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Hypoglycaemia and cardiovascular disease. The fatal linkage
Hipoglucemia y enfermedad cardiovascular. Una asociación fatal
Ignacio Conget
Diabetes Unit, Endocrinology Department, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Hospital Clínic, Barcelona, Spain
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The fatal linkage" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "39" "paginaFinal" => "41" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Ignacio Conget" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Ignacio" "apellidos" => "Conget" "email" => array:1 [ 0 => "iconget@clinic.ub.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Diabetes Unit, Endocrinology Department, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Hospital Clínic, Barcelona, Spain" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hipoglucemia y enfermedad cardiovascular. Una asociación fatal" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0010" class="elsevierStylePara elsevierViewall">Cardiovascular disease (CVD) represents the major cause of morbidity and mortality in subjects with both type 2 (T2D) and type 1 diabetes mellitus (T1D).<a class="elsevierStyleCrossRefs" href="#bb0005"><span class="elsevierStyleSup">1–3</span></a> Patients with diabetes have a shorter life expectancy when compared with individuals without the disease and this excess mortality is largely due to accelerated atherosclerotic processes.</p><p id="p0015" class="elsevierStylePara elsevierViewall">Hypoglycaemia associated with glucose-lowering therapy represents a significant barrier to successful treatment of diabetes and it causes recurrent morbidity in most people with the disease.<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> Moreover, it is an obstacle to the maintenance of euglycemia over a lifetime and thus precludes euglycemia's long-term benefits.<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> There is no doubt that glucose management, particularly if intensive, is related to an increased risk of non-severe and severe episodes of hypoglycaemia in patients with T1D and this is also the case for patients with T2D, especially in those insulin-treated.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">The latest results derived from several recent large randomised clinical trials performed in subjects with T2D aimed to evaluate the effect of improving glycemic control in CVD have raised the cocern that severe hypoglycemia may increase the risk of a poor outcome in patients with T2D assigned to an intensive glucose-lowering intervention. In fact, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial was halted due to a significant increase in death and cardiovascular mortality in the intensive treatment arm (from 22 to 35 %).<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a> Whichever the arm allocated, intensive or conventional, those patients with severe hypoglycaemia had a higher mortality risk than those without episodes. However, it should be underlined that in a post hoc analysis, the relative risk of death associated with severe hypoglycaemic episodes was higher in the standard arm (2.87) when compared with intensive strategy (1.28) in spite of a larger number of severe hypoglycaemic episodes in the intensive group. Additionally, data analysis from the same study suggested that the excess mortality in the intensive treatment group was not directly explained by the high rate of episodes of hypoglycaemia. In VADT trial (Veterans Affairs Diabetes Trial), an increased incidence of severe hypoglycaemia was also found in the group receiving intensive treatment of hyperglycemia, but at the end of the study there was no significant difference in CVD events between standard and intensive treatment arms.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a> Considering HbA<span class="elsevierStyleInf">1C</span> goals at the beginning of both studies (more rigorous in VADT) and differences achieved at the end of both trials (− 1.16 and 1.01, VADT and ACCORD, respectively), more intensive glycaemic control regimen could be the explanation for differences in rates of severe hypoglycaemia (16 and 21%, participants with ≥<span class="elsevierStyleHsp" style=""></span>1 episodes during study; ACCORD and VADT, respectively). In addition to this, participant characteristics at baseline (age, disease duration, HbA<span class="elsevierStyleInf">1C</span> and history of macrovascular disease) could be also related with the higher rate of episodes of severe hypoglycaemia observed in VADT trial.</p><p id="p0025" class="elsevierStylePara elsevierViewall">In the one of latest analysis of data from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) the authors also dealt with the relationship between hypoglycaemia and CVD. The results indicated that severe hypoglycaemia was associated with increased risks of microvascular and macrovascular events and death (from both CVD and non CVD causes).<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a> However, this association was markedly attenuated after adjustment for different confounding factors. More recently, Johnston et al. using data from healthcare claims for individuals with employer-sponsored primary or Medicare supplemental insurance claimed for an independent association between ICD-9 CM coded outpatient hypoglycaemic episodes and acute cardiovascular events.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a></p><p id="p0030" class="elsevierStylePara elsevierViewall">Although it could be argued that the association between hypoglycaemia and CVD is because the former is a marker of high risk for adverse clinical outcomes and there is no current full evidence claiming for causality, the total absence of a direct causal link is far from proven. In fact, the response to hypoglycaemia includes direct and indirect changes mainly related to the activation of sympathoadrenal axis (increase in adrenalin and noradrenalin) and counterregulatory hormonal secretion (glucagon, hypothalamopituitary-adrenal-axis) which produces significant changes in the cardiovascular system.<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a> During acute hypoglycaemia there is a rapid proinflammatory, platelet aggregatory, antifibrinolytic and prothrombotic response, as well as, disturbances in normal endothelial function.<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a> There are very recent studies specifically designed to address the effects of acute hypoglycaemia confirming its proinflammatory and prothrombotic effects.<a class="elsevierStyleCrossRefs" href="#bb0065"><span class="elsevierStyleSup">13,14</span></a> The vast majority of these abnormalities are interdependent and due to the activation of sympathoadrenal axis. If recurrent, hypoglycemic episodes may provoke changes in hemostatic factors and viscosity; this might reduce perfusion in diabetic microangiopathy. In addition to this, repeated hypoglycaemia throughout life could potentially aggravate atherosclerosis processes and increase the cardiovascular risk, particularly of those most vulnerable subjects.</p><p id="p0035" class="elsevierStylePara elsevierViewall">Normal hemodynamic response to hypoglycemia includes an increase in heart rate, an increase in systolic and a small decrease in diastolic blood pressure which is due to the sympathetic neural activation. There are several reports showing low glucose values causing ST wave changes with QT interval and cardiac repolarization prolongation.<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a> Recently, these changes in QT, as well as, rhythm disturbances have been described in response to nocturnal hypoglycemia in ambulant patients with T1D, which may support the idea of an arrhythmic basis for “death in bed syndrome.<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> Moreover, performing 24-hour monitoring of subcutaneous glucose level using continuous glucose monitoring and simultaneous ambulatory blood pressure measurement in a group of patients with T1D and T2D, Feldman-Billard et al. demonstrated a close temporal relationship between low values of glucose measurements and an increase in blood pressure.<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a> There are also reports indicating temporal relationship between acute cardiac events (acute coronary syndromes, angina…) and hypoglycaemia.<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a> Moreover, the association of a higher mortality rate and hypoglycaemia in critically ill patients has also emerged from large multicenter randomised trials.<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a> Although the development of hypoglycaemia in critical illness could be a surrogate marker for severity, it may also contribute to the fatal result.</p><p id="p0040" class="elsevierStylePara elsevierViewall">The relationship between hypoglycaemia and atherosclerosis in T1D subjects has been recently investigated. In comparison with a control group of patients without, subjects with repeated hypoglycaemia displayed impairment in endothelial function and higher values of carotid/femoral intima media thickness.<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a> Though preliminary, these results pointed towards repeated hypoglycaemia as an aggravating factor for preclinical atherosclerosis. However, the intrinsic limitations of this type of study do not allow for blaming repeated hypoglycaemia as an independent risk factor for CVD and extrapolate any causal association.</p><p id="p0045" class="elsevierStylePara elsevierViewall">In summary, current available information confirms that non severe and severe hypoglycaemia is a far from uncommon adverse event in T1D and T2D especially in patients under an intensive management of glucose levels. In the short term, hypoglycaemia may precipitate and aggravate a vascular event during an acute episode. In the long term, especially if repeated, it could be related, theoretically, to the induction and progression of atherosclerosis. An association between hypoglycaemia and adverse clinical events, mainly cardiovascular, has been claimed in some studies. However, although direct causality can not be completely excluded, for the moment, current data suggest that hypoglycaemia could merely identify more vulnerable patients. From a practical point of view, it seems essential not only to place glucose within normal values, but also to avoid hypoglycaemia. From the clinical research perspective, specific trials aimed to investigate on mechanisms linking hypoglycaemia and CVD are required.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1." 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Frier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc10-0013" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2010" "volumen" => "33" "paginaInicial" => "1591" "paginaFinal" => "1597" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20587725" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bb0075" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms of abnormal cardiac repolarization during insulin- induced hypoglycemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.T. Robinson" 1 => "N.D. Harris" 2 => "R.H. Ireland" 3 => "S. Lee" 4 => "C. Newman" 5 => "S.R. Heller" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "2003" "volumen" => "52" "paginaInicial" => "1469" "paginaFinal" => "1474" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12765959" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bb0080" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes--the ‘dead in bed’ syndrome revisited" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G.V. Gill" 1 => "A. Woodward" 2 => "I.F. Casson" 3 => "P.J. Weston" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-008-1177-7" "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "2009" "volumen" => "52" "paginaInicial" => "42" "paginaFinal" => "45" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18972096" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bb0085" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypoglycemia-induced blood pressure elevation in patients with diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Feldman-Billard" 1 => "P. Massin" 2 => "T. Meas" 3 => "P.J. Guillausseau" 4 => "E. Heron" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/archinternmed.2010.98" "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "2010" "volumen" => "170" "paginaInicial" => "829" "paginaFinal" => "831" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20458093" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bb0090" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Case Report Hypoglycaemia-induced myocardial infarction as a result of sulphonylurea misuse" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "B.T. Corley" 1 => "C. Davenport" 2 => "L. Delaney" 3 => "M. Hatunic" 4 => "D. Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:2 [ "tituloSerie" => "Diabet Med" "fecha" => "2010" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bb0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.E. Griesdale" 1 => "R.J. De Souza" 2 => "R.M. Van Dam" 3 => "D.K. Heyland" 4 => "D.J. Cook" 5 => "A. Malhotra" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1503/cmaj.090206" "Revista" => array:6 [ "tituloSerie" => "CMAJ" "fecha" => "2009" "volumen" => "180" "paginaInicial" => "821" "paginaFinal" => "827" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19318387" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bb0100" "etiqueta" => "20." 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Pare" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc10-1371" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2011" "volumen" => "34" "paginaInicial" => "198" "paginaFinal" => "203" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20929996" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/11343230/0000002700000002/v1_201305021324/S1134323011700060/v1_201305021324/en/main.assets" "Apartado" => array:4 [ "identificador" => "7313" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/11343230/0000002700000002/v1_201305021324/S1134323011700060/v1_201305021324/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1134323011700060?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 0 | 2 |
| 2024 October | 17 | 2 | 19 |
| 2024 September | 18 | 2 | 20 |
| 2024 August | 21 | 1 | 22 |
| 2024 July | 12 | 3 | 15 |
| 2024 June | 10 | 1 | 11 |
| 2024 May | 11 | 2 | 13 |
| 2024 April | 8 | 3 | 11 |
| 2024 March | 12 | 9 | 21 |
| 2024 February | 25 | 8 | 33 |
| 2024 January | 16 | 1 | 17 |
| 2023 December | 14 | 1 | 15 |
| 2023 November | 21 | 7 | 28 |
| 2023 October | 11 | 7 | 18 |
| 2023 September | 5 | 1 | 6 |
| 2023 August | 9 | 4 | 13 |
| 2023 July | 7 | 4 | 11 |
| 2023 June | 3 | 2 | 5 |
| 2023 May | 8 | 6 | 14 |
| 2023 April | 3 | 5 | 8 |
| 2023 March | 4 | 1 | 5 |
| 2023 February | 6 | 2 | 8 |
| 2023 January | 6 | 5 | 11 |
| 2022 December | 15 | 4 | 19 |
| 2022 November | 11 | 6 | 17 |
| 2022 October | 12 | 15 | 27 |
| 2022 September | 7 | 10 | 17 |
| 2022 August | 15 | 8 | 23 |
| 2022 July | 9 | 7 | 16 |
| 2022 June | 9 | 8 | 17 |
| 2022 May | 12 | 11 | 23 |
| 2022 April | 10 | 12 | 22 |
| 2022 March | 11 | 10 | 21 |
| 2022 February | 8 | 3 | 11 |
| 2022 January | 13 | 10 | 23 |
| 2021 December | 5 | 12 | 17 |
| 2021 November | 8 | 9 | 17 |
| 2021 October | 13 | 10 | 23 |
| 2021 September | 7 | 5 | 12 |
| 2021 August | 5 | 4 | 9 |
| 2021 July | 6 | 5 | 11 |
| 2021 June | 7 | 9 | 16 |
| 2021 May | 8 | 7 | 15 |
| 2021 April | 18 | 8 | 26 |
| 2021 March | 12 | 4 | 16 |
| 2021 February | 10 | 11 | 21 |
| 2021 January | 3 | 6 | 9 |
| 2020 December | 8 | 6 | 14 |
| 2020 November | 4 | 6 | 10 |
| 2020 October | 8 | 6 | 14 |
| 2020 September | 6 | 7 | 13 |
| 2020 August | 6 | 11 | 17 |
| 2020 July | 8 | 5 | 13 |
| 2020 June | 7 | 9 | 16 |
| 2020 May | 5 | 6 | 11 |
| 2020 April | 7 | 3 | 10 |
| 2020 March | 7 | 5 | 12 |
| 2020 February | 5 | 5 | 10 |
| 2020 January | 4 | 4 | 8 |
| 2019 December | 10 | 2 | 12 |
| 2019 November | 2 | 4 | 6 |
| 2019 October | 1 | 4 | 5 |
| 2019 September | 4 | 2 | 6 |
| 2019 August | 2 | 0 | 2 |
| 2019 July | 2 | 8 | 10 |
| 2019 June | 14 | 36 | 50 |
| 2019 May | 37 | 39 | 76 |
| 2019 April | 4 | 11 | 15 |
| 2019 March | 1 | 2 | 3 |
| 2019 February | 3 | 8 | 11 |
| 2019 January | 0 | 0 | 0 |
| 2018 December | 2 | 3 | 5 |
| 2018 November | 2 | 4 | 6 |
| 2018 October | 9 | 8 | 17 |
| 2018 September | 1 | 0 | 1 |
| 2018 August | 6 | 3 | 9 |
| 2018 July | 6 | 2 | 8 |
| 2018 June | 5 | 1 | 6 |
| 2018 May | 2 | 0 | 2 |
| 2018 April | 2 | 1 | 3 |
| 2018 March | 2 | 1 | 3 |
| 2018 February | 2 | 0 | 2 |
| 2018 January | 5 | 0 | 5 |
| 2017 December | 4 | 0 | 4 |
| 2017 November | 10 | 0 | 10 |
| 2017 October | 2 | 3 | 5 |
| 2017 September | 4 | 0 | 4 |
| 2017 August | 3 | 0 | 3 |
| 2017 July | 2 | 2 | 4 |
| 2017 June | 3 | 0 | 3 |
| 2017 May | 6 | 3 | 9 |
| 2017 April | 8 | 1 | 9 |
| 2017 March | 6 | 35 | 41 |
| 2017 February | 3 | 4 | 7 |
| 2017 January | 2 | 1 | 3 |
| 2016 December | 7 | 1 | 8 |
| 2016 November | 15 | 0 | 15 |
| 2016 October | 13 | 4 | 17 |
| 2016 September | 8 | 1 | 9 |
| 2016 August | 12 | 2 | 14 |
| 2016 July | 11 | 3 | 14 |
| 2016 June | 27 | 9 | 36 |
| 2016 May | 21 | 22 | 43 |
| 2016 April | 23 | 12 | 35 |
| 2016 March | 34 | 17 | 51 |
| 2016 February | 26 | 11 | 37 |
| 2016 January | 23 | 23 | 46 |
| 2015 December | 25 | 15 | 40 |
| 2015 November | 16 | 11 | 27 |
| 2015 October | 16 | 35 | 51 |
| 2015 September | 16 | 6 | 22 |
| 2015 August | 21 | 5 | 26 |
| 2015 July | 16 | 7 | 23 |
| 2015 June | 6 | 1 | 7 |
| 2015 May | 11 | 4 | 15 |
| 2015 April | 16 | 11 | 27 |
| 2015 March | 10 | 2 | 12 |
| 2015 February | 41 | 2 | 43 |
| 2015 January | 34 | 1 | 35 |
| 2014 December | 29 | 15 | 44 |
| 2014 November | 20 | 2 | 22 |
| 2014 October | 26 | 3 | 29 |
| 2014 September | 29 | 2 | 31 |
| 2014 August | 23 | 2 | 25 |
| 2014 July | 43 | 2 | 45 |
| 2014 June | 32 | 2 | 34 |
| 2014 May | 30 | 4 | 34 |
| 2014 April | 14 | 0 | 14 |
| 2014 March | 36 | 5 | 41 |
| 2014 February | 38 | 3 | 41 |
| 2014 January | 23 | 7 | 30 |
| 2013 December | 37 | 2 | 39 |
| 2013 November | 24 | 2 | 26 |
| 2013 October | 42 | 1 | 43 |
| 2013 September | 37 | 3 | 40 |
| 2013 August | 52 | 4 | 56 |
| 2013 July | 33 | 4 | 37 |
| 2011 March | 929 | 0 | 929 |
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