Editorial
Results from Cardiovascular Outcome Trials in Diabetes
Ensayos clínicos de resultados de enfermedad cardiovascular en diabetes
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Grammatikopoulou, Vasiliki Bougioukli, Parthena Iosifidou, Maria F. Vasiloglou, Maria-Assimina Gerama, Dimitrios Mitsos, Ioanna Chrysanthakopoulou, Maria Tsigga, Kyriakos Kazakos" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Dimitrios" "apellidos" => "Poulimeneas" ] 1 => array:2 [ "nombre" => "Maria G." "apellidos" => "Grammatikopoulou" ] 2 => array:2 [ "nombre" => "Vasiliki" "apellidos" => "Bougioukli" ] 3 => array:2 [ "nombre" => "Parthena" "apellidos" => "Iosifidou" ] 4 => array:2 [ "nombre" => "Maria F." "apellidos" => "Vasiloglou" ] 5 => array:2 [ "nombre" => "Maria-Assimina" "apellidos" => "Gerama" ] 6 => array:2 [ "nombre" => "Dimitrios" "apellidos" => "Mitsos" ] 7 => array:2 [ "nombre" => "Ioanna" "apellidos" => "Chrysanthakopoulou" ] 8 => array:2 [ "nombre" => "Maria" "apellidos" => "Tsigga" ] 9 => array:2 [ "nombre" => "Kyriakos" "apellidos" => "Kazakos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173509316300733?idApp=UINPBA00004N" "url" => "/21735093/0000006300000007/v2_201609300106/S2173509316300733/v2_201609300106/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Results from Cardiovascular Outcome Trials in Diabetes" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "317" "paginaFinal" => "319" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Manuel Muñoz Torres, Araceli Muñoz Garach" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Manuel" "apellidos" => "Muñoz Torres" "email" => array:1 [ 0 => "mmt@mamuto.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Araceli" "apellidos" => "Muñoz Garach" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "UGC Endocrinología y Nutrición, Hospital Universitario San Cecilio, Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "UGC Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Ensayos clínicos de resultados de enfermedad cardiovascular en diabetes" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Patients with type 2 diabetes mellitus (T2DM) have a high risk of cardiovascular disease (CVD) due to both hyperglycemia and other associated vascular risk factors, and also have a poorer prognosis of cardiovascular events. Diabetes increases the severity of all phases of atherosclerosis, its development and its complications.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a> Patients with diabetes have a higher mortality rate attributable to cardiovascular causes as compared to the non-diabetic population (HR: 2.32; 95% CI: 2.11–2.56), and myocardial infarction and stroke account for 80% of deaths in patients with T2M.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">2,3</span></a> In this context, it has been estimated that patients with diabetes are at risk of experiencing a cardiovascular event some 15 years earlier than non-diabetic subjects.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a> Thus, a comprehensive intervention on the risk factors for CVD in this population is recommended to improve prognosis. The significance of blood glucose control for this comprehensive approach should be stressed. However, the impact of antidiabetic drugs on CVD development and progression is as yet insufficiently known. In recent years, a number of clinical trials (ADVANCE, ACCORD, VADT) have assessed the impact of strict blood glucose control on microvascular complications and CVD.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">5–7</span></a> Microvascular disease results were satisfactory, but none of these studies showed in their active phase a decrease in CVD incidence, and one of them even reported increased mortality (ACCORD). However, a recent publication with 10-year follow-up data for patients in the VADT study reported a reduction of major cardiovascular events, but no differences in all-cause or cardiovascular mortality.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a> In these studies, rates of hypoglycemia and weight increase were greater in the intensive therapy group. The debate goes back to 2007 following the publication of a controversial meta-analysis reporting that treatment with rosiglitazone significantly increased the risk of myocardial infarction, which led to the drug being taken off the market in Europe.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">9</span></a> A definition of the benefits or risks of antidiabetic drugs with regard to CVD is therefore very important. The Food and Drug Administration (FDA) in 2008 issued guidelines for assessing the risk of new drugs for the treatment of T2DM because of the uncertainty regarding the CV safety of some of these drugs, and other agencies subsequently proposed similar measures.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> For new antidiabetic drugs, the FDA guidelines stipulate that an independent committee be established to assess the adverse events of CVD during all Phase 2 and 3 clinical trials. Classical major adverse CVD events (cMACE), including death from CVD, non-fatal myocardial infarction, and non-fatal stroke, should be assessed. Thus, before an application for approval of a new drug is submitted, a meta-analysis of data from Phase and 3 studies should be conducted to show that the drug is not associated with an unacceptable increase in the risk of CVD. The regulations state that if for the risk of cMACE the upper limit of the 95% confidence interval of the estimated risk is greater than 1.8, the drug cannot be approved. If values ranging from 1.3 to 1.8 are found, additional studies are required, and approval is only recommended when the value is less than 1.3. However, these studies are not designed as clinical trials of CVD outcomes, and only specific, randomized clinical trials will be able to determine the benefits or risks regarding CVD of an antidiabetic agent.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Several CVD outcome trials with different types of antidiabetics, such as dipeptidylpeptidase-4 inhibitors (DPP-4 inhibitors), GLP-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been published recently. Their inclusion criteria were not consistent, which should be taken into consideration in their interpretation. Studies with three DPP-4 inhibitors have been reported: saxagliptin, alogliptin, and sitagliptin. In the SAVOR-TIMI study, 16,492 patients with T2DM and risk factors for CVD or prior cardiovascular events were randomized to saxagliptin or placebo and were followed up for a median of 2.1 years.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> The primary endpoint (cMACE) occurred in 7.3% of the patients treated with saxagliptin and in 7.2% of those treated with placebo (HR: 1.00; 95% CI: 0.89–1.12). An unexpected finding in this study was that more patients were admitted to hospital for heart failure (HF) in the saxagliptin arm (3.5% and 2.8% respectively; HR: 1.27; 95% CI: 1.07–1.51), although this was not associated with increased mortality. In the EXAMINE study, 5380 patients with T2DM and a history of myocardial infarction or hospitalization for unstable angina were randomized to alogliptin or placebo added to prior antidiabetic treatment and followed up for a median of 18 months.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a> An event included in the primary endpoint (cMACE) occurred in 11.3% of the patients randomized to alogliptin and 11.8% of the placebo patients (HR: 0.96; upper limit of confidence interval 1.16; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 for non inferiority). There was no difference in the hospitalization rates for HF (3.1% vs 2.9%). Finally, in the TECOS study, 14,671 patients with T2DM and established CVD were randomized to sitagliptin or placebo (added to their regular treatment) and followed up for a median of three years.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a> cMACE occurred in 11.4% of the patients treated with sitagliptin and in 11.6% of the placebo patients (HR: 0.98; 95% CI: 0.89–1.08). No difference was found either in the hospitalization rates for HF (3.1% vs 3.1%). The results of studies with DPP-4 inhibitors have promoted a greater attention to the relationship between T2DM and HF, whose pathophysiological mechanisms are poorly known.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">14</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">GLP-1 RAs were tested in the ELIXA study. In this study, 6608 patients with T2DM and a recent acute coronary event were randomized to lixisenatide or placebo and were followed up for a median of 25 months.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">15</span></a> The primary endpoint (death for CVD, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina) occurred in 13.4% of patients treated with lixisenatide and in 13.2% of placebo patients (HR: 1.02; 95% CI: 0.89–1.17). There were also no differences in other secondary endpoints including hospitalization for HF (4.2% vs 4%).</p><p id="par0020" class="elsevierStylePara elsevierViewall">The most recent of these studies is the so-called EMPA-REG OUTCOME trial. In this study, 7020 patients with T2DM and prior CVD were randomized to empagliflozin (10 or 25<span class="elsevierStyleHsp" style=""></span>mg/day) or placebo (added to their regular treatment) and followed up for a median of 3.1 years.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">16</span></a> The primary endpoint (cMACE) was significantly reduced (RRR: 14%) in the group treated with empagliflozin when both empagliflozin doses were assessed together (10.5% vs 12.1%, HR: 0.86; 95% CI: 0.74–0.99). A significant reduction was also seen in cardiovascular mortality (3.7% vs 59%, RRR: 38%), hospitalization for HF (2.7% vs 4.1%, RRR: 35%), and all-cause mortality (5.7% vs 8.3%, RRR: 32%). However, there were no significant differences in the rates of non-fatal myocardial infarction and non-fatal stroke. This study has had a great impact due to the consistency of the results on cardiovascular and all-cause mortality. The benefits of empagliflozin were seen early in the EMPA-REG study and were maintained throughout follow-up in a population mostly treated with statins and antihypertensive medication. A debate as to whether empagliflozin is an effective drug for the secondary prevention of CVD in patients with T2DM is now underway. The lack of efficacy for the reduction of non-fatal myocardial infarction and stroke fans the flames of controversy. In this regard, the favorable effects of empagliflozin on the hospitalization rate for HF are of great interest and very different from the effects reported for other antidiabetic drugs. It may be interpreted that empagliflozin is effective as regards an improved prognosis in patients with T2DM who have experienced a cardiovascular event. The number of patients it was necessary to treat to prevent one death during a three year period was 39 with empagliflozin, much lower than that reported for other drugs such as ramipril or simvastatin. The results of the EMPA-REG study should however be interpreted with caution when assessing the impact of the drug on the management of patients with T2DM and its complications. The results discussed raise new questions related to the generalization of benefits to populations with a lower risk of CVD, or as to whether these findings represent a potential class effect of SGLT2 inhibitors.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The overall assessment of clinical trials on CVD outcomes in diabetes conducted under the new FDA regulations and reported to date leaves us with a reassuring message regarding the cardiovascular safety of these drug interventions. However, detailed analysis, including specific outcomes such as HF, undoubtedly raises significant unanswered questions. The results of additional ongoing studies that should provide relevant information about this problem will be reported in the coming years. The drugs being assessed include DDP4 inhibitors such as linagliptin, GLP-1 RAs such as liraglutide, exenatide, dulaglutide and semaglutide, and SGLT2 inhibitors such as dapagliflozin and canagliflozin. Thus, the final word as to the ability of antidiabetic drugs to prevent CVD and its consequences in patients with diabetes should await the results of long-term clinical trials in patients with different risk levels using treatment approaches that optimize blood glucose control, minimize the risk of hypoglycemia, and prevent weight gain.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Muñoz Torres M, Muñoz Garach A. Ensayos clínicos de resultados de enfermedad cardiovascular en diabetes. Endocrinol Nutr. 2016;63:317–319.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes and atherosclerosis: epidemiology, pathophysiology, and management" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.A. Beckman" 1 => "M.A. Creager" 2 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 9 | 3 | 12 |
| 2024 September | 38 | 5 | 43 |
| 2024 August | 33 | 3 | 36 |
| 2024 July | 12 | 5 | 17 |
| 2024 June | 17 | 4 | 21 |
| 2024 May | 18 | 2 | 20 |
| 2024 April | 18 | 16 | 34 |
| 2024 March | 50 | 7 | 57 |
| 2024 February | 23 | 6 | 29 |
| 2024 January | 16 | 5 | 21 |
| 2023 December | 23 | 4 | 27 |
| 2023 November | 19 | 8 | 27 |
| 2023 October | 32 | 11 | 43 |
| 2023 September | 24 | 4 | 28 |
| 2023 August | 11 | 3 | 14 |
| 2023 July | 16 | 4 | 20 |
| 2023 June | 8 | 1 | 9 |
| 2023 May | 10 | 9 | 19 |
| 2023 April | 13 | 3 | 16 |
| 2023 March | 16 | 4 | 20 |
| 2023 February | 16 | 4 | 20 |
| 2023 January | 13 | 5 | 18 |
| 2022 December | 26 | 5 | 31 |
| 2022 November | 26 | 3 | 29 |
| 2022 October | 32 | 12 | 44 |
| 2022 September | 23 | 7 | 30 |
| 2022 August | 19 | 8 | 27 |
| 2022 July | 12 | 6 | 18 |
| 2022 June | 16 | 8 | 24 |
| 2022 May | 18 | 7 | 25 |
| 2022 April | 15 | 14 | 29 |
| 2022 March | 26 | 6 | 32 |
| 2022 February | 17 | 6 | 23 |
| 2022 January | 36 | 9 | 45 |
| 2021 December | 47 | 23 | 70 |
| 2021 November | 40 | 10 | 50 |
| 2021 October | 43 | 15 | 58 |
| 2021 September | 48 | 18 | 66 |
| 2021 August | 49 | 14 | 63 |
| 2021 July | 24 | 10 | 34 |
| 2021 June | 31 | 21 | 52 |
| 2021 May | 56 | 13 | 69 |
| 2021 April | 149 | 19 | 168 |
| 2021 March | 76 | 10 | 86 |
| 2021 February | 70 | 18 | 88 |
| 2021 January | 57 | 10 | 67 |
| 2020 December | 52 | 9 | 61 |
| 2020 November | 46 | 17 | 63 |
| 2020 October | 18 | 4 | 22 |
| 2020 September | 27 | 10 | 37 |
| 2020 August | 20 | 6 | 26 |
| 2020 July | 23 | 7 | 30 |
| 2020 June | 16 | 7 | 23 |
| 2020 May | 32 | 19 | 51 |
| 2020 April | 29 | 8 | 37 |
| 2020 March | 23 | 7 | 30 |
| 2020 February | 30 | 12 | 42 |
| 2020 January | 29 | 8 | 37 |
| 2019 December | 27 | 6 | 33 |
| 2019 November | 20 | 5 | 25 |
| 2019 October | 22 | 5 | 27 |
| 2019 September | 31 | 10 | 41 |
| 2019 August | 18 | 4 | 22 |
| 2019 July | 17 | 14 | 31 |
| 2019 June | 20 | 14 | 34 |
| 2019 May | 82 | 30 | 112 |
| 2019 April | 36 | 9 | 45 |
| 2019 March | 15 | 2 | 17 |
| 2019 February | 27 | 8 | 35 |
| 2019 January | 28 | 1 | 29 |
| 2018 December | 22 | 2 | 24 |
| 2018 November | 42 | 6 | 48 |
| 2018 October | 19 | 3 | 22 |
| 2018 September | 40 | 3 | 43 |
| 2018 August | 11 | 2 | 13 |
| 2018 July | 17 | 2 | 19 |
| 2018 June | 12 | 0 | 12 |
| 2018 May | 12 | 1 | 13 |
| 2018 April | 11 | 1 | 12 |
| 2018 March | 8 | 0 | 8 |
| 2018 February | 11 | 0 | 11 |
| 2018 January | 17 | 1 | 18 |
| 2017 December | 14 | 0 | 14 |
| 2017 November | 11 | 1 | 12 |
| 2017 October | 11 | 1 | 12 |
| 2017 September | 14 | 4 | 18 |
| 2017 August | 15 | 2 | 17 |
| 2017 July | 9 | 0 | 9 |
| 2017 June | 13 | 12 | 25 |
| 2017 May | 18 | 9 | 27 |
| 2017 April | 17 | 10 | 27 |
| 2017 March | 30 | 49 | 79 |
| 2017 February | 49 | 6 | 55 |
| 2017 January | 1 | 1 | 2 |
| 2016 November | 0 | 1 | 1 |
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