoretically be harmful for patients with HF. However, the ORIGIN study showed that insulin glargine is safe.<a class="elsevierStyleCrossRef" href="#bib0430">15</a> Thiazolidinediones produce salt and fluid retention and have been associated with an increase in hospitalizations for HF; their use is therefore contraindicated for patients with DM2 and HF. Dipeptidyl peptidase-4 inhibitors have shown mixed results regarding HF in cardiovascular safety studies. With regard to hospitalization rates for HF, saxagliptin was associated with an increased risk, while sitagliptin has been shown to be safe.<a class="elsevierStyleCrossRef" href="#bib0430">15</a>Glucagon-like peptide-1 receptor agonists, another type of drug that acts on the incretin system, present differing results in terms of cardiovascular morbidity and mortality, possibly due to their different pharmacokinetic or pharmacodynamici mechanisms. Along these lines, lixisenatide had neutral effects on HF in patients with acute coronary syndrome at 2 years of follow-up.<a class="elsevierStyleCrossRef" href="#bib0440">17</a> Liraglutide, with a longer half-life than lixisenatide, showed cardiovascular benefits and reduced mortality, although the results were also neutral when assessing the risk of hospitalization for HF.<a class="elsevierStyleCrossRef" href="#bib0445">18</a> The specific study LIVE, liraglutide vs. placebo, conducted with patients with reduced ejection fraction, observed no benefits.<a class="elsevierStyleCrossRef" href="#bib0450">19</a> For patients with high vascular risk, semaglutide improved the results; specifically, the drug reduced the risk of stroke, although, as with liraglutide, it did not significantly change the risk of hospitalization for HF.<a class="elsevierStyleCrossRef" href="#bib0455">20</a> Weekly exenatide has been studied in randomized clinical trials (RCTs) with a considerable number of patients in primary prevention but achieved neutral results, even with regard to HF.<a class="elsevierStyleCrossRef" href="#bib0460">21</a>Sodium-glucose cotransporter 2 inhibitorsThe only antidiabetic drugs that currently have shown a significant reduction in the number of hospitalizations for HF in randomized trials are SGLT2-i. The EMPA-REG OUTCOME study<a class="elsevierStyleCrossRef" href="#bib0465">22</a> found that the patient group randomized to empagliflozin (combined with their standard diabetes treatment) showed a 38% reduction in cardiovascular mortality (hazard ratio [HR], 0.62; 95% CI 0.70–0.77; p<.001), a 35% reduction in the number of hospitalizations for HF (HR, 0.65; 95% CI 0.50–0.85; p=.002) and a 32% reduction in all-cause mortality (HR, 0.68; 95% CI 0.57–0.82; p<.001) compared with the patients assigned to placebo (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). A reduction in the incidence of HF was observed in all the study subgroups, regardless of the base treatment. At the start of the study, only 10% of the EMPA-REG population showed signs and symptoms of HF; however, the type of HF (with preserved or depressed systolic function), the left ventricular ejection fraction and the levels were not known. The blood levels of natriuretic peptides were not known, given that they were not recorded in these registries in the clinical trial.<a class="elsevierStyleCrossRef" href="#bib0465">22</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>In the CANVAS study,<a class="elsevierStyleCrossRef" href="#bib0470">23</a> the reduction in hospitalizations for HF was similar to that achieved in the EMPA-REG study (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patients treated with canagliflozin had a 33% reduction in the relative risk of hospitalization for HF compared with those treated with placebo (HR, 0.67; 95% CI 0.52–0.87; p=NS). The results were not as conclusive as those obtained by EMPA-REG, perhaps because there were more patients in primary prevention in the CANVAS population sample (approx. 35%).The results of the RCTs have been reproduced in real-life studies in CVD-REAL, with more than 300,000 patients.<a class="elsevierStyleCrossRef" href="#bib0475">24</a> The patients who combined SGLT2-i with their standard therapy for diabetes had a lower incidence of hospitalization for HF (HR, 0.61; 95% CI 0.51–0.73; p<.001) and all-cause death (HR, 0.49; 95% CI 0.41–0.57; p<.001) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Although it has numerous methodological limitations, CVD-REAL supports the results observed in the RCTs, which indicate a class effect among the various types of SGLT2-i.Differences have not been reported in HF prevention among the various types of SGLT2-i. These data should be taken with caution until the results of ongoing RCTs for each specific compound have been published. These studies are designed to assess the effect of SGLT2-i on HF specifically in patients with or without diabetes: EMPEROR-Preserved (NCT03057951), EMPEROR-Reduced (NCT03057977), DAPA-HF (NCT3036124), DEFINE-HF (NCT02653482), PRESERVED-HF (NCT03030235).<a class="elsevierStyleCrossRef" href="#bib0480">25</a>Various theories have been proposed to explain the benefits of SGLT2-i for cardiovascular morbidity, including reduced oxidative stress and glucotoxicity,<a class="elsevierStyleCrossRef" href="#bib0480">25</a> metabolic changes due to the formation of ketones as more appropriate “fuel” for myocytes,<a class="elsevierStyleCrossRef" href="#bib0485">26</a> reduced arterial stiffness due to reduced blood pressure, reduced cardiac preload and afterload, weight loss and uricosuria.<a class="elsevierStyleCrossRef" href="#bib0480">25</a>Focusing on HF, what is the potential mechanism by which SGLT2-i exerts a protective effect in patients with DM2? It is apparent that this beneficial effect is not due to glycemic control, because other studies have found no relationship between glycemic control and an improvement in HF<a class="elsevierStyleCrossRefs" href="#bib0435">16,27</a> and is not due to an “antiatherosclerotic action”, because the beneficial effects were observed in the very short term. It appears that glucagon-like peptide-1 receptor agonists have a more specific effect on arteriosclerotic arteries, showing long-term benefits.<a class="elsevierStyleCrossRefs" href="#bib0445">18,20</a> A significant reduction in cardiovascular events (acute myocardial infarction and stroke) has not been observed with SGLT2-i<a class="elsevierStyleCrossRef" href="#bib0495">28</a>; therefore, the short-term benefit must be due to an action that is not exerted on atherosclerosis. We believe, as do other authors, that this benefit could be related to the diuretic effect of SGLT2-i, an effect that is not present in other antidiabetic drugs.Diuretic mechanismThe classical antidiabetic drugs have no diuretic effect, which could explain their neutral or occasionally adverse effect on HF. Insulin and thiazolidinediones retain sodium in the interstitial tissues. In contrast, incretin drugs have a modest natriuretic capacity. Animal studies have shown that dipeptidyl peptidase-4 inhibitors have a natriuretic effect dependent on the activity of a chemokine known as stromal cell-derived factor-1.α<a class="elsevierStyleCrossRefs" href="#bib0360">1–64</a> Sitagliptin has been shown to increase this cytokine's activity, with a mechanism of action similar to that of thiazide diuretics.<a class="elsevierStyleCrossRef" href="#bib0500">29</a>Glucagon-like peptide-1 receptor agonists also have a natriuretic effect, but this effect is different from that of dipeptidyl peptidase-4 inhibitors and is related to the inhibition of sodium/hydrogen exchanger 3 (NHE3) located in the PCT and to the stimulation of the atrial natriuretic peptide. Natriuresis, as measured before the urine reaches the macula densa (MD), would trigger tubuloglomerular feedback (TGF), as with SGLT2-i, but there are no changes in renal glomerular pressure. All this could be explained by the activation of other hemodynamic mechanisms in the kidneys, although they are all speculative.<a class="elsevierStyleCrossRef" href="#bib0505">30</a>Knowing the mechanism of action, we believe that SGLT2-i behave more like a diuretic than a classic antidiabetic drug. In a certain sense, SGLT2-i resemble classic diuretics (thiazide, loop diuretics), although there are a number of differences. The type of diuretic most similar to SGLT2-i is the CA inhibitor, such as acetazolamide.SGLT2-i cause natriuresis, osmotic diuresis, a temporary increase in urinary volume and a sustained decrease in intravascular volume. Additionally, it is likely that “contraction” of the plasma volume is sustained due to the increase in hematocrit. Cardiac preload and afterload, systolic and diastolic blood pressures and body weight also decrease.<a class="elsevierStyleCrossRefs" href="#bib0495">28,31,32</a> As with other diuretics,<a class="elsevierStyleCrossRef" href="#bib0525">34</a> SGLT2-i have been shown to reduce natriuretic peptide levels.<a class="elsevierStyleCrossRef" href="#bib0520">33</a>Due to the action of SGLT2-i, patients with diabetes present sodium overload due to increased sodium reabsorption in the PCT.<a class="elsevierStyleCrossRef" href="#bib0530">35</a> Under normal conditions, SGLT2-i can reabsorb 5% of tubular sodium; due to SGLT2-i overexpression, this quantity can increase to 30%<a class="elsevierStyleCrossRef" href="#bib0360">1</a> in patients with diabetes with poor glycemic control. Natriuresis is mild and generally lasts at most 2 weeks, given that the passage of sodium through the tubular lumen is interrupted by the actions of other receptors responsible for sodium reabsorption (especially in the MD due to the action of the sodium–chloride–potassium [Na+/2Cl−/K+] transporter).<a class="elsevierStyleCrossRef" href="#bib0535">36</a> This reabsorption process would trigger the juxtaglomerular apparatus, allowing the local secretion of adenosine, which in turn stimulates vasoconstriction of the afferent arteriole, improving hyperfiltration and partly explaining the observed renal benefits (which are not the subject of the present review).<a class="elsevierStyleCrossRef" href="#bib0540">37</a>There are few studies that have measured the quantity of excreted sodium, and these few studies were short-term. Sodium excretion in patients with DM2 treated with dapagliflozin is approximately 24.7–48mEq/day depending on the dosage and does not last beyond 2 weeks.<a class="elsevierStyleCrossRef" href="#bib0535">36</a>Although natriuresis is not sustained over time, there appears to be a decrease in sodium in the skin and tissues, demonstrating a reduction in the tissue's total sodium content, which could be beneficial for patients with HF.<a class="elsevierStyleCrossRef" href="#bib0545">38</a>Osmotic diuresis, as with natriuresis, has a sudden onset but stabilizes in a few days due to the glucose excretion triggered by the low plasma glucose levels.<a class="elsevierStyleCrossRefs" href="#bib0360">1,28</a> Natriuresis and osmotic diuresis reduce the plasma volume by approximately 7%, reflecting a 2–4% increase in hematocrit.<a class="elsevierStyleCrossRefs" href="#bib0465">22,28,39</a> As with natriuretic and osmotic diuresis, a reduction in extracellular volume beyond 12 weeks has not been observed. There are even studies that have reported that this volume is not sustained.<a class="elsevierStyleCrossRef" href="#bib0555">40</a> However, the increase in hematocrit is sustained over time (e.g., 3.1 years in the EMPA-REG OUTCOME<a class="elsevierStyleCrossRef" href="#bib0465">22</a> study and 2.4 years in the CANVAS study<a class="elsevierStyleCrossRef" href="#bib0470">23</a>). The only accepted explanation is volume depletion, which could be kept minimal over the long term. In a post hoc analysis, the increase in hematocrit was recognized as the most important variable when explaining the cardiovascular benefits.<a class="elsevierStyleCrossRef" href="#bib0560">41</a> The activation of erythropoiesis has been proposed as an alternative mechanism to explain this increase in hematocrit, although its long-term action has not been confirmed.<a class="elsevierStyleCrossRef" href="#bib0360">1</a> After treatment with empagliflozin versus incretin, the increase in hematocrit is equivalent to an increase in blood viscosity and wall shear stress (frictional force exerted on the endothelium).<a class="elsevierStyleCrossRef" href="#bib0565">42</a>The combined use of diuretics and SGLT2-i can cause volume depletion, hypotension or renal failure. There are few studies on diuresis in the context of SGLT2-i and diuretics. Using a pharmacodynamics test, a study has shown the sum of the natriuretic effect when empagliflozin is combined with torasemide or hydrochlorothiazide; we need to consider that this parameter was measured only after 5 days of treatment, which prevents us from properly assessing the results.<a class="elsevierStyleCrossRef" href="#bib0570">43</a> Another pharmacokinetic trial showed that the joint administration of canagliflozin and hydrochlorothiazide is safe, although cases of orthostatic hypotension were recorded.<a class="elsevierStyleCrossRef" href="#bib0575">44</a> Long-term studies are currently underway on the effects of combining SGLT2-i with diuretics.<a class="elsevierStyleCrossRef" href="#bib0580">45</a> In the EMPA-REG study,<a class="elsevierStyleCrossRef" href="#bib0465">22</a> approximately 50% of the patients took diuretics after the baseline therapy. Those patients treated with empagliflozin required fewer diuretics at the end of the study than those who were treated with placebo.<a class="elsevierStyleCrossRef" href="#bib0515">32</a> This finding, however, is not relevant, because marked differences were not observed in terms of cardiovascular mortality between the patients who took baseline diuretics and those who did not take these drugs.To properly assess the combined use of these drugs, we need to determine the intravascular volume and blood pressure.<a class="elsevierStyleCrossRef" href="#bib0585">46</a> Therefore, when there is a risk of hypotension, the recommendation is to discontinue treatment with loop diuretics or substitute them with thiazides (low-potency diuretic).<a class="elsevierStyleCrossRef" href="#bib0585">46</a>The EMPA-REG OUTCOME study observed a reduction in mortality and hospitalization due to HF beginning in the first 3 months of the study.<a class="elsevierStyleCrossRefs" href="#bib0495">28,47</a> The Randomized Aldactone Evaluation Study (RALES) also recorded this early reduction in mortality with spironolactone in patients with HF and left ventricular systolic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0595">48</a> In contrast, other classical diuretics (thiazide and loop diuretics) have not been able to demonstrate a reduction in cardiovascular mortality, and their effects on reducing the number of hospitalizations due to HF have been less conclusive than those observed with SGLT2-i.<a class="elsevierStyleCrossRef" href="#bib0530">35</a> The main explanation for the low hospitalization rates for HF associated with SGLT2-i observed in RCTs is the rapid reduction in extracellular volume that SGLT2-i produce. Classical diuretics produce a similar effect, but, unlike SGLT2-i, this effect is not sustained over time.<a class="elsevierStyleCrossRefs" href="#bib0495">28,34</a> Thiazide diuretics cause an initial contraction in plasma volume of 5–8%, which eases at 12 weeks.<a class="elsevierStyleCrossRef" href="#bib0550">39</a> With classical diuretics, the increase in hematocrit is corrected after several months, probably as the result of resistance to these diuretics.<a class="elsevierStyleCrossRefs" href="#bib0515">32,39</a> This reduction in intravascular volume would favorably affect myocyte overloading<a class="elsevierStyleCrossRef" href="#bib0505">30</a> and reduce arterial stiffness.<a class="elsevierStyleCrossRef" href="#bib0525">34</a> It has been shown that SGLT2-i decrease natriuretic peptide levels, as do other diuretics.<a class="elsevierStyleCrossRef" href="#bib0525">34</a> Using a validated zebra fish HF model, a study recently demonstrated that empagliflozin acts on the natriuretic peptide pathways and improves cardiac remodeling.<a class="elsevierStyleCrossRef" href="#bib0600">49</a> For example, it has been shown that therapy with empagliflozin reduces the left ventricular mass index and improves ventricular diastolic dysfunction at 3 months after starting the therapy.<a class="elsevierStyleCrossRef" href="#bib0605">50</a>The reduction in blood volume activates the renin-angiotensin-aldosterone system (RAAS) both in patients treated with RAAS inhibitors and in those not treated with these inhibitors.<a class="elsevierStyleCrossRefs" href="#bib0520">33,37,39</a> This activation is confirmed by the sustained increase in hematocrit. The same situation happens with loop diuretics, although in this case the increase in hematocrit is not sustained over time.<a class="elsevierStyleCrossRef" href="#bib0610">51</a> It has been shown that RAAS activation, using loop diuretics, can be sustained up to 6 months (but not significantly); RAAS activation appears to be greater the longer the effect of the loop diuretic.<a class="elsevierStyleCrossRef" href="#bib0615">52</a> It is interesting that both phlorizin and benign familial glycosuria also activate the RAAS.<a class="elsevierStyleCrossRefs" href="#bib0620">53,54</a> We still do not know the clinical implications of RAAS activation induced by SGLT2-i. In contrast, this activation, added to therapy with RAAS inhibitors, would be beneficial due to the increase in angiotensin 1.7.<a class="elsevierStyleCrossRef" href="#bib0630">55</a> The ongoing EMPagliflozin and RAs in Kidney Disease (NCT03078101) clinical trial is attempting to confirm this effect.As we explained earlier and although SGLT2-i-induced natriuresis is transient, these drugs help achieve a sustained increase in hematocrit (2–3%) and a reduction in systolic and diastolic blood pressure (5–6 and 1–2mm Hg, respectively), which could be the result of persistent volume depletion. This reduction in blood pressure would support this diuretic effect. There appear to be numerous mechanisms involved in reducing the blood pressure, including changes in plasma volume and reduced arterial stiffness,<a class="elsevierStyleCrossRef" href="#bib0635">56</a> weight loss and osmotic diuresis. The decrease in blood pressure is sustained for 24h and is synergistic with drugs that act on the RAAS, probably due to the increase in angiotensin 1.7, which is a vasodilator, and due to the reduction in sodium reabsorption in the PCT.<a class="elsevierStyleCrossRef" href="#bib0360">1</a>Lastly, another similarity between SGLT2-i and diuretics is that their efficacy depends on renal function. The poorer the renal function (measured as a glomerular filtration rate [GFR]), the less the glycosuria and the less the diuresis. The glycosuric effect is directly proportional to the estimated GFR (eGFR).<a class="elsevierStyleCrossRef" href="#bib0360">1</a> Their use is therefore generally not recommended with eGFR<60mL/min/1.73m2. Moreover, studies have shown that the use of SGLT2-i in patients with an eGFR of 30–60mL/min/1.73m2 maintains the hypotensive effect and weight loss and reduces albuminuria by 30%.<a class="elsevierStyleCrossRefs" href="#bib0640">57–59</a> This finding, in addition to the beneficial cardiovascular effects observed in the EMPA-REG OUTCOME<a class="elsevierStyleCrossRef" href="#bib0465">22</a> and CANVAS studies,<a class="elsevierStyleCrossRef" href="#bib0470">23</a> was observed even with an eGFR of 30mL/min/1.73m2; the use of SGLT2-i should therefore be considered for patients with similar eGFR levels.We can summarize the similarities between SGLT2-i and classical diuretics as follows: natriuresis, RAAS activation and the beneficial effects on volume overload and arterial hypertension.TGF activation (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) is different. The increase in chlorine and sodium reabsorption in the MD is due to the active sodium–chloride–potassium transporter. Loop diuretics block this transport and prevent TGF activation and the consequent benefit in reducing albuminuria.<a class="elsevierStyleCrossRef" href="#bib0655">60</a> Although there are no detailed studies, the combined use of SGLT2-i and loop diuretics misses the benefits derived from TGF activation due to the sodium–chloride–potassium transporter blocking the loop diuretics in the MD sensor<a class="elsevierStyleCrossRefs" href="#bib0360">1,43</a>; it would therefore be more logical to combine SGLT2-i, if necessary, with thiazide diuretics to act distally from the MD. There is an ongoing trial that could clarify whether this combination could be beneficial.<a class="elsevierStyleCrossRef" href="#bib0580">45</a> Thiazides and potassium-sparing diuretics exert their activity after the MD and therefore interfere with the TGF.<a class="elsevierStyleCrossRefs" href="#bib0655">60,61</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Another important difference is related to the form in which RAAS activation occurs due to the action of loop diuretics. This activation occurs through inhibition of an isoform of the sodium–chloride–potassium transporter, similar to that of the MD, which is found in endothelial cells of the afferent arteriole and the extraglomerular mesangial cells. This pump serves to suppress renin secretion, and its inhibition causes an increase in renin and angiotensin ii.<a class="elsevierStyleCrossRef" href="#bib0665">62</a>In terms of glomerular excretion, SGLT2-i are excreted through the glomerulus; conversely, loop diuretics are excreted through transporters located in the epithelial cells of the PCT, which enables this mechanism to resist them.<a class="elsevierStyleCrossRef" href="#bib0665">62</a>Lastly, SGLT2-i are uricosuric, reduce blood glucose levels and do not change ion levels. In contrast, loop diuretics and thiazide diuretics can increase uric acid and blood glucose levels and reduce potassium levels. Potassium-sparing diuretics can increase potassium levels.<a class="elsevierStyleCrossRef" href="#bib0515">32</a>Similarities between acetazolamide and sodium-glucose cotransporter 2 inhibitorsIn addition to sharing the location in which they perform their activity, SGLT2-i share many other aspects with CA inhibitor diuretics, such as acetazolamide. Approximately 30% of filtered sodium is reabsorbed in the PCT due to the action of NHE3, located in the apical membrane of the tubular epithelium<a class="elsevierStyleCrossRef" href="#bib0670">63</a> and which is directly involved in sodium reabsorption and indirectly in bicarbonate (HCO3−) ion reabsorption. This receptor is strongly activated in HF and can perpetuate resistance to diuretics and natriuretic peptides.<a class="elsevierStyleCrossRef" href="#bib0675">64</a> NHE3 shares the same microdomain as SGLT2-i in the epithelial membrane of the PCT (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B).<a class="elsevierStyleCrossRefs" href="#bib0680">65,66</a> The two cotransporters are closely related. The absorption caused by SGLT2-i in normal physiological conditions activates NHE3.<a class="elsevierStyleCrossRef" href="#bib0680">65</a> SGLT2-i (phlorizin, dapagliflozin and empagliflozin) reduce NHE3 activity preventing sodium bicarbonate reabsorption, causing natriuresis and bicarbonaturia.<a class="elsevierStyleCrossRefs" href="#bib0670">63,65,67</a> This inhibition can occur regardless of the effect on glucose.<a class="elsevierStyleCrossRef" href="#bib0680">65</a> Although the studies were not conducted with humans, we can say that the natriuresis caused by SGLT2-i would be a consequence of the sum of 2 mechanisms: SGLT2-i inhibition and NHE3 inhibition (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B).<a class="elsevierStyleCrossRef" href="#bib0680">65</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>CA is an enzyme found in the luminal membrane of PCT cells. This enzyme catalyzes the formation of carbonic acid and its subsequent conversion to water and carbon dioxide. CA also indirectly activates NHE3 by promoting the mobilization of its substrates, allowing for the tubular excretion of the proton (H+) and sodium reabsorption.<a class="elsevierStyleCrossRef" href="#bib0670">63</a>Acetazolamide is a diuretic that exerts its activity in the PCT, inhibits CA and indirectly reduces NHE3 activity. By inhibiting CA, H+ accumulates in the renal luminal cells, limiting its exchange with sodium located in the tubular lumen. This luminal accumulation of sodium results in natriuresis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>C).The use of acetazolamide can cause metabolic acidosis with a normal anion gap (hyperchloremic) by increasing the urine elimination of bicarbonate (HCO3−) and intraepithelial H+ retention (which is generally moderate and self-limiting).<a class="elsevierStyleCrossRef" href="#bib0695">68</a> This metabolic acidosis can also be caused by SGLT2-i, although in this case with an increased anion gap, as occurs in euglycemic ketoacidosis.<a class="elsevierStyleCrossRef" href="#bib0700">69</a>Both SGLT2-i and acetazolamide cause mild to moderate natriuresis by inhibiting NHE3 and activating the juxtaglomerular system, reducing hyperfiltration and proteinuria and allowing for the increase in sodium and chloride reabsorption by the MD. The natriuresis would be moderate and last a few days due to the action of the compensatory tubular reabsorption mechanism, although, as we explained above, the diuretic effect of SGLT2-i, unlike that of acetazolamide, is sustained over time.<a class="elsevierStyleCrossRef" href="#bib0550">39</a>Therefore, we propose that SGLT2-i act in a very similar manner to acetazolamide (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0705">70</a> There are no specific studies on the efficacy and safety of acetazolamide in patients with HF, although a trial is being conducted with acetazolamide combined with spironolactone in HF (NCT01973335). While we wait for the results, the use of acetazolamide is restricted to treatment for glaucoma and for symptoms resulting from altitude sickness. It would be interesting to have trials comparing diuretics and SGLT2-i, as well as a direct comparison with acetazolamide.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>ConclusionsThe surprising results regarding the reduced incidence of HF from the large clinical trials conducted on cardiovascular safety with SGLT2-i should be interpreted with caution. Until the trials that are currently underway have been completed, which were designed expressly for HF with SGLT2-i, we cannot conclude that these drugs are indicated as the first therapeutic option, as is the case with classical diuretics. The European protocol for HF published in 2016 indicated that treatment with empagliflozin should be considered for preventing or delaying the onset of HF, with a class IIa recommendation (level of evidence B).<a class="elsevierStyleCrossRef" href="#bib0710">71</a>Based on the scientific evidence we have presented, we can confirm that the mode of action of SGLT2-i is very similar to that of a diuretic but with certain differential characteristics: sustained depletion volume and increased hematocrit over time, RAAS activation, sustained weight loss and reduced blood pressure with no changes in electrolytes. We believe that its action is very similar to that of diuretic acetazolamide when it acts in the PCT, inhibiting NHE3, reducing proteinuria and causing metabolic acidosis.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1183879" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1104300" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1183878" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1104301" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Diabetes mellitus and heart failure" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Antidiabetic drugs and heart failure" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Sodium-glucose cotransporter 2 inhibitors" ] ] ] 7 => array:3 [ "identificador" => "sec0025" "titulo" => "Diuretic mechanism" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Similarities between acetazolamide and sodium-glucose cotransporter 2 inhibitors" ] ] ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-06-14" "fechaAceptado" => "2018-09-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1104300" "palabras" => array:4 [ 0 => "Sodium-glucose cotransporter-2 inhibitors" 1 => "Diuretic" 2 => "Acetazolamide" 3 => "Renin–angiotensin–aldosterone system" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1104301" "palabras" => array:4 [ 0 => "Inhibidores del cotransportador sodio-glucosa tipo 2" 1 => "Diurético" 2 => "Acetazolamida" 3 => "Sistema renina–angiotensina–aldosterona" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Sodium-glucose cotransporter-2 inhibitors have changed the concept of the effects that hypoglycemic drugs have on hearth failure (HF). For the first time, a therapeutic group has modified the evolution of HF. Its effect goes beyond glycemic control, and different theories have been postulated to justify this benefit. In the article we sent, we analyze the influence of the different pharmacological groups used in type 2 diabetes mellitus on HF, and we present the theory of the mechanism of action associated with the benefit of these drugs. In our opinion, this benefit in HF is secondary to its diuretic effect, specifically an effect very similar to carbon dioxide inhibitors.We think that our theory is novel, explains the mechanism of action and we have not found in the literature any article that explains the mechanism of action in such a precise way." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los inhibidores del cotransportador sodio-glucosa tipo 2 han cambiado el concepto que se tenía de los efectos que ejercen los fármacos hipoglucemiantes sobre la insuficiencia cardiaca (IC). Es la primera vez que un grupo terapéutico modifica la evolución de la IC. Sus efectos trascienden al control glucémico, postulándose diferentes teorías para justificar estos beneficios. En este artículo analizamos la influencia que tienen sobre la IC los distintos grupos farmacológicos utilizados en el tratamiento de la diabetes mellitus tipo 2, y planteamos el posible mecanismo de acción asociado con los beneficios aportados por estos fármacos. Somos de la opinión de que este beneficio sobre la IC es secundario a su efecto diurético, en concreto a una actividad muy parecida a la de los inhibidores del dióxido de carbono.Pensamos que se trata de una teoría novedosa que explica el mecanismo de acción. No hemos encontrado en la literatura ningún artículo que desarrolle de manera tan precisa dicho mecanismo." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: León Jiménez D, Gómez Huelgas R, Fernández Romero AJ, López Chozas JM, Pérez de Isla L, Miramontes González JP. Tratamiento diurético del paciente con diabetes e insuficiencia cardiaca. El papel de los inhibidores de la SGLT2 y semejanzas con los inhibidores de la anhidrasa carbónica. Rev Clin Esp. 2019;219:208–217." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1539 "Ancho" => 2084 "Tamanyo" => 122371 ] ] "descripcion" => array:1 [ "en" => "Bar graph representing the hazard ratios of cardiovascular studies with SGLT2-i. The p-value is in the upper part of each bar. EMPAREG (orange), CANVAS (green) and CVD-REAL (gray). Abbreviations: HHF, hospitalization for heart failure; ACD, all-cause death; CVD, cardiovascular death." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2182 "Ancho" => 2508 "Tamanyo" => 273841 ] ] "descripcion" => array:1 [ "en" => "Location of action and blocking of various diuretics. Loop diuretics blocks the entry of sodium to the interior of the MD cells and prevent TGF activation and the subsequent benefit in reducing albuminuria. Thiazides and potassium-sparing diuretics act after the ascending limb of the loop of Henle and MD and therefore do not affect the TGF. Abbreviations: CA, carbonic anhydrase; ATP, adenosine triphosphate active transporter; Cl−, chloride; GLUC, glucose; H+, proton; HL, loop of Henle; K+, potassium; MD, macula densa; Na+, sodium; TGF, tubuloglomerular feedback; SGLT2: sodium-glucose cotransporter-2; DCT, distal convoluted tubule; PCT, proximal convoluted tubule." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3599 "Ancho" => 2508 "Tamanyo" => 672563 ] ] "descripcion" => array:1 [ "en" => "Mechanism of action of SGLT2-i, acetazolamide and clinical consequences. (A) Glucose reabsorption in the proximal renal tubule. Normal physiology. (B) SGLT2-i blocks sodium/glucose reabsorption through SGLT2 and potentially inhibits NHE3. (C) Acetazolamide activity on CA with similar effect to that of SGLT2 inhibition. Abbreviations: CA, carbonic anhydrase; SGLT2-i, sodium-glucose cotransporter-2 inhibitors; Na+/K+ATPasa, sodium–potassium adenosine triphosphate active transporter; NHE3, Na+/H+ exchanger 3; SGLT2, sodium-glucose cotransporter-2." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: AG, anion gap; CA, carbonic anhydrase; NaHCO3, sodium bicarbonate; NHE3, Na+/H+ exchanger 3; SGLT2, sodium-glucose cotransporter-2; SGLT2-i, SGLT2 inhibitors; PCT, proximal convoluted tubule." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SGLT2-i \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Acetazolamide \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Location \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Action \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Direct/indirect \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Indirect (CA) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Transporter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SGLT2+NHE3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NHE3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tubular action \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Na++glucose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Na+ (NaHCO3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metabolic consequences \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metabolic acidosis high AG Euglycemic ketoacidosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metabolic acidosis Normal AG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antiproteinuric \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2017990.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Similarities in the mechanism of action between sodium-glucose cotransporter 2 inhibitors and acetazolamide." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:71 [ 0 => array:3 [ "identificador" => "bib0360" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "H.J. 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Diuretic treatment of the patient with diabetes and heart failure. Role of SGLT2 inhibitors and similarities with carbonic anhydrase inhibitors

Tratamiento diurético del paciente con diabetes e insuficiencia cardiaca. El papel de los inhibidores de la SGLT2 y semejanzas con los inhibidores de la anhidrasa carbónica

D. León Jiméneza,

Corresponding author

daleji73@gmail.com

Corresponding author.

, R. Gómez Huelgasb, A.J. Fernández Romeroc, J.M. López Chozasd, L. Pérez de Islae, J.P. Miramontes Gonzálezf

a Unidad de Riesgo Vascular, Medicina Interna, Hospital Universitario Virgen Macarena, Sevilla, Spain

b Unidad de Gestión Clínica de Medicina Interna, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain

c Cardiología, Hospital Universitario Virgen Macarena, Sevilla, Spain

d Unidad de Gestión Clínica de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain

e Departamento de Cardiología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IDISSC), Universidad Complutense, Madrid, Spain

f Medicina Interna, Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain

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        "titulo" => "Tratamiento diur&#233;tico del paciente con diabetes e insuficiencia cardiaca&#46; El papel de los inhibidores de la SGLT2 y semejanzas con los inhibidores de la anhidrasa carb&#243;nica"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Bar graph representing the hazard ratios of cardiovascular studies with SGLT2-i&#46; The <span class="elsevierStyleItalic">p</span>-value is in the upper part of each bar&#46; EMPAREG &#40;orange&#41;&#44; CANVAS &#40;green&#41; and CVD-REAL &#40;gray&#41;&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; HHF&#44; hospitalization for heart failure&#59; ACD&#44; all-cause death&#59; CVD&#44; cardiovascular death&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Sodium-glucose cotransporter-2 inhibitors &#40;SGLT2-i&#41; are a new family of drugs that have recently been incorporated into the therapeutic arsenal for treating diabetes mellitus &#40;DM&#41;&#46; These drugs exert their activity in the kidneys in the proximal convoluted tubule &#40;PCT&#41; by blocking SGLT2&#44; the main agent responsible for renal glucose reabsorption&#44; which is accompanied by sodium &#40;Na<span class="elsevierStyleSup">&#43;</span>&#41; reabsorption&#46; Thus&#44; the blocking of this cotransporter causes natriuresis and glycosuria&#44; which in turn triggers systemic and renal effects&#44; including reduced blood pressure without an increase in heart rate &#40;due to the nonactivation of the sympathetic system&#41;&#44; weight loss at the expense of fat and visceral mass&#44; albuminuria and uric acid excretion&#46; All these effects are related to a low probability of hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Therefore&#44; we have reasons to believe that these drugs develop a double effect&#44; both antidiabetic and diuretic&#44; both of which are relevant&#46; This diuretic effect occurs in the PCT&#44; and its action is very similar to that of carbonic anhydrase &#40;CA&#41; inhibitor diuretics&#44; such as acetazolamide&#44; and unlike that of loop diuretics&#44; as has been postulated by other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diabetes mellitus and heart failure</span><p id="par0015" class="elsevierStylePara elsevierViewall">The prevalence of DM is increasing and is considered a global problem&#46; Worldwide&#44; it is estimated that the number of adults with diabetes will increase from 135 million in 1995&#8211;300 million in 2025&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">3</span></a> Patients with DM have up to a 2-fold greater likelihood of experiencing cardiovascular diseases&#44; both coronary and cerebrovascular&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">4</span></a> Cardiovascular diseases represent approximately 80&#37; of deaths among patients with diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">DM also considerably increases the risk of developing HF and negatively affects the progression of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">6</span></a> The prevalence of HF in patients without diabetes is 1&#8211;2&#37; and increases drastically after the age of 70 years to more than 10&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">7</span></a> In patients with diabetes&#44; the prevalence of HF is 2&#46;5-fold higher&#44; ranging from 9&#46;5&#37; to 22&#46;3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">5</span></a> The combination of type 2 DM &#40;DM2&#41; and HF is expected to increase&#46; In patients with DM2&#44; HF is associated with 40&#37; mortality at 3 years&#44; a rate 10 times higher than for individuals with diabetes but without HF&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">DM contributes to the onset of several cardiovascular complications&#44; many of which arise from effusions in small blood vessels&#44; a condition known as microangiopathy&#46; In the absence of other disorders&#44; DM can also affect the cardiac structure and function and the development of coronary artery disease&#44; a condition known as diabetic cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">9</span></a> This condition can be described&#44; although not exclusively&#44; by diastolic dysfunction&#44; which is more apparent in the presence of hypertension or myocardial ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">10</span></a> Hyperinsulinemia and hyperglycemia are associated in DM with metabolic disorders such as the formation of advanced glycosylation end products and the activation of reactive oxygen species&#46; All these changes lead to endothelial dysfunction&#58; the impairment of myocytes and their contractility&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Despite the presence of numerous treatments for HF and DM&#44; the morbidity and mortality of these patients remains high&#46; As a result&#44; new drugs are needed to improve symptoms&#44; which would improve quality of life and in turn reduce morbidity and mortality&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antidiabetic drugs and heart failure</span><p id="par0035" class="elsevierStylePara elsevierViewall">In terms of the results of HF&#44; the classical antidiabetic drugs have shown no benefit in patients with DM2&#46; It is interesting that intensive glycemic control has not shown a reduction in the incidence of HF in patients with DM2&#46; The beneficial effect consists of controlling blood glucose&#44; and this cannot be attributed to any compound or family of drugs&#46; This lack of results was observed in the meta-analysis by Turnbull et al&#46;&#44; published in 2009&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">12</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Since no drug has shown a benefit and considering that some of them are contraindicated for patients with HF&#44; the selection process for antidiabetic drugs gains importance&#46; Due to its ability to trigger lactic acidosis&#44; metformin is contraindicated for patients with acute HF but is considered safe for patients with stable HF &#40;a number of observational studies have related the use of metformin with increased survival for patients with DM and HF&#44; when compared with controls&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">13&#44;14</span></a> In contrast&#44; the use of sulfonylureas has been questioned due to the high mortality found by observational studies when comparing with metformin&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">15</span></a> However&#44; the ADVANCE study observed that intensive diabetes treatment&#44; in which gliclazide is included&#44; was safe for patients with HF and showed cardiovascular benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Insulin induces sodium retention&#44; and therefore its use could theoretically be harmful for patients with HF&#46; However&#44; the ORIGIN study showed that insulin glargine is safe&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">15</span></a> Thiazolidinediones produce salt and fluid retention and have been associated with an increase in hospitalizations for HF&#59; their use is therefore contraindicated for patients with DM2 and HF&#46; Dipeptidyl peptidase-4 inhibitors have shown mixed results regarding HF in cardiovascular safety studies&#46; With regard to hospitalization rates for HF&#44; saxagliptin was associated with an increased risk&#44; while sitagliptin has been shown to be safe&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Glucagon-like peptide-1 receptor agonists&#44; another type of drug that acts on the incretin system&#44; present differing results in terms of cardiovascular morbidity and mortality&#44; possibly due to their different pharmacokinetic or pharmacodynamici mechanisms&#46; Along these lines&#44; lixisenatide had neutral effects on HF in patients with acute coronary syndrome at 2 years of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">17</span></a> Liraglutide&#44; with a longer half-life than lixisenatide&#44; showed cardiovascular benefits and reduced mortality&#44; although the results were also neutral when assessing the risk of hospitalization for HF&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">18</span></a> The specific study LIVE&#44; liraglutide vs&#46; placebo&#44; conducted with patients with reduced ejection fraction&#44; observed no benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">19</span></a> For patients with high vascular risk&#44; semaglutide improved the results&#59; specifically&#44; the drug reduced the risk of stroke&#44; although&#44; as with liraglutide&#44; it did not significantly change the risk of hospitalization for HF&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">20</span></a> Weekly exenatide has been studied in randomized clinical trials &#40;RCTs&#41; with a considerable number of patients in primary prevention but achieved neutral results&#44; even with regard to HF&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">21</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Sodium-glucose cotransporter 2 inhibitors</span><p id="par0055" class="elsevierStylePara elsevierViewall">The only antidiabetic drugs that currently have shown a significant reduction in the number of hospitalizations for HF in randomized trials are SGLT2-i&#46; The EMPA-REG OUTCOME study<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">22</span></a> found that the patient group randomized to empagliflozin &#40;combined with their standard diabetes treatment&#41; showed a 38&#37; reduction in cardiovascular mortality &#40;hazard ratio &#91;HR&#93;&#44; 0&#46;62&#59; 95&#37; CI 0&#46;70&#8211;0&#46;77&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; a 35&#37; reduction in the number of hospitalizations for HF &#40;HR&#44; 0&#46;65&#59; 95&#37; CI 0&#46;50&#8211;0&#46;85&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41; and a 32&#37; reduction in all-cause mortality &#40;HR&#44; 0&#46;68&#59; 95&#37; CI 0&#46;57&#8211;0&#46;82&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; compared with the patients assigned to placebo &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A reduction in the incidence of HF was observed in all the study subgroups&#44; regardless of the base treatment&#46; At the start of the study&#44; only 10&#37; of the EMPA-REG population showed signs and symptoms of HF&#59; however&#44; the type of HF &#40;with preserved or depressed systolic function&#41;&#44; the left ventricular ejection fraction and the levels were not known&#46; The blood levels of natriuretic peptides were not known&#44; given that they were not recorded in these registries in the clinical trial&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">22</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">In the CANVAS study&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">23</span></a> the reduction in hospitalizations for HF was similar to that achieved in the EMPA-REG study &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The patients treated with canagliflozin had a 33&#37; reduction in the relative risk of hospitalization for HF compared with those treated with placebo &#40;HR&#44; 0&#46;67&#59; 95&#37; CI 0&#46;52&#8211;0&#46;87&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>NS&#41;&#46; The results were not as conclusive as those obtained by EMPA-REG&#44; perhaps because there were more patients in primary prevention in the CANVAS population sample &#40;approx&#46; 35&#37;&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The results of the RCTs have been reproduced in real-life studies in CVD-REAL&#44; with more than 300&#44;000 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">24</span></a> The patients who combined SGLT2-i with their standard therapy for diabetes had a lower incidence of hospitalization for HF &#40;HR&#44; 0&#46;61&#59; 95&#37; CI 0&#46;51&#8211;0&#46;73&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and all-cause death &#40;HR&#44; 0&#46;49&#59; 95&#37; CI 0&#46;41&#8211;0&#46;57&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Although it has numerous methodological limitations&#44; CVD-REAL supports the results observed in the RCTs&#44; which indicate a class effect among the various types of SGLT2-i&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Differences have not been reported in HF prevention among the various types of SGLT2-i&#46; These data should be taken with caution until the results of ongoing RCTs for each specific compound have been published&#46; These studies are designed to assess the effect of SGLT2-i on HF specifically in patients with or without diabetes&#58; EMPEROR-Preserved &#40;NCT03057951&#41;&#44; EMPEROR-Reduced &#40;NCT03057977&#41;&#44; DAPA-HF &#40;NCT3036124&#41;&#44; DEFINE-HF &#40;NCT02653482&#41;&#44; PRESERVED-HF &#40;NCT03030235&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">25</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Various theories have been proposed to explain the benefits of SGLT2-i for cardiovascular morbidity&#44; including reduced oxidative stress and glucotoxicity&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">25</span></a> metabolic changes due to the formation of ketones as more appropriate &#8220;fuel&#8221; for myocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">26</span></a> reduced arterial stiffness due to reduced blood pressure&#44; reduced cardiac preload and afterload&#44; weight loss and uricosuria&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">25</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Focusing on HF&#44; what is the potential mechanism by which SGLT2-i exerts a protective effect in patients with DM2&#63; It is apparent that this beneficial effect is not due to glycemic control&#44; because other studies have found no relationship between glycemic control and an improvement in HF<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">16&#44;27</span></a> and is not due to an &#8220;antiatherosclerotic action&#8221;&#44; because the beneficial effects were observed in the very short term&#46; It appears that glucagon-like peptide-1 receptor agonists have a more specific effect on arteriosclerotic arteries&#44; showing long-term benefits&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">18&#44;20</span></a> A significant reduction in cardiovascular events &#40;acute myocardial infarction and stroke&#41; has not been observed with SGLT2-i<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">28</span></a>&#59; therefore&#44; the short-term benefit must be due to an action that is not exerted on atherosclerosis&#46; We believe&#44; as do other authors&#44; that this benefit could be related to the diuretic effect of SGLT2-i&#44; an effect that is not present in other antidiabetic drugs&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diuretic mechanism</span><p id="par0085" class="elsevierStylePara elsevierViewall">The classical antidiabetic drugs have no diuretic effect&#44; which could explain their neutral or occasionally adverse effect on HF&#46; Insulin and thiazolidinediones retain sodium in the interstitial tissues&#46; In contrast&#44; incretin drugs have a modest natriuretic capacity&#46; Animal studies have shown that dipeptidyl peptidase-4 inhibitors have a natriuretic effect dependent on the activity of a chemokine known as stromal cell-derived factor-1&#46;&#945;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">1&#8211;64</span></a> Sitagliptin has been shown to increase this cytokine&#39;s activity&#44; with a mechanism of action similar to that of thiazide diuretics&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">29</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Glucagon-like peptide-1 receptor agonists also have a natriuretic effect&#44; but this effect is different from that of dipeptidyl peptidase-4 inhibitors and is related to the inhibition of sodium&#47;hydrogen exchanger 3 &#40;NHE3&#41; located in the PCT and to the stimulation of the atrial natriuretic peptide&#46; Natriuresis&#44; as measured before the urine reaches the macula densa &#40;MD&#41;&#44; would trigger tubuloglomerular feedback &#40;TGF&#41;&#44; as with SGLT2-i&#44; but there are no changes in renal glomerular pressure&#46; All this could be explained by the activation of other hemodynamic mechanisms in the kidneys&#44; although they are all speculative&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">30</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Knowing the mechanism of action&#44; we believe that SGLT2-i behave more like a diuretic than a classic antidiabetic drug&#46; In a certain sense&#44; SGLT2-i resemble classic diuretics &#40;thiazide&#44; loop diuretics&#41;&#44; although there are a number of differences&#46; The type of diuretic most similar to SGLT2-i is the CA inhibitor&#44; such as acetazolamide&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">SGLT2-i cause natriuresis&#44; osmotic diuresis&#44; a temporary increase in urinary volume and a sustained decrease in intravascular volume&#46; Additionally&#44; it is likely that &#8220;contraction&#8221; of the plasma volume is sustained due to the increase in hematocrit&#46; Cardiac preload and afterload&#44; systolic and diastolic blood pressures and body weight also decrease&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">28&#44;31&#44;32</span></a> As with other diuretics&#44;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">34</span></a> SGLT2-i have been shown to reduce natriuretic peptide levels&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">33</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Due to the action of SGLT2-i&#44; patients with diabetes present sodium overload due to increased sodium reabsorption in the PCT&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">35</span></a> Under normal conditions&#44; SGLT2-i can reabsorb 5&#37; of tubular sodium&#59; due to SGLT2-i overexpression&#44; this quantity can increase to 30&#37;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">1</span></a> in patients with diabetes with poor glycemic control&#46; Natriuresis is mild and generally lasts at most 2 weeks&#44; given that the passage of sodium through the tubular lumen is interrupted by the actions of other receptors responsible for sodium reabsorption &#40;especially in the MD due to the action of the sodium&#8211;chloride&#8211;potassium &#91;Na<span class="elsevierStyleSup">&#43;</span>&#47;2Cl<span class="elsevierStyleSup">&#8722;</span>&#47;K<span class="elsevierStyleSup">&#43;</span>&#93; transporter&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">36</span></a> This reabsorption process would trigger the juxtaglomerular apparatus&#44; allowing the local secretion of adenosine&#44; which in turn stimulates vasoconstriction of the afferent arteriole&#44; improving hyperfiltration and partly explaining the observed renal benefits &#40;which are not the subject of the present review&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">37</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">There are few studies that have measured the quantity of excreted sodium&#44; and these few studies were short-term&#46; Sodium excretion in patients with DM2 treated with dapagliflozin is approximately 24&#46;7&#8211;48<span class="elsevierStyleHsp" style=""></span>mEq&#47;day depending on the dosage and does not last beyond 2 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">36</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Although natriuresis is not sustained over time&#44; there appears to be a decrease in sodium in the skin and tissues&#44; demonstrating a reduction in the tissue&#39;s total sodium content&#44; which could be beneficial for patients with HF&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">38</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Osmotic diuresis&#44; as with natriuresis&#44; has a sudden onset but stabilizes in a few days due to the glucose excretion triggered by the low plasma glucose levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">1&#44;28</span></a> Natriuresis and osmotic diuresis reduce the plasma volume by approximately 7&#37;&#44; reflecting a 2&#8211;4&#37; increase in hematocrit&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">22&#44;28&#44;39</span></a> As with natriuretic and osmotic diuresis&#44; a reduction in extracellular volume beyond 12 weeks has not been observed&#46; There are even studies that have reported that this volume is not sustained&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">40</span></a> However&#44; the increase in hematocrit is sustained over time &#40;e&#46;g&#46;&#44; 3&#46;1 years in the EMPA-REG OUTCOME<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">22</span></a> study and 2&#46;4 years in the CANVAS study<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">23</span></a>&#41;&#46; The only accepted explanation is volume depletion&#44; which could be kept minimal over the long term&#46; In a post hoc analysis&#44; the increase in hematocrit was recognized as the most important variable when explaining the cardiovascular benefits&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">41</span></a> The activation of erythropoiesis has been proposed as an alternative mechanism to explain this increase in hematocrit&#44; although its long-term action has not been confirmed&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">1</span></a> After treatment with empagliflozin versus incretin&#44; the increase in hematocrit is equivalent to an increase in blood viscosity and wall shear stress &#40;frictional force exerted on the endothelium&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">42</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The combined use of diuretics and SGLT2-i can cause volume depletion&#44; hypotension or renal failure&#46; There are few studies on diuresis in the context of SGLT2-i and diuretics&#46; Using a pharmacodynamics test&#44; a study has shown the sum of the natriuretic effect when empagliflozin is combined with torasemide or hydrochlorothiazide&#59; we need to consider that this parameter was measured only after 5 days of treatment&#44; which prevents us from properly assessing the results&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">43</span></a> Another pharmacokinetic trial showed that the joint administration of canagliflozin and hydrochlorothiazide is safe&#44; although cases of orthostatic hypotension were recorded&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">44</span></a> Long-term studies are currently underway on the effects of combining SGLT2-i with diuretics&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">45</span></a> In the EMPA-REG study&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">22</span></a> approximately 50&#37; of the patients took diuretics after the baseline therapy&#46; Those patients treated with empagliflozin required fewer diuretics at the end of the study than those who were treated with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">32</span></a> This finding&#44; however&#44; is not relevant&#44; because marked differences were not observed in terms of cardiovascular mortality between the patients who took baseline diuretics and those who did not take these drugs&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">To properly assess the combined use of these drugs&#44; we need to determine the intravascular volume and blood pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">46</span></a> Therefore&#44; when there is a risk of hypotension&#44; the recommendation is to discontinue treatment with loop diuretics or substitute them with thiazides &#40;low-potency diuretic&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">46</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The EMPA-REG OUTCOME study observed a reduction in mortality and hospitalization due to HF beginning in the first 3 months of the study&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">28&#44;47</span></a> The Randomized Aldactone Evaluation Study &#40;RALES&#41; also recorded this early reduction in mortality with spironolactone in patients with HF and left ventricular systolic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">48</span></a> In contrast&#44; other classical diuretics &#40;thiazide and loop diuretics&#41; have not been able to demonstrate a reduction in cardiovascular mortality&#44; and their effects on reducing the number of hospitalizations due to HF have been less conclusive than those observed with SGLT2-i&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">35</span></a> The main explanation for the low hospitalization rates for HF associated with SGLT2-i observed in RCTs is the rapid reduction in extracellular volume that SGLT2-i produce&#46; Classical diuretics produce a similar effect&#44; but&#44; unlike SGLT2-i&#44; this effect is not sustained over time&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">28&#44;34</span></a> Thiazide diuretics cause an initial contraction in plasma volume of 5&#8211;8&#37;&#44; which eases at 12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">39</span></a> With classical diuretics&#44; the increase in hematocrit is corrected after several months&#44; probably as the result of resistance to these diuretics&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">32&#44;39</span></a> This reduction in intravascular volume would favorably affect myocyte overloading<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">30</span></a> and reduce arterial stiffness&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">34</span></a> It has been shown that SGLT2-i decrease natriuretic peptide levels&#44; as do other diuretics&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">34</span></a> Using a validated zebra fish HF model&#44; a study recently demonstrated that empagliflozin acts on the natriuretic peptide pathways and improves cardiac remodeling&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">49</span></a> For example&#44; it has been shown that therapy with empagliflozin reduces the left ventricular mass index and improves ventricular diastolic dysfunction at 3 months after starting the therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">50</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The reduction in blood volume activates the renin-angiotensin-aldosterone system &#40;RAAS&#41; both in patients treated with RAAS inhibitors and in those not treated with these inhibitors&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">33&#44;37&#44;39</span></a> This activation is confirmed by the sustained increase in hematocrit&#46; The same situation happens with loop diuretics&#44; although in this case the increase in hematocrit is not sustained over time&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">51</span></a> It has been shown that RAAS activation&#44; using loop diuretics&#44; can be sustained up to 6 months &#40;but not significantly&#41;&#59; RAAS activation appears to be greater the longer the effect of the loop diuretic&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">52</span></a> It is interesting that both phlorizin and benign familial glycosuria also activate the RAAS&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">53&#44;54</span></a> We still do not know the clinical implications of RAAS activation induced by SGLT2-i&#46; In contrast&#44; this activation&#44; added to therapy with RAAS inhibitors&#44; would be beneficial due to the increase in angiotensin 1&#46;7&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">55</span></a> The ongoing EMPagliflozin and RAs in Kidney Disease &#40;NCT03078101&#41; clinical trial is attempting to confirm this effect&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">As we explained earlier and although SGLT2-i-induced natriuresis is transient&#44; these drugs help achieve a sustained increase in hematocrit &#40;2&#8211;3&#37;&#41; and a reduction in systolic and diastolic blood pressure &#40;5&#8211;6 and 1&#8211;2<span class="elsevierStyleHsp" style=""></span>mm Hg&#44; respectively&#41;&#44; which could be the result of persistent volume depletion&#46; This reduction in blood pressure would support this diuretic effect&#46; There appear to be numerous mechanisms involved in reducing the blood pressure&#44; including changes in plasma volume and reduced arterial stiffness&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">56</span></a> weight loss and osmotic diuresis&#46; The decrease in blood pressure is sustained for 24<span class="elsevierStyleHsp" style=""></span>h and is synergistic with drugs that act on the RAAS&#44; probably due to the increase in angiotensin 1&#46;7&#44; which is a vasodilator&#44; and due to the reduction in sodium reabsorption in the PCT&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">1</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Lastly&#44; another similarity between SGLT2-i and diuretics is that their efficacy depends on renal function&#46; The poorer the renal function &#40;measured as a glomerular filtration rate &#91;GFR&#93;&#41;&#44; the less the glycosuria and the less the diuresis&#46; The glycosuric effect is directly proportional to the estimated GFR &#40;eGFR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">1</span></a> Their use is therefore generally not recommended with eGFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; Moreover&#44; studies have shown that the use of SGLT2-i in patients with an eGFR of 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> maintains the hypotensive effect and weight loss and reduces albuminuria by 30&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">57&#8211;59</span></a> This finding&#44; in addition to the beneficial cardiovascular effects observed in the EMPA-REG OUTCOME<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">22</span></a> and CANVAS studies&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">23</span></a> was observed even with an eGFR of 30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#59; the use of SGLT2-i should therefore be considered for patients with similar eGFR levels&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">We can summarize the similarities between SGLT2-i and classical diuretics as follows&#58; natriuresis&#44; RAAS activation and the beneficial effects on volume overload and arterial hypertension&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">TGF activation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; is different&#46; The increase in chlorine and sodium reabsorption in the MD is due to the active sodium&#8211;chloride&#8211;potassium transporter&#46; Loop diuretics block this transport and prevent TGF activation and the consequent benefit in reducing albuminuria&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">60</span></a> Although there are no detailed studies&#44; the combined use of SGLT2-i and loop diuretics misses the benefits derived from TGF activation due to the sodium&#8211;chloride&#8211;potassium transporter blocking the loop diuretics in the MD sensor<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">1&#44;43</span></a>&#59; it would therefore be more logical to combine SGLT2-i&#44; if necessary&#44; with thiazide diuretics to act distally from the MD&#46; There is an ongoing trial that could clarify whether this combination could be beneficial&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">45</span></a> Thiazides and potassium-sparing diuretics exert their activity after the MD and therefore interfere with the TGF&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">60&#44;61</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">Another important difference is related to the form in which RAAS activation occurs due to the action of loop diuretics&#46; This activation occurs through inhibition of an isoform of the sodium&#8211;chloride&#8211;potassium transporter&#44; similar to that of the MD&#44; which is found in endothelial cells of the afferent arteriole and the extraglomerular mesangial cells&#46; This pump serves to suppress renin secretion&#44; and its inhibition causes an increase in renin and angiotensin <span class="elsevierStyleSmallCaps">ii</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">62</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">In terms of glomerular excretion&#44; SGLT2-i are excreted through the glomerulus&#59; conversely&#44; loop diuretics are excreted through transporters located in the epithelial cells of the PCT&#44; which enables this mechanism to resist them&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">62</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Lastly&#44; SGLT2-i are uricosuric&#44; reduce blood glucose levels and do not change ion levels&#46; In contrast&#44; loop diuretics and thiazide diuretics can increase uric acid and blood glucose levels and reduce potassium levels&#46; Potassium-sparing diuretics can increase potassium levels&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">32</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Similarities between acetazolamide and sodium-glucose cotransporter 2 inhibitors</span><p id="par0180" class="elsevierStylePara elsevierViewall">In addition to sharing the location in which they perform their activity&#44; SGLT2-i share many other aspects with CA inhibitor diuretics&#44; such as acetazolamide&#46; Approximately 30&#37; of filtered sodium is reabsorbed in the PCT due to the action of NHE3&#44; located in the apical membrane of the tubular epithelium<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">63</span></a> and which is directly involved in sodium reabsorption and indirectly in bicarbonate &#40;HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">&#8722;</span>&#41; ion reabsorption&#46; This receptor is strongly activated in HF and can perpetuate resistance to diuretics and natriuretic peptides&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">64</span></a> NHE3 shares the same microdomain as SGLT2-i in the epithelial membrane of the PCT &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">65&#44;66</span></a> The two cotransporters are closely related&#46; The absorption caused by SGLT2-i in normal physiological conditions activates NHE3&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">65</span></a> SGLT2-i &#40;phlorizin&#44; dapagliflozin and empagliflozin&#41; reduce NHE3 activity preventing sodium bicarbonate reabsorption&#44; causing natriuresis and bicarbonaturia&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">63&#44;65&#44;67</span></a> This inhibition can occur regardless of the effect on glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">65</span></a> Although the studies were not conducted with humans&#44; we can say that the natriuresis caused by SGLT2-i would be a consequence of the sum of 2 mechanisms&#58; SGLT2-i inhibition and NHE3 inhibition &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">65</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">CA is an enzyme found in the luminal membrane of PCT cells&#46; This enzyme catalyzes the formation of carbonic acid and its subsequent conversion to water and carbon dioxide&#46; CA also indirectly activates NHE3 by promoting the mobilization of its substrates&#44; allowing for the tubular excretion of the proton &#40;H<span class="elsevierStyleSup">&#43;</span>&#41; and sodium reabsorption&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">63</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Acetazolamide is a diuretic that exerts its activity in the PCT&#44; inhibits CA and indirectly reduces NHE3 activity&#46; By inhibiting CA&#44; H<span class="elsevierStyleSup">&#43;</span> accumulates in the renal luminal cells&#44; limiting its exchange with sodium located in the tubular lumen&#46; This luminal accumulation of sodium results in natriuresis &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The use of acetazolamide can cause metabolic acidosis with a normal anion gap &#40;hyperchloremic&#41; by increasing the urine elimination of bicarbonate &#40;HCO3<span class="elsevierStyleSup">&#8722;</span>&#41; and intraepithelial H<span class="elsevierStyleSup">&#43;</span> retention &#40;which is generally moderate and self-limiting&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">68</span></a> This metabolic acidosis can also be caused by SGLT2-i&#44; although in this case with an increased anion gap&#44; as occurs in euglycemic ketoacidosis&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">69</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Both SGLT2-i and acetazolamide cause mild to moderate natriuresis by inhibiting NHE3 and activating the juxtaglomerular system&#44; reducing hyperfiltration and proteinuria and allowing for the increase in sodium and chloride reabsorption by the MD&#46; The natriuresis would be moderate and last a few days due to the action of the compensatory tubular reabsorption mechanism&#44; although&#44; as we explained above&#44; the diuretic effect of SGLT2-i&#44; unlike that of acetazolamide&#44; is sustained over time&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">39</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Therefore&#44; we propose that SGLT2-i act in a very similar manner to acetazolamide &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">70</span></a> There are no specific studies on the efficacy and safety of acetazolamide in patients with HF&#44; although a trial is being conducted with acetazolamide combined with spironolactone in HF &#40;NCT01973335&#41;&#46; While we wait for the results&#44; the use of acetazolamide is restricted to treatment for glaucoma and for symptoms resulting from altitude sickness&#46; It would be interesting to have trials comparing diuretics and SGLT2-i&#44; as well as a direct comparison with acetazolamide&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0210" class="elsevierStylePara elsevierViewall">The surprising results regarding the reduced incidence of HF from the large clinical trials conducted on cardiovascular safety with SGLT2-i should be interpreted with caution&#46; Until the trials that are currently underway have been completed&#44; which were designed expressly for HF with SGLT2-i&#44; we cannot conclude that these drugs are indicated as the first therapeutic option&#44; as is the case with classical diuretics&#46; The European protocol for HF published in 2016 indicated that treatment with empagliflozin should be considered for preventing or delaying the onset of HF&#44; with a class IIa recommendation &#40;level of evidence B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">71</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Based on the scientific evidence we have presented&#44; we can confirm that the mode of action of SGLT2-i is very similar to that of a diuretic but with certain differential characteristics&#58; sustained depletion volume and increased hematocrit over time&#44; RAAS activation&#44; sustained weight loss and reduced blood pressure with no changes in electrolytes&#46; We believe that its action is very similar to that of diuretic acetazolamide when it acts in the PCT&#44; inhibiting NHE3&#44; reducing proteinuria and causing metabolic acidosis&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres1183879"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Background"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Diabetes mellitus and heart failure"
        ]
        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Antidiabetic drugs and heart failure"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Sodium-glucose cotransporter 2 inhibitors"
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          "titulo" => "Diuretic mechanism"
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              "identificador" => "sec0030"
              "titulo" => "Similarities between acetazolamide and sodium-glucose cotransporter 2 inhibitors"
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          "titulo" => "Conclusions"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-06-14"
    "fechaAceptado" => "2018-09-28"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Sodium-glucose cotransporter-2 inhibitors"
            1 => "Diuretic"
            2 => "Acetazolamide"
            3 => "Renin&#8211;angiotensin&#8211;aldosterone system"
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          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Inhibidores del cotransportador sodio-glucosa tipo 2"
            1 => "Diur&#233;tico"
            2 => "Acetazolamida"
            3 => "Sistema renina&#8211;angiotensina&#8211;aldosterona"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sodium-glucose cotransporter-2 inhibitors have changed the concept of the effects that hypoglycemic drugs have on hearth failure &#40;HF&#41;&#46; For the first time&#44; a therapeutic group has modified the evolution of HF&#46; Its effect goes beyond glycemic control&#44; and different theories have been postulated to justify this benefit&#46; In the article we sent&#44; we analyze the influence of the different pharmacological groups used in type 2 diabetes mellitus on HF&#44; and we present the theory of the mechanism of action associated with the benefit of these drugs&#46; In our opinion&#44; this benefit in HF is secondary to its diuretic effect&#44; specifically an effect very similar to carbon dioxide inhibitors&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We think that our theory is novel&#44; explains the mechanism of action and we have not found in the literature any article that explains the mechanism of action in such a precise way&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Los inhibidores del cotransportador sodio-glucosa tipo 2 han cambiado el concepto que se ten&#237;a de los efectos que ejercen los f&#225;rmacos hipoglucemiantes sobre la insuficiencia cardiaca &#40;IC&#41;&#46; Es la primera vez que un grupo terap&#233;utico modifica la evoluci&#243;n de la IC&#46; Sus efectos trascienden al control gluc&#233;mico&#44; postul&#225;ndose diferentes teor&#237;as para justificar estos beneficios&#46; En este art&#237;culo analizamos la influencia que tienen sobre la IC los distintos grupos farmacol&#243;gicos utilizados en el tratamiento de la diabetes mellitus tipo 2&#44; y planteamos el posible mecanismo de acci&#243;n asociado con los beneficios aportados por estos f&#225;rmacos&#46; Somos de la opini&#243;n de que este beneficio sobre la IC es secundario a su efecto diur&#233;tico&#44; en concreto a una actividad muy parecida a la de los inhibidores del di&#243;xido de carbono&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Pensamos que se trata de una teor&#237;a novedosa que explica el mecanismo de acci&#243;n&#46; No hemos encontrado en la literatura ning&#250;n art&#237;culo que desarrolle de manera tan precisa dicho mecanismo&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Le&#243;n Jim&#233;nez D&#44; G&#243;mez Huelgas R&#44; Fern&#225;ndez Romero AJ&#44; L&#243;pez Chozas JM&#44; P&#233;rez de Isla L&#44; Miramontes Gonz&#225;lez JP&#46; Tratamiento diur&#233;tico del paciente con diabetes e insuficiencia cardiaca&#46; El papel de los inhibidores de la SGLT2 y semejanzas con los inhibidores de la anhidrasa carb&#243;nica&#46; Rev Clin Esp&#46; 2019&#59;219&#58;208&#8211;217&#46;</p>"
      ]
    ]
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      0 => array:7 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Bar graph representing the hazard ratios of cardiovascular studies with SGLT2-i&#46; The <span class="elsevierStyleItalic">p</span>-value is in the upper part of each bar&#46; EMPAREG &#40;orange&#41;&#44; CANVAS &#40;green&#41; and CVD-REAL &#40;gray&#41;&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; HHF&#44; hospitalization for heart failure&#59; ACD&#44; all-cause death&#59; CVD&#44; cardiovascular death&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Location of action and blocking of various diuretics&#46; Loop diuretics blocks the entry of sodium to the interior of the MD cells and prevent TGF activation and the subsequent benefit in reducing albuminuria&#46; Thiazides and potassium-sparing diuretics act after the ascending limb of the loop of Henle and MD and therefore do not affect the TGF&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; CA&#44; carbonic anhydrase&#59; ATP&#44; adenosine triphosphate active transporter&#59; Cl<span class="elsevierStyleSup">&#8722;</span>&#44; chloride&#59; GLUC&#44; glucose&#59; H<span class="elsevierStyleSup">&#43;</span>&#44; proton&#59; HL&#44; loop of Henle&#59; K<span class="elsevierStyleSup">&#43;</span>&#44; potassium&#59; MD&#44; macula densa&#59; Na<span class="elsevierStyleSup">&#43;</span>&#44; sodium&#59; TGF&#44; tubuloglomerular feedback&#59; SGLT2&#58; sodium-glucose cotransporter-2&#59; DCT&#44; distal convoluted tubule&#59; PCT&#44; proximal convoluted tubule&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of SGLT2-i&#44; acetazolamide and clinical consequences&#46; &#40;A&#41; Glucose reabsorption in the proximal renal tubule&#46; Normal physiology&#46; &#40;B&#41; SGLT2-i blocks sodium&#47;glucose reabsorption through SGLT2 and potentially inhibits NHE3&#46; &#40;C&#41; Acetazolamide activity on CA with similar effect to that of SGLT2 inhibition&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; CA&#44; carbonic anhydrase&#59; SGLT2-i&#44; sodium-glucose cotransporter-2 inhibitors&#59; Na<span class="elsevierStyleSup">&#43;</span>&#47;K<span class="elsevierStyleSup">&#43;</span>ATPasa&#44; sodium&#8211;potassium adenosine triphosphate active transporter&#59; NHE3&#44; Na<span class="elsevierStyleSup">&#43;</span>&#47;H<span class="elsevierStyleSup">&#43;</span> exchanger 3&#59; SGLT2&#44; sodium-glucose cotransporter-2&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; AG&#44; anion gap&#59; CA&#44; carbonic anhydrase&#59; NaHCO<span class="elsevierStyleInf">3</span>&#44; sodium bicarbonate&#59; NHE3&#44; Na<span class="elsevierStyleSup">&#43;</span>&#47;H<span class="elsevierStyleSup">&#43;</span> exchanger 3&#59; SGLT2&#44; sodium-glucose cotransporter-2&#59; SGLT2-i&#44; SGLT2 inhibitors&#59; PCT&#44; proximal convoluted tubule&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SGLT2-i&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Acetazolamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Location&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Direct&#47;indirect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Indirect &#40;CA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Transporter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SGLT2<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>NHE3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NHE3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tubular action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Na<span class="elsevierStyleSup">&#43;</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>glucose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Na<span class="elsevierStyleSup">&#43;</span> &#40;NaHCO<span class="elsevierStyleInf">3</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metabolic consequences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metabolic acidosis high AG<br>Euglycemic ketoacidosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Metabolic acidosis<br>Normal AG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antiproteinuric&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2017990.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Similarities in the mechanism of action between sodium-glucose cotransporter 2 inhibitors and acetazolamide&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:71 [
            0 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus&#58; cardiovascular and kidney effects&#44; potential mechanisms&#44; and clinical applications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "H&#46;J&#46; Heerspink"
                            1 => "B&#46;A&#46; Perkins"
                            2 => "D&#46;H&#46; Fitchett"
                            3 => "M&#46; Husain"
                            4 => "D&#46;Z&#46; Cherney"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.116.021887"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
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                        "volumen" => "134"
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                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
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              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                      "titulo" => "Diuretic action of sodium-glucose cotransporter 2 inhibitors and its importance in the management of heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "G&#46; Kimura"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1253/circj.CJ-16-0780"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global burden of diabetes&#44; 1995&#8211;2025&#58; prevalence&#44; numerical estimates&#44; and projections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; King"
                            1 => "R&#46;E&#46; Aubert"
                            2 => "W&#46;H&#46; Herman"
                          ]
                        ]
                      ]
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                  ]
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            3 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes mellitus&#44; fasting blood glucose concentration&#44; and risk of vascular disease&#58; a collaborative meta-analysis of 102 prospective studies"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "Emerging Risk Factors Collaboration"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Sarwar"
                            1 => "P&#46; Gao"
                            2 => "S&#46;R&#46;K&#46; Seshasai"
                            3 => "R&#46; Gobin"
                            4 => "S&#46; Kaptoge"
                            5 => "E&#46; Di Angelantonio"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(10)60484-9"
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                          ]
                        ]
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                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0380"
              "etiqueta" => "5"
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                  "contribucion" => array:1 [
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                      "titulo" => "High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;J&#46;M&#46; Boonman-de Winter"
                            1 => "F&#46;H&#46; Rutten"
                            2 => "M&#46;J&#46;M&#46; Cramer"
                            3 => "M&#46;J&#46; Landman"
                            4 => "A&#46;H&#46; Liem"
                            5 => "G&#46;E&#46;H&#46;M&#46; Rutten"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00125-012-2579-0"
                      "Revista" => array:6 [
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                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes&#58; a driver for heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;A&#46; Voors"
                            1 => "I&#46;C&#46;C&#46; van der Horst"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1136/hrt.2009.183624"
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                        "tituloSerie" => "Heart"
                        "fecha" => "2011"
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                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gu&#237;a ESC 2016 sobre el diagn&#243;stico y tratamiento de la insuficiencia cardiaca aguda y cr&#243;nica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Ponikowski"
                            1 => "A&#46;A&#46; Voors"
                            2 => "S&#46;D&#46; Anker"
                            3 => "H&#46; Bueno"
                            4 => "J&#46;G&#46;F&#46; Cleland"
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                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.rec.2016.11.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Esp Cardiol"
                        "fecha" => "2016"
                        "volumen" => "69"
                        "paginaInicial" => "1167&#46;e1"
                        "paginaFinal" => "1167&#46;e85"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27894487"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between cardiovascular vs&#46; non-cardiovascular co-morbidities and outcomes in heart failure with preserved ejection fraction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;H&#46; Lund"
                            1 => "E&#46; Donal"
                            2 => "E&#46; Oger"
                            3 => "C&#46; Hage"
                            4 => "H&#46; Persson"
                            5 => "I&#46; Haugen-L&#246;fman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ejhf.137"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Heart Fail"
                        "fecha" => "2014"
                        "volumen" => "16"
                        "paginaInicial" => "992"
                        "paginaFinal" => "1001"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25046483"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "F&#46;S&#46; Fein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "1990"
                        "volumen" => "13"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2019.01.001

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