Safety of diabetes drugs in patients with heart failure

Carrasco-Sánchez, F.J.; Ostos-Ruiz, A.I.; Soto-Martín, M.

doi:10.1016/j.rceng.2017.07.002

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Carrasco-Sánchez, A.I. Ostos-Ruiz, M. Soto-Martín" "autores" => array:3 [ 0 => array:4 [ "nombre" => "F.J." "apellidos" => "Carrasco-Sánchez" "email" => array:1 [ 0 => "fjcarrascos@icloud.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "A.I." "apellidos" => "Ostos-Ruiz" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Soto-Martín" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Gestión Clínica de Medicina Interna, Hospital Juan Ramón Jiménez, Huelva, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Seguridad de los fármacos antidiabéticos en pacientes con insuficiencia cardiaca" ] ] "textoCompleto" => "BackgroundHeart failure (HF) and diabetes mellitus (DM) are 2 prevalent clinical conditions that often coexist. The incidence rate of HF increases with age and reaches 10% in individuals older than 65 years,<a class="elsevierStyleCrossRefs" href="#bib0360">1,2</a> which is precisely the fastest growing population group in developed societies. The risk of developing HF at the age of 55 years is 33% in men and 28% in women.<a class="elsevierStyleCrossRef" href="#bib0365">2</a> The worldwide prevalence of DM is approximately 415 million individuals and is expected to reach 642 million by 2040.<a class="elsevierStyleCrossRef" href="#bib0370">3</a> The incidence of DM also increases with age, reaching 26% in individuals older than 65 years.Given the prevalence of the 2 conditions and the global aging of the population, it is not surprising that the concurrence of DM and HF is growing. The prevalence of DM in patients with HF is 25–35% and is even higher in patients hospitalized for exacerbated HF.<a class="elsevierStyleCrossRef" href="#bib0375">4</a> The incidence rate of HF in patients with DM is 2.5-fold higher than in patients without DM.<a class="elsevierStyleCrossRef" href="#bib0380">5</a> The development of HF in patients with diabetes is associated with a poorer prognosis, increased mortality and increased readmissions.<a class="elsevierStyleCrossRef" href="#bib0385">6</a> Moreover, DM confers a poorer prognosis to patients with HF.The use of hypoglycemic agents in patients with established heart disease, especially HF, is not exempt from complications. Numerous cardiovascular (CV) safety studies have been published that offer relevant information on this issue. The objective of this review is to assess the available evidence on the safety of antidiabetic drugs in patients with HF.MethodologyWe performed a systematic search on PubMed with the following keywords: heart failure, diabetes, hospitalization and mortality. We first assessed experimental studies with control groups and, in lieu thereof, observational studies. We also conducted an individualized search for each antidiabetic drug, adding the term “heart failure” to the corresponding drug term.Influence of diabetes mellitus on heart failurePatients with diabetes and HF have a poorer prognosis than their counterparts without diabetes. The presence of DM in patients with HF is associated with increased morbidity and mortality.<a class="elsevierStyleCrossRefs" href="#bib0390">7–13</a> This association occurs both in outpatients and in patients hospitalized for exacerbated HF and is independent of left ventricular ejection fraction (LVEF).<a class="elsevierStyleCrossRefs" href="#bib0405">10,14–16</a>The Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) showed that patients with diabetes had more events (hazard ratio [HR], 1.15; 95% confidence interval [95% CI] 1.04–1.31) for the combined variable of CV mortality and/or readmissions for HF than their counterparts without diabetes.<a class="elsevierStyleCrossRef" href="#bib0430">15</a> The Heart Failure Registry of the Spanish Society of Internal Medicine revealed interesting data on actual clinical practice. After a 1-year follow-up of 1082 patients with a mean age of 77 years, hospitalized for acute HF in Spanish internal medicine departments, DM was independently associated with increased overall mortality (HR, 1.54; 95% CI 1.20–1.97; p=.001) and readmissions (HR, 1.46; 95% CI 1.18–1.80; p<.001), with no differences in mortality (p=.415) or hospitalizations (p=.514) between patients with HF with preserved ejection fraction and those with depressed ejection fraction.<a class="elsevierStyleCrossRef" href="#bib0435">16</a>Glycemic control and heart failure prognosisIn patients with HF, the relationship between glycemic control and the occurrence of CV events is not clearly defined. A number of observational studies have demonstrated the typical U-shaped curve between HbA1c and mortality.<a class="elsevierStyleCrossRefs" href="#bib0440">17–19</a> In a study of 5815 outpatients with HF undergoing medical treatment with hypoglycemic agents, modest glycemic control (HbA1c, 7.1–7.8%) was associated with lower mortality, compared with patients who had HbA1c levels <7.1% or >7.8%.<a class="elsevierStyleCrossRef" href="#bib0440">17</a> In another cohort of 123 patients with DM (undergoing hypoglycemic treatment) and advanced HF with reduced LVEF, an HbA1c level ≤7.0% was associated with increased mortality compared with those with HbA1c levels >7% (HR, 2.3; 95% CI 1.0–5.2).<a class="elsevierStyleCrossRef" href="#bib0445">18</a> Another similar study of 358 patients with advanced HF and reduced LVEF analyzed the relationship between HbA1c levels (quartile 1, ≤6.4%; quartile 2, 6.5–7.2%; quartile 3, 7.3–8.5%; and quartile 4, ≥8.6%) and the need for heart transplantation and/or mortality. CV-event-free survival at 2 years of follow-up was 61% and 65% in quartiles 3 and 4 compared with 48% and 42% in quartiles 1 and 2 (p=.0005), respectively.<a class="elsevierStyleCrossRef" href="#bib0450">19</a> The reasons for this paradoxical relationship are not well known. Considering this information comes from observational studies, specific recommendations cannot be made.Risk induced by antidiabetic drugsOptimal hypoglycemic treatment in patients with diabetes and HF still has areas of uncertainty. A number of therapeutic groups continue to be prescribed despite their questionable safety in HF. Moreover, patients with HF usually have comorbidities, especially due to the association with chronic kidney disease, which limits the use of certain therapeutic groups. Understanding the safety profile of hypoglycemic drugs is therefore essential for their correct use in patients with HF. Below, we review the evidence for each drug group used in patients with diabetes and HF.Safety of hypoglycemic drugs in heart failureMetforminIn the absence of contraindications, metformin is the first-choice drug for DM. Metformin has been classically contraindicated for patients with HF due to the potential risk of lactic acidosis.<a class="elsevierStyleCrossRef" href="#bib0455">20</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.<a class="elsevierStyleCrossRef" href="#bib0460">21</a> Numerous observational studies have shown that metformin can be associated with improved survival for patients with DM and HF.<a class="elsevierStyleCrossRefs" href="#bib0465">22,23</a>A systematic review of these observational studies, which included 34,000 patients, showed that metformin is associated with reduced mortality, compared with other drugs, mostly sulfonylureas (SU) (mortality 23% vs. 37%, respectively; relative risk [RR], 0.80; 95% CI 0.74–0.87; p<.001). Metformin was also associated with a slight reduction in hospitalizations (RR, 0.93; 95% CI 0.89–0.98; p=.01). No increase in the incidence of lactic acidosis was observed in the group treated with metformin. Neither the patients with reduced LVEF nor those with chronic kidney disease experienced increased mortality.<a class="elsevierStyleCrossRef" href="#bib0475">24</a>The main restriction for using metformin is renal dysfunction. Considering that chronic kidney disease is a very common comorbidity in HF, the glomerular filtration rate (GFR) should always be calculated. Although the exact degree of renal dysfunction for avoiding the use of metformin has not been firmly established,<a class="elsevierStyleCrossRef" href="#bib0480">25</a> the Food and Drug Administration (FDA)<a class="elsevierStyleCrossRef" href="#bib0485">26</a> and the National Institute for Health and Clinical Excellence (NICE)<a class="elsevierStyleCrossRef" href="#bib0490">27</a> consider metformin contraindicated if the GFR is <30mL/min/1.73m2, requiring a dosage reduction and tightening surveillance with a GFR of 30–45mL/min/1.73m2.SulfonylureasThese drugs are frequently used in patients with diabetes and HF. However, their CV safety has been questioned, although not systematically, in observational studies. In a meta-analysis,<a class="elsevierStyleCrossRef" href="#bib0495">28</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. Another meta-analysis<a class="elsevierStyleCrossRef" href="#bib0500">29</a> concluded that sulfonylureas significantly increased total and CV mortality, compared with other hypoglycemic drugs, especially metformin.A retrospective analysis of patients with diabetes treated with metformin (126,867 patients) or sulfonylureas (79,192) between 2001 and 2011 showed a significant increase among the sulfonylureas in hospitalizations for HF (adjusted HR, 1.30; 95% CI 1.20–1.42) and CV mortality (adjusted HR, 1.76; 95% CI 1.14–2.71).<a class="elsevierStyleCrossRef" href="#bib0505">30</a> In contrast, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study showed that gliclazide, a new-generation sulfonylurea, did not increase macrovascular complications and had a nephroprotective effect.<a class="elsevierStyleCrossRef" href="#bib0510">31</a>Another study that included more than 16,000 Medicare patients diagnosed with HF compared the results of using thiazolidinediones, metformin and other noninsulin-sensitizing antidiabetic drugs, such as sulfonylureas and insulin itself. Approximately one third of the patients were treated with sulfonylureas at discharge. There was no increase in mortality (HR, 0.99; 95% CI 0.91–1.08) in the patients treated with sulfonylureas, but there was an increase in hospitalizations for HF in those treated with thiazolidinediones (HR, 1.06; 95% CI 1–1.09) and a slight reduction in those treated with metformin (HR, 0.92; 95% CI 0.92–0.99).<a class="elsevierStyleCrossRef" href="#bib0515">32</a>The main adverse effects of sulfonylureas (the risk of hypoglycemia and weight gain) are deleterious for patients with HF. New-generation sulfonylureas (such as gliclazide and glimepiride) have overtaken the first-generation sulfonylureas due to their potency and the possibility of administering in single daily doses. Despite their better profile, evidence suggests that the CV benefit of new-generation sulfonylureas<a class="elsevierStyleCrossRef" href="#bib0520">33</a> over first-generation sulfonylureas<a class="elsevierStyleCrossRef" href="#bib0525">34</a> is insignificant. However, these studies have been highly controversial due to their methodological deficiencies.<a class="elsevierStyleCrossRef" href="#bib0530">35</a>In conclusion, there are no prospective, randomized controlled studies on the use of sulfonylureas in patients with diabetes and HF. Nevertheless, given the results of the ADVANCE study,<a class="elsevierStyleCrossRef" href="#bib0500">29</a> gliclazide should be the drug of choice when using a sulfonylurea.GlinidesGlinides (repaglinide and nateglinide) exert their hypoglycemic effect by increasing insulin secretion and act primarily by reducing postprandial glycemia. Their main adverse effects are weight gain and hypoglycemia, both of which are minor compared with sulfonylureas.A recent observational, 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, sulfonylureas or acarbose. Through logistic regression using acarbose as a reference, the study showed that patients who took glinides had a greater risk of hospitalization for HF (adjusted HR, 1.53; 95% CI 1.24–1.88; p<.001) than those who took acarbose and sulfonylureas, while the risk did not differ with respect to those treated exclusively with sulfonylureas (HR, 0.94; 95% CI 0.80–1.11; p=.42).<a class="elsevierStyleCrossRef" href="#bib0535">36</a>Therefore, there is insufficient evidence to confirm the safety of glinides in HF. Their profile of CV effects, which is similar to sulfonylureas and includes a high risk of hypoglycemia, discourages their use as first-choice drugs for patients with HF.AcarboseStudies on acarbose in HF are highly limited and insufficient for making specific recommendations. The previously mentioned study<a class="elsevierStyleCrossRef" href="#bib0525">34</a> concluded that acarbose behaves similarly to sulfonylureas in terms of hospitalizations for HF.ThiazolidinedionesThiazolidinediones have been associated with fluid retention and the onset of HF in controlled clinical studies.<a class="elsevierStyleCrossRefs" href="#bib0540">37,38</a> The mechanisms that contribute to the worsening of HF are not well known. Volume expansion due to the increase in the renal reabsorption of sodium is considered the most plausible mechanism, more so than a direct effect of these drugs on cardiac structure and function.In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive),<a class="elsevierStyleCrossRef" href="#bib0545">38</a> which included more than 5000 patients, the incidence of HF was higher in the pioglitazone group. The pioglitazone arm showed an independent risk of new HF cases (odds ratio, 1.53; 95% CI 1.18–1.95; p=.0012) versus placebo, although without an increase in mortality. Other studies have confirmed the excessive risk of acute HF in patients who take pioglitazone.<a class="elsevierStyleCrossRef" href="#bib0550">39</a>The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study assessed 4447 patients with diabetes, comparing those treated with metformin or sulfonylureas (n=2227) against those who were added rosiglitazone (n=2220). The latter group had an increased risk of hospitalizations and death by HF (HR, 2.10; 95% CI 1.35–3.27).<a class="elsevierStyleCrossRef" href="#bib0555">40</a> Rosiglitazone has not been available since 2010.Given these findings, 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 (NYHA) functional class of III–IV.IncretinsHypoglycemic agents with incretin effect are analogs of glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitors (DPP4-i). These agents constitute an emerging class of drugs for treating DM, with highly encouraging results, in which there has been an explosion of information regarding their CV safety.Dipeptidyl peptidase-4 inhibitorsWe currently have information from clinical trials on CV safety with saxagliptin, alogliptin and sitagliptin. The results with linagliptin are yet to be published, and there are no studies currently underway for vildagliptin.During the Annual Heart Failure Meeting of the European Society of Cardiology, held in Lisbon in 2013, an unpublished study was presented on vildagliptin in patients with DM and systolic dysfunction. The Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD)<a class="elsevierStyleCrossRef" href="#bib0560">41</a> compared 128 patients with HF in NYHA functional class I–III, a mean LVEF of 30% and DM (treated with vildagliptin) versus 126 patients treated with placebo. There were no differences in terms of the incidence of CV events. A published meta-analysis of 17,000 patients treated with vildagliptin, compared with placebo or other hypoglycemic agents, showed the CV safety of the drug, both in adverse events and hospitalizations for HF.<a class="elsevierStyleCrossRef" href="#bib0565">42</a>In 2013, the first studies were published on CV safety with DPP4-i. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI53) showed the safety of saxagliptin in the primary composite event of CV death, myocardial infarction or nonfatal stroke. However, a significant increase in hospitalizations for HF was observed (HR, 1.27; 95% CI 1.07–1.51; p=.007).<a class="elsevierStyleCrossRef" href="#bib0570">43</a> When the patients who required hospitalization for HF were specifically analyzed, it was observed that the incidence rate decreased over time: at 180 days (HR, 1.80; 95% CI 1.29–2.55; p=.001), at 360 days (HR, 1.46; 95% CI 1.15–1.88; p=.002) and at 720 days (HR, 1.27; 95% CI 1.07–1.51; p=.007). Additionally, the patients with a higher rate of hospitalizations for HF had at least 2 other additional risk factors such as GFR≤60mL/min/m2, a higher amino-terminal fragment of the brain natriuretic peptide (NT-proBNP) concentration (>332pg/mL) and prior HF.<a class="elsevierStyleCrossRef" href="#bib0575">44</a>The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study assessed the safety of alogliptin in secondary prevention in patients who had experienced an acute coronary syndrome. The primary event (CV death, infarction and nonfatal stroke) was similar in the 2 groups. There was a nonsignificant tendency toward an increase in hospitalizations for HF in the patients treated with alogliptin (HR, 1.19; 95% CI 0.89–1.58; p=.220).<a class="elsevierStyleCrossRef" href="#bib0580">45</a> However, in a secondary analysis by subgroup, alogliptin was associated with an increase in hospitalizations for HF in patients with no prior history of HF (HR, 1.76; 95% CI 1.07–2.90; p=.026), which was not observed in patients with a prior history of HF.<a class="elsevierStyleCrossRef" href="#bib0585">46</a>After the publication of these studies, the scientific community questioned the safety of DPP4-i for patients with HF. 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. Three of these meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0590">47–49</a> observed an increase in hospitalizations for HF, due to the influence of the patients in the SAVOR study.The last of the published controlled studies on CV safety with DPP4-i was the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), which assessed the safety of sitagliptin in patients with established vascular disease. Both in the primary objective and in the hospitalizations for HF (HR, 1; 95% CI 0.83–1.20; p=.98), sitagliptin was showed to be neutral versus standard treatment.<a class="elsevierStyleCrossRef" href="#bib0605">50</a> A secondary analysis of TECOS concluded that the use of sitagliptin did not affect the risk of hospitalizations for HF, both as a whole and in the high-risk patient subgroup.<a class="elsevierStyleCrossRef" href="#bib0610">51</a>The populations of the trials listed above had a number of significant differences. The SAVOR study had patients in primary and secondary prevention, while all patients in TECOS had established CV disease. In the EXAMINE study, all patients had experienced an acute coronary syndrome. In terms of endpoints, hospitalization for HF was a separately defined secondary event since the start of the study in only the TECOS study. In both SAVOR and EXAMINE, this event was considered within another compound event.<a class="elsevierStyleCrossRefs" href="#bib0570">43,45,50</a>A retrospective, observational study based on databases from U.S. insurance companies found no association between hospitalizations for HF or other CV events in patients with diabetes treated with DPP4-i, compared with sulfonylureas or between saxagliptin and sitagliptin.<a class="elsevierStyleCrossRef" href="#bib0615">52</a> Despite all this additional information, 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.<a class="elsevierStyleCrossRef" href="#bib0620">53</a> For now, the European Medicines Agency has not ruled on the issue.Results from studies currently underway with linagliptin are pending: the Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA)<a class="elsevierStyleCrossRef" href="#bib0625">54</a> and the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA).<a class="elsevierStyleCrossRef" href="#bib0630">55</a>Based on current knowledge, sitagliptin would be the DPP4-i of choice for patients with HF. In contrast, the use of saxagliptin should be avoided in patients with HF or with a high risk of developing HF, when there are other factors that could require hospitalization, such as renal impairment and increased NT-proBNP levels. We currently lack data to make firm recommendations regarding linagliptin.Glucagon-like peptide-1 receptor analogsThe results of several studies on CV safety with lixisenatide, liraglutide and semaglutide have been published: Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome (ELIXA),<a class="elsevierStyleCrossRef" href="#bib0635">56</a> Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER)<a class="elsevierStyleCrossRef" href="#bib0640">57</a> and Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6).<a class="elsevierStyleCrossRef" href="#bib0645">58</a>ELIXA<a class="elsevierStyleCrossRef" href="#bib0635">56</a> is the first study on CV safety performed with GLP-1 receptor analogs. There were no significant differences in the main composite CV objective (myocardial infarction or nonfatal stroke, hospitalization for unstable angina or cardiovascular death). Although the patients with HF had a higher risk of hospitalization than the patients with no prior history of HF (10% vs. 2.5%), there were no differences in hospitalizations for HF when the lixisenatide group was compared with the placebo group (RR, 0.96; 95% CI 0.75–1.23; p=.75).The LEADER study<a class="elsevierStyleCrossRef" href="#bib0640">57</a> assessed the effect of liraglutide on patients with diabetes and a high CV risk. Fewer adverse events were observed in the liraglutide group than in the control group (HR, 0.87; 95% CI 0.78–0.97; p=.007). This reduction was mainly observed at the expense of the all-cause mortality rate (HR, 0.85; 95% CI 0.74–0.97; p=.02), and its effect was neutral in terms of HF (HR, 0.87; 95% CI 0.73–1.05; p=.14).The Functional Impact of GLP-1 for Heart Failure (FIGHT) study<a class="elsevierStyleCrossRef" href="#bib0650">59</a> analyzed the usefulness of liraglutide versus placebo in patients with advanced HF and severe systolic dysfunction. The patients had a mean age of 61 years and a mean LVEF of 25%, and 59% had diabetes. The patients randomized to the liraglutide group were treated with the drug, even if they did not have diabetes. There were no differences in mortality or hospitalizations for HF. Increased heart rate is a known effect of liraglutide. However, the patients with advanced HF showed no significant differences in heart rate compared with those who took the placebo (p=.33). Thus, the drug appears to be safe for this patient subgroup.Results were recently published for The Effect of Liraglutide on Left Ventricular Function in Chronic Heart Failure Patients with and without Diabetes Mellitus (LIVE) study<a class="elsevierStyleCrossRef" href="#bib0655">60</a> on patients with stable HF and systolic dysfunction (LVEF≤45%). In this study, only 39 of 122 (32%) patients in the liraglutide group had diabetes, and 35 of 119 (29%) patients in the placebo group had diabetes. Liraglutide did not affect ventricular systolic function compared with placebo in any of the groups. This trial did observe a significant increase in heart rate (median 7 [5–9]bpm, p<.0001) in contrast to the FIGHT study. An important aspect here is the fact that tachycardization was produced with a rate of beta-blocker use of 91% (objective dose approximately 74%). In the LEADER study,<a class="elsevierStyleCrossRef" href="#bib0630">55</a> 56% of the patients took beta-blockers. In the liraglutide arm, an increase of only 3bpm was observed (95% CI 2.5–3.4) compared with the placebo group. Moreover, there was a significant increase in cardiac events in the patient group treated with liraglutide. In their discussion, the authors of the LIVE study did not relate the increased heart rate with the adverse events; however, the proportional relationship between heart rate and a poorer prognosis in patients with chronic HF is well known.Filion et al.<a class="elsevierStyleCrossRef" href="#bib0660">61</a> published an observational study of several cohorts with 1,499,650 patients with diabetes from Canada, the United States and the United Kingdom. Pairing was performed of each patient hospitalized for HF with 20 controls of the same cohort based on sex, age and diabetes progression time. 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, in the patients with a history of HF (HR, 0.86; 95% CI 0.62–1.19) or with no prior history of HF (HR, 0.82; 95% CI 0.67–1.00). There were also no differences between DPP4-i and GLP-1 analogs. The study did not include patients treated with thiazolidinediones. The reference group was treated with metformin and/or sulfonylureas.The SUSTAIN-6 study<a class="elsevierStyleCrossRef" href="#bib0645">58</a> with semaglutide, which assessed the safety of this GLP-1 versus standard treatment in patients with diabetes, also obtained significant reductions in the composite objective of CV death, myocardial infarction and nonfatal stroke (HR, 0.74; 95% CI 0.58–0.95; p=.02). Semaglutide did not increase the risk of hospitalizations for HF (HR, 1.61; 95% CI 0.77–1.61; p=.57), included as a secondary objective. A significant increase was also detected in the heart rate (2bpm for 0.5mg of semaglutide and 2.5bpm for the 1-mg dose; p<.0001), although the increase was not clinically relevant. We currently only have the design and baseline characteristics of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) study with dulaglutide.<a class="elsevierStyleCrossRef" href="#bib0665">62</a>In conclusion, based on the available information, lixisenatide, liraglutide and semaglutide are safe drugs for patients with HF, even advanced HF. However, the heart rate should be closely monitored and the beta-blockers should be titrated properly.Sodium-dependent glucose cotransporter 2 inhibitorsAlthough this group was the last to be incorporated into the therapeutic arsenal for treating DM, it was the first to demonstrate a reduction in CV events. We currently have 3 compounds: dapagliflozin, empagliflozin and canagliflozin.The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG-OUTCOME) study<a class="elsevierStyleCrossRef" href="#bib0670">63</a> marked a milestone among studies on oral hypoglycemic agents, 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. The primary composite event occurred in 490 of 4687 patients (10.5%) in the empagliflozin group and in 282 of the 2333 patients (12.1%) in the placebo group (HR, 0.86; 95% CI 0.74–0.99; p=.04; for superiority). In the empagliflozin group, there were significantly lower CV mortality rates (HR, 0.62; 95% CI 0.49–0.77; p<.001). One of the least expected findings was a 35% reduction in the RR of hospitalization for HF (HR, 0.65; 95% CI 0.50–0.85; p=.002) for the group treated with empagliflozin. A post hoc analysis also showed a significant reduction in the combined variable of hospitalizations for HF and CV death. The benefits were independent of treatment with diuretics or beta-blockers. The benefits in reducing CV only achieved significance among the patients treated with an angiotensin-converting enzyme inhibitor. The patients with a prior history of HF showed no significant differences in the individual or combined variables of hospitalization for HF and/or CV death (HR, 0.72; 95% CI 0.50–1.04).<a class="elsevierStyleCrossRef" href="#bib0675">64</a> The mechanisms that explain this effect are unknown but could be related to weight loss, reduced plasma volume, reduced blood pressure and/or increased ketogenic metabolism.<a class="elsevierStyleCrossRef" href="#bib0680">65</a>The publication of the Canagliflozin Cardiovascular Assessment Study (CANVAS)<a class="elsevierStyleCrossRef" href="#bib0685">66</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 (HR, 0.67; 95% CI 0.52–0.87; p<.001). 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. The Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) trial<a class="elsevierStyleCrossRef" href="#bib0690">67</a> with dapagliflozin is currently underway.Insulin therapyInsulin not only promotes a reduction in serum glucose but also increases myocardial blood flow, decreases the heart rate and slightly improves cardiac output.<a class="elsevierStyleCrossRef" href="#bib0695">68</a> The safety of insulin treatment for patients with DM and HF had been highly questioned, given that initial studies associated the treatment with increased CV mortality and hospitalizations, in patients with HF and depressed LVEF<a class="elsevierStyleCrossRef" href="#bib0410">11</a> or preserved LVEF.<a class="elsevierStyleCrossRef" href="#bib0405">10</a> However, the use of insulin is a marker of DM severity and long duration and is not directly related to adverse CV events. In the Medicare cohort, the patients with diabetes treated with insulin did not show higher mortality,<a class="elsevierStyleCrossRef" href="#bib0515">32</a> as in the EVEREST study in which the rate of CV events was independent of the use of insulin.<a class="elsevierStyleCrossRef" href="#bib0430">15</a>The CV safety of insulin glargine was demonstrated with the publication of the Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia (ORIGIN) study,<a class="elsevierStyleCrossRef" href="#bib0700">69</a> which found no increase in hospitalizations for HF. Recently, in the Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), the new basal insulin degludec showed noninferiority versus glargine in preventing CV events and hospitalizations for HF.<a class="elsevierStyleCrossRef" href="#bib0705">70</a>A small observational study (n=92) compared patients with diabetes and HF treated with insulin versus those treated with noninsulin antidiabetic drugs. The patients had similar HbA1c levels, and all-cause mortality at 5 years of follow-up was analyzed. After adjusting for hemoglobin, creatinine and NT-proBNP levels, there were no significant differences between the 2 groups.<a class="elsevierStyleCrossRef" href="#bib0710">71</a> Similarly, in the analysis by therapeutic group of the Heart Failure Registry of the Spanish Society of Internal Medicine, there were no differences in the prognosis for patients treated with insulin compared with those treated with other antidiabetic drugs.<a class="elsevierStyleCrossRef" href="#bib0435">16</a>The insulin treatment risk for patients with diabetes and HF did not differ from that of patients without HF. However, it is important to prevent hypoglycemia due to the high risk of complications in this vulnerable population.RecommendationsWith the current evidence, we can propose the following recommendations (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>):<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Metformin is the drug of choice for treating patients with DM and HF. For patients with chronic kidney disease, its dosage should be reduced (at least by half) if the GFR is 30–45mL/min/m2. Metformin should not be used if the GFR is <30mL/min/m2.</li><li class="elsevierStyleListItem" id="lsti0010">2.Due to a lack of evidence and because of their potential risk, the use of sulfonylureas should be avoided in patients with diabetes and HF.</li><li class="elsevierStyleListItem" id="lsti0015">3.Glinides are second-choice drugs for patients with HF and should be used under strict surveillance.</li><li class="elsevierStyleListItem" id="lsti0020">4.The use of pioglitazone is not recommended for patients with HF.</li><li class="elsevierStyleListItem" id="lsti0025">5.With regard to DPP4-i, sitagliptin is safe for patients with HF, while alogliptin may be used, albeit with caution. Saxagliptin should be used with caution in general and should be avoided for patients with an additional risk of readmission for HF, such as the prior presence of HF and renal dysfunction. For linagliptin, although observational studies have shown no added risk, we need to wait for the results of the CV safety trials. There are no available data for vildagliptin.</li><li class="elsevierStyleListItem" id="lsti0030">6.The GLP-1 analogs that have been studied are neutral in patients with HF. Liraglutide and semaglutide confer added value by decreasing CV mortality. There are no available data for exenatide and dulaglutide. When long-acting analogs are employed, such as liraglutide and semaglutide, the patient's heart rate should be closely monitored.</li><li class="elsevierStyleListItem" id="lsti0035">7.The protective role of sodium-dependent glucose cotransporter 2 inhibitors in patients with HF appears to be a class effect, because both empagliflozin and canagliflozin have shown benefits in this population.</li><li class="elsevierStyleListItem" id="lsti0040">8.Basal insulins, including glargine and degludec, are neutral in patients with HF.</li></ul><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Conflict of interestsThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres991082" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec955000" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres991083" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec954999" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Influence of diabetes mellitus on heart failure" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Glycemic control and heart failure prognosis" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Risk induced by antidiabetic drugs" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Safety of hypoglycemic drugs in heart failure" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Metformin" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Sulfonylureas" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Glinides" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Acarbose" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Thiazolidinediones" ] 5 => array:3 [ "identificador" => "sec0060" "titulo" => "Incretins" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Dipeptidyl peptidase-4 inhibitors" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Glucagon-like peptide-1 receptor analogs" ] ] ] 6 => array:2 [ "identificador" => "sec0075" "titulo" => "Sodium-dependent glucose cotransporter 2 inhibitors" ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Insulin therapy" ] ] ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Recommendations" ] 11 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-04-02" "fechaAceptado" => "2017-07-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec955000" "palabras" => array:4 [ 0 => "Diabetes drugs" 1 => "Heart failure" 2 => "Diabetes" 3 => "Cardiovascular safety" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec954999" "palabras" => array:4 [ 0 => "Fármacos antidiabéticos" 1 => "Insuficiencia cardiaca" 2 => "Diabetes" 3 => "Seguridad cardiovascular" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Heart failure (HF) and diabetes mellitus are 2 clinical conditions that often coexist, particularly in patients older than 65 years. Diabetes mellitus promotes the development of HF and confers a poorer prognosis. Hypoglycaemic agents (either by their mechanism of action, hypoglycaemic action or adverse effects) can be potentially dangerous for patients with HF. In this study, we performed a review of the available evidence on the safety of diabetes drugs in HF, focused on the main observational and experimental studies. Recent studies on cardiovascular safety have evaluated, although as a secondary objective, the impact of new hypoglycaemic agents on HF, helping us understand the neutrality, risks and potential benefits of these agents." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La insuficiencia cardiaca (IC) y la diabetes mellitus son 2 entidades clínicas que coexisten en numerosas ocasiones, particularmente en pacientes mayores de 65 años. La diabetes mellitus favorece el desarrollo de IC y le confiere un peor pronóstico. Los fármacos hipoglucemiantes, bien por su mecanismo de acción, bien por su acción hipoglucemiante o por efectos colaterales, pueden ser potencialmente peligrosos en pacientes con IC. En el presente trabajo se realiza una revisión de la evidencia disponible sobre la seguridad de los fármacos antidiabéticos en la IC, centrada en los principales estudios observacionales y experimentales. Los estudios recientes de seguridad cardiovascular han evaluado, aunque como objetivo secundario, el impacto de los nuevos fármacos hipoglucemiantes en la IC, permitiendo conocer su neutralidad, sus riesgos o sus potenciales beneficios." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Carrasco-Sánchez FJ, Ostos-Ruiz AI, Soto-Martín M. Seguridad de los fármacos antidiabéticos en pacientes con insuficiencia cardiaca. Rev Clin Esp. 2018;218:98–107." ] ] "multimedia" => array:1 [ 0 => 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: CV, cardiovascular; DPP4, dipeptidyl peptidase-4; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; HF, heart failure; RF, renal failure; SGLT2-i, sodium-dependent glucose cotransporter 2 inhibitor." "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">Heart failure \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 \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 \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 \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">Biguanides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">First-choice treatment in HF</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metformin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Of choice \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<30mL/min Half dosage if GFR<45mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acceptable safety \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.<a class="elsevierStyleCrossRef" href="#bib0475">24</a> \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sulfonylureas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">HF risk similar to that of glitazones, hypoglycemia and weight gain</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not recommended \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0500">29</a> \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glinides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">Do not use as first choice in IC</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nateglinide \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adjust dose \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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">Repaglinide \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adjust dose \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 \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.<a class="elsevierStyleCrossRef" href="#bib0535">36</a> \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glitazones \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">Induce edema and increase the risk of HF</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pioglitazone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Contraindicated \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0545">38</a> \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DPP4 inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">Some are safe, while others increase the risk of hospitalization for HF</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Alogliptin \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. Risk of hospitalization for HF (not significant) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adjust dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV safety \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.<a class="elsevierStyleCrossRef" href="#bib0580">45</a> \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">Linagliptin \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 \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 \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 \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">54</a> and CARMELINA<a class="elsevierStyleCrossRef" href="#bib0630">55</a> \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">Saxagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not recommended Risk of hospitalization for HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adjust dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV safety \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.<a class="elsevierStyleCrossRef" href="#bib0575">44</a> \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">Sitagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Safe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adjust dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV safety \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.<a class="elsevierStyleCrossRef" href="#bib0605">50</a> \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">Vildagliptin \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \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 \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GLP-1 analogs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">Safe in HF (some are undergoing study)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Albiglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \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<30mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \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 \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">LAR exenatide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \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 \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">Dulaglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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 \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.<a class="elsevierStyleCrossRef" href="#bib0665">62</a> \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">Lixisenatide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Safe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neutral effect \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.<a class="elsevierStyleCrossRef" href="#bib0635">56</a> \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">Liraglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Safe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV benefit \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.<a class="elsevierStyleCrossRef" href="#bib0640">57</a> \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">Semaglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Safe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV benefit \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.<a class="elsevierStyleCrossRef" href="#bib0645">58</a> \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SGLT2-i \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">Safe in HF (dapagliflozin undergoing study)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dapagliflozin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown Its use is acceptable \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<60mL/min \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 \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.<a class="elsevierStyleCrossRef" href="#bib0690">67</a> \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">Canagliflozin \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 Recommended \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<45mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV benefit \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.<a class="elsevierStyleCrossRef" href="#bib0685">66</a> \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">Empagliflozin \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 Recommended \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<45mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CV benefit \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.<a class="elsevierStyleCrossRef" href="#bib0670">63</a> \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"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Insulins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="4" align="left" valign="top">Safe in HF</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glargine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neutral effect \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neutral effect \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">69</a> \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">Levemir \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unknown \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not studied \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 \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">Degludec \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neutral effect \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neutral effect \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.<a class="elsevierStyleCrossRef" href="#bib0705">70</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1678944.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Safety of antidiabetic drugs in patients with heart failure." ] ] ] "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" => "2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC), developed with the special contribution of the Heart Failure Association (HFA) of the ESC" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "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">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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          "titulo" => "Background"
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          "identificador" => "sec0010"
          "titulo" => "Methodology"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Influence of diabetes mellitus on heart failure"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Glycemic control and heart failure prognosis"
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        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Risk induced by antidiabetic drugs"
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        9 => array:3 [
          "identificador" => "sec0030"
          "titulo" => "Safety of hypoglycemic drugs in heart failure"
          "secciones" => array:8 [
            0 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Metformin"
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            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Sulfonylureas"
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            2 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Glinides"
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            3 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Acarbose"
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            4 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Thiazolidinediones"
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            5 => array:3 [
              "identificador" => "sec0060"
              "titulo" => "Incretins"
              "secciones" => array:2 [
                0 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Dipeptidyl peptidase-4 inhibitors"
                ]
                1 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Glucagon-like peptide-1 receptor analogs"
                ]
              ]
            ]
            6 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Sodium-dependent glucose cotransporter 2 inhibitors"
            ]
            7 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Insulin therapy"
            ]
          ]
        ]
        10 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Recommendations"
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        11 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Conflict of interests"
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        12 => array:1 [
          "titulo" => "References"
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    "tienePdf" => true
    "fechaRecibido" => "2017-04-02"
    "fechaAceptado" => "2017-07-18"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec955000"
          "palabras" => array:4 [
            0 => "Diabetes drugs"
            1 => "Heart failure"
            2 => "Diabetes"
            3 => "Cardiovascular safety"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec954999"
          "palabras" => array:4 [
            0 => "F&#225;rmacos antidiab&#233;ticos"
            1 => "Insuficiencia cardiaca"
            2 => "Diabetes"
            3 => "Seguridad cardiovascular"
          ]
        ]
      ]
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        "titulo" => "Abstract"
        "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>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "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>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "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>"
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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">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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