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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">Heart failure &#40;HF&#41; and diabetes mellitus &#40;DM&#41; are 2 prevalent clinical conditions that often coexist&#46; The incidence rate of HF increases with age and reaches 10&#37; in individuals older than 65 years&#44;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">1&#44;2</span></a> which is precisely the fastest growing population group in developed societies&#46; The risk of developing HF at the age of 55 years is 33&#37; in men and 28&#37; in women&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">2</span></a> The worldwide prevalence of DM is approximately 415 million individuals and is expected to reach 642 million by 2040&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">3</span></a> The incidence of DM also increases with age&#44; reaching 26&#37; in individuals older than 65 years&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Given the prevalence of the 2 conditions and the global aging of the population&#44; it is not surprising that the concurrence of DM and HF is growing&#46; The prevalence of DM in patients with HF is 25&#8211;35&#37; and is even higher in patients hospitalized for exacerbated HF&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">4</span></a> The incidence rate of HF in patients with DM is 2&#46;5-fold higher than in patients without DM&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">5</span></a> The development of HF in patients with diabetes is associated with a poorer prognosis&#44; increased mortality and increased readmissions&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">6</span></a> Moreover&#44; DM confers a poorer prognosis to patients with HF&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The use of hypoglycemic agents in patients with established heart disease&#44; especially HF&#44; is not exempt from complications&#46; Numerous cardiovascular &#40;CV&#41; safety studies have been published that offer relevant information on this issue&#46; The objective of this review is to assess the available evidence on the safety of antidiabetic drugs in patients with HF&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methodology</span><p id="par0020" class="elsevierStylePara elsevierViewall">We performed a systematic search on PubMed with the following keywords&#58; heart failure&#44; diabetes&#44; hospitalization and mortality&#46; We first assessed experimental studies with control groups and&#44; in lieu thereof&#44; observational studies&#46; We also conducted an individualized search for each antidiabetic drug&#44; adding the term &#8220;heart failure&#8221; to the corresponding drug term&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Influence of diabetes mellitus on heart failure</span><p id="par0025" class="elsevierStylePara elsevierViewall">Patients with diabetes and HF have a poorer prognosis than their counterparts without diabetes&#46; The presence of DM in patients with HF is associated with increased morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">7&#8211;13</span></a> This association occurs both in outpatients and in patients hospitalized for exacerbated HF and is independent of left ventricular ejection fraction &#40;LVEF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">10&#44;14&#8211;16</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The Efficacy of Vasopressin Antagonism in Heart Failure&#58; Outcome Study with Tolvaptan &#40;EVEREST&#41; showed that patients with diabetes had more events &#40;hazard ratio &#91;HR&#93;&#44; 1&#46;15&#59; 95&#37; confidence interval &#91;95&#37; CI&#93; 1&#46;04&#8211;1&#46;31&#41; for the combined variable of CV mortality and&#47;or readmissions for HF than their counterparts without diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">15</span></a> The Heart Failure Registry of the Spanish Society of Internal Medicine revealed interesting data on actual clinical practice&#46; After a 1-year follow-up of 1082 patients with a mean age of 77 years&#44; hospitalized for acute HF in Spanish internal medicine departments&#44; DM was independently associated with increased overall mortality &#40;HR&#44; 1&#46;54&#59; 95&#37; CI 1&#46;20&#8211;1&#46;97&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and readmissions &#40;HR&#44; 1&#46;46&#59; 95&#37; CI 1&#46;18&#8211;1&#46;80&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; with no differences in mortality &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;415&#41; or hospitalizations &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;514&#41; between patients with HF with preserved ejection fraction and those with depressed ejection fraction&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Glycemic control and heart failure prognosis</span><p id="par0035" class="elsevierStylePara elsevierViewall">In patients with HF&#44; the relationship between glycemic control and the occurrence of CV events is not clearly defined&#46; A number of observational studies have demonstrated the typical U-shaped curve between HbA<span class="elsevierStyleInf">1c</span> and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">17&#8211;19</span></a> In a study of 5815 outpatients with HF undergoing medical treatment with hypoglycemic agents&#44; modest glycemic control &#40;HbA<span class="elsevierStyleInf">1c</span>&#44; 7&#46;1&#8211;7&#46;8&#37;&#41; was associated with lower mortality&#44; compared with patients who had HbA<span class="elsevierStyleInf">1c</span> levels &#60;7&#46;1&#37; or &#62;7&#46;8&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">17</span></a> In another cohort of 123 patients with DM &#40;undergoing hypoglycemic treatment&#41; and advanced HF with reduced LVEF&#44; an HbA1c level &#8804;7&#46;0&#37; was associated with increased mortality compared with those with HbA1c levels &#62;7&#37; &#40;HR&#44; 2&#46;3&#59; 95&#37; CI 1&#46;0&#8211;5&#46;2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">18</span></a> Another similar study of 358 patients with advanced HF and reduced LVEF analyzed the relationship between HbA<span class="elsevierStyleInf">1c</span> levels &#40;quartile 1&#44; &#8804;6&#46;4&#37;&#59; quartile 2&#44; 6&#46;5&#8211;7&#46;2&#37;&#59; quartile 3&#44; 7&#46;3&#8211;8&#46;5&#37;&#59; and quartile 4&#44; &#8805;8&#46;6&#37;&#41; and the need for heart transplantation and&#47;or mortality&#46; CV-event-free survival at 2 years of follow-up was 61&#37; and 65&#37; in quartiles 3 and 4 compared with 48&#37; and 42&#37; in quartiles 1 and 2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0005&#41;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">19</span></a> The reasons for this paradoxical relationship are not well known&#46; Considering this information comes from observational studies&#44; specific recommendations cannot be made&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Risk induced by antidiabetic drugs</span><p id="par0040" class="elsevierStylePara elsevierViewall">Optimal hypoglycemic treatment in patients with diabetes and HF still has areas of uncertainty&#46; A number of therapeutic groups continue to be prescribed despite their questionable safety in HF&#46; Moreover&#44; patients with HF usually have comorbidities&#44; especially due to the association with chronic kidney disease&#44; which limits the use of certain therapeutic groups&#46; Understanding the safety profile of hypoglycemic drugs is therefore essential for their correct use in patients with HF&#46; Below&#44; we review the evidence for each drug group used in patients with diabetes and HF&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Safety of hypoglycemic drugs in heart failure</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Metformin</span><p id="par0045" class="elsevierStylePara elsevierViewall">In the absence of contraindications&#44; metformin is the first-choice drug for DM&#46; Metformin has been classically contraindicated for patients with HF due to the potential risk of lactic acidosis&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">20</span></a> Subsequent studies have shown that this risk is extremely low and with no differences between patients with diabetes treated or not with the drug&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">21</span></a> Numerous observational studies have shown that metformin can be associated with improved survival for patients with DM and HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">A systematic review of these observational studies&#44; which included 34&#44;000 patients&#44; showed that metformin is associated with reduced mortality&#44; compared with other drugs&#44; mostly sulfonylureas &#40;SU&#41; &#40;mortality 23&#37; vs&#46; 37&#37;&#44; respectively&#59; relative risk &#91;RR&#93;&#44; 0&#46;80&#59; 95&#37; CI 0&#46;74&#8211;0&#46;87&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Metformin was also associated with a slight reduction in hospitalizations &#40;RR&#44; 0&#46;93&#59; 95&#37; CI 0&#46;89&#8211;0&#46;98&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46; No increase in the incidence of lactic acidosis was observed in the group treated with metformin&#46; Neither the patients with reduced LVEF nor those with chronic kidney disease experienced increased mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">24</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The main restriction for using metformin is renal dysfunction&#46; Considering that chronic kidney disease is a very common comorbidity in HF&#44; the glomerular filtration rate &#40;GFR&#41; should always be calculated&#46; Although the exact degree of renal dysfunction for avoiding the use of metformin has not been firmly established&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">25</span></a> the Food and Drug Administration &#40;FDA&#41;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">26</span></a> and the National Institute for Health and Clinical Excellence &#40;NICE&#41;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">27</span></a> consider metformin contraindicated if the GFR is &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; requiring a dosage reduction and tightening surveillance with a GFR of 30&#8211;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Sulfonylureas</span><p id="par0060" class="elsevierStylePara elsevierViewall">These drugs are frequently used in patients with diabetes and HF&#46; However&#44; their CV safety has been questioned&#44; although not systematically&#44; in observational studies&#46; In a meta-analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">28</span></a> sulfonylureas did not increase the overall incidence of CV events when compared with other hypoglycemic agents but did increase the risk of stroke and were associated with a significant increase in mortality&#46; Another meta-analysis<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">29</span></a> concluded that sulfonylureas significantly increased total and CV mortality&#44; compared with other hypoglycemic drugs&#44; especially metformin&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">A retrospective analysis of patients with diabetes treated with metformin &#40;126&#44;867 patients&#41; or sulfonylureas &#40;79&#44;192&#41; between 2001 and 2011 showed a significant increase among the sulfonylureas in hospitalizations for HF &#40;adjusted HR&#44; 1&#46;30&#59; 95&#37; CI 1&#46;20&#8211;1&#46;42&#41; and CV mortality &#40;adjusted HR&#44; 1&#46;76&#59; 95&#37; CI 1&#46;14&#8211;2&#46;71&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">30</span></a> In contrast&#44; the Action in Diabetes and Vascular Disease&#58; Preterax and Diamicron MR Controlled Evaluation &#40;ADVANCE&#41; study showed that gliclazide&#44; a new-generation sulfonylurea&#44; did not increase macrovascular complications and had a nephroprotective effect&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">31</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Another study that included more than 16&#44;000 Medicare patients diagnosed with HF compared the results of using thiazolidinediones&#44; metformin and other noninsulin-sensitizing antidiabetic drugs&#44; such as sulfonylureas and insulin itself&#46; Approximately one third of the patients were treated with sulfonylureas at discharge&#46; There was no increase in mortality &#40;HR&#44; 0&#46;99&#59; 95&#37; CI 0&#46;91&#8211;1&#46;08&#41; in the patients treated with sulfonylureas&#44; but there was an increase in hospitalizations for HF in those treated with thiazolidinediones &#40;HR&#44; 1&#46;06&#59; 95&#37; CI 1&#8211;1&#46;09&#41; and a slight reduction in those treated with metformin &#40;HR&#44; 0&#46;92&#59; 95&#37; CI 0&#46;92&#8211;0&#46;99&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">32</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The main adverse effects of sulfonylureas &#40;the risk of hypoglycemia and weight gain&#41; are deleterious for patients with HF&#46; New-generation sulfonylureas &#40;such as gliclazide and glimepiride&#41; have overtaken the first-generation sulfonylureas due to their potency and the possibility of administering in single daily doses&#46; Despite their better profile&#44; evidence suggests that the CV benefit of new-generation sulfonylureas<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">33</span></a> over first-generation sulfonylureas<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">34</span></a> is insignificant&#46; However&#44; these studies have been highly controversial due to their methodological deficiencies&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In conclusion&#44; there are no prospective&#44; randomized controlled studies on the use of sulfonylureas in patients with diabetes and HF&#46; Nevertheless&#44; given the results of the ADVANCE study&#44;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">29</span></a> gliclazide should be the drug of choice when using a sulfonylurea&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Glinides</span><p id="par0085" class="elsevierStylePara elsevierViewall">Glinides &#40;repaglinide and nateglinide&#41; exert their hypoglycemic effect by increasing insulin secretion and act primarily by reducing postprandial glycemia&#46; Their main adverse effects are weight gain and hypoglycemia&#44; both of which are minor compared with sulfonylureas&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A recent observational&#44; retrospective study that analyzed the databases of the national health system of Taiwan studied the incidence of hospitalizations for HF in patients with DM who started treatment with glinides&#44; sulfonylureas or acarbose&#46; Through logistic regression using acarbose as a reference&#44; the study showed that patients who took glinides had a greater risk of hospitalization for HF &#40;adjusted HR&#44; 1&#46;53&#59; 95&#37; CI 1&#46;24&#8211;1&#46;88&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; than those who took acarbose and sulfonylureas&#44; while the risk did not differ with respect to those treated exclusively with sulfonylureas &#40;HR&#44; 0&#46;94&#59; 95&#37; CI 0&#46;80&#8211;1&#46;11&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;42&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">36</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Therefore&#44; there is insufficient evidence to confirm the safety of glinides in HF&#46; Their profile of CV effects&#44; which is similar to sulfonylureas and includes a high risk of hypoglycemia&#44; discourages their use as first-choice drugs for patients with HF&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Acarbose</span><p id="par0100" class="elsevierStylePara elsevierViewall">Studies on acarbose in HF are highly limited and insufficient for making specific recommendations&#46; The previously mentioned study<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">34</span></a> concluded that acarbose behaves similarly to sulfonylureas in terms of hospitalizations for HF&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Thiazolidinediones</span><p id="par0105" class="elsevierStylePara elsevierViewall">Thiazolidinediones have been associated with fluid retention and the onset of HF in controlled clinical studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">37&#44;38</span></a> The mechanisms that contribute to the worsening of HF are not well known&#46; Volume expansion due to the increase in the renal reabsorption of sodium is considered the most plausible mechanism&#44; more so than a direct effect of these drugs on cardiac structure and function&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In the Prospective Pioglitazone Clinical Trial in Macrovascular Events &#40;PROactive&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">38</span></a> which included more than 5000 patients&#44; the incidence of HF was higher in the pioglitazone group&#46; The pioglitazone arm showed an independent risk of new HF cases &#40;odds ratio&#44; 1&#46;53&#59; 95&#37; CI 1&#46;18&#8211;1&#46;95&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0012&#41; versus placebo&#44; although without an increase in mortality&#46; Other studies have confirmed the excessive risk of acute HF in patients who take pioglitazone&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">39</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes &#40;RECORD&#41; study assessed 4447 patients with diabetes&#44; comparing those treated with metformin or sulfonylureas &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2227&#41; against those who were added rosiglitazone &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2220&#41;&#46; The latter group had an increased risk of hospitalizations and death by HF &#40;HR&#44; 2&#46;10&#59; 95&#37; CI 1&#46;35&#8211;3&#46;27&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">40</span></a> Rosiglitazone has not been available since 2010&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Given these findings&#44; thiazolidinediones should not be prescribed to patients with signs and symptoms suggestive of HF and are contraindicated for patients with HF and a New York Heart Association &#40;NYHA&#41; functional class of III&#8211;IV&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Incretins</span><p id="par0125" class="elsevierStylePara elsevierViewall">Hypoglycemic agents with incretin effect are analogs of glucagon-like peptide-1 &#40;GLP-1&#41; and dipeptidyl peptidase-4 inhibitors &#40;DPP4-i&#41;&#46; These agents constitute an emerging class of drugs for treating DM&#44; with highly encouraging results&#44; in which there has been an explosion of information regarding their CV safety&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Dipeptidyl peptidase-4 inhibitors</span><p id="par0130" class="elsevierStylePara elsevierViewall">We currently have information from clinical trials on CV safety with saxagliptin&#44; alogliptin and sitagliptin&#46; The results with linagliptin are yet to be published&#44; and there are no studies currently underway for vildagliptin&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">During the Annual Heart Failure Meeting of the European Society of Cardiology&#44; held in Lisbon in 2013&#44; an unpublished study was presented on vildagliptin in patients with DM and systolic dysfunction&#46; The Vildagliptin in Ventricular Dysfunction Diabetes Trial &#40;VIVIDD&#41;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">41</span></a> compared 128 patients with HF in NYHA functional class I&#8211;III&#44; a mean LVEF of 30&#37; and DM &#40;treated with vildagliptin&#41; versus 126 patients treated with placebo&#46; There were no differences in terms of the incidence of CV events&#46; A published meta-analysis of 17&#44;000 patients treated with vildagliptin&#44; compared with placebo or other hypoglycemic agents&#44; showed the CV safety of the drug&#44; both in adverse events and hospitalizations for HF&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">42</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In 2013&#44; the first studies were published on CV safety with DPP4-i&#46; The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction &#40;SAVOR-TIMI53&#41; showed the safety of saxagliptin in the primary composite event of CV death&#44; myocardial infarction or nonfatal stroke&#46; However&#44; a significant increase in hospitalizations for HF was observed &#40;HR&#44; 1&#46;27&#59; 95&#37; CI 1&#46;07&#8211;1&#46;51&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;007&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">43</span></a> When the patients who required hospitalization for HF were specifically analyzed&#44; it was observed that the incidence rate decreased over time&#58; at 180 days &#40;HR&#44; 1&#46;80&#59; 95&#37; CI 1&#46;29&#8211;2&#46;55&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; at 360 days &#40;HR&#44; 1&#46;46&#59; 95&#37; CI 1&#46;15&#8211;1&#46;88&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41; and at 720 days &#40;HR&#44; 1&#46;27&#59; 95&#37; CI 1&#46;07&#8211;1&#46;51&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;007&#41;&#46; Additionally&#44; the patients with a higher rate of hospitalizations for HF had at least 2 other additional risk factors such as GFR<span class="elsevierStyleHsp" style=""></span>&#8804;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;m<span class="elsevierStyleSup">2</span>&#44; a higher amino-terminal fragment of the brain natriuretic peptide &#40;NT-proBNP&#41; concentration &#40;&#62;332<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#41; and prior HF&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">44</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care &#40;EXAMINE&#41; study assessed the safety of alogliptin in secondary prevention in patients who had experienced an acute coronary syndrome&#46; The primary event &#40;CV death&#44; infarction and nonfatal stroke&#41; was similar in the 2 groups&#46; There was a nonsignificant tendency toward an increase in hospitalizations for HF in the patients treated with alogliptin &#40;HR&#44; 1&#46;19&#59; 95&#37; CI 0&#46;89&#8211;1&#46;58&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;220&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">45</span></a> However&#44; in a secondary analysis by subgroup&#44; alogliptin was associated with an increase in hospitalizations for HF in patients with no prior history of HF &#40;HR&#44; 1&#46;76&#59; 95&#37; CI 1&#46;07&#8211;2&#46;90&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;026&#41;&#44; which was not observed in patients with a prior history of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">46</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">After the publication of these studies&#44; the scientific community questioned the safety of DPP4-i for patients with HF&#46; Numerous meta-analyses and observational studies were therefore published to assess its safety and determine whether the effect was one of class or was only related to saxagliptin&#46; Three of these meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">47&#8211;49</span></a> observed an increase in hospitalizations for HF&#44; due to the influence of the patients in the SAVOR study&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The last of the published controlled studies on CV safety with DPP4-i was the Trial Evaluating Cardiovascular Outcomes with Sitagliptin &#40;TECOS&#41;&#44; which assessed the safety of sitagliptin in patients with established vascular disease&#46; Both in the primary objective and in the hospitalizations for HF &#40;HR&#44; 1&#59; 95&#37; CI 0&#46;83&#8211;1&#46;20&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;98&#41;&#44; sitagliptin was showed to be neutral versus standard treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">50</span></a> A secondary analysis of TECOS concluded that the use of sitagliptin did not affect the risk of hospitalizations for HF&#44; both as a whole and in the high-risk patient subgroup&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">51</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The populations of the trials listed above had a number of significant differences&#46; The SAVOR study had patients in primary and secondary prevention&#44; while all patients in TECOS had established CV disease&#46; In the EXAMINE study&#44; all patients had experienced an acute coronary syndrome&#46; In terms of endpoints&#44; hospitalization for HF was a separately defined secondary event since the start of the study in only the TECOS study&#46; In both SAVOR and EXAMINE&#44; this event was considered within another compound event&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">43&#44;45&#44;50</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">A retrospective&#44; observational study based on databases from U&#46;S&#46; insurance companies found no association between hospitalizations for HF or other CV events in patients with diabetes treated with DPP4-i&#44; compared with sulfonylureas or between saxagliptin and sitagliptin&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">52</span></a> Despite all this additional information&#44; the Food and Drug Administration decided in May 2016 to issue a report warning of the association between the use of saxagliptin or alogliptin and the onset of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">53</span></a> For now&#44; the European Medicines Agency has not ruled on the issue&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Results from studies currently underway with linagliptin are pending&#58; the Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients With Type 2 Diabetes &#40;CAROLINA&#41;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">54</span></a> and the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus &#40;CARMELINA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">55</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Based on current knowledge&#44; sitagliptin would be the DPP4-i of choice for patients with HF&#46; In contrast&#44; the use of saxagliptin should be avoided in patients with HF or with a high risk of developing HF&#44; when there are other factors that could require hospitalization&#44; such as renal impairment and increased NT-proBNP levels&#46; We currently lack data to make firm recommendations regarding linagliptin&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Glucagon-like peptide-1 receptor analogs</span><p id="par0180" class="elsevierStylePara elsevierViewall">The results of several studies on CV safety with lixisenatide&#44; liraglutide and semaglutide have been published&#58; Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome &#40;ELIXA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">56</span></a> Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes &#40;LEADER&#41;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">57</span></a> and Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes &#40;SUSTAIN-6&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">58</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">ELIXA<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">56</span></a> is the first study on CV safety performed with GLP-1 receptor analogs&#46; There were no significant differences in the main composite CV objective &#40;myocardial infarction or nonfatal stroke&#44; hospitalization for unstable angina or cardiovascular death&#41;&#46; Although the patients with HF had a higher risk of hospitalization than the patients with no prior history of HF &#40;10&#37; vs&#46; 2&#46;5&#37;&#41;&#44; there were no differences in hospitalizations for HF when the lixisenatide group was compared with the placebo group &#40;RR&#44; 0&#46;96&#59; 95&#37; CI 0&#46;75&#8211;1&#46;23&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;75&#41;&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The LEADER study<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">57</span></a> assessed the effect of liraglutide on patients with diabetes and a high CV risk&#46; Fewer adverse events were observed in the liraglutide group than in the control group &#40;HR&#44; 0&#46;87&#59; 95&#37; CI 0&#46;78&#8211;0&#46;97&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;007&#41;&#46; This reduction was mainly observed at the expense of the all-cause mortality rate &#40;HR&#44; 0&#46;85&#59; 95&#37; CI 0&#46;74&#8211;0&#46;97&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#44; and its effect was neutral in terms of HF &#40;HR&#44; 0&#46;87&#59; 95&#37; CI 0&#46;73&#8211;1&#46;05&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;14&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The Functional Impact of GLP-1 for Heart Failure &#40;FIGHT&#41; study<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">59</span></a> analyzed the usefulness of liraglutide versus placebo in patients with advanced HF and severe systolic dysfunction&#46; The patients had a mean age of 61 years and a mean LVEF of 25&#37;&#44; and 59&#37; had diabetes&#46; The patients randomized to the liraglutide group were treated with the drug&#44; even if they did not have diabetes&#46; There were no differences in mortality or hospitalizations for HF&#46; Increased heart rate is a known effect of liraglutide&#46; However&#44; the patients with advanced HF showed no significant differences in heart rate compared with those who took the placebo &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;33&#41;&#46; Thus&#44; the drug appears to be safe for this patient subgroup&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Results were recently published for The Effect of Liraglutide on Left Ventricular Function in Chronic Heart Failure Patients with and without Diabetes Mellitus &#40;LIVE&#41; study<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">60</span></a> on patients with stable HF and systolic dysfunction &#40;LVEF<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>45&#37;&#41;&#46; In this study&#44; only 39 of 122 &#40;32&#37;&#41; patients in the liraglutide group had diabetes&#44; and 35 of 119 &#40;29&#37;&#41; patients in the placebo group had diabetes&#46; Liraglutide did not affect ventricular systolic function compared with placebo in any of the groups&#46; This trial did observe a significant increase in heart rate &#40;median 7 &#91;5&#8211;9&#93;<span class="elsevierStyleHsp" style=""></span>bpm&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41; in contrast to the FIGHT study&#46; An important aspect here is the fact that tachycardization was produced with a rate of beta-blocker use of 91&#37; &#40;objective dose approximately 74&#37;&#41;&#46; In the LEADER study&#44;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">55</span></a> 56&#37; of the patients took beta-blockers&#46; In the liraglutide arm&#44; an increase of only 3<span class="elsevierStyleHsp" style=""></span>bpm was observed &#40;95&#37; CI 2&#46;5&#8211;3&#46;4&#41; compared with the placebo group&#46; Moreover&#44; there was a significant increase in cardiac events in the patient group treated with liraglutide&#46; In their discussion&#44; the authors of the LIVE study did not relate the increased heart rate with the adverse events&#59; however&#44; the proportional relationship between heart rate and a poorer prognosis in patients with chronic HF is well known&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Filion et al&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">61</span></a> published an observational study of several cohorts with 1&#44;499&#44;650 patients with diabetes from Canada&#44; the United States and the United Kingdom&#46; Pairing was performed of each patient hospitalized for HF with 20 controls of the same cohort based on sex&#44; age and diabetes progression time&#46; The rate of hospitalization for HF did not increase for the patients treated with incretin therapies compared with the use of combinations of other oral antidiabetic drugs&#44; in the patients with a history of HF &#40;HR&#44; 0&#46;86&#59; 95&#37; CI 0&#46;62&#8211;1&#46;19&#41; or with no prior history of HF &#40;HR&#44; 0&#46;82&#59; 95&#37; CI 0&#46;67&#8211;1&#46;00&#41;&#46; There were also no differences between DPP4-i and GLP-1 analogs&#46; The study did not include patients treated with thiazolidinediones&#46; The reference group was treated with metformin and&#47;or sulfonylureas&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The SUSTAIN-6 study<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">58</span></a> with semaglutide&#44; which assessed the safety of this GLP-1 versus standard treatment in patients with diabetes&#44; also obtained significant reductions in the composite objective of CV death&#44; myocardial infarction and nonfatal stroke &#40;HR&#44; 0&#46;74&#59; 95&#37; CI 0&#46;58&#8211;0&#46;95&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#46; Semaglutide did not increase the risk of hospitalizations for HF &#40;HR&#44; 1&#46;61&#59; 95&#37; CI 0&#46;77&#8211;1&#46;61&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;57&#41;&#44; included as a secondary objective&#46; A significant increase was also detected in the heart rate &#40;2<span class="elsevierStyleHsp" style=""></span>bpm for 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg of semaglutide and 2&#46;5<span class="elsevierStyleHsp" style=""></span>bpm for the 1-mg dose&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#44; although the increase was not clinically relevant&#46; We currently only have the design and baseline characteristics of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes &#40;REWIND&#41; study with dulaglutide&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">62</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">In conclusion&#44; based on the available information&#44; lixisenatide&#44; liraglutide and semaglutide are safe drugs for patients with HF&#44; even advanced HF&#46; However&#44; the heart rate should be closely monitored and the beta-blockers should be titrated properly&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Sodium-dependent glucose cotransporter 2 inhibitors</span><p id="par0220" class="elsevierStylePara elsevierViewall">Although this group was the last to be incorporated into the therapeutic arsenal for treating DM&#44; it was the first to demonstrate a reduction in CV events&#46; We currently have 3 compounds&#58; dapagliflozin&#44; empagliflozin and canagliflozin&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">The Empagliflozin&#44; Cardiovascular Outcomes&#44; and Mortality in Type 2 Diabetes &#40;EMPA-REG-OUTCOME&#41; study<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">63</span></a> marked a milestone among studies on oral hypoglycemic agents&#44; given that empagliflozin became the first antidiabetic drug that reduces the CV risk in patients with DM and CV disease and in the population with high CV risk&#46; The primary composite event occurred in 490 of 4687 patients &#40;10&#46;5&#37;&#41; in the empagliflozin group and in 282 of the 2333 patients &#40;12&#46;1&#37;&#41; in the placebo group &#40;HR&#44; 0&#46;86&#59; 95&#37; CI 0&#46;74&#8211;0&#46;99&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&#59; for superiority&#41;&#46; In the empagliflozin group&#44; there were significantly lower CV mortality rates &#40;HR&#44; 0&#46;62&#59; 95&#37; CI 0&#46;49&#8211;0&#46;77&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; One of the least expected findings was a 35&#37; reduction in the RR of hospitalization 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; for the group treated with empagliflozin&#46; A post hoc analysis also showed a significant reduction in the combined variable of hospitalizations for HF and CV death&#46; The benefits were independent of treatment with diuretics or beta-blockers&#46; The benefits in reducing CV only achieved significance among the patients treated with an angiotensin-converting enzyme inhibitor&#46; The patients with a prior history of HF showed no significant differences in the individual or combined variables of hospitalization for HF and&#47;or CV death &#40;HR&#44; 0&#46;72&#59; 95&#37; CI 0&#46;50&#8211;1&#46;04&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">64</span></a> The mechanisms that explain this effect are unknown but could be related to weight loss&#44; reduced plasma volume&#44; reduced blood pressure and&#47;or increased ketogenic metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">65</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">The publication of the Canagliflozin Cardiovascular Assessment Study &#40;CANVAS&#41;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">66</span></a> with canagliflozin underlined the beneficial role of sodium-glucose cotransporter type 2 inhibitors in reducing CV events and confirming a reduction in hospitalizations for HF &#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>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The probability of a beneficial class effect for sodium-glucose cotransporter type 2 inhibitors in patients with diabetes and HF opens an interesting line of research for the future&#46; The Dapagliflozin Effect on Cardiovascular Events &#40;DECLARE-TIMI 58&#41; trial<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">67</span></a> with dapagliflozin is currently underway&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Insulin therapy</span><p id="par0235" class="elsevierStylePara elsevierViewall">Insulin not only promotes a reduction in serum glucose but also increases myocardial blood flow&#44; decreases the heart rate and slightly improves cardiac output&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">68</span></a> The safety of insulin treatment for patients with DM and HF had been highly questioned&#44; given that initial studies associated the treatment with increased CV mortality and hospitalizations&#44; in patients with HF and depressed LVEF<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">11</span></a> or preserved LVEF&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">10</span></a> However&#44; the use of insulin is a marker of DM severity and long duration and is not directly related to adverse CV events&#46; In the Medicare cohort&#44; the patients with diabetes treated with insulin did not show higher mortality&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">32</span></a> as in the EVEREST study in which the rate of CV events was independent of the use of insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">15</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">The CV safety of insulin glargine was demonstrated with the publication of the Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia &#40;ORIGIN&#41; study&#44;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">69</span></a> which found no increase in hospitalizations for HF&#46; Recently&#44; in the Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events &#40;DEVOTE&#41;&#44; the new basal insulin degludec showed noninferiority versus glargine in preventing CV events and hospitalizations for HF&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">70</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">A small observational study &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#41; compared patients with diabetes and HF treated with insulin versus those treated with noninsulin antidiabetic drugs&#46; The patients had similar HbA1c levels&#44; and all-cause mortality at 5 years of follow-up was analyzed&#46; After adjusting for hemoglobin&#44; creatinine and NT-proBNP levels&#44; there were no significant differences between the 2 groups&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">71</span></a> Similarly&#44; in the analysis by therapeutic group of the Heart Failure Registry of the Spanish Society of Internal Medicine&#44; there were no differences in the prognosis for patients treated with insulin compared with those treated with other antidiabetic drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">16</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">The insulin treatment risk for patients with diabetes and HF did not differ from that of patients without HF&#46; However&#44; it is important to prevent hypoglycemia due to the high risk of complications in this vulnerable population&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Recommendations</span><p id="par0255" class="elsevierStylePara elsevierViewall">With the current evidence&#44; we can propose the following recommendations &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0260" class="elsevierStylePara elsevierViewall">Metformin is the drug of choice for treating patients with DM and HF&#46; For patients with chronic kidney disease&#44; its dosage should be reduced &#40;at least by half&#41; if the GFR is 30&#8211;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;m<span class="elsevierStyleSup">2</span>&#46; Metformin should not be used if the GFR is &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;m<span class="elsevierStyleSup">2</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Due to a lack of evidence and because of their potential risk&#44; the use of sulfonylureas should be avoided in patients with diabetes and HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0270" class="elsevierStylePara elsevierViewall">Glinides are second-choice drugs for patients with HF and should be used under strict surveillance&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0275" class="elsevierStylePara elsevierViewall">The use of pioglitazone is not recommended for patients with HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5&#46;</span><p id="par0280" class="elsevierStylePara elsevierViewall">With regard to DPP4-i&#44; sitagliptin is safe for patients with HF&#44; while alogliptin may be used&#44; albeit with caution&#46; Saxagliptin should be used with caution in general and should be avoided for patients with an additional risk of readmission for HF&#44; such as the prior presence of HF and renal dysfunction&#46; For linagliptin&#44; although observational studies have shown no added risk&#44; we need to wait for the results of the CV safety trials&#46; There are no available data for vildagliptin&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">6&#46;</span><p id="par0285" class="elsevierStylePara elsevierViewall">The GLP-1 analogs that have been studied are neutral in patients with HF&#46; Liraglutide and semaglutide confer added value by decreasing CV mortality&#46; There are no available data for exenatide and dulaglutide&#46; When long-acting analogs are employed&#44; such as liraglutide and semaglutide&#44; the patient&#39;s heart rate should be closely monitored&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">7&#46;</span><p id="par0290" class="elsevierStylePara elsevierViewall">The protective role of sodium-dependent glucose cotransporter 2 inhibitors in patients with HF appears to be a class effect&#44; because both empagliflozin and canagliflozin have shown benefits in this population&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">8&#46;</span><p id="par0295" class="elsevierStylePara elsevierViewall">Basal insulins&#44; including glargine and degludec&#44; are neutral in patients with HF&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interests</span><p id="par0300" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "sec0015"
          "titulo" => "Influence of diabetes mellitus on heart failure"
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          "identificador" => "sec0020"
          "titulo" => "Glycemic control and heart failure prognosis"
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          "titulo" => "Risk induced by antidiabetic drugs"
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          "titulo" => "Safety of hypoglycemic drugs in heart failure"
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              "titulo" => "Metformin"
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              "titulo" => "Thiazolidinediones"
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              "titulo" => "Incretins"
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                  "titulo" => "Dipeptidyl peptidase-4 inhibitors"
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                  "titulo" => "Glucagon-like peptide-1 receptor analogs"
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              "titulo" => "Sodium-dependent glucose cotransporter 2 inhibitors"
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              "titulo" => "Insulin therapy"
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    "fechaRecibido" => "2017-04-02"
    "fechaAceptado" => "2017-07-18"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Diabetes drugs"
            1 => "Heart failure"
            2 => "Diabetes"
            3 => "Cardiovascular safety"
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          "palabras" => array:4 [
            0 => "F&#225;rmacos antidiab&#233;ticos"
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            3 => "Seguridad cardiovascular"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Heart failure &#40;HF&#41; and diabetes mellitus are 2 clinical conditions that often coexist&#44; particularly in patients older than 65 years&#46; Diabetes mellitus promotes the development of HF and confers a poorer prognosis&#46; Hypoglycaemic agents &#40;either by their mechanism of action&#44; hypoglycaemic action or adverse effects&#41; can be potentially dangerous for patients with HF&#46; In this study&#44; we performed a review of the available evidence on the safety of diabetes drugs in HF&#44; focused on the main observational and experimental studies&#46; Recent studies on cardiovascular safety have evaluated&#44; although as a secondary objective&#44; the impact of new hypoglycaemic agents on HF&#44; helping us understand the neutrality&#44; risks and potential benefits of these agents&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La insuficiencia cardiaca &#40;IC&#41; y la diabetes mellitus son 2 entidades cl&#237;nicas que coexisten en numerosas ocasiones&#44; particularmente en pacientes mayores de 65 a&#241;os&#46; La diabetes mellitus favorece el desarrollo de IC y le confiere un peor pron&#243;stico&#46; Los f&#225;rmacos hipoglucemiantes&#44; bien por su mecanismo de acci&#243;n&#44; bien por su acci&#243;n hipoglucemiante o por efectos colaterales&#44; pueden ser potencialmente peligrosos en pacientes con IC&#46; En el presente trabajo se realiza una revisi&#243;n de la evidencia disponible sobre la seguridad de los f&#225;rmacos antidiab&#233;ticos en la IC&#44; centrada en los principales estudios observacionales y experimentales&#46; Los estudios recientes de seguridad cardiovascular han evaluado&#44; aunque como objetivo secundario&#44; el impacto de los nuevos f&#225;rmacos hipoglucemiantes en la IC&#44; permitiendo conocer su neutralidad&#44; sus riesgos o sus potenciales beneficios&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Carrasco-S&#225;nchez FJ&#44; Ostos-Ruiz AI&#44; Soto-Mart&#237;n M&#46; Seguridad de los f&#225;rmacos antidiab&#233;ticos en pacientes con insuficiencia cardiaca&#46; Rev Clin Esp&#46; 2018&#59;218&#58;98&#8211;107&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; CV&#44; cardiovascular&#59; DPP4&#44; dipeptidyl peptidase-4&#59; GFR&#44; glomerular filtration rate&#59; GLP-1&#44; glucagon-like peptide-1&#59; HF&#44; heart failure&#59; RF&#44; renal failure&#59; SGLT2-i&#44; sodium-dependent glucose cotransporter 2 inhibitor&#46;</p>"
          "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">&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">Heart failure&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">Renal impairment&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">CV safety&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">Reference&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"><span class="elsevierStyleItalic">Biguanides</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">First-choice treatment in HF</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Metformin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Of choice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use if GFR<span class="elsevierStyleHsp" style=""></span>&#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min<br>Half dosage if GFR<span class="elsevierStyleHsp" style=""></span>&#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acceptable safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eurich et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sulfonylureas</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">HF risk similar to that of glitazones&#44; hypoglycemia and weight gain</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use in severe RF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">There are no CV safety studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Forst et al&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Glinides</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Do not use as first choice in IC</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nateglinide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adjust dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">There are no CV safety studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&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"><span class="elsevierStyleHsp" style=""></span>Repaglinide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adjust dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">There are no CV safety studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lee et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Glitazones</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Induce edema and increase the risk of HF</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pioglitazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Contraindicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Risk of HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Erdmann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">DPP4 inhibitors</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Some are safe&#44; while others increase the risk of hospitalization for HF</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Alogliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Use with caution&#46; Risk of hospitalization for HF &#40;not significant&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adjust dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">White et al&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">45</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Linagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its safety is unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dose adjustment is needed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Awaiting CV safety studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CAROLINA<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">54</span></a> and CARMELINA<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">55</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Saxagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not recommended<br>Risk of hospitalization for HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adjust dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Scirica et al&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">44</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Sitagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Safe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adjust dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Green et al&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">50</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Vildagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Its safety is unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use in severe RF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No available study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">GLP-1 analogs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Safe in HF &#40;some are undergoing study&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Albiglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use with FG<span class="elsevierStyleHsp" style=""></span>&#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No available study&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"><span class="elsevierStyleHsp" style=""></span>LAR exenatide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No available study&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"><span class="elsevierStyleHsp" style=""></span>Dulaglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Awaiting CV safety studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gerstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">62</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Lixisenatide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Safe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutral effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pfeffer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">56</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Liraglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Safe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Marso et al&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">57</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Semaglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Safe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Marso et al&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">SGLT2-i</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Safe in HF &#40;dapagliflozin undergoing study&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dapagliflozin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown<br>Its use is acceptable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use if GFR<span class="elsevierStyleHsp" style=""></span>&#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Awaiting CV safety studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">67</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Canagliflozin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beneficial in HF<br>Recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use if GFR<span class="elsevierStyleHsp" style=""></span>&#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anders et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">66</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Empagliflozin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beneficial in HF<br>Recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Do not use if GFR<span class="elsevierStyleHsp" style=""></span>&#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CV benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gerstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">63</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Insulins</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Safe in HF</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Glargine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutral effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutral effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Riehle and Abel<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">69</span></a>&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"><span class="elsevierStyleHsp" style=""></span>Levemir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not studied&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No available study&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"><span class="elsevierStyleHsp" style=""></span>Degludec&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutral effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May be used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutral effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gerstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">70</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Safety of antidiabetic drugs in patients with heart failure&#46;</p>"
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Review
Safety of diabetes drugs in patients with heart failure
Seguridad de los fármacos antidiabéticos en pacientes con insuficiencia cardiaca
F.J. Carrasco-Sánchez
Corresponding author
fjcarrascos@icloud.com

Corresponding author.
, A.I. Ostos-Ruiz, M. Soto-Martín
Unidad de Gestión Clínica de Medicina Interna, Hospital Juan Ramón Jiménez, Huelva, Spain

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