Review
Cardiovascular safety of noninsulin antidiabetic drugs: Facts and promises
Seguridad cardiovascular de los antidiabéticos no insulínicos: hechos y promesas
a Servicio de Cardiología, Hospital Universitario Príncipe de Asturias, Spain
b Departamento de Medicina y Especialidades Médicas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
c EAP Cogolludo, Guadalajara, SESCAM, Spain
d Cátedra SEMERGEN-Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
e Unidad de Farmacología Clínica, Hospital Universitario Príncipe de Asturias, Spain
f Departamento de Ciencias Biomédicas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
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For years, it has been accepted that controlling blood glucose is beneficial in and of itself. The alerts for drugs such as muraglitazar<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> and rosiglitazone<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a> that, while controlling blood glucose, increase the CVR motivated the US Food and Drug Administration (FDA) to issue a directive requiring pharmaceutical companies to conduct cardiovascular safety studies with the new antidiabetic drugs (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> The directive required noninferiority studies with narrower statistical margins, more patients, longer study periods and the inclusion of patients with high CVR. In the following 3 years, the number of trials doubled, and the number of patients included in these trials increased 6-fold.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a> The emerging results are creating enormous expectations but also some degree of controversy.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Trials with noninsulin antidiabetic drugs in type 2 diabetes mellitus</span><p id="par0030" class="elsevierStylePara elsevierViewall">In 1970, the University Group Diabetes Program study was published,<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a> the first randomized study on DM2 designed to demonstrate the usefulness of treating asymptomatic hyperglycemia. The study included branches with insulin, tolbutamide, phenformin and placebo. The study showed no overall benefit and suggested an increase in cardiovascular mortality in the sulfonylurea branch. The study design was widely criticized.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a> Nevertheless, it has been shown that treatment with sulfonylureas blocks the myocardial adenosine triphosphate-sensitive K+ channels and impedes ischemic preconditioning in the long term, a protective mechanism whose block would explain the excess mortality.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">14</span></a> These potential harmful effects have been supported by a Danish registry that included more than 100,000 patients followed for up to 9 years.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a> The registry showed an excess of total mortality, cardiovascular mortality and ischemic events in the patients treated with glimepiride, glibenclamide, glipizide and tolbutamide, compared with those treated with metformin, although there were no differences in those treated with gliclazide or repaglinide. The differences among the various sulfonylureas could be explained by the lower affinity for cardiac receptors of some of the sulfonylureas.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In 1993, the first 2 studies demonstrating the benefit of insulin in type 1 diabetes mellitus were published: the Diabetes Control and Complications Trial<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> and the Stockholm Diabetes Intervention Study.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> There was a marked reduction in microvascular complications (between 35% and 75%), as well as a nonsignificant reduction in cardiovascular events in the Diabetes Control and Complications Trial. Until the publication of the United Kingdom Prospective Diabetes Study in 1998, the benefit of controlling hyperglycemia in DM2 had not been shown.<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">18,19</span></a> The study included 5102 patients with recently diagnosed DM2, who were followed for 10 years and who underwent treatment with insulin, several sulfonylureas or metformin. The study showed that a reduction in glycated hemoglobin (HbA1c) from 7.9% to 7% was accompanied by a 25% reduction in microvascular complications. There was no significant reduction in macrovascular events, but the analysis of the group treated with metformin showed a significant reduction (39%) in the risk of death and infarction. The follow-up of 3277 patients after 10 years of completing the study showed that the CVR benefit was maintained in the metformin-treated group and appeared significantly in the sulfonylurea and insulin group.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a> These results reinforce the lasting benefit of early intervention and confirm the need for very long-term studies.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In 2005, the PROactive study was published, which analyzed the potential cardiovascular benefit of pioglitazone (a thiazolidinedione) for 34 months.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">21</span></a> This study met the guidelines subsequently demanded by the FDA: the 5238 patients had to have macrovascular disease. A benefit for one of the primary composite endpoints could not be shown, although a benefit was shown for the secondary composite endpoint of all-cause mortality, nonfatal infarction and stroke. Despite this benefit potential, a significant increase was observed in nonfatal heart failure (HF), which could be related to the weight gain and edema observed in 5–15% of the patients treated with thiazolidinediones.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> Various studies with rosiglitazone (another thiazolidinedione) planted serious questions about its safety. The meta-analysis by Nissen et al. showed an increased risk of infarction, with a tendency to increased cardiovascular mortality due to cardiovascular causes.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a> This outcome resulted in the withdrawal of the drug in Europe, although not in the US, possibly due to the results of the RECORD (Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes) study.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">22</span></a> The RECORD study randomized 4500 patients to rosiglitazone or a combination of metformin and sulfonylurea. At 5.5 years, there were no differences in terms of cardiovascular events, although rosiglitazone was associated with more hospitalizations for HF.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Research into drugs of the peroxisome proliferator-activated receptor (α and γ) agonist family (muraglitazar, tesaglitazar and aleglitazar) was suspended upon determining an increase in CVR in the phase 2 studies.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> The research on this drug family showed that the achievement of intermediate objectives, such as good HbA1c control, did not translate into a benefit in terms of survival and quality of life.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Studies have also been unable to demonstrate that the intensive reduction of blood glucose is a beneficial option. In 2008, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study was published, which compared cardiovascular events in 11,140 patients treated with gliclazide to properly reach an HbA1c level between 7% and 7.9% or below 6.5%.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> Although there was a reduction in diabetic nephropathy, no effect was observed on macrovascular disease. There was a greater risk of hypoglycemia in the intensive treatment group. In 2010, the Action to Control Cardiovascular Risk in Diabetes study had to be ended early due to an increase in mortality.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a> The study had an even stricter objective in the intensive therapy group (6% of HbA1c vs. a range of 7–7.9%). The Veterans Affairs Diabetes Trial, which had similar objectives, also showed no benefit.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a> Moreover, various studies have demonstrated that the fundamental strategy for reducing the CVR of patients with DM2 is the comprehensive management of the other risk factors.<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">26–30</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In the years following the FDA directive,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> studies have been published that shed light on the cardiovascular safety of 3 families of drugs: dipeptidyl peptidase-4 inhibitors, sodium-dependent glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Dipeptidyl peptidase-4 inhibitors reduce glucose levels by increasing insulin secretion and decreasing the secretion of glucose-dependent glucagon. The group includes saxagliptin, alogliptin, and sitagliptin. Their respective cardiovascular safety studies (the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus [SAVOR],<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a> EXAMINE<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a> and the Sitagliptin Cardiovascular Outcomes Study [TECOS]<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a>) that included between 6000 and 16,000 patients followed-up for 24–48 months showed their noninferiority in terms of reducing cardiovascular mortality, infarction and stroke, when compared with placebo.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Sodium-dependent glucose cotransporter 2 inhibitors reduce glucose reabsorption in the proximal renal tubules and decrease HbA1c levels, blood pressure and weight, with a low risk of hypoglycemia. The group includes empagliflozine, dapagliflozin and canagliflozin. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG-OUTCOME) study<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> included 7020 patients randomized to 2 doses of empagliflozine or placebo, with a mean follow-up of 3 years. The drug significantly lowered all-cause death (including cardiovascular) and HF, without affecting the infarction or stroke rates, although there was a greater incidence of urinary tract infections. The drug also showed a reduction in acute kidney injury and renal failure episodes. Empagliflozine is the first NIAD that has shown a reduction in mortality, although the patients in the EMPA-REG-OUTCOME study were frequently treated with other agents that reduced cardiovascular events, such as statins and angiotensin-converting enzyme inhibitors. A number of meta-analyses conducted with other drugs of this group have suggested a class effect,<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a> which should be confirmed with safety studies for each of the drugs, such as the Canagliflozin Cardiovascular Assessment Study,<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a> which is still awaiting publication.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Glucagon-like peptide-1 receptor agonists are injectable drugs that increase insulin secretion and decrease the secretion of glucose-dependent glucagon. These drugs increase satiety, thereby promoting weight loss. The group includes liraglutide and semaglutide. The drugs are not available in the European Union, and 2 studies have been published on their cardiovascular safety. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results study included 9340 patients randomized to liraglutide or placebo, with a follow-up of 3.8 years.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">37</span></a> The study showed a significant reduction in total and cardiovascular mortality in the treatment group, as well as a significant reduction in kidney damage, with a tendency to decrease infarctions, strokes and HF. Another study, the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6), included 3297 patients randomized to 2 doses of semaglutide or placebo, with a follow-up of 2 years.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a> In the treatment group, there was no apparent reduction in death from cardiovascular causes or nonfatal infarction, but there was a reduction in nonfatal stroke and nephropathy. The use of semaglutide was associated with a significant increase in complicated retinopathy. Lixisenatide (another drug in the group) did not lower the rate of recurrent events in patients with diabetes who had had a recent acute ischemic event.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusions. Future prospects</span><p id="par0175" class="elsevierStylePara elsevierViewall">From the above, we can conclude the following:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1)</span><p id="par0180" class="elsevierStylePara elsevierViewall">Despite the enormous repercussion of DM2, studies designed to assess the benefit of NIADs for CVR are scarce, and only the United Kingdom Prospective Diabetes Study,<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a> in its metformin branch, has shown this benefit. The most recent studies were safety studies and were designed to detect noninferiority.<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">31–34,36–38</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2)</span><p id="par0185" class="elsevierStylePara elsevierViewall">The available evidence indicates that the greatest reduction in CVR in DM2 is due to the use of statins and strict blood pressure control.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3)</span><p id="par0190" class="elsevierStylePara elsevierViewall">Doubts remain about certain sulfonylureas (glimepiride, glibenclamide, glipizide, and tolbutamide),<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a> due to the lack of solid evidence on their cardiovascular benefit. These doubts could influence research into new drugs, if the new drugs are compared to drugs with dubious effect.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4)</span><p id="par0195" class="elsevierStylePara elsevierViewall">Empagliflozine, liraglutide and semaglutide appear to reduce CVR, a statement that should be prudent due to the following facts: (a) studies are needed to demonstrate superiority in reducing cardiovascular events; (b) we need to understand the mechanisms by which the benefits are produced and determine the potential class effects; (c) follow-ups are still limited when we consider the disease's natural progression; and (d) we need to demonstrate a benefit on microvascular disease. Along these lines, the possible deterioration in retinopathy observed with semaglutide should be analyzed in depth.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5)</span><p id="par0200" class="elsevierStylePara elsevierViewall">The residual risk for patients with DM2, in other words, the fact that they continue to experience events despite being adequately treated with available resources, warrants long-term studies and drug combinations that, as well as being safe, provide various benefits. Empagliflozine (which lowered mortality and HF<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a>) and liraglutide (which lowered myocardial infarction and stroke<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">37</span></a>) could be examples.</p></li></ul></p><p id="par0205" class="elsevierStylePara elsevierViewall">In any case, these studies have repercussions on daily practice. The first treatment step for DM2 should be metformin. In light of the new evidence and until we have more solid data, the second step should consist of the previously mentioned drugs that have demonstrated safety and a potential for benefits on survival.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflicts of interest</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres932897" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec907305" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres932896" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec907304" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Trials with noninsulin antidiabetic drugs in type 2 diabetes mellitus" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Conclusions. Future prospects" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-11-23" "fechaAceptado" => "2017-02-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec907305" "palabras" => array:3 [ 0 => "Diabetes mellitus" 1 => "Cardiovascular risk" 2 => "Oral diabetes drugs" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec907304" "palabras" => array:3 [ 0 => "Diabetes mellitus" 1 => "Riesgo cardiovascular" 2 => "Antidiabéticos orales" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Non insulin antidiabetic drugs are widely used in patients with type 2 diabetes. However, the drugs’ effect in terms of reducing cardiovascular risk has been the subject of controversy. In 2008, based on the evidence of cardiovascular risk resulting from the use of a number of non insulin antidiabetic drugs, the US Food and Drug Administration published directives on the need to perform cardiovascular safety studies. These directives have helped obtain more evidence, such that at present there are 2 families of drugs that can reduce cardiovascular risk. These recent data have helped us add the reduction of cardiovascular morbidity and mortality to the objective of controlling blood glucose. Nevertheless, research continues with the development of new long-term studies.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los antidiabéticos no insulínicos son fármacos de uso muy extendido en los pacientes con diabetes tipo 2, cuyo efecto sobre la reducción del riesgo cardiovascular ha sido objeto de controversia. En el año 2008, ante la evidencia del riesgo cardiovascular derivado del uso de algunos antidiabéticos no insulínicos, la <span class="elsevierStyleItalic">Food and Drug Administration</span> americana publicó una directriz sobre la necesidad de realizar estudios de seguridad cardiovascular. Ello ha contribuido a disponer de más evidencia, de manera que en el momento actual existen dos familias de fármacos que podrían reducir el riesgo cardiovascular. Estos datos recientes nos permiten añadir, al objetivo de controlar la glucemia, el de reducir la morbimortalidad cardiovascular. No obstante, la investigación continúa con el desarrollo de nuevos estudios a largo plazo.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: García-Lledó A, de Santiago-Nocito AM, de Abajo FJ. Seguridad cardiovascular de los antidiabéticos no insulínicos: hechos y promesas. Rev Clin Esp. 2017;217:473–477.</p>" ] ] "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" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>: U.S. Department of Health and Human Services.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><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">For studies with new designs</span> \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>For phase 2 and 3 studies, there should be an independent prospective adjudication committee for cardiovascular events. The minimum cardiovascular events to be recorded are defined. \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>Phase 2 and 3 studies should include patients with high cardiovascular risk, long-standing diabetes, advanced age and kidney damage. \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>A longer duration is proposed for safety studies (at least 2 years). \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>Phase 2 and 3 studies should be designed to facilitate their subsequent inclusion in a meta-analysis. \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>The sponsors should deliver a protocol that describes the statistical methods of the proposed meta-analyses. Recommendations are made on the types of studies and identifiers for variables to be included. \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>The differences and similarities of the events by subgroup should be examined, when possible, indicating as examples sex, race and age. \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="elsevierStyleVsp" style="height:0.5px"></span> \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="elsevierStyleItalic">For completed studies, before submitting them for evaluation</span> \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>The statistical margins for the confidence interval are narrowed in the noninferiority studies regarding cardiovascular events. When it is not possible to demonstrate them with meta-analyses, new studies should be performed. \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>If the premarketing request shows clinical data outside the previous demands but within less demanding predefined ranges and the overall risk–benefit analysis supports the approval of the drug, a specific study may be requested to demonstrate the safety adjusted to the new required limits, once the drug has been marketed. \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>The characteristics these studies must have for their evaluation and inclusion in meta-analyses are defined. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1576665.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of the food and drug administration directives for the assessment of cardiovascular risk in new antidiabetic therapies.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of diabetes mellitus and impaired glucose regulation in Spain: the Di@bet.es Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. 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