Statin treatment and increased diabetes risk. Possible mechanisms | Clínica e Investigación en Arteriosclerosis

array:23 ["pii" => "S0214916819300014" "issn" => "02149168" "doi" => "10.1016/j.arteri.2018.12.001" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "474" "copyright" => "Sociedad Española de Arteriosclerosis" "copyrightAnyo" => "2019" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Clin Invest Arterioscl. 2019;31:228-32" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 24 "formatos" => array:2 [ "HTML" => 8 "PDF" => 16 ] ] "itemSiguiente" => array:19 [ "pii" => "S0214916819300543" "issn" => "02149168" "doi" => "10.1016/j.arteri.2019.04.004" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "498" "copyright" => "Sociedad Española de Arteriosclerosis" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Clin Invest Arterioscl. 2019;31:233-40" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 15 "formatos" => array:2 [ "HTML" => 5 "PDF" => 10 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "REVISIÓN" "titulo" => "Sedentarismo, la enfermedad del siglo xxi" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "233" "paginaFinal" => "240" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Sedentary lifestyle a disease from xxi century" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1902 "Ancho" => 2074 "Tamanyo" => 368215 ] ] "descripcion" => array:1 [ "es" => "Consecuencias clínicas del sedentarismo. Los efectos fisiopatológicos derivados del sedentarismo abarcan una gama muy amplia de trastornos, con especial repercusión en el área cardiovascular y metabólica, favoreciendo o acelerando la progresión hacia la diabetes o enfermedad cardiovascular aterosclerótica." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Ildefonzo Arocha Rodulfo" "autores" => array:1 [ 0 => array:2 [ "nombre" => "J. Ildefonzo" "apellidos" => "Arocha Rodulfo" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2529912319300658" "doi" => "10.1016/j.artere.2019.04.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529912319300658?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0214916819300543?idApp=UINPBA00004N" "url" => "/02149168/0000003100000005/v1_201910020719/S0214916819300543/v1_201910020719/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0214916818301219" "issn" => "02149168" "doi" => "10.1016/j.arteri.2018.09.003" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "465" "copyright" => "Sociedad Española de Arteriosclerosis" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Clin Invest Arterioscl. 2019;31:222-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 21 "formatos" => array:2 [ "HTML" => 3 "PDF" => 18 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Artículo especial" "titulo" => "Comunicación entre niveles asistenciales: una oportunidad de mejora en la prevención cardiovascular" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "222" "paginaFinal" => "227" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Communication between levels of care: An opportunity for improvement in cardiovascular prevention" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1068 "Ancho" => 1526 "Tamanyo" => 99784 ] ] "descripcion" => array:1 [ "es" => "Actividades de intervención del proyecto CAPaCERES." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José Javier Gómez-Barrado, Paula Gómez-Turégano, Carolina Ortiz-Cortés, Luis Enrique Lezcano-Gort, Zineb Kounka, Maria José Romero-Castro" "autores" => array:6 [ 0 => array:2 [ "nombre" => "José Javier" "apellidos" => "Gómez-Barrado" ] 1 => array:2 [ "nombre" => "Paula" "apellidos" => "Gómez-Turégano" ] 2 => array:2 [ "nombre" => "Carolina" "apellidos" => "Ortiz-Cortés" ] 3 => array:2 [ "nombre" => "Luis Enrique" "apellidos" => "Lezcano-Gort" ] 4 => array:2 [ "nombre" => "Zineb" "apellidos" => "Kounka" ] 5 => array:2 [ "nombre" => "Maria José" "apellidos" => "Romero-Castro" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S252991231930049X" "doi" => "10.1016/j.artere.2019.09.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S252991231930049X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0214916818301219?idApp=UINPBA00004N" "url" => "/02149168/0000003100000005/v1_201910020719/S0214916818301219/v1_201910020719/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review article" "titulo" => "Statin treatment and increased diabetes risk. Possible mechanisms" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "228" "paginaFinal" => "232" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Elisenda Climent, David Benaiges, Juan Pedro-Botet" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Elisenda" "apellidos" => "Climent" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 1 => array:3 [ "nombre" => "David" "apellidos" => "Benaiges" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:4 [ "nombre" => "Juan" "apellidos" => "Pedro-Botet" "email" => array:1 [ 0 => "86620@parcdesalutmar.cat" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Endocrinology and Nutrition, Hospital del Mar, Paseo Marítimo, 25-29, E-08003 Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Medicine, Universitat Autònoma de Barcelona, Campus Universitari Mar, Dr. Aiguader, 80, E-08003 Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Dr. Aiguader, 80, E-08003 Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento con estatinas y mayor riesgo de diabetes. Posibles mecanismos" ] ] "textoCompleto" => "IntroductionStatins have been widely used for the treatment of lipid disorders. Their main role relies in lowering low-density lipoprotein (LDL) cholesterol levels, thereby reducing the risk of cardiovascular disease (CVD) in primary and secondary prevention settings. In this respect, current clinical guidelines recommend the use of statins for the prevention of atherosclerotic CVD, even in individuals with suboptimum lipid levels.<a class="elsevierStyleCrossRef" href="#bib0220">1</a>Although statin therapy is well tolerated, several side effects have been associated with its use, including an increased diabetes risk. Since the incidence of this adverse effect is not negligible, especially for specific populations, the present review aimed to examine the relationship between statin treatment and the presence of diabetes. A review of previous clinical evidence and the possible pathophysiologic mechanisms involved will also be described.Statins and diabetes riskAs stated previously, the risk of new-onset diabetes mellitus (NODM) in subjects receiving statin treatment has been a matter of debate in recent years.<a class="elsevierStyleCrossRef" href="#bib0225">2</a> In 2001, Freeman et al.<a class="elsevierStyleCrossRef" href="#bib0230">3</a> published one of the first papers speculating on the possible relationship between statin treatment and diabetes. In that sub-analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), pravastatin was surprisingly shown to lower the risk of diabetes by 30%. However, further trials yielded opposite results to this first one, showing an increased risk of type 2 diabetes mellitus secondary to statin therapy. The first trial in this line was Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).<a class="elsevierStyleCrossRef" href="#bib0235">4</a> Seventeen thousand eight hundred and two subjects were randomized to 20mg of rosuvastatin daily or placebo. The treatment with rosuvastatin for almost 2 years was associated with a 44% decrease in cardiac events but a significant 26% increase (odds ratio 1.26, 95% CI 1.04–1.51) in NODM. These results have since been further confirmed in other studies, which suggests an excess risk of NODM of around 9–13% in individuals treated with statins.<a class="elsevierStyleCrossRefs" href="#bib0240">5–8</a> Based on these results, in 2012 the Food and Drug Administration added information on statin labels concerning the increased incidence of diabetes and possible rise in blood glucose levels secondary to this treatment.A relationship also appears to exist between the excess risk of NODM observed in individuals receiving statins and the presence of other comorbidities, mainly the well-known cardiovascular risk factors, which include a higher body mass index, fasting blood glucose levels, triglycerides, blood pressure levels or low high-density lipoprotein (HDL) cholesterol levels.<a class="elsevierStyleCrossRefs" href="#bib0245">6,9</a> Thus, as the number of metabolic syndrome components in an individual treated with statins rises, the risk of NODM increases.On the other hand, data regarding the possible relationship between NODM risk and statin type or dose are inconsistent. Some studies reported little difference in diabetes rates between patients with medium or high statin doses<a class="elsevierStyleCrossRefs" href="#bib0265">10,11</a> while other publications reported a greater risk in subjects treated with rosuvastatin, atorvastatin and simvastatin, and no excess risk with other statins such as pravastatin, fluvastatin, lovastatin and pitavastatin.<a class="elsevierStyleCrossRefs" href="#bib0275">12–14</a> In this sense, it is worth highlighting that the possible increased risk of NODM seems to be related to the potency of each statin. A recent meta-analysis showed an association between LDL cholesterol reductions ≥30% with statin therapy and the risk of new-onset diabetes.<a class="elsevierStyleCrossRef" href="#bib0290">15</a>Statin treatment and familial hypercholesterolemiaIn addition, a hypothetical protection from NODM has been described in patients with heterozygous familial hypercholesterolemia (HeFH), although most of these patients receive statins as the main lipid-lowering treatment. This can be partially explained by the cholesterol-lowering effect of statin therapy being mainly due to inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the primary altered mechanism in HeFH.<a class="elsevierStyleCrossRef" href="#bib0295">16</a> In this context, Besseling et al.<a class="elsevierStyleCrossRef" href="#bib0300">17</a> found the prevalence of type 2 diabetes mellitus to be lower in patients with familial hypercholesterolemia compared with unaffected relatives (1.75% versus 2.93%). Moreover, a previous paper published by our group<a class="elsevierStyleCrossRef" href="#bib0305">18</a> also found the prevalence of diabetes in patients with HeFH to be 40% lower than that observed in the general population matched for age and sex. In our study,<a class="elsevierStyleCrossRef" href="#bib0305">18</a> risk factors independently associated with the presence of diabetes in these subjects were age, male sex, body mass index, baseline triglycerides, hypertension and years of statin treatment.Previous clinical evidencePopulation-based studiesPopulation-based studies reported to date focused on the incidence of NODM in patients treated with statins,<a class="elsevierStyleCrossRefs" href="#bib0270">11,13,19–23</a> and observed an increased risk of NODM related to the use of this lipid-lowering therapy. However, in some of those studies the increased risk was only observed for certain types of statin. For instance, Carter et al.<a class="elsevierStyleCrossRef" href="#bib0280">13</a> conducted a cohort study including 471,250 subjects. After 3 years follow-up, the adjusted hazard ratio (HR) for NODM was 1.22 (95% CI 1.15–1.9) for atorvastatin, 1.18 (95% CI 1.10–1.26) for rosuvastatin and 1.10 (95% CI 1.04–1.17) for simvastatin. However, no significant risk of NODM was observed with fluvastatin HR 0.95 (95% CI 0.81–1.11) and lovastatin HR 0.99 (95% CI 0.86–1.14). Similarly, in the meta-analysis of Vallejo-Vaz et al.<a class="elsevierStyleCrossRef" href="#bib0335">24</a> pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins. By contrast, in the Women's Health Initiative Study,<a class="elsevierStyleCrossRef" href="#bib0340">25</a> 153,840 postmenopausal women without diabetes were recruited and followed from 1993 to 2005. There were 10,242 incident cases of diabetes, and statins were associated with an increased risk of NODM, with an HR of 1.48 (95% CI 1.38–1.59), with this increased risk being present for all types of statins, and therefore showing a class effect. Finally, the United Kingdom Clinical Practice Cohort study<a class="elsevierStyleCrossRef" href="#bib0320">21</a> included 2,016,094, 430,890 of whom were receiving statins and were matched to 1,585,204 individuals who were not. During follow-up, 130,395 subjects developed NODM, with statin use being associated with an increased risk of NODM with an HR of 1.57 (95% CI 1.54–1.59). Furthermore, this risk increased with longer duration of statin use and a higher baseline body mass index.Meta-analysesMoving on from population-based studies, previous published trials, systematic reviews and meta-analyses also focused on NODM and statin treatment,<a class="elsevierStyleCrossRefs" href="#bib0240">5,6,26–30</a> and confirmed the previously-reported findings.In 2010, Sattar et al.<a class="elsevierStyleCrossRef" href="#bib0245">6</a> realized the first meta-analysis that demonstrated the increased risk of NODM secondary to statin treatment. Thirteen studies with 91,140 individuals (2226 in the statin group and 2052 in the control group) were included. Statin treatment was associated with a 9% increase in diabetes (OR 1.09, 95% CI 1.02–1.17). Regarding the different statin subtypes, rosuvastatin was found to increase the risk by 18% (OR 1.18, 95% CI, 1.04–1.33) while simvastatin increased the risk by 11%, although the latter result was not significant. After this first meta-analysis, Preiss et al.<a class="elsevierStyleCrossRef" href="#bib0350">27</a> confirmed the present results, demonstrating a 12% increased risk of diabetes (OR 1.12, 95% CI, 1.04–1.22) in patients with statin treatment.As mentioned above in population-based studies, some previous works found a different effect on the risk of NODM depending on the type or dose of statin. In this respect, the meta-analysis of Navarese et al.<a class="elsevierStyleCrossRef" href="#bib0355">28</a> that included 17 trials, found that pravastatin presented the lowest risk of incident diabetes. However, rosuvastatin 20mg daily was associated with a 25% increased risk compared to placebo (OR 1.25, 95% CI 0.82–1.90) and atorvastatin 80mg daily with a 15% increased risk (OR 1.15, 95% CI 0.90–1.50). In this same line, the meta-analysis published by Swerdlow et al.<a class="elsevierStyleCrossRef" href="#bib0365">30</a> also yielded different results depending on the type of statin. Fifteen studies were included with 96,418 subjects treated with a standard dose of statins compared to placebo and 4 studies including 32,752 subjects comparing high-dose to medium-dose statin treatment. The results obtained reflected a higher incidence of NODM in the statin group versus the placebo group (5.3% versus 4.7%) as well as a higher incidence in the high statin dose compared to the medium statin dose (6.4% versus 5.7%).Thus, the results of previous published papers, both population-based studies and meta-analyses, confirm the close relationship between NODM and statin treatment.Possible pathophysiologic mechanismsThe possible molecular mechanisms associated with the increased risk of NODM in subjects receiving statins are still under debate. Several mechanisms seem to be involved, all resulting in a decline in insulin secretion by pancreatic β-cells or an increase in insulin resistance.One of the possible mechanisms is based on the inhibition caused by statins of the Ca2+ channel in pancreatic β-cells, leading to a direct drop in insulin secretion.<a class="elsevierStyleCrossRef" href="#bib0370">31</a> This was confirmed in a previous in vitro study, where rosuvastatin inhibited the Ca2+ channel in pancreatic β-cells and led to reduced exocytosis of insulin granules.<a class="elsevierStyleCrossRef" href="#bib0370">31</a>A further possible mechanism is related to HMG-CoA reductase inhibition, which also leads to modifications in insulin sensitivity. Possible mechanisms associated with this include the production of loss-of-function genetic polymorphisms. In this sense, a study including 5327 non-diabetic subjects found that those who presented certain single nucleotide polymorphisms such as TCF7L2, SLC30A8, HHEX and others had an impaired conversion of proinsulin to insulin together with a limited insulin secretion.<a class="elsevierStyleCrossRef" href="#bib0375">32</a> Similarly, Swerdlow et al.<a class="elsevierStyleCrossRef" href="#bib0365">30</a> also described single nucleotide polymorphisms related to HMG-CoA reductase in 22,463 patients. In this study, each allele was associated to lower LDL colesterol levels together with increased blood glucose and insulin concentrations.Moreover, a decreased expression of glucose protein transporter 4 (GLUT4) and ubiquinone (CoQ10) levels together with modifications in adiponectin concentrations have also been described.<a class="elsevierStyleCrossRefs" href="#bib0380">33–35</a> In this respect, previous human studies have obtained inconsistent results, showing increase, decrease or no change of adiponectine levels in patients treated with statins.<a class="elsevierStyleCrossRef" href="#bib0380">33</a>Other possible pathophysiologic mechanisms that have been proposed are related to the effect of statins on lipoprotein particle size, thus increasing the size of very low-density lipoprotein (VLDL) particles and reducing the size of LDL and HDL particles, this leading to an increased risk of NODM.<a class="elsevierStyleCrossRefs" href="#bib0395">36,37</a> In contrast, large LDL and HDL and small VLDL particles appear to have an inverse effect on NODM. This has been demonstrated in experimental models with both rosuvastatin<a class="elsevierStyleCrossRef" href="#bib0405">38</a> and atorvastatin,<a class="elsevierStyleCrossRef" href="#bib0410">39</a> but must be confirmed in further studies.Finally, other possible mechanisms that have been described are related to alterations on glucose metabolism due to the inhibition of pancreatic β-cell transporters. In this line, ATP-binding cassette transporter ABCA1 defficiency was related to impared insulin secretion in pancreatic β-cells.<a class="elsevierStyleCrossRefs" href="#bib0415">40,41</a> All of the possible mechanisms described above are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Clinical implications and limitationsIt seems clear that statins are associated with an increased risk of NODM and that there could be a potency-dependent effect together with associated factors, such as metabolic syndrome traits, that increase this risk.On the other hand, statins play an essential role in cardiovascular risk reduction due to their effect on lowering LDL cholesterol levels. Hence, there appears to be agreement that the benefits of statin treatment regarding the cardiovascular profile outweigh to the increased risk associated with the presence of diabetes.<a class="elsevierStyleCrossRefs" href="#bib0425">42,43</a> However, questions remain to be answered in this field.It is also noteworthy that most of the studies describing the possible pathophysiologic mechanisms were conducted in experimental in vitro or animal models, and thus these data must be further confirmed in human studies in the near future to draw more solid conclusions.ConclusionsStatins present an increased risk of NODM, as described in previous observational studies and confirmed in recent meta-analyses and systematic reviews. However, this risk seems to be present only for certain types of statin. Moreover, individuals may have several risk factors possibly linked to this increased risk: a high body mass index, hypertension and previous glucose metabolism disorders.The different pathophysiologic mechanisms involved are still under study, but seem to be related to decreased insulin secretion together with increased insulin resistance. However, further studies are mandatory in this field to reach more solid conclusions and hence achieve clinical applicability in daily practice.FundingThis work has not received any funds.Conflict of interestThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1251159" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1159969" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1251160" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1159970" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Statins and diabetes risk" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Statin treatment and familial hypercholesterolemia" ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Previous clinical evidence" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Population-based studies" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Meta-analyses" ] ] ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Possible pathophysiologic mechanisms" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Clinical implications and limitations" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack428549" "titulo" => "Acknowledgment" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-09-28" "fechaAceptado" => "2018-12-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1159969" "palabras" => array:6 [ 0 => "Cardiovascular risk" 1 => "HMG-CoA reductase" 2 => "Low-density lipoprotein" 3 => "New-onset diabetes mellitus" 4 => "Pathophysiologic mechanisms" 5 => "Statins" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1159970" "palabras" => array:6 [ 0 => "Riesgo cardiovascular" 1 => "HMG-CoA reductasa" 2 => "Lipoproteína de baja densidad" 3 => "Diabetes mellitus de nueva aparición" 4 => "Mecanismos fisiopatológicos" 5 => "Estatinas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Statins have been associated with an increased risk of new-onset diabetes mellitus (NODM), as confirmed in previous observational studies and meta-analyses. Controversy exists as to whether this risk varies depending on statin type or dose. However, there appears to be unanimity regarding the different associated factors that raise this risk. Furthermore, diverse pathophysiologic mechanisms have been described that could explain the increased risk of diabetes in patients with statin treatment. These fundamentally cause a rise in insulin resistance together with a decrease in insulin secretion. The present review aimed to describe the relationship between statin treatment and the presence of diabetes and provide an update of previous published evidence and the possible mechanisms involved." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las estatinas se han asociado con un incremento en el riesgo de aparición de diabetes mellitus de novo, siendo esto confirmado en estudios previos observacionales así como metaanálisis. Sin embargo, existe cierta controversia sobre si este riesgo varia en función de la dosis o tipo de estatina. Por otro lado, parece que hay unanimidad con respecto a los factores asociados a este incremento de riesgo. Asimismo, se han descrito diversos mecanismos fisiopatológicos que podrían explicar el aumento de riesgo de padecer diabetes en los pacientes tratados con estatinas. Estos mecanismos se basan fundamentalmente en un incremento en la resistencia a la insulina así como un descenso en su sensibilidad. La presente revisión está enfocada en describir la relación entre el tratamiento con estatinas y el riesgo de padecer diabetes y revisar los datos publicados hasta las fecha así como los posibles mecanismos fisiopatológicos involucrados en este aumento de riesgo." ] ] "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" => "GLUT4: glucose protein transporter 4; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; CoQ10: ubiquinone." "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="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased pancreatic β-cell insulin secretion: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Modifications in Ca2+ channel \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inhibition of pancreatic β-cells transporters (ATP-binding cassette transporter ABCA1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HMG-CoA reductase inhibition: Loss-of-function genetic polymorphisms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased insulin signaling: GLUT4, CoQ10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipoprotein modifications \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2140341.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Possible pathophysiologic mechanisms associated with the diabetes risk of statin treatment." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0220" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice Guidelines" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.J. Stone" 1 => "J.G. Robinson" 2 => "A.H. Lichtenstein" 3 => "C.N. Bairey Mez" 4 => "C.B. Blum" 5 => "R.H. Eckel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2013.11.002" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2014" "volumen" => "63" "paginaInicial" => "2889" "paginaFinal" => "2934" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24239923" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0225" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacotherapy: statins and new-onset diabetes – the important questions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D. Preiss" 1 => "N. Sattar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrcardio.2012.15" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Cardiol" "fecha" => "2012" "volumen" => "9" "paginaInicial" => "190" "paginaFinal" => "192" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22330613" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0230" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.J. Freeman" 1 => "J. Norrie" 2 => "N. Sattar" 3 => "R.D. Neely" 4 => "S.M. Cobbe" 5 => "I. Ford" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.cir.103.3.357" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2001" "volumen" => "103" "paginaInicial" => "357" "paginaFinal" => "362" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11157685" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0235" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Ridker" 1 => "E. Danielson" 2 => "F. Fonseca" 3 => "J. Genest" 4 => "A.M. Gotto Jr." 5 => "J.J. Kastelein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0807646" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2008" "volumen" => "359" "paginaInicial" => "2195" "paginaFinal" => "2207" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18997196" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0240" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin therapy and risk of developing type 2 diabetes: a meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Rajpathak" 1 => "D. Kumbhani" 2 => "J. Crandall" 3 => "N. Barzilai" 4 => "M. Alderman" 5 => "P.M. Ridker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc09-0738" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2009" "volumen" => "32" "paginaInicial" => "1924" "paginaFinal" => "1929" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19794004" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0245" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Sattar" 1 => "D. Preiss" 2 => "H.M. Murray" 3 => "P. Welsh" 4 => "B.M. Buckley" 5 => "A.J. de Craen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(09)61965-6" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2010" "volumen" => "375" "paginaInicial" => "735" "paginaFinal" => "742" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20167359" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0250" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rosuvastatin in older patients with systolic heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Kjekshus" 1 => "E. Apetrei" 2 => "V. Barrios" 3 => "M. Böhm" 4 => "J.G. Cleland" 5 => "J.H. Cornel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa0706201" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2007" "volumen" => "357" "paginaInicial" => "2248" "paginaFinal" => "2261" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17984166" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0255" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Tavazzi" 1 => "A.P. Maggioni" 2 => "R. Marchioli" 3 => "S. Barlera" 4 => "M.G. Franzosi" 5 => "R. Latini" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(08)61240-4" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2008" "volumen" => "372" "paginaInicial" => "1231" "paginaFinal" => "1239" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18757089" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0260" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.D. Waters" 1 => "J.E. Ho" 2 => "S.M. Boekholdt" 3 => "D.A. DeMicco" 4 => "J.J. Kastelein" 5 => "M. Messig" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2012.09.042" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2013" "volumen" => "61" "paginaInicial" => "148" "paginaFinal" => "152" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23219296" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0265" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential survival" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. Danaei" 1 => "L.A. García Rodríguez" 2 => "O. Fernandez Cantero" 3 => "M.A. Hernán" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc12-1756" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2013" "volumen" => "36" "paginaInicial" => "1236" "paginaFinal" => "1240" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23248196" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0270" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes mellitus and cardiovascular events in older patients with myocardial infarction prescribed intensive-dose and moderate-dose statins" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D.T. Ko" 1 => "H.C. Wijeysundera" 2 => "C.A. Jackevicius" 3 => "A. Yousef" 4 => "J. Wang" 5 => "J.V. Tu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCOUTCOMES.111.000015" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2013" "volumen" => "6" "paginaInicial" => "315" "paginaFinal" => "322" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23674307" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0275" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.R. Dormuth" 1 => "K.B. Filion" 2 => "J.M. Paterson" 3 => "M.T. James" 4 => "G.F. Teare" 5 => "C.B. Raymond" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bmj.g3244" "Revista" => array:5 [ "tituloSerie" => "BMJ" "fecha" => "2014" "volumen" => "348" "paginaInicial" => "g3244" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24874977" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0280" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk of incident diabetes among patients treated with statins: population based study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.A. Carter" 1 => "T. Gomes" 2 => "X. Camacho" 3 => "D.N. Juurlink" 4 => "B.R. Shah" 5 => "M.M. Mamdani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bmj.f2610" "Revista" => array:5 [ "tituloSerie" => "BMJ" "fecha" => "2013" "volumen" => "346" "paginaInicial" => "f2610" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23704171" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0285" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pitavastatin: a review in hypercholesterolemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S.M. Hoy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40256-017-0213-8" "Revista" => array:6 [ "tituloSerie" => "Am J Cardiovasc Drugs" "fecha" => "2017" "volumen" => "17" "paginaInicial" => "157" "paginaFinal" => "168" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28130659" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0290" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Wang" 1 => "R. Cai" 2 => "Y. Yuan" 3 => "Z. Varghese" 4 => "J. Moorhead" 5 => "X.Z. Ruan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/srep39982" "Revista" => array:5 [ "tituloSerie" => "Sci Rep" "fecha" => "2017" "volumen" => "7" "paginaInicial" => "39982" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28071756" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0295" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "European Atherosclerosis Society Consensus Panel Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.G. Nordestgaard" 1 => "M.J. Chapman" 2 => "S.E. Humphries" 3 => "H.N. Ginsberg" 4 => "L. Masana" 5 => "O.S. Descamps" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/eht273" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2013" "volumen" => "34" "paginaInicial" => "3478" "paginaFinal" => "3490" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23956253" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0300" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Besseling" 1 => "J.J. Kastelein" 2 => "J.C. Defesche" 3 => "B.A. Hutten" 4 => "G.K. Hovingh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2015.1206" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2015" "volumen" => "313" "paginaInicial" => "1029" "paginaFinal" => "1036" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25756439" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0305" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Climent" 1 => "S. Pérez-Calahorra" 2 => "V. Marco-Benedí" 3 => "N. Plana" 4 => "R. Sánchez" 5 => "E. Ros" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41598-017-00136-5" "Revista" => array:6 [ "tituloSerie" => "Sci Rep" "fecha" => "2017" "volumen" => "7" "paginaInicial" => "55" "paginaFinal" => "96" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28246399" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0310" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin use, diabetes incidence and overall mortality in normoglycemic and impaired fasting glucose patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.R. Castro" 1 => "G. Simon" 2 => "S.S. Cha" 3 => "B.P. Yawn" 4 => "L.J. Melton 3rd" 5 => "P.J. Caraballo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11606-015-3583-0" "Revista" => array:6 [ "tituloSerie" => "J Gen Intern Med" "fecha" => "2016" "volumen" => "31" "paginaInicial" => "502" "paginaFinal" => "508" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26850412" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0315" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. Cederberg" 1 => "A. Stancakova" 2 => "N. Yaluri" 3 => "S. Modi" 4 => "J. Kuusisto" 5 => "M. Laakso" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-015-3528-5" "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "2015" "volumen" => "58" "paginaInicial" => "1109" "paginaFinal" => "1117" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25754552" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0320" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice research datalink" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.F. Macedo" 1 => "I. Douglas" 2 => "L. Smeeth" 3 => "H. Forbes" 4 => "S. Ebrahim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1471-2261-14-85" "Revista" => array:5 [ "tituloSerie" => "BMC Cardiovasc Disord" "fecha" => "2014" "volumen" => "14" "paginaInicial" => "85" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25022519" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0325" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins and the risk of diabetes: evidence from a large population-based cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Corrao" 1 => "B. Ibrahim" 2 => "F. Nicotra" 3 => "D. Soranna" 4 => "L. Merlino" 5 => "A.L. Catapano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc13-2215" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2014" "volumen" => "37" "paginaInicial" => "2225" "paginaFinal" => "2232" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24969582" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0330" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of statin use on development of new-onset diabetes mellitus in Asian population" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.W. Rha" 1 => "B.G. Choi" 2 => "H.S. Seo" 3 => "S.H. Park" 4 => "J.Y. Park" 5 => "K.Y. Chen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.amjcard.2015.11.009" "Revista" => array:6 [ "tituloSerie" => "Am J Cardiol" "fecha" => "2016" "volumen" => "117" "paginaInicial" => "382" "paginaFinal" => "387" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26732422" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0335" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of pitavastatin on glucose HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.J. Vallejo-Vaz" 1 => "S.R. Kondapally Seshasai" 2 => "K. Kurogi" 3 => "I. Michishita" 4 => "T. Nozue" 5 => "S. Sugiyama" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.atherosclerosis.2015.06.001" "Revista" => array:6 [ "tituloSerie" => "Atherosclerosis" "fecha" => "2015" "volumen" => "241" "paginaInicial" => "409" "paginaFinal" => "418" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26074315" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0340" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.L. Culver" 1 => "I.S. Ockene" 2 => "R. Balasubramanian" 3 => "B.C. Olendzki" 4 => "D.M. Sepavich" 5 => "J. Wactawski-Wende" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/archinternmed.2011.625" "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "2012" "volumen" => "172" "paginaInicial" => "144" "paginaFinal" => "152" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22231607" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0345" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predictors of new-onset diabetes in patients treated with atorvastatin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.D. Waters" 1 => "J.E. Ho" 2 => "D.A. DeMicco" 3 => "A. Breazna" 4 => "B.J. Arsenault" 5 => "C.C. Wun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2010.10.047" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2011" "volumen" => "57" "paginaInicial" => "1535" "paginaFinal" => "1545" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21453832" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0350" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Preiss" 1 => "S.R. Seshassai" 2 => "P. Welsh" 3 => "S.A. Murhpy" 4 => "J.E. Ho" 5 => "D.D. Waters" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2011.860" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2011" "volumen" => "305" "paginaInicial" => "2556" "paginaFinal" => "2564" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21693744" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0355" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.P. Navarese" 1 => "A. Buffon" 2 => "F. Andreotti" 3 => "M. Kozinski" 4 => "N. Welton" 5 => "T. Fabiszak" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.amjcard.2012.12.037" "Revista" => array:6 [ "tituloSerie" => "Am J Cardiol" "fecha" => "2013" "volumen" => "111" "paginaInicial" => "1123" "paginaFinal" => "1130" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23352266" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0360" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lower intensified target LDL-C level of statin therapy results in a higher risk of incident diabetes: a metaanalysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Cai" 1 => "Y. Yuan" 2 => "Y. Zhou" 3 => "W. Xia" 4 => "P. Wang" 5 => "H. Sun" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "PLoS One" "fecha" => "2014" "volumen" => "12" "paginaInicial" => "51" ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0365" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HMG-coenzyme reductase inhibition, type 2 diabetes, and body weight: evidence from genetic analysis and randomised trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.I. Swerdlow" 1 => "D. Preiss" 2 => "K.B. Kuchenbaeker" 3 => "M.V. Holmes" 4 => "J.E. Engmann" 5 => "T. Shah" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(14)61183-1" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2015" "volumen" => "385" "paginaInicial" => "351" "paginaFinal" => "361" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25262344" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0370" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rosuvastatin treatment affects both basal and glucose-induced insulin secretion in INS-1832/13 cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "V.A. Salunkhe" 1 => "O. Elvstam" 2 => "L. Eliasson" 3 => "A. Wendt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0151592" "Revista" => array:5 [ "tituloSerie" => "PLoS One" "fecha" => "2016" "volumen" => "11" "paginaInicial" => "e0151592" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26986474" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0375" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Stanckova" 1 => "T. Kuulasmaa" 2 => "J. Paananen" 3 => "A.U. Jackson" 4 => "L.L. Bonnycastle" 5 => "F.S. Collins" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/db09-0117" "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "2009" "volumen" => "58" "paginaInicial" => "2129" "paginaFinal" => "2136" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19502414" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0380" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin treatment and new-onset diabetes: a review of proposed mechanisms" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Brault" 1 => "J. Ray" 2 => "J.H. Gomez" 3 => "C.S. Mantzoros" 4 => "S.S. Daskalopoulou" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.metabol.2014.02.014" "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "2014" "volumen" => "63" "paginaInicial" => "735" "paginaFinal" => "745" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24641882" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0385" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of statin therapy on plasma adiponectin concentrations: a systematic review and meta-analysis of randomized controlled arms" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Chrusciel" 1 => "A. Sahebkar" 2 => "A. Rembek Wieliczko" 3 => "M.C. Serban" 4 => "S. Ursoniu" 5 => "D.P. Mikhailidis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.atherosclerosis.2016.07.897" "Revista" => array:6 [ "tituloSerie" => "Atherosclerosis" "fecha" => "2016" "volumen" => "253" "paginaInicial" => "194" "paginaFinal" => "208" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27498397" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0390" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is statin-induced diabetes mellitus clinically relevant?. A comprehensive review of the literature" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.S.H. Bell" 1 => "J.J. Nicolantonio" 2 => "J.H. O’Keefe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/dom.12254" "Revista" => array:6 [ "tituloSerie" => "Diabetes Obes Metab" "fecha" => "2014" "volumen" => "16" "paginaInicial" => "689" "paginaFinal" => "694" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24373206" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0395" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lipoprotein particles and incident diabetes in the multi-ethnic study of atherosclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.H. Mackey" 1 => "S. Mora" 2 => "A.G. Bertoni" 3 => "C.L. Wassel" 4 => "M.R. Carnethon" 5 => "C.T. Sibley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc14-0645" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2015" "volumen" => "38" "paginaInicial" => "628" "paginaFinal" => "636" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25592196" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0400" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lipoprotein particle size and concentration by nuclear magnetic resonance and incident type 2 diabetes in women" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Mora" 1 => "J.D. Otvos" 2 => "R.S. Rosenson" 3 => "A. Pradhan" 4 => "J.E. Buring" 5 => "P.M. Ridker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/db09-1114" "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "2010" "volumen" => "59" "paginaInicial" => "1153" "paginaFinal" => "1160" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20185808" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0405" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of lipoproteins, insulin resistance, and atorvastatin with incident type 2 diabetes mellitus. Secondary analysis of a randomized clinical trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.B. Dugani" 1 => "A.O. Akintunde" 2 => "N. Paynter" 3 => "R.J. Glynn" 4 => "P.M. Ridker" 5 => "S. Mora" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamacardio.2016.0096" "Revista" => array:5 [ "tituloSerie" => "JAMA Cardiol" "fecha" => "2016" "volumen" => "1" "paginaInicial" => "136" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27347563" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0410" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of statins on LDL particle size in patients with familial combined hyperlipidemia: a comparison between atorvastatin and pravastatin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.R. Sirtori" 1 => "L. Calabresi" 2 => "L. Pisciotta" 3 => "L. Cattin" 4 => "P. Pauciullo" 5 => "M. Montagnani" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nutr Metab Cardiovasc Disord" "fecha" => "2005" "volumen" => "15" "paginaInicial" => "47" "paginaFinal" => "55" ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0415" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New onset diabetes mellitus induced by statins: current evidence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S.G. Chrysant" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/00325481.2017.1292107" "Revista" => array:6 [ "tituloSerie" => "Postgrad Med" "fecha" => "2017" "volumen" => "129" "paginaInicial" => "430" "paginaFinal" => "435" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28276790" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0420" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins and diabetes risk: how real is it and what are the mechanisms?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. Robinson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MOL.0000000000000172" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Lipidol" "fecha" => "2015" "volumen" => "26" "paginaInicial" => "228" "paginaFinal" => "235" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25887679" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0425" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interpretation of the evidence for the efficacy and safety of statin therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Collins" 1 => "C. Reith" 2 => "J. Emberson" 3 => "J. Armitage" 4 => "C. Baigent" 5 => "L. Blackwell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "2016" "volumen" => "19" "paginaInicial" => "2532" "paginaFinal" => "2561" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0430" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The diabetogenic action of statins – mechanisms and clinical implications" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.J. Betteridge" 1 => "R. Carmena" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrendo.2015.194" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Endocrinol" "fecha" => "2016" "volumen" => "12" "paginaInicial" => "99" "paginaFinal" => "110" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26668119" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack428549" "titulo" => "Acknowledgment" "texto" => "We thank Miss Christine O’Hara for review of the English version of the manuscript." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/02149168/0000003100000005/v1_201910020719/S0214916819300014/v1_201910020719/en/main.assets" "Apartado" => array:4 [ "identificador" => "7455" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Revisión" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/02149168/0000003100000005/v1_201910020719/S0214916819300014/v1_201910020719/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0214916819300014?idApp=UINPBA00004N"]

Statistics

Review article

Statin treatment and increased diabetes risk. Possible mechanisms

Tratamiento con estatinas y mayor riesgo de diabetes. Posibles mecanismos

Elisenda Climenta,b, David Benaigesa,b,c, Juan Pedro-Boteta,b,c,

Corresponding author

86620@parcdesalutmar.cat

Corresponding author.

a Department of Endocrinology and Nutrition, Hospital del Mar, Paseo Marítimo, 25-29, E-08003 Barcelona, Spain

b Department of Medicine, Universitat Autònoma de Barcelona, Campus Universitari Mar, Dr. Aiguader, 80, E-08003 Barcelona, Spain

c Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Dr. Aiguader, 80, E-08003 Barcelona, Spain

Read

1957

Times
was read the article

327

Total PDF

1630

Total HTML

Share statistics

 array:23 [
  "pii" => "S0214916819300014"
  "issn" => "02149168"
  "doi" => "10.1016/j.arteri.2018.12.001"
  "estado" => "S300"
  "fechaPublicacion" => "2019-09-01"
  "aid" => "474"
  "copyright" => "Sociedad Espa&#241;ola de Arteriosclerosis"
  "copyrightAnyo" => "2019"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "rev"
  "cita" => "Clin Invest Arterioscl. 2019;31:228-32"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 24
    "formatos" => array:2 [
      "HTML" => 8
      "PDF" => 16
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S0214916819300543"
    "issn" => "02149168"
    "doi" => "10.1016/j.arteri.2019.04.004"
    "estado" => "S300"
    "fechaPublicacion" => "2019-09-01"
    "aid" => "498"
    "copyright" => "Sociedad Espa&#241;ola de Arteriosclerosis"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "rev"
    "cita" => "Clin Invest Arterioscl. 2019;31:233-40"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 15
      "formatos" => array:2 [
        "HTML" => 5
        "PDF" => 10
      ]
    ]
    "es" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">REVISI&#211;N</span>"
      "titulo" => "Sedentarismo&#44; la enfermedad del siglo <span class="elsevierStyleSmallCaps">xxi</span>"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "233"
          "paginaFinal" => "240"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Sedentary lifestyle a disease from <span class="elsevierStyleSmallCaps">xxi</span> century"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Figura 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 1902
              "Ancho" => 2074
              "Tamanyo" => 368215
            ]
          ]
          "descripcion" => array:1 [
            "es" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Consecuencias cl&#237;nicas del sedentarismo&#46; Los efectos fisiopatol&#243;gicos derivados del sedentarismo abarcan una gama muy amplia de trastornos&#44; con especial repercusi&#243;n en el &#225;rea cardiovascular y metab&#243;lica&#44; favoreciendo o acelerando la progresi&#243;n hacia la diabetes o enfermedad cardiovascular ateroscler&#243;tica&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "J&#46; Ildefonzo Arocha Rodulfo"
          "autores" => array:1 [
            0 => array:2 [
              "nombre" => "J&#46; Ildefonzo"
              "apellidos" => "Arocha Rodulfo"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "Traduccion" => array:1 [
      "en" => array:9 [
        "pii" => "S2529912319300658"
        "doi" => "10.1016/j.artere.2019.04.001"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => false
          "ES2" => false
          "LATM" => false
        ]
        "gratuito" => false
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "en"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529912319300658?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0214916819300543?idApp=UINPBA00004N"
    "url" => "/02149168/0000003100000005/v1_201910020719/S0214916819300543/v1_201910020719/es/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S0214916818301219"
    "issn" => "02149168"
    "doi" => "10.1016/j.arteri.2018.09.003"
    "estado" => "S300"
    "fechaPublicacion" => "2019-09-01"
    "aid" => "465"
    "copyright" => "Sociedad Espa&#241;ola de Arteriosclerosis"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Clin Invest Arterioscl. 2019;31:222-7"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 21
      "formatos" => array:2 [
        "HTML" => 3
        "PDF" => 18
      ]
    ]
    "es" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Art&#237;culo especial</span>"
      "titulo" => "Comunicaci&#243;n entre niveles asistenciales&#58; una oportunidad de mejora en la prevenci&#243;n cardiovascular"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "222"
          "paginaFinal" => "227"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Communication between levels of care&#58; An opportunity for improvement in cardiovascular prevention"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0010"
          "etiqueta" => "Figura 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 1068
              "Ancho" => 1526
              "Tamanyo" => 99784
            ]
          ]
          "descripcion" => array:1 [
            "es" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Actividades de intervenci&#243;n del proyecto CAPaCERES&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Jos&#233; Javier G&#243;mez-Barrado, Paula G&#243;mez-Tur&#233;gano, Carolina Ortiz-Cort&#233;s, Luis Enrique Lezcano-Gort, Zineb Kounka, Maria Jos&#233; Romero-Castro"
          "autores" => array:6 [
            0 => array:2 [
              "nombre" => "Jos&#233; Javier"
              "apellidos" => "G&#243;mez-Barrado"
            ]
            1 => array:2 [
              "nombre" => "Paula"
              "apellidos" => "G&#243;mez-Tur&#233;gano"
            ]
            2 => array:2 [
              "nombre" => "Carolina"
              "apellidos" => "Ortiz-Cort&#233;s"
            ]
            3 => array:2 [
              "nombre" => "Luis Enrique"
              "apellidos" => "Lezcano-Gort"
            ]
            4 => array:2 [
              "nombre" => "Zineb"
              "apellidos" => "Kounka"
            ]
            5 => array:2 [
              "nombre" => "Maria Jos&#233;"
              "apellidos" => "Romero-Castro"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "Traduccion" => array:1 [
      "en" => array:9 [
        "pii" => "S252991231930049X"
        "doi" => "10.1016/j.artere.2019.09.001"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => false
          "ES2" => false
          "LATM" => false
        ]
        "gratuito" => false
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "en"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S252991231930049X?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0214916818301219?idApp=UINPBA00004N"
    "url" => "/02149168/0000003100000005/v1_201910020719/S0214916818301219/v1_201910020719/es/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>"
    "titulo" => "Statin treatment and increased diabetes risk&#46; Possible mechanisms"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "228"
        "paginaFinal" => "232"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Elisenda Climent, David Benaiges, Juan Pedro-Botet"
        "autores" => array:3 [
          0 => array:3 [
            "nombre" => "Elisenda"
            "apellidos" => "Climent"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "David"
            "apellidos" => "Benaiges"
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
            ]
          ]
          2 => array:4 [
            "nombre" => "Juan"
            "apellidos" => "Pedro-Botet"
            "email" => array:1 [
              0 => "86620@parcdesalutmar.cat"
            ]
            "referencia" => array:4 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
              3 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:3 [
          0 => array:3 [
            "entidad" => "Department of Endocrinology and Nutrition&#44; Hospital del Mar&#44; Paseo Mar&#237;timo&#44; 25-29&#44; E-08003 Barcelona&#44; Spain"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Department of Medicine&#44; Universitat Aut&#242;noma de Barcelona&#44; Campus Universitari Mar&#44; Dr&#46; Aiguader&#44; 80&#44; E-08003 Barcelona&#44; Spain"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Institut Hospital del Mar d&#8217;Investigacions M&#232;diques &#40;IMIM&#41;&#44; Dr&#46; Aiguader&#44; 80&#44; E-08003 Barcelona&#44; Spain"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Tratamiento con estatinas y mayor riesgo de diabetes&#46; Posibles mecanismos"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Statins have been widely used for the treatment of lipid disorders&#46; Their main role relies in lowering low-density lipoprotein &#40;LDL&#41; cholesterol levels&#44; thereby reducing the risk of cardiovascular disease &#40;CVD&#41; in primary and secondary prevention settings&#46; In this respect&#44; current clinical guidelines recommend the use of statins for the prevention of atherosclerotic CVD&#44; even in individuals with suboptimum lipid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although statin therapy is well tolerated&#44; several side effects have been associated with its use&#44; including an increased diabetes risk&#46; Since the incidence of this adverse effect is not negligible&#44; especially for specific populations&#44; the present review aimed to examine the relationship between statin treatment and the presence of diabetes&#46; A review of previous clinical evidence and the possible pathophysiologic mechanisms involved will also be described&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Statins and diabetes risk</span><p id="par0015" class="elsevierStylePara elsevierViewall">As stated previously&#44; the risk of new-onset diabetes mellitus &#40;NODM&#41; in subjects receiving statin treatment has been a matter of debate in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">2</span></a> In 2001&#44; Freeman et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">3</span></a> published one of the first papers speculating on the possible relationship between statin treatment and diabetes&#46; In that sub-analysis of the West of Scotland Coronary Prevention Study &#40;WOSCOPS&#41;&#44; pravastatin was surprisingly shown to lower the risk of diabetes by 30&#37;&#46; However&#44; further trials yielded opposite results to this first one&#44; showing an increased risk of type 2 diabetes mellitus secondary to statin therapy&#46; The first trial in this line was Justification for the Use of Statins in Primary Prevention&#58; an Intervention Trial Evaluating Rosuvastatin &#40;JUPITER&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">4</span></a> Seventeen thousand eight hundred and two subjects were randomized to 20<span class="elsevierStyleHsp" style=""></span>mg of rosuvastatin daily or placebo&#46; The treatment with rosuvastatin for almost 2 years was associated with a 44&#37; decrease in cardiac events but a significant 26&#37; increase &#40;odds ratio 1&#46;26&#44; 95&#37; CI 1&#46;04&#8211;1&#46;51&#41; in NODM&#46; These results have since been further confirmed in other studies&#44; which suggests an excess risk of NODM of around 9&#8211;13&#37; in individuals treated with statins&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">5&#8211;8</span></a> Based on these results&#44; in 2012 the Food and Drug Administration added information on statin labels concerning the increased incidence of diabetes and possible rise in blood glucose levels secondary to this treatment&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A relationship also appears to exist between the excess risk of NODM observed in individuals receiving statins and the presence of other comorbidities&#44; mainly the well-known cardiovascular risk factors&#44; which include a higher body mass index&#44; fasting blood glucose levels&#44; triglycerides&#44; blood pressure levels or low high-density lipoprotein &#40;HDL&#41; cholesterol levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">6&#44;9</span></a> Thus&#44; as the number of metabolic syndrome components in an individual treated with statins rises&#44; the risk of NODM increases&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">On the other hand&#44; data regarding the possible relationship between NODM risk and statin type or dose are inconsistent&#46; Some studies reported little difference in diabetes rates between patients with medium or high statin doses<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">10&#44;11</span></a> while other publications reported a greater risk in subjects treated with rosuvastatin&#44; atorvastatin and simvastatin&#44; and no excess risk with other statins such as pravastatin&#44; fluvastatin&#44; lovastatin and pitavastatin&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">12&#8211;14</span></a> In this sense&#44; it is worth highlighting that the possible increased risk of NODM seems to be related to the potency of each statin&#46; A recent meta-analysis showed an association between LDL cholesterol reductions &#8805;30&#37; with statin therapy and the risk of new-onset diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Statin treatment and familial hypercholesterolemia</span><p id="par0030" class="elsevierStylePara elsevierViewall">In addition&#44; a hypothetical protection from NODM has been described in patients with heterozygous familial hypercholesterolemia &#40;HeFH&#41;&#44; although most of these patients receive statins as the main lipid-lowering treatment&#46; This can be partially explained by the cholesterol-lowering effect of statin therapy being mainly due to inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A &#40;HMG-CoA&#41; reductase&#44; the primary altered mechanism in HeFH&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">16</span></a> In this context&#44; Besseling et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">17</span></a> found the prevalence of type 2 diabetes mellitus to be lower in patients with familial hypercholesterolemia compared with unaffected relatives &#40;1&#46;75&#37; <span class="elsevierStyleItalic">versus</span> 2&#46;93&#37;&#41;&#46; Moreover&#44; a previous paper published by our group<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">18</span></a> also found the prevalence of diabetes in patients with HeFH to be 40&#37; lower than that observed in the general population matched for age and sex&#46; In our study&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">18</span></a> risk factors independently associated with the presence of diabetes in these subjects were age&#44; male sex&#44; body mass index&#44; baseline triglycerides&#44; hypertension and years of statin treatment&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Previous clinical evidence</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Population-based studies</span><p id="par0035" class="elsevierStylePara elsevierViewall">Population-based studies reported to date focused on the incidence of NODM in patients treated with statins&#44;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">11&#44;13&#44;19&#8211;23</span></a> and observed an increased risk of NODM related to the use of this lipid-lowering therapy&#46; However&#44; in some of those studies the increased risk was only observed for certain types of statin&#46; For instance&#44; Carter et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">13</span></a> conducted a cohort study including 471&#44;250 subjects&#46; After 3 years follow-up&#44; the adjusted hazard ratio &#40;HR&#41; for NODM was 1&#46;22 &#40;95&#37; CI 1&#46;15&#8211;1&#46;9&#41; for atorvastatin&#44; 1&#46;18 &#40;95&#37; CI 1&#46;10&#8211;1&#46;26&#41; for rosuvastatin and 1&#46;10 &#40;95&#37; CI 1&#46;04&#8211;1&#46;17&#41; for simvastatin&#46; However&#44; no significant risk of NODM was observed with fluvastatin HR 0&#46;95 &#40;95&#37; CI 0&#46;81&#8211;1&#46;11&#41; and lovastatin HR 0&#46;99 &#40;95&#37; CI 0&#46;86&#8211;1&#46;14&#41;&#46; Similarly&#44; in the meta-analysis of Vallejo-Vaz et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">24</span></a> pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins&#46; By contrast&#44; in the Women&#39;s Health Initiative Study&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">25</span></a> 153&#44;840 postmenopausal women without diabetes were recruited and followed from 1993 to 2005&#46; There were 10&#44;242 incident cases of diabetes&#44; and statins were associated with an increased risk of NODM&#44; with an HR of 1&#46;48 &#40;95&#37; CI 1&#46;38&#8211;1&#46;59&#41;&#44; with this increased risk being present for all types of statins&#44; and therefore showing a class effect&#46; Finally&#44; the United Kingdom Clinical Practice Cohort study<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">21</span></a> included 2&#44;016&#44;094&#44; 430&#44;890 of whom were receiving statins and were matched to 1&#44;585&#44;204 individuals who were not&#46; During follow-up&#44; 130&#44;395 subjects developed NODM&#44; with statin use being associated with an increased risk of NODM with an HR of 1&#46;57 &#40;95&#37; CI 1&#46;54&#8211;1&#46;59&#41;&#46; Furthermore&#44; this risk increased with longer duration of statin use and a higher baseline body mass index&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Meta-analyses</span><p id="par0040" class="elsevierStylePara elsevierViewall">Moving on from population-based studies&#44; previous published trials&#44; systematic reviews and meta-analyses also focused on NODM and statin treatment&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">5&#44;6&#44;26&#8211;30</span></a> and confirmed the previously-reported findings&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In 2010&#44; Sattar et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a> realized the first meta-analysis that demonstrated the increased risk of NODM secondary to statin treatment&#46; Thirteen studies with 91&#44;140 individuals &#40;2226 in the statin group and 2052 in the control group&#41; were included&#46; Statin treatment was associated with a 9&#37; increase in diabetes &#40;OR 1&#46;09&#44; 95&#37; CI 1&#46;02&#8211;1&#46;17&#41;&#46; Regarding the different statin subtypes&#44; rosuvastatin was found to increase the risk by 18&#37; &#40;OR 1&#46;18&#44; 95&#37; CI&#44; 1&#46;04&#8211;1&#46;33&#41; while simvastatin increased the risk by 11&#37;&#44; although the latter result was not significant&#46; After this first meta-analysis&#44; Preiss et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">27</span></a> confirmed the present results&#44; demonstrating a 12&#37; increased risk of diabetes &#40;OR 1&#46;12&#44; 95&#37; CI&#44; 1&#46;04&#8211;1&#46;22&#41; in patients with statin treatment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">As mentioned above in population-based studies&#44; some previous works found a different effect on the risk of NODM depending on the type or dose of statin&#46; In this respect&#44; the meta-analysis of Navarese et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a> that included 17 trials&#44; found that pravastatin presented the lowest risk of incident diabetes&#46; However&#44; rosuvastatin 20<span class="elsevierStyleHsp" style=""></span>mg daily was associated with a 25&#37; increased risk compared to placebo &#40;OR 1&#46;25&#44; 95&#37; CI 0&#46;82&#8211;1&#46;90&#41; and atorvastatin 80<span class="elsevierStyleHsp" style=""></span>mg daily with a 15&#37; increased risk &#40;OR 1&#46;15&#44; 95&#37; CI 0&#46;90&#8211;1&#46;50&#41;&#46; In this same line&#44; the meta-analysis published by Swerdlow et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">30</span></a> also yielded different results depending on the type of statin&#46; Fifteen studies were included with 96&#44;418 subjects treated with a standard dose of statins compared to placebo and 4 studies including 32&#44;752 subjects comparing high-dose to medium-dose statin treatment&#46; The results obtained reflected a higher incidence of NODM in the statin group <span class="elsevierStyleItalic">versus</span> the placebo group &#40;5&#46;3&#37; <span class="elsevierStyleItalic">versus</span> 4&#46;7&#37;&#41; as well as a higher incidence in the high statin dose compared to the medium statin dose &#40;6&#46;4&#37; <span class="elsevierStyleItalic">versus</span> 5&#46;7&#37;&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Thus&#44; the results of previous published papers&#44; both population-based studies and meta-analyses&#44; confirm the close relationship between NODM and statin treatment&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Possible pathophysiologic mechanisms</span><p id="par0060" class="elsevierStylePara elsevierViewall">The possible molecular mechanisms associated with the increased risk of NODM in subjects receiving statins are still under debate&#46; Several mechanisms seem to be involved&#44; all resulting in a decline in insulin secretion by pancreatic &#946;-cells or an increase in insulin resistance&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">One of the possible mechanisms is based on the inhibition caused by statins of the Ca<span class="elsevierStyleSup">2&#43;</span> channel in pancreatic &#946;-cells&#44; leading to a direct drop in insulin secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">31</span></a> This was confirmed in a previous <span class="elsevierStyleItalic">in vitro</span> study&#44; where rosuvastatin inhibited the Ca<span class="elsevierStyleSup">2&#43;</span> channel in pancreatic &#946;-cells and led to reduced exocytosis of insulin granules&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">31</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">A further possible mechanism is related to HMG-CoA reductase inhibition&#44; which also leads to modifications in insulin sensitivity&#46; Possible mechanisms associated with this include the production of loss-of-function genetic polymorphisms&#46; In this sense&#44; a study including 5327 non-diabetic subjects found that those who presented certain single nucleotide polymorphisms such as TCF7L2&#44; SLC30A8&#44; HHEX and others had an impaired conversion of proinsulin to insulin together with a limited insulin secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">32</span></a> Similarly&#44; Swerdlow et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">30</span></a> also described single nucleotide polymorphisms related to HMG-CoA reductase in 22&#44;463 patients&#46; In this study&#44; each allele was associated to lower LDL colesterol levels together with increased blood glucose and insulin concentrations&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Moreover&#44; a decreased expression of glucose protein transporter 4 &#40;GLUT4&#41; and ubiquinone &#40;CoQ10&#41; levels together with modifications in adiponectin concentrations have also been described&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">33&#8211;35</span></a> In this respect&#44; previous human studies have obtained inconsistent results&#44; showing increase&#44; decrease or no change of adiponectine levels in patients treated with statins&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">33</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Other possible pathophysiologic mechanisms that have been proposed are related to the effect of statins on lipoprotein particle size&#44; thus increasing the size of very low-density lipoprotein &#40;VLDL&#41; particles and reducing the size of LDL and HDL particles&#44; this leading to an increased risk of NODM&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">36&#44;37</span></a> In contrast&#44; large LDL and HDL and small VLDL particles appear to have an inverse effect on NODM&#46; This has been demonstrated in experimental models with both rosuvastatin<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a> and atorvastatin&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a> but must be confirmed in further studies&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Finally&#44; other possible mechanisms that have been described are related to alterations on glucose metabolism due to the inhibition of pancreatic &#946;-cell transporters&#46; In this line&#44; ATP-binding cassette transporter ABCA1 defficiency was related to impared insulin secretion in pancreatic &#946;-cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">40&#44;41</span></a> All of the possible mechanisms described above are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical implications and limitations</span><p id="par0090" class="elsevierStylePara elsevierViewall">It seems clear that statins are associated with an increased risk of NODM and that there could be a potency-dependent effect together with associated factors&#44; such as metabolic syndrome traits&#44; that increase this risk&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">On the other hand&#44; statins play an essential role in cardiovascular risk reduction due to their effect on lowering LDL cholesterol levels&#46; Hence&#44; there appears to be agreement that the benefits of statin treatment regarding the cardiovascular profile outweigh to the increased risk associated with the presence of diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">42&#44;43</span></a> However&#44; questions remain to be answered in this field&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">It is also noteworthy that most of the studies describing the possible pathophysiologic mechanisms were conducted in experimental <span class="elsevierStyleItalic">in vitro</span> or animal models&#44; and thus these data must be further confirmed in human studies in the near future to draw more solid conclusions&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0105" class="elsevierStylePara elsevierViewall">Statins present an increased risk of NODM&#44; as described in previous observational studies and confirmed in recent meta-analyses and systematic reviews&#46; However&#44; this risk seems to be present only for certain types of statin&#46; Moreover&#44; individuals may have several risk factors possibly linked to this increased risk&#58; a high body mass index&#44; hypertension and previous glucose metabolism disorders&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The different pathophysiologic mechanisms involved are still under study&#44; but seem to be related to decreased insulin secretion together with increased insulin resistance&#46; However&#44; further studies are mandatory in this field to reach more solid conclusions and hence achieve clinical applicability in daily practice&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Funding</span><p id="par0115" class="elsevierStylePara elsevierViewall">This work has not received any funds&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:14 [
        0 => array:3 [
          "identificador" => "xres1251159"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1159969"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres1251160"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1159970"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Statins and diabetes risk"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Statin treatment and familial hypercholesterolemia"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0020"
          "titulo" => "Previous clinical evidence"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Population-based studies"
            ]
            1 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Meta-analyses"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Possible pathophysiologic mechanisms"
        ]
        8 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Clinical implications and limitations"
        ]
        9 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conclusions"
        ]
        10 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Funding"
        ]
        11 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflict of interest"
        ]
        12 => array:2 [
          "identificador" => "xack428549"
          "titulo" => "Acknowledgment"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-09-28"
    "fechaAceptado" => "2018-12-16"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1159969"
          "palabras" => array:6 [
            0 => "Cardiovascular risk"
            1 => "HMG-CoA reductase"
            2 => "Low-density lipoprotein"
            3 => "New-onset diabetes mellitus"
            4 => "Pathophysiologic mechanisms"
            5 => "Statins"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1159970"
          "palabras" => array:6 [
            0 => "Riesgo cardiovascular"
            1 => "HMG-CoA reductasa"
            2 => "Lipoprote&#237;na de baja densidad"
            3 => "Diabetes mellitus de nueva aparici&#243;n"
            4 => "Mecanismos fisiopatol&#243;gicos"
            5 => "Estatinas"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Statins have been associated with an increased risk of new-onset diabetes mellitus &#40;NODM&#41;&#44; as confirmed in previous observational studies and meta-analyses&#46; Controversy exists as to whether this risk varies depending on statin type or dose&#46; However&#44; there appears to be unanimity regarding the different associated factors that raise this risk&#46; Furthermore&#44; diverse pathophysiologic mechanisms have been described that could explain the increased risk of diabetes in patients with statin treatment&#46; These fundamentally cause a rise in insulin resistance together with a decrease in insulin secretion&#46; The present review aimed to describe the relationship between statin treatment and the presence of diabetes and provide an update of previous published evidence and the possible mechanisms involved&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las estatinas se han asociado con un incremento en el riesgo de aparici&#243;n de diabetes mellitus <span class="elsevierStyleItalic">de novo</span>&#44; siendo esto confirmado en estudios previos observacionales as&#237; como metaan&#225;lisis&#46; Sin embargo&#44; existe cierta controversia sobre si este riesgo varia en funci&#243;n de la dosis o tipo de estatina&#46; Por otro lado&#44; parece que hay unanimidad con respecto a los factores asociados a este incremento de riesgo&#46; Asimismo&#44; se han descrito diversos mecanismos fisiopatol&#243;gicos que podr&#237;an explicar el aumento de riesgo de padecer diabetes en los pacientes tratados con estatinas&#46; Estos mecanismos se basan fundamentalmente en un incremento en la resistencia a la insulina as&#237; como un descenso en su sensibilidad&#46; La presente revisi&#243;n est&#225; enfocada en describir la relaci&#243;n entre el tratamiento con estatinas y el riesgo de padecer diabetes y revisar los datos publicados hasta las fecha as&#237; como los posibles mecanismos fisiopatol&#243;gicos involucrados en este aumento de riesgo&#46;</p></span>"
      ]
    ]
    "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="spar0025" class="elsevierStyleSimplePara elsevierViewall">GLUT4&#58; glucose protein transporter 4&#59; HMG-CoA&#58; 3-hydroxy-3-methylglutaryl-coenzyme A&#59; CoQ10&#58; ubiquinone&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Decreased pancreatic &#946;-cell insulin secretion&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Modifications in Ca<span class="elsevierStyleSup">2&#43;</span> channel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Inhibition of pancreatic &#946;-cells transporters &#40;ATP-binding cassette transporter ABCA1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HMG-CoA reductase inhibition</span>&#58; Loss-of-function genetic polymorphisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Decreased insulin signaling</span>&#58; GLUT4&#44; CoQ10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lipoprotein modifications</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2140341.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Possible pathophysiologic mechanisms associated with the diabetes risk of statin treatment&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:43 [
            0 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2013 ACC&#47;AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults&#58; a report of the American College of Cardiology&#47;American Heart Association Task Force on practice Guidelines"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46;J&#46; Stone"
                            1 => "J&#46;G&#46; Robinson"
                            2 => "A&#46;H&#46; Lichtenstein"
                            3 => "C&#46;N&#46; Bairey Mez"
                            4 => "C&#46;B&#46; Blum"
                            5 => "R&#46;H&#46; Eckel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2013.11.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2014"
                        "volumen" => "63"
                        "paginaInicial" => "2889"
                        "paginaFinal" => "2934"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24239923"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacotherapy&#58; statins and new-onset diabetes &#8211; the important questions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46; Preiss"
                            1 => "N&#46; Sattar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrcardio.2012.15"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Cardiol"
                        "fecha" => "2012"
                        "volumen" => "9"
                        "paginaInicial" => "190"
                        "paginaFinal" => "192"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22330613"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pravastatin and the development of diabetes mellitus&#58; evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;J&#46; Freeman"
                            1 => "J&#46; Norrie"
                            2 => "N&#46; Sattar"
                            3 => "R&#46;D&#46; Neely"
                            4 => "S&#46;M&#46; Cobbe"
                            5 => "I&#46; Ford"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.cir.103.3.357"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2001"
                        "volumen" => "103"
                        "paginaInicial" => "357"
                        "paginaFinal" => "362"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11157685"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Ridker"
                            1 => "E&#46; Danielson"
                            2 => "F&#46; Fonseca"
                            3 => "J&#46; Genest"
                            4 => "A&#46;M&#46; Gotto Jr&#46;"
                            5 => "J&#46;J&#46; Kastelein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa0807646"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2008"
                        "volumen" => "359"
                        "paginaInicial" => "2195"
                        "paginaFinal" => "2207"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18997196"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statin therapy and risk of developing type 2 diabetes&#58; a meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Rajpathak"
                            1 => "D&#46; Kumbhani"
                            2 => "J&#46; Crandall"
                            3 => "N&#46; Barzilai"
                            4 => "M&#46; Alderman"
                            5 => "P&#46;M&#46; Ridker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc09-0738"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2009"
                        "volumen" => "32"
                        "paginaInicial" => "1924"
                        "paginaFinal" => "1929"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19794004"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statins and risk of incident diabetes&#58; a collaborative meta-analysis of randomized statin trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Sattar"
                            1 => "D&#46; Preiss"
                            2 => "H&#46;M&#46; Murray"
                            3 => "P&#46; Welsh"
                            4 => "B&#46;M&#46; Buckley"
                            5 => "A&#46;J&#46; de Craen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(09)61965-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2010"
                        "volumen" => "375"
                        "paginaInicial" => "735"
                        "paginaFinal" => "742"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20167359"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rosuvastatin in older patients with systolic heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Kjekshus"
                            1 => "E&#46; Apetrei"
                            2 => "V&#46; Barrios"
                            3 => "M&#46; B&#246;hm"
                            4 => "J&#46;G&#46; Cleland"
                            5 => "J&#46;H&#46; Cornel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa0706201"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2007"
                        "volumen" => "357"
                        "paginaInicial" => "2248"
                        "paginaFinal" => "2261"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17984166"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of rosuvastatin in patients with chronic heart failure &#40;the GISSI-HF trial&#41;&#58; a randomised&#44; double-blind&#44; placebo-controlled trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Tavazzi"
                            1 => "A&#46;P&#46; Maggioni"
                            2 => "R&#46; Marchioli"
                            3 => "S&#46; Barlera"
                            4 => "M&#46;G&#46; Franzosi"
                            5 => "R&#46; Latini"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(08)61240-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2008"
                        "volumen" => "372"
                        "paginaInicial" => "1231"
                        "paginaFinal" => "1239"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18757089"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy&#58; effect of baseline risk factors for diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;D&#46; Waters"
                            1 => "J&#46;E&#46; Ho"
                            2 => "S&#46;M&#46; Boekholdt"
                            3 => "D&#46;A&#46; DeMicco"
                            4 => "J&#46;J&#46; Kastelein"
                            5 => "M&#46; Messig"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2012.09.042"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2013"
                        "volumen" => "61"
                        "paginaInicial" => "148"
                        "paginaFinal" => "152"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23219296"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statins and risk of diabetes&#58; an analysis of electronic medical records to evaluate possible bias due to differential survival"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "G&#46; Danaei"
                            1 => "L&#46;A&#46; Garc&#237;a Rodr&#237;guez"
                            2 => "O&#46; Fernandez Cantero"
                            3 => "M&#46;A&#46; Hern&#225;n"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc12-1756"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2013"
                        "volumen" => "36"
                        "paginaInicial" => "1236"
                        "paginaFinal" => "1240"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23248196"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes mellitus and cardiovascular events in older patients with myocardial infarction prescribed intensive-dose and moderate-dose statins"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "D&#46;T&#46; Ko"
                            1 => "H&#46;C&#46; Wijeysundera"
                            2 => "C&#46;A&#46; Jackevicius"
                            3 => "A&#46; Yousef"
                            4 => "J&#46; Wang"
                            5 => "J&#46;V&#46; Tu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCOUTCOMES.111.000015"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2013"
                        "volumen" => "6"
                        "paginaInicial" => "315"
                        "paginaFinal" => "322"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23674307"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Higher potency statins and the risk of new diabetes&#58; multicentre&#44; observational study of administrative databases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;R&#46; Dormuth"
                            1 => "K&#46;B&#46; Filion"
                            2 => "J&#46;M&#46; Paterson"
                            3 => "M&#46;T&#46; James"
                            4 => "G&#46;F&#46; Teare"
                            5 => "C&#46;B&#46; Raymond"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bmj.g3244"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2014"
                        "volumen" => "348"
                        "paginaInicial" => "g3244"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24874977"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk of incident diabetes among patients treated with statins&#58; population based study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46;A&#46; Carter"
                            1 => "T&#46; Gomes"
                            2 => "X&#46; Camacho"
                            3 => "D&#46;N&#46; Juurlink"
                            4 => "B&#46;R&#46; Shah"
                            5 => "M&#46;M&#46; Mamdani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bmj.f2610"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2013"
                        "volumen" => "346"
                        "paginaInicial" => "f2610"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23704171"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pitavastatin&#58; a review in hypercholesterolemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46;M&#46; Hoy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40256-017-0213-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Cardiovasc Drugs"
                        "fecha" => "2017"
                        "volumen" => "17"
                        "paginaInicial" => "157"
                        "paginaFinal" => "168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28130659"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes&#58; a meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Wang"
                            1 => "R&#46; Cai"
                            2 => "Y&#46; Yuan"
                            3 => "Z&#46; Varghese"
                            4 => "J&#46; Moorhead"
                            5 => "X&#46;Z&#46; Ruan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/srep39982"
                      "Revista" => array:5 [
                        "tituloSerie" => "Sci Rep"
                        "fecha" => "2017"
                        "volumen" => "7"
                        "paginaInicial" => "39982"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28071756"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "European Atherosclerosis Society Consensus Panel Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population&#58; guidance for clinicians to prevent coronary heart disease&#58; consensus statement of the European Atherosclerosis Society"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;G&#46; Nordestgaard"
                            1 => "M&#46;J&#46; Chapman"
                            2 => "S&#46;E&#46; Humphries"
                            3 => "H&#46;N&#46; Ginsberg"
                            4 => "L&#46; Masana"
                            5 => "O&#46;S&#46; Descamps"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/eht273"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2013"
                        "volumen" => "34"
                        "paginaInicial" => "3478"
                        "paginaFinal" => "3490"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23956253"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46; Besseling"
                            1 => "J&#46;J&#46; Kastelein"
                            2 => "J&#46;C&#46; Defesche"
                            3 => "B&#46;A&#46; Hutten"
                            4 => "G&#46;K&#46; Hovingh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.2015.1206"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2015"
                        "volumen" => "313"
                        "paginaInicial" => "1029"
                        "paginaFinal" => "1036"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25756439"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of LDL cholesterol&#44; statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Climent"
                            1 => "S&#46; P&#233;rez-Calahorra"
                            2 => "V&#46; Marco-Bened&#237;"
                            3 => "N&#46; Plana"
                            4 => "R&#46; S&#225;nchez"
                            5 => "E&#46; Ros"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41598-017-00136-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Sci Rep"
                        "fecha" => "2017"
                        "volumen" => "7"
                        "paginaInicial" => "55"
                        "paginaFinal" => "96"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28246399"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statin use&#44; diabetes incidence and overall mortality in normoglycemic and impaired fasting glucose patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;R&#46; Castro"
                            1 => "G&#46; Simon"
                            2 => "S&#46;S&#46; Cha"
                            3 => "B&#46;P&#46; Yawn"
                            4 => "L&#46;J&#46; Melton 3rd"
                            5 => "P&#46;J&#46; Caraballo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s11606-015-3583-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gen Intern Med"
                        "fecha" => "2016"
                        "volumen" => "31"
                        "paginaInicial" => "502"
                        "paginaFinal" => "508"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26850412"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion&#58; a 6 year follow-up study of the METSIM cohort"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "H&#46; Cederberg"
                            1 => "A&#46; Stancakova"
                            2 => "N&#46; Yaluri"
                            3 => "S&#46; Modi"
                            4 => "J&#46; Kuusisto"
                            5 => "M&#46; Laakso"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00125-015-3528-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetologia"
                        "fecha" => "2015"
                        "volumen" => "58"
                        "paginaInicial" => "1109"
                        "paginaFinal" => "1117"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25754552"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statins and the risk of type 2 diabetes mellitus&#58; cohort study using the UK clinical practice research datalink"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;F&#46; Macedo"
                            1 => "I&#46; Douglas"
                            2 => "L&#46; Smeeth"
                            3 => "H&#46; Forbes"
                            4 => "S&#46; Ebrahim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-2261-14-85"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Cardiovasc Disord"
                        "fecha" => "2014"
                        "volumen" => "14"
                        "paginaInicial" => "85"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25022519"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statins and the risk of diabetes&#58; evidence from a large population-based cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Corrao"
                            1 => "B&#46; Ibrahim"
                            2 => "F&#46; Nicotra"
                            3 => "D&#46; Soranna"
                            4 => "L&#46; Merlino"
                            5 => "A&#46;L&#46; Catapano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc13-2215"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2014"
                        "volumen" => "37"
                        "paginaInicial" => "2225"
                        "paginaFinal" => "2232"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24969582"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of statin use on development of new-onset diabetes mellitus in Asian population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;W&#46; Rha"
                            1 => "B&#46;G&#46; Choi"
                            2 => "H&#46;S&#46; Seo"
                            3 => "S&#46;H&#46; Park"
                            4 => "J&#46;Y&#46; Park"
                            5 => "K&#46;Y&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjcard.2015.11.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Cardiol"
                        "fecha" => "2016"
                        "volumen" => "117"
                        "paginaInicial" => "382"
                        "paginaFinal" => "387"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26732422"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of pitavastatin on glucose HbA1c and incident diabetes&#58; a meta-analysis of randomized controlled clinical trials in individuals without diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;J&#46; Vallejo-Vaz"
                            1 => "S&#46;R&#46; Kondapally Seshasai"
                            2 => "K&#46; Kurogi"
                            3 => "I&#46; Michishita"
                            4 => "T&#46; Nozue"
                            5 => "S&#46; Sugiyama"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.atherosclerosis.2015.06.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Atherosclerosis"
                        "fecha" => "2015"
                        "volumen" => "241"
                        "paginaInicial" => "409"
                        "paginaFinal" => "418"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26074315"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statin use and risk of diabetes mellitus in postmenopausal women in the Women&#39;s Health Initiative"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;L&#46; Culver"
                            1 => "I&#46;S&#46; Ockene"
                            2 => "R&#46; Balasubramanian"
                            3 => "B&#46;C&#46; Olendzki"
                            4 => "D&#46;M&#46; Sepavich"
                            5 => "J&#46; Wactawski-Wende"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/archinternmed.2011.625"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "2012"
                        "volumen" => "172"
                        "paginaInicial" => "144"
                        "paginaFinal" => "152"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22231607"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predictors of new-onset diabetes in patients treated with atorvastatin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;D&#46; Waters"
                            1 => "J&#46;E&#46; Ho"
                            2 => "D&#46;A&#46; DeMicco"
                            3 => "A&#46; Breazna"
                            4 => "B&#46;J&#46; Arsenault"
                            5 => "C&#46;C&#46; Wun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2010.10.047"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2011"
                        "volumen" => "57"
                        "paginaInicial" => "1535"
                        "paginaFinal" => "1545"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21453832"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy&#58; a meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Preiss"
                            1 => "S&#46;R&#46; Seshassai"
                            2 => "P&#46; Welsh"
                            3 => "S&#46;A&#46; Murhpy"
                            4 => "J&#46;E&#46; Ho"
                            5 => "D&#46;D&#46; Waters"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.2011.860"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2011"
                        "volumen" => "305"
                        "paginaInicial" => "2556"
                        "paginaFinal" => "2564"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21693744"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;P&#46; Navarese"
                            1 => "A&#46; Buffon"
                            2 => "F&#46; Andreotti"
                            3 => "M&#46; Kozinski"
                            4 => "N&#46; Welton"
                            5 => "T&#46; Fabiszak"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjcard.2012.12.037"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Cardiol"
                        "fecha" => "2013"
                        "volumen" => "111"
                        "paginaInicial" => "1123"
                        "paginaFinal" => "1130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23352266"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lower intensified target LDL-C level of statin therapy results in a higher risk of incident diabetes&#58; a metaanalysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Cai"
                            1 => "Y&#46; Yuan"
                            2 => "Y&#46; Zhou"
                            3 => "W&#46; Xia"
                            4 => "P&#46; Wang"
                            5 => "H&#46; Sun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "PLoS One"
                        "fecha" => "2014"
                        "volumen" => "12"
                        "paginaInicial" => "51"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HMG-coenzyme reductase inhibition&#44; type 2 diabetes&#44; and body weight&#58; evidence from genetic analysis and randomised trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;I&#46; Swerdlow"
                            1 => "D&#46; Preiss"
                            2 => "K&#46;B&#46; Kuchenbaeker"
                            3 => "M&#46;V&#46; Holmes"
                            4 => "J&#46;E&#46; Engmann"
                            5 => "T&#46; Shah"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(14)61183-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2015"
                        "volumen" => "385"
                        "paginaInicial" => "351"
                        "paginaFinal" => "361"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25262344"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rosuvastatin treatment affects both basal and glucose-induced insulin secretion in INS-1832&#47;13 cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "V&#46;A&#46; Salunkhe"
                            1 => "O&#46; Elvstam"
                            2 => "L&#46; Eliasson"
                            3 => "A&#46; Wendt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0151592"
                      "Revista" => array:5 [
                        "tituloSerie" => "PLoS One"
                        "fecha" => "2016"
                        "volumen" => "11"
                        "paginaInicial" => "e0151592"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26986474"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release&#44; proinsulin conversion&#44; and insulin sensitivity in 5&#44;327 nondiabetic Finnish men"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Stanckova"
                            1 => "T&#46; Kuulasmaa"
                            2 => "J&#46; Paananen"
                            3 => "A&#46;U&#46; Jackson"
                            4 => "L&#46;L&#46; Bonnycastle"
                            5 => "F&#46;S&#46; Collins"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/db09-0117"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "2009"
                        "volumen" => "58"
                        "paginaInicial" => "2129"
                        "paginaFinal" => "2136"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19502414"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statin treatment and new-onset diabetes&#58; a review of proposed mechanisms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46; Brault"
                            1 => "J&#46; Ray"
                            2 => "J&#46;H&#46; Gomez"
                            3 => "C&#46;S&#46; Mantzoros"
                            4 => "S&#46;S&#46; Daskalopoulou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.metabol.2014.02.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "2014"
                        "volumen" => "63"
                        "paginaInicial" => "735"
                        "paginaFinal" => "745"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24641882"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of statin therapy on plasma adiponectin concentrations&#58; a systematic review and meta-analysis of randomized controlled arms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Chrusciel"
                            1 => "A&#46; Sahebkar"
                            2 => "A&#46; Rembek Wieliczko"
                            3 => "M&#46;C&#46; Serban"
                            4 => "S&#46; Ursoniu"
                            5 => "D&#46;P&#46; Mikhailidis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.atherosclerosis.2016.07.897"
                      "Revista" => array:6 [
                        "tituloSerie" => "Atherosclerosis"
                        "fecha" => "2016"
                        "volumen" => "253"
                        "paginaInicial" => "194"
                        "paginaFinal" => "208"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27498397"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is statin-induced diabetes mellitus clinically relevant&#63;&#46; A comprehensive review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46;S&#46;H&#46; Bell"
                            1 => "J&#46;J&#46; Nicolantonio"
                            2 => "J&#46;H&#46; O&#8217;Keefe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/dom.12254"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Obes Metab"
                        "fecha" => "2014"
                        "volumen" => "16"
                        "paginaInicial" => "689"
                        "paginaFinal" => "694"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24373206"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lipoprotein particles and incident diabetes in the multi-ethnic study of atherosclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;H&#46; Mackey"
                            1 => "S&#46; Mora"
                            2 => "A&#46;G&#46; Bertoni"
                            3 => "C&#46;L&#46; Wassel"
                            4 => "M&#46;R&#46; Carnethon"
                            5 => "C&#46;T&#46; Sibley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc14-0645"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2015"
                        "volumen" => "38"
                        "paginaInicial" => "628"
                        "paginaFinal" => "636"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25592196"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lipoprotein particle size and concentration by nuclear magnetic resonance and incident type 2 diabetes in women"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Mora"
                            1 => "J&#46;D&#46; Otvos"
                            2 => "R&#46;S&#46; Rosenson"
                            3 => "A&#46; Pradhan"
                            4 => "J&#46;E&#46; Buring"
                            5 => "P&#46;M&#46; Ridker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/db09-1114"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "2010"
                        "volumen" => "59"
                        "paginaInicial" => "1153"
                        "paginaFinal" => "1160"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20185808"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of lipoproteins&#44; insulin resistance&#44; and atorvastatin with incident type 2 diabetes mellitus&#46; Secondary analysis of a randomized clinical trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46;B&#46; Dugani"
                            1 => "A&#46;O&#46; Akintunde"
                            2 => "N&#46; Paynter"
                            3 => "R&#46;J&#46; Glynn"
                            4 => "P&#46;M&#46; Ridker"
                            5 => "S&#46; Mora"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamacardio.2016.0096"
                      "Revista" => array:5 [
                        "tituloSerie" => "JAMA Cardiol"
                        "fecha" => "2016"
                        "volumen" => "1"
                        "paginaInicial" => "136"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27347563"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of statins on LDL particle size in patients with familial combined hyperlipidemia&#58; a comparison between atorvastatin and pravastatin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;R&#46; Sirtori"
                            1 => "L&#46; Calabresi"
                            2 => "L&#46; Pisciotta"
                            3 => "L&#46; Cattin"
                            4 => "P&#46; Pauciullo"
                            5 => "M&#46; Montagnani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nutr Metab Cardiovasc Disord"
                        "fecha" => "2005"
                        "volumen" => "15"
                        "paginaInicial" => "47"
                        "paginaFinal" => "55"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New onset diabetes mellitus induced by statins&#58; current evidence"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46;G&#46; Chrysant"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/00325481.2017.1292107"
                      "Revista" => array:6 [
                        "tituloSerie" => "Postgrad Med"
                        "fecha" => "2017"
                        "volumen" => "129"
                        "paginaInicial" => "430"
                        "paginaFinal" => "435"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28276790"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statins and diabetes risk&#58; how real is it and what are the mechanisms&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; Robinson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MOL.0000000000000172"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Lipidol"
                        "fecha" => "2015"
                        "volumen" => "26"
                        "paginaInicial" => "228"
                        "paginaFinal" => "235"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25887679"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interpretation of the evidence for the efficacy and safety of statin therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Collins"
                            1 => "C&#46; Reith"
                            2 => "J&#46; Emberson"
                            3 => "J&#46; Armitage"
                            4 => "C&#46; Baigent"
                            5 => "L&#46; Blackwell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2016"
                        "volumen" => "19"
                        "paginaInicial" => "2532"
                        "paginaFinal" => "2561"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The diabetogenic action of statins &#8211; mechanisms and clinical implications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;J&#46; Betteridge"
                            1 => "R&#46; Carmena"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrendo.2015.194"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Endocrinol"
                        "fecha" => "2016"
                        "volumen" => "12"
                        "paginaInicial" => "99"
                        "paginaFinal" => "110"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26668119"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack428549"
        "titulo" => "Acknowledgment"
        "texto" => "<p id="par0125" class="elsevierStylePara elsevierViewall">We thank Miss Christine O&#8217;Hara for review of the English version of the manuscript&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/02149168/0000003100000005/v1_201910020719/S0214916819300014/v1_201910020719/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "7455"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Revisi&#243;n"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/02149168/0000003100000005/v1_201910020719/S0214916819300014/v1_201910020719/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0214916819300014?idApp=UINPBA00004N"
]

Article information

ISSN: 02149168
Original language: English

DOI:10.1016/j.arteri.2018.12.001

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	31	3	34
2024 September	101	16	117
2024 August	70	11	81
2024 July	52	2	54
2024 June	58	4	62
2024 May	80	15	95
2024 April	51	13	64
2024 March	80	7	87
2024 February	80	14	94
2024 January	65	3	68
2023 December	65	6	71
2023 November	89	21	110
2023 October	82	23	105
2023 September	48	10	58
2023 August	31	23	54
2023 July	26	3	29
2023 June	27	3	30
2023 May	54	3	57
2023 April	69	7	76
2023 March	40	3	43
2023 February	36	4	40
2023 January	20	9	29
2022 December	51	8	59
2022 November	54	13	67
2022 October	68	9	77
2022 September	33	6	39
2022 August	39	13	52
2022 July	14	10	24
2022 June	16	7	23
2022 May	17	4	21
2022 April	16	15	31
2022 March	36	8	44
2022 February	17	7	24
2020 December	3	2	5
2020 June	2	4	6
2020 May	1	2	3
2019 December	3	0	3
2019 October	5	2	7
2019 July	0	6	6
2019 April	0	4	4
2019 February	0	4	4

Show all

Indexed in:

Follow us:

Subscribe:

Statistics

Indexed in:

Follow us:

Subscribe:

Statistics

Subscribe to our newsletter