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Severe iatrogenic hypoglycaemia requiring medical assistance is associated with concurrent prolongation of the QTc interval
Journal Pre-proofs Severe iatrogenic hypoglycaemia requiring medical assistance is associated with concurrent prolongation of the QTc interval Maria Mylona, Stavros Liatis, Georgios Anastasiadis, Christos Kapelios, Alexander Kokkinos PII: DOI: Reference:
S0168-8227(19)31394-4 https://doi.org/10.1016/j.diabres.2020.108038 DIAB 108038
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
8 October 2019 3 January 2020 27 January 2020
Please cite this article as: M. Mylona, S. Liatis, G. Anastasiadis, C. Kapelios, A. Kokkinos, Severe iatrogenic hypoglycaemia requiring medical assistance is associated with concurrent prolongation of the QTc interval, Diabetes Research and Clinical Practice (2020), doi: https://doi.org/10.1016/j.diabres.2020.108038
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier B.V.
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Severe iatrogenic hypoglycaemia requiring medical assistance is associated with concurrent prolongation of the QTc interval 1
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Maria Mylona , Stavros Liatis , Georgios Anastasiadis , Christos Kapelios , Alexander Kokkinos 1
Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National
and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece 2
1
Department of Cardiology, Laiko Hospital, Athens, Greece
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Structured Abstract Aims: Hypoglycaemia has been shown to exert arrhythmogenic effects. Herein, we explore the association between severe hypoglycaemia requiring medical assistance and the length of the QT interval in patients with diabetes. Methods: Data from a prospective study, conducted in eight tertiary hospitals, which recorded cases of hypoglycaemia from patients with diabetes seeking treatment at emergency departments (ED) were analyzed. The patients’ electrocardiograms (ECGs), were compared to those of non-hypoglycaemic diabetic individuals, matched for age, gender and duration of diabetes, obtained during their scheduled follow-up visits. The corrected QT intervals (QTc) were calculated blindly by two cardiologists. Results: ECGs from 154 patients presenting with hypoglycaemia were analyzed and compared to 95 matched controls. The mean QTc interval was significantly longer in patients with hypoglycaemia than in controls (441.9±48.2 vs. 401.0±29.6 msec, p<0.001) A significantly higher proportion of hypoglycaemic patients had an abnormally prolonged QTc (≥440 msec) compared to controls (49.4% vs. 11.6%, p<0.001). Among patients with hypoglycaemia, there was a statistically significant but rather weak negative correlation between QTc interval and plasma glucose at presentation (r: -0.183, p=0.02). Conclusions: In diabetic patients, hypoglycemia requiring medical assistance is associated with a significant prolongation of the QTc interval. The degree of this prolongation is associated with hypoglycaemia severity.
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Introduction Hypoglycaemia in patients with diabetes usually results as a consequence of glucoselowering management with certain medications and is referred to as iatrogenic hypoglycaemia. Severe hypoglycaemia is defined as any hypoglycaemia that the patient is unable to self-treat and requires the assistance of another person. A subdivision of this category concerns the cases requiring medical assistance. [1,2] It has been repeatedly shown that severe hypoglycaemia is associated with increased mortality,[3],[4],[5] the association being attributed both to causal relationship but also to the confounding effect of increased co-morbidity and frailty.[6] Acute hypoglycaemia can lead to health damage either directly (e.g., through deleterious effects of low blood glucose supply to the brain) or indirectly, usually via trauma due to impaired consciousness or seizures. Acute health damage, including sudden death may also be the result of cardiovascular events, including myocardial ischemia and/or cardiac arrhythmias.[1] The physiologic reactions aiming to maintain glucose supply to the brain during hypoglycaemia are mainly induced by counter-regulatory hormone secretion (glucagon, cortisol, growth hormone and epinephrine) among which, epinephrine has been mainly implicated in promoting alterations of ventricular repolarization and promote QTc (QT corrected for heart rate) interval prolongation.[1] Indeed, the association between hypoglycaemia and QT prolongation has been demonstrated in experimental animals[7] and in patients with diabetes, both during hyperinsulinaemic glucose clamp[8] and real-life conditions using simultaneous electrocardiogram (ECG) and continuous glucose monitoring recordings.[9–11] To our knowledge, however, very limited data exist regarding the length of QT interval during severe hypoglycaemia, when the patient is unable to self-treat the condition and needs the assistance of a third person. More specifically, only in one retrospective Japanese study it was found that 50% of patients with type 1 diabetes and 60% of those with type 2 diabetes admitted at the emergency department of a single medical centre in Tokyo, presented with an abnormally prolonged QT interval.[12] The aim of the present study is to prospectively explore the association between severe hypoglycaemic events requiring medical assistance and QT interval length in patients with diabetes, as well as to investigate for arrhythmic events and factors possibly related to QT prolongation in such patients.
Subjects, materials and methods
4 We used data from a multicentre study from eight hospitals (nine clinics), in five cities of Greece, which participated in a prospective survey of documented iatrogenic hypoglycaemic episodes in patients admitted at the emergency department (ED)[13]. The design of the study has been previously described in detail.[13] In brief, all patients with diabetes consecutively admitted at the ED and diagnosed with hypoglycaemia were included. Diagnosis of hypoglycaemia was established by the ED attending physician at each participating hospital on the basis of the presence of Whipple’s triad: symptoms/signs compatible with low blood glucose concentration; low plasma glucose levels (<70 mg/dL); and resolution of symptoms after increasing blood glucose levels. For every hypoglycaemic case, information regarding the history and type of diabetes, presence of comorbidities, types of medications taken, time and circumstances under which the event occurred and history of any previous serious hypoglycaemic episode(s) were recorded on a pre-specified form. In addition, a standard 12-lead ECG was obtained at presentation or soon after the management of hypoglycaemia and no later than 30 minutes after the administration of glucose. The ECGs obtained from hypoglycaemic patients were compared to those performed in a group of non-hypoglycaemic patients with diabetes, matched for age, gender and duration of diabetes, during their scheduled follow-up visit at the outpatient diabetes clinics of the same hospitals, during the study time period. The ECGs were reviewed for rhythm analysis and measurements by two independent cardiologists. The QT and RR intervals were measured blindly. The maximum corrected (accounting for heart rate) QT interval (QTc) was calculated according to the Bazett formula: QTc = QT interval/square root of the R-R interval (QTc =QT/√RR). QTc measurements of ≥440 msec were considered as abnormally prolonged and those of ≥500 msec as highly prolonged[14]. ECGs from patients wearing a pacemaker, those receiving medications possibly affecting the QTc length and those with hypokalemia (serum potassium <3.5 mEq/l) or atrial fibrillation were excluded from the analysis. A full qualitative assessment of the ECGs was also performed blindly by the same cardiologists. Tachyarrhythmias were classified as a) torsades de pointes, b) ventricular tachycardia, 3) ventricular fibrillation and 4) atrial fibrillation. Bradyarrhythmias were defined as 1) pauses >2.5 sec and 2) atrioventricular block. Atrial and ventricular premature beats and complexes were also documented and analyzed. Data are presented as n (%), mean (SD), or, in the case of skewed variables, as median with the lower and upper ends of the interquartile range (IQR). The one-sample KolmogorovSmirnov test was used in order to examine the normality of distributions. Continuous variables were compared between groups using two-sided student's t test (for normally
5 distributed variables) or Mann-Whitney U test (for skewed variables). Categorical variables were compared using x2 test. Linear regression was used to test for simple correlations between normally distributed continuous variables. P values of ≤0.05 were considered statistically significant for all tests. All analyses were performed using SPSS package software, version 21.
Results During a 16-month period, 295 hypoglycaemic episodes in 294 admitted patients were recorded[13]. The majority were patients with T2D (268, 90.8%), while there were also 26 patients with type 1 diabetes (T1D). In 34 cases from a single centre, ECGs were not available due to hospital regulations. In addition, another 76 ECGs were excluded for a variety of reasons, as described in Table 1. We further excluded 31 ECGs due to concomitant hypokalemia, a condition also known to prolong QTc. Therefore, at the end, 154 ECGs from 154 patients with hypoglycaemia and 95 ECGs from 95 age and sex matched controls were available for the present analysis. The main demographic and clinical characteristics of patients and control individuals are presented in Table 2. There were no statistically significant differences between the two groups in terms of age, gender distribution and duration of diabetes. However, controls received less frequently sulfonylureas and more frequently metformin and DPP-4 inhibitors than hypoglycaemic patients (Table 2). The distribution of the QTc variable was normal across both groups. The mean QTc interval in patients with hypoglycaemia was 441.9 [48.2] msec versus 401.0 [29.6] msec in the control group, a difference of high statistical significance (p<0.001) (Figure 1). Seventy-six patients with hypoglycaemia (49.4%) presented with abnormally prolonged (>440 msec) QTc interval (mean value: 480.1 [34.5] msec), versus 11 patients (11.6%, mean value 451.5 [8.5] msec) in the control group (p<0.001). A very prolonged QTc interval (>500 msec) was calculated in 16 (10.4%) ECGs from hypoglycaemic patients whereas none was found among controls (Table 3). Among patients with hypoglycaemia, there was a statistically significant negative correlation between QTc interval and plasma glucose at presentation (r: -0.183, p=0.02). Furthermore, patients with QTc prolongation (>440 msec) had lower plasma glucose than those without (36.2 [13.2] mg/dl vs. 40.8 [12.9] mg/dl, p=0.03). Patients with markedly prolonged QTc (>500 msec) presented with even lower plasma glucose (34.5 [11.2] mg/dl). The length of the QTc interval was not related to age, gender, duration of diabetes, type of diabetes, time
6 of the occurrence of hypoglycaemia (day or night) and presence of cardiovascular disease. Patients treated with a sulphonylurea had a numerically lower QTc interval length compared to non-sulphonylurea treated patients: 435.3 [42.3] vs. 449.9 [51.9] msec (p=0.07), a difference that was attenuated when adjusted for blood glucose value: 436.5 [42.6] vs 448.0 [51.4] msec (p=0.1). When patients were divided according to insulin treatment, the opposite picture was obtained, after adjustment for blood glucose value: 448.2 [51.6] msec (insulin treated) vs. 436.1 [42.1] msec (non-insulin treated), p=0.12. In a multivariable linear regression model, QTc length was not associated with the use of any glucose-lowering medication, including insulin, either adjusted for blood glucose levels or not. Two thirds of patients with hypoglycaemia were admitted to the hospital (n=102, 66.3%). QTc interval length was not different between those hospitalized and those who were discharged (436±47.6 msec vs. 448.7±49.1 msec, p=0.14). Only one patient died from cardiac arrest during hospitalization, whose QTc at presentation was 424 msec. Qualitative assessment of the ECGs (Table 4) did not reveal any major tachyarrhythmic disorders in either patients or controls. There was one hypoglycaemic patient presenting with third degree atrioventricular block. There were 16 ECGs from hypoglycaemic patients with at least one ventricular premature beat versus only two in controls. Six hypoglycaemic patients presented with right bundle branch block (RBBB) and three with left bundle branch block (LBBB) while, among controls, no RBBB or LBBB was detected.
Discussion In this prospective study, it was demonstrated that the mean length of the QTc interval was significantly prolonged in patients with diabetes presenting at the emergency department of tertiary hospitals during or soon after a severe hypoglycaemic episode, as compared to nonhypoglycaemic diabetic patients of similar age, sex and duration of diabetes. In addition, the prevalence of abnormal arrhythmic or proarrhythmic ECG manifestations during or soon after hypoglycaemia was higher than in control individuals. The association between the occurrence of severe hypoglycaemia and increased short and long-term morbidity/mortality has been repeatedly observed in the past and has been an issue of controversial interpretation. [15] The core of the controversy lies on whether the association is causal or hypoglycaemia is simply a marker of frailty, which mediates the association. Although the latter hypothesis is undoubtedly true, it has been shown that it may not fully explain this association, strongly supporting a possible direct detrimental
7 effect of hypoglycaemia.[16] A proarrhythmic effect has been implicated as a major mechanism linking hypoglycaemia to adverse outcomes.[17] Low blood glucose causes action potential prolongation by blocking repolarising K+ channels[18], a mechanism commonly observed with proarrhythmic medications.[19] In addition, the catecholamine flood following a hypoglycaemic episode may cause longer QT intervals in experimental animals and in humans, mainly through an increase in intracellular Ca++.[20] Moreover, hypokalemia which may be induced by hyperinsulinaemic hypoglycaemia may also contribute to QTc prolongation and increase the incidence of arrhythmic events.[21] Some studies have suggested that sulphonylureas may affect QTc independently of hypoglycaemia, in relation with the closing of K+ channels [26,27]. In the present study, patients treated with a sulphonylurea had a numerically (but not statistically significant) lower QTc interval length compared to non-sulphonylurea treated patients, a difference that was attenuated after adjustment for blood glucose value (p=0.1). Our results are in accordance with a recent study using continuous glucose monitoring and simultaneous ambulatory electrocardiography in sulphonylurea and insulin-treated patients, which suggested that increased QTc was associated with iatrogenic hypoglycemia rather than sulfonylurea treatment specifically [28]. It has to be noted though that in our study patients were taking several combinations of hypoglycaemic drugs, rendering the investigation of any drug-specific effect on QTc length very difficult. To our knowledge, there is only one previous study that investigated QTc length in patients with diabetes presenting with severe iatrogenic hypoglycaemia. In that study, the investigators retrospectively examined 59,602 cases that presented at the emergency room of a single hospital and identified 414 cases with hypoglycaemia. A QTc measurement was available in 199 cases. Very similarly to our study, they found that 58% of patients (versus 49.4% in the present study) had an abnormally prolonged QTc interval (>440 msec) and 14.4% (versus 10.4% in the present study) a very prolonged one (>500 msec). In the present multicentre study, all cases were identified prospectively, according to a prespecified protocol.[13] This procedure allowed for a proper adjudication of cases with regards to diagnosis, cause(s) and consequences of hypoglycaemia. In addition, in the present study, the ECG findings of hypoglycaemic patients were compared to those of a control group. The latter consisted of patients with diabetes matched for age, gender and duration of disease and the population was recruited from the outpatient clinics of the participating hospitals during a routine visit, when no symptoms or signs of hypoglycaemia were present. Since diabetes itself is a proarrhythmic condition, frequently associated with
8 QTc prolongation and other arrhythmic events[22],[23], the inclusion of non-hypoglycaemic patients with diabetes as controls allowed to account for this confounding factor. The exclusion of patients presenting with low potassium levels might underestimate the role of hypoglycaemia-induced QTc prolongation in this analysis. However, since we aimed to isolate -as much as possible- the role of low blood glucose levels in inducing QTc prolongation, we preferred to exclude this confounder. In this way, the potassiumindependent QTc prolongation that was observed in the present analysis further enhances the notion of causality between severe hypoglycaemia and QTc prolongation. To this direction, the statistically significant correlation between the degree of low blood glucose levels and the extent of QTc interval length which was observed in the present analysis, although relatively weak, leaves little doubt about a causal effect of hypoglycaemia on QTc prolongation. Importantly, to our knowledge, it is the first time that this observation is described in humans under real-life conditions. The clear difference in QTc interval length between severely hypoglycaemic patients and controls is of great clinical significance. Previous studies in patients with type 2 diabetes, during continuous and simultaneous recordings of ECG and subcutaneous glucose levels have shown that QTc length was prolonged during periods of low glucose levels, with mean values ranging substantially and depending on type of diabetes, time of day and study [9– 11]. In those studies, arrhythmias were detected more frequently during low-glucose than during normal-glucose periods. Most low-glucose periods were asymptomatic and literal hypoglycaemia was actually not confirmed, since glucose was measured in the subcutaneous tissue. The present study differs substantially from the above-mentioned observations in that all cases of hypoglycaemia were symptomatic and patients sought hospital assistance for an emergency condition. Several arrhythmic disorders were detected in the qualitative ECG assessment of the present analysis. Of note, sinus bradycardia was detected in 13 patients (8.5%), a proportion similar to that in controls (7.4%). Although sinus bradycardia was a prominent finding during hypoglycaemia in studies of simultaneous ECG/interstitial glucose monitoring, it was mainly detected during night periods of asymptomatic drops in interstitial glucose levels. The investigators hypothesized that such bradycardic episodes might be attributed to increased vagal counteraction [9,24]. However, it has to be noted that apart from a few case reports, bradycardia is an uncommonly reported manifestation of severe hypoglycaemia.[25] On the other hand, we found several cases of ventricular premature beats (VPC) (10.4% of patients), a number clearly higher than in controls (2.1%), but without any episodes of ventricular
9 tachycardia in either patients or controls. Since VPCs are more likely to occur in older individuals and patients with comorbidities, their more frequent presence in the hypoglycemic cohort might be, apart from a result of increased epinephrine load, simply a marker of frailty. One hypoglycaemic patient presented with third degree atrioventricular block. One patient died from prolonged hypoglycaemia (asystole). The main strengths of the present study include its prospective and multicentre design, the opportunity to analyze ECGs from severely hypoglycaemic individuals under real-life conditions and the possibility to compare the ECG findings to those of matched diabetic patients without hypoglycaemia who served as controls. Nevertheless, our study has some limitations: first, some important clinical aspects of the hypoglycaemic cases are missing, such as a detailed medical history, socioeconomic status and HbA1c value; second, the exact timing of the ECG recordings in relation to the diagnosis and management of hypoglycaemia is not available; third, the ECG recordings are those that are usually obtained in routine clinical practice of an emergency department, hence they are of short duration and not suitable for a thorough study of heart rhythm; and fourth, ECGs after recovery from hypoglycaemia are not available. The study protocol was based on standard clinical practice applied in emergency departments of the participating hospitals, which did not generally perform additional ECGs, unless specifically indicated. In conclusion, the present study has demonstrated that patients with diabetes presenting with iatrogenic hypoglycaemia at the emergency department of tertiary hospitals have a clinically and statistically prolonged QTc interval while, at the same time, the degree of QTc prolongation is associated with the profoundness of hypoglycaemia. Although not many cases with arrhythmic disorders were detected in the present analysis, the proarrhythmic nature of severe hypoglycaemia in patients with diabetes has been confirmed under real-life conditions, a fact emphasizing the importance of preventive measures against hypoglycaemia in this population.
Acknowledgements Stavroula Kalopita, Athanasia Papazafiropoulou, Spyros Karamagkiolis, Andreas Melidonis, Apostolos Xilomenos, Ioannis Ioannidis, Gregory Kaltsas, Leonidas Lanaras, Christos Basagiannis, Stavros Pappas, Kanellina Zerva, Konstantinos Tsakalis. The abovementioned investigators are acknowledged for their contribution in the study conduction, collection and transfer of the data at each participating hospital.
10 Conflict of interest and funding The authors declare no conflict of interest or funding from any source.
References [1]
Liatis S, Katsilambros N. Hypoglycemia caused by Insulin. 2011. https://doi.org/10.1002/9781119971825.ch4.
[2]
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: A report of aworkgroup of the American diabetes association and the endocrine society. Diabetes Care 2013;36:1384–95. https://doi.org/10.2337/dc122480.
[3]
Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: Retrospective epidemiological analysis of the ACCORD study. BMJ 2010. https://doi.org/10.1136/bmj.b4909.
[4]
Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010. https://doi.org/10.1056/NEJMoa1003795.
[5]
Pieber TR, Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, et al. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia 2018. https://doi.org/10.1007/s00125-017-4422-0.
[6]
Misra-Hebert AD, Pantalone KM, Ji X, Milinovich A, Dey T, Chagin KM, et al. Patient characteristics associated with severe hypoglycemia in a type 2 diabetes cohort in a large, integrated health care system from 2006 to 2015. Diabetes Care 2018. https://doi.org/10.2337/dc17-1834.
[7]
Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes 2013. https://doi.org/10.2337/db13-0216.
[8]
Marques JLB, George E, Peacey SR, Harris ND, Macdonald IA, Cochrane T, et al. Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med 1997. https://doi.org/10.1002/(SICI)1096-9136(199708)14:8<648::AIDDIA418>3.0.CO;2-1.
11 [9]
Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014. https://doi.org/10.2337/db13-0468.
[10]
Makrilakis K, Stathi C, Vlahodimitris I, Kalopita S, Thomakos P, Konstantopoulos P, et al. Hypoglycaemia causes both daytime and nighttime QTc interval prolongation in patients with type 2 diabetes receiving insulin treatment. Diabetes Metab 2017. https://doi.org/10.1016/j.diabet.2017.08.005.
[11]
Gill G V., Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes-the “dead in bed” syndrome revisited. Diabetologia 2009. https://doi.org/10.1007/s00125-008-1177-7.
[12]
Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care 2014. https://doi.org/10.2337/dc13-0701.
[13]
Liatis S, Mylona M, Kalopita S, Papazafiropoulou A, Karamagkiolis S, Melidonis A, et al. Hypoglycaemia requiring medical assistance in patients with diabetes: A prospective multicentre survey in tertiary hospitals. Diabetes Metab 2015;41. https://doi.org/10.1016/j.diabet.2014.10.006.
[14]
Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings: A scientific statement from the American heart association and the American college of cardiology foundation. Circulation 2010. https://doi.org/10.1161/CIRCULATIONAHA.109.192704.
[15]
Amiel SA, Aschner P, Childs B, Cryer PE, de Galan BE, Frier BM, et al. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019. https://doi.org/10.1016/S22138587(18)30315-2.
[16]
Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013;347:f4533–f4533. https://doi.org/10.1136/bmj.f4533.
[17]
Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010;53:1552–61. https://doi.org/10.1007/s00125-010-17526.
12 [18]
Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z. Impairment of Human Ether-à-GoGo-related Gene (HERG) K + Channel Function by Hypoglycemia and Hyperglycemia. J Biol Chem 2003;278:10417–26. https://doi.org/10.1074/jbc.M211044200.
[19]
Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med 2004;350:1013–22. https://doi.org/10.1056/NEJMra032426.
[20]
Darbar D, Smith M, Mörike K, Roden DM. Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem. Am J Cardiol 1996;77:1351–5. https://doi.org/10.1016/S00029149(96)00204-4.
[21]
Chvilicek JP, Hurlbert BJ, Hill GE. Diuretic-induced hypokalaemia inducing torsades de pointes. Can J Anaesth 1995;42:1137–9. https://doi.org/10.1007/BF03015102.
[22]
Festa A, D’Agostino R, Rautaharju P, Mykkänen L, Haffner SM. Relation of systemic blood pressure, left ventricular mass, insulin sensitivity, and coronary artery disease to QT interval duration in nondiabetic and type 2 diabetic subjects. Am J Cardiol 2000;86:1117–22. https://doi.org/10.1016/S0002-9149(00)01170-X.
[23]
Hancox JC. A basis for human QT interval prolongation and arrhythmia risk in type 2 diabetes? Exp Physiol 2017;102:1395–6. https://doi.org/10.1113/EP086618.
[24]
Fisher BM, Gillen G, Hepburn DA, Dargie HJ, Frier BM. Cardiac responses to acute insulin-induced hypoglycemia in humans. Am J Physiol 1990;258:H1775-9. https://doi.org/10.1152/ajpheart.1990.258.6.H1775.
[25]
Bolognesi R, Tsialtas D, Bolognesi MG, Giumelli C. Marked sinus bradycardia and QT prolongation in a diabetic patient with severe hypoglycemia. J Diabetes Complications 2011;25:349–51. https://doi.org/10.1016/j.jdiacomp.2011.01.001.
[26]
Najeed SA, Khan IA, Molnar J, Somberg JC. Differential effect of glyburide (glibenclamide) and metformin on qt dispersion: A potential adenosine triphosphate sensitive k+ channel effect. Am J Cardiol 2002;90:1103–6. https://doi.org/10.1016/S0002-9149(02)02776-5.
[27]
Floyd JS, Sitlani CM, Avery CL, Noordam R, Li X, Smith A V, et al. Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. Pharmacogenomics J 2018;18:127–35. https://doi.org/10.1038/tpj.2016.90.
[28]
Middleton TL, Wong J, Molyneaux L, Brooks BA, Yue DK, Twigg SM, et al. Cardiac
13 effects of sulfonylurea-related hypoglycemia. Diabetes Care, vol. 40, American Diabetes Association Inc.; 2017, p. 663–70. https://doi.org/10.2337/dc16-1972.
14
Figure 1. QTc dispersion chart in hypoglycaemic patients and in controls
15 Table 1. Reasons for patient exclusion Hypoglycaemic events ECGs not provided from Tzaneio Hospital (due to hospital confidentiality policy) ECGs performed at a late time (>30 min after admission) Patients under medication affecting QT interval Patients with a pacemaker Patients with atrial fibrillation Patients with hypokalemia Total ECGs available for analysis
295 34 41 15 5 15 31 154
Table 2. Main characteristics of patients and controls
Type of diabetes T1D T2D
Patients (n=154)
Controls (n=95)
17 (11.0%) 135 (87.7%)
4 (4.2) 91 (95.8%)
2 (1.3%) 73.2 (16.2)
0 70.7 (10.4)
74 (48.1%) 80 (51.9%) 15.1 (13.6-17.4) 38.5 (13.2)
51 (53.7%) 44 (46.3%) 15.0 (9.8-22.3) NA
73(47.4%) 85 (55.6%) 67 (43.8%) 15 (9.7%) 6 (3.9%) 2 (1.3%)
45 (47.6%) 13 (13.7%) 59 (62.1%) 34 (35.8%) 2 (2.1%) 1 (1.1%)
p 0.12
Unclassified Age (years) Gender Females Males Duration of diabetes (years) Plasma glucose (mg/dl) Type of medication (Yes) Insulin SUs Metformin DPP-4-i TZD GLP-1RA
0.08 0.23
0.79
0.99 <0.001 <0.001 <0.001 ΝΑ ΝΑ
Data are presented as n(%), mean (SD) for normally distributed variables or median (interquartile range) for skewed variables. T1D: Type 1 diabetes, T2D: Type 2 diabetes, NA: Chi-square not Applicable, SU: Sulphonylureas, DPP-4-i: Dipeptidyl peptidase-4 inhibitors, TZD: Thiazolidinediones, GLP-1RA: Glucagon-like peptide-1 receptor agonists Table 3. QTc interval in hypoglycaemic patients and controls QTc (mean±SD) QTc (median-IQ range) QTc >440 msec (n[%]) QTc >500 msec
Patients 441.9±48.2 msec 438.4 (409.4-473.0) msec 76 (49.4) 16 (10.4)
* Independent two-sided t-test ** Mann-Whitney U test
Controls 401.0±29.6 msec 400.0 (378.0-425.0) msec 11 (11.6) 0 (0)
p <0.001* <0.001** <0.001 <0.001
16 Table 4. Qualitative assessment of the ECGs
ECG Findings Sinus tachycardia Sinus bradycardia 1st degree AV Block 3rddegree AV Block VPB SVPB Bigeminy RBBB LBBB
Patients 6 13 6 1 16 3 2 5 3
Controls 2 7 3 0 2 5 0 0 0
S0168-8227(19)31394-4 https://doi.org/10.1016/j.diabres.2020.108038 DIAB 108038
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
8 October 2019 3 January 2020 27 January 2020
Please cite this article as: M. Mylona, S. Liatis, G. Anastasiadis, C. Kapelios, A. Kokkinos, Severe iatrogenic hypoglycaemia requiring medical assistance is associated with concurrent prolongation of the QTc interval, Diabetes Research and Clinical Practice (2020), doi: https://doi.org/10.1016/j.diabres.2020.108038
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© 2020 Published by Elsevier B.V.
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Severe iatrogenic hypoglycaemia requiring medical assistance is associated with concurrent prolongation of the QTc interval 1
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Maria Mylona , Stavros Liatis , Georgios Anastasiadis , Christos Kapelios , Alexander Kokkinos 1
Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National
and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece 2
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Department of Cardiology, Laiko Hospital, Athens, Greece
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Structured Abstract Aims: Hypoglycaemia has been shown to exert arrhythmogenic effects. Herein, we explore the association between severe hypoglycaemia requiring medical assistance and the length of the QT interval in patients with diabetes. Methods: Data from a prospective study, conducted in eight tertiary hospitals, which recorded cases of hypoglycaemia from patients with diabetes seeking treatment at emergency departments (ED) were analyzed. The patients’ electrocardiograms (ECGs), were compared to those of non-hypoglycaemic diabetic individuals, matched for age, gender and duration of diabetes, obtained during their scheduled follow-up visits. The corrected QT intervals (QTc) were calculated blindly by two cardiologists. Results: ECGs from 154 patients presenting with hypoglycaemia were analyzed and compared to 95 matched controls. The mean QTc interval was significantly longer in patients with hypoglycaemia than in controls (441.9±48.2 vs. 401.0±29.6 msec, p<0.001) A significantly higher proportion of hypoglycaemic patients had an abnormally prolonged QTc (≥440 msec) compared to controls (49.4% vs. 11.6%, p<0.001). Among patients with hypoglycaemia, there was a statistically significant but rather weak negative correlation between QTc interval and plasma glucose at presentation (r: -0.183, p=0.02). Conclusions: In diabetic patients, hypoglycemia requiring medical assistance is associated with a significant prolongation of the QTc interval. The degree of this prolongation is associated with hypoglycaemia severity.
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Introduction Hypoglycaemia in patients with diabetes usually results as a consequence of glucoselowering management with certain medications and is referred to as iatrogenic hypoglycaemia. Severe hypoglycaemia is defined as any hypoglycaemia that the patient is unable to self-treat and requires the assistance of another person. A subdivision of this category concerns the cases requiring medical assistance. [1,2] It has been repeatedly shown that severe hypoglycaemia is associated with increased mortality,[3],[4],[5] the association being attributed both to causal relationship but also to the confounding effect of increased co-morbidity and frailty.[6] Acute hypoglycaemia can lead to health damage either directly (e.g., through deleterious effects of low blood glucose supply to the brain) or indirectly, usually via trauma due to impaired consciousness or seizures. Acute health damage, including sudden death may also be the result of cardiovascular events, including myocardial ischemia and/or cardiac arrhythmias.[1] The physiologic reactions aiming to maintain glucose supply to the brain during hypoglycaemia are mainly induced by counter-regulatory hormone secretion (glucagon, cortisol, growth hormone and epinephrine) among which, epinephrine has been mainly implicated in promoting alterations of ventricular repolarization and promote QTc (QT corrected for heart rate) interval prolongation.[1] Indeed, the association between hypoglycaemia and QT prolongation has been demonstrated in experimental animals[7] and in patients with diabetes, both during hyperinsulinaemic glucose clamp[8] and real-life conditions using simultaneous electrocardiogram (ECG) and continuous glucose monitoring recordings.[9–11] To our knowledge, however, very limited data exist regarding the length of QT interval during severe hypoglycaemia, when the patient is unable to self-treat the condition and needs the assistance of a third person. More specifically, only in one retrospective Japanese study it was found that 50% of patients with type 1 diabetes and 60% of those with type 2 diabetes admitted at the emergency department of a single medical centre in Tokyo, presented with an abnormally prolonged QT interval.[12] The aim of the present study is to prospectively explore the association between severe hypoglycaemic events requiring medical assistance and QT interval length in patients with diabetes, as well as to investigate for arrhythmic events and factors possibly related to QT prolongation in such patients.
Subjects, materials and methods
4 We used data from a multicentre study from eight hospitals (nine clinics), in five cities of Greece, which participated in a prospective survey of documented iatrogenic hypoglycaemic episodes in patients admitted at the emergency department (ED)[13]. The design of the study has been previously described in detail.[13] In brief, all patients with diabetes consecutively admitted at the ED and diagnosed with hypoglycaemia were included. Diagnosis of hypoglycaemia was established by the ED attending physician at each participating hospital on the basis of the presence of Whipple’s triad: symptoms/signs compatible with low blood glucose concentration; low plasma glucose levels (<70 mg/dL); and resolution of symptoms after increasing blood glucose levels. For every hypoglycaemic case, information regarding the history and type of diabetes, presence of comorbidities, types of medications taken, time and circumstances under which the event occurred and history of any previous serious hypoglycaemic episode(s) were recorded on a pre-specified form. In addition, a standard 12-lead ECG was obtained at presentation or soon after the management of hypoglycaemia and no later than 30 minutes after the administration of glucose. The ECGs obtained from hypoglycaemic patients were compared to those performed in a group of non-hypoglycaemic patients with diabetes, matched for age, gender and duration of diabetes, during their scheduled follow-up visit at the outpatient diabetes clinics of the same hospitals, during the study time period. The ECGs were reviewed for rhythm analysis and measurements by two independent cardiologists. The QT and RR intervals were measured blindly. The maximum corrected (accounting for heart rate) QT interval (QTc) was calculated according to the Bazett formula: QTc = QT interval/square root of the R-R interval (QTc =QT/√RR). QTc measurements of ≥440 msec were considered as abnormally prolonged and those of ≥500 msec as highly prolonged[14]. ECGs from patients wearing a pacemaker, those receiving medications possibly affecting the QTc length and those with hypokalemia (serum potassium <3.5 mEq/l) or atrial fibrillation were excluded from the analysis. A full qualitative assessment of the ECGs was also performed blindly by the same cardiologists. Tachyarrhythmias were classified as a) torsades de pointes, b) ventricular tachycardia, 3) ventricular fibrillation and 4) atrial fibrillation. Bradyarrhythmias were defined as 1) pauses >2.5 sec and 2) atrioventricular block. Atrial and ventricular premature beats and complexes were also documented and analyzed. Data are presented as n (%), mean (SD), or, in the case of skewed variables, as median with the lower and upper ends of the interquartile range (IQR). The one-sample KolmogorovSmirnov test was used in order to examine the normality of distributions. Continuous variables were compared between groups using two-sided student's t test (for normally
5 distributed variables) or Mann-Whitney U test (for skewed variables). Categorical variables were compared using x2 test. Linear regression was used to test for simple correlations between normally distributed continuous variables. P values of ≤0.05 were considered statistically significant for all tests. All analyses were performed using SPSS package software, version 21.
Results During a 16-month period, 295 hypoglycaemic episodes in 294 admitted patients were recorded[13]. The majority were patients with T2D (268, 90.8%), while there were also 26 patients with type 1 diabetes (T1D). In 34 cases from a single centre, ECGs were not available due to hospital regulations. In addition, another 76 ECGs were excluded for a variety of reasons, as described in Table 1. We further excluded 31 ECGs due to concomitant hypokalemia, a condition also known to prolong QTc. Therefore, at the end, 154 ECGs from 154 patients with hypoglycaemia and 95 ECGs from 95 age and sex matched controls were available for the present analysis. The main demographic and clinical characteristics of patients and control individuals are presented in Table 2. There were no statistically significant differences between the two groups in terms of age, gender distribution and duration of diabetes. However, controls received less frequently sulfonylureas and more frequently metformin and DPP-4 inhibitors than hypoglycaemic patients (Table 2). The distribution of the QTc variable was normal across both groups. The mean QTc interval in patients with hypoglycaemia was 441.9 [48.2] msec versus 401.0 [29.6] msec in the control group, a difference of high statistical significance (p<0.001) (Figure 1). Seventy-six patients with hypoglycaemia (49.4%) presented with abnormally prolonged (>440 msec) QTc interval (mean value: 480.1 [34.5] msec), versus 11 patients (11.6%, mean value 451.5 [8.5] msec) in the control group (p<0.001). A very prolonged QTc interval (>500 msec) was calculated in 16 (10.4%) ECGs from hypoglycaemic patients whereas none was found among controls (Table 3). Among patients with hypoglycaemia, there was a statistically significant negative correlation between QTc interval and plasma glucose at presentation (r: -0.183, p=0.02). Furthermore, patients with QTc prolongation (>440 msec) had lower plasma glucose than those without (36.2 [13.2] mg/dl vs. 40.8 [12.9] mg/dl, p=0.03). Patients with markedly prolonged QTc (>500 msec) presented with even lower plasma glucose (34.5 [11.2] mg/dl). The length of the QTc interval was not related to age, gender, duration of diabetes, type of diabetes, time
6 of the occurrence of hypoglycaemia (day or night) and presence of cardiovascular disease. Patients treated with a sulphonylurea had a numerically lower QTc interval length compared to non-sulphonylurea treated patients: 435.3 [42.3] vs. 449.9 [51.9] msec (p=0.07), a difference that was attenuated when adjusted for blood glucose value: 436.5 [42.6] vs 448.0 [51.4] msec (p=0.1). When patients were divided according to insulin treatment, the opposite picture was obtained, after adjustment for blood glucose value: 448.2 [51.6] msec (insulin treated) vs. 436.1 [42.1] msec (non-insulin treated), p=0.12. In a multivariable linear regression model, QTc length was not associated with the use of any glucose-lowering medication, including insulin, either adjusted for blood glucose levels or not. Two thirds of patients with hypoglycaemia were admitted to the hospital (n=102, 66.3%). QTc interval length was not different between those hospitalized and those who were discharged (436±47.6 msec vs. 448.7±49.1 msec, p=0.14). Only one patient died from cardiac arrest during hospitalization, whose QTc at presentation was 424 msec. Qualitative assessment of the ECGs (Table 4) did not reveal any major tachyarrhythmic disorders in either patients or controls. There was one hypoglycaemic patient presenting with third degree atrioventricular block. There were 16 ECGs from hypoglycaemic patients with at least one ventricular premature beat versus only two in controls. Six hypoglycaemic patients presented with right bundle branch block (RBBB) and three with left bundle branch block (LBBB) while, among controls, no RBBB or LBBB was detected.
Discussion In this prospective study, it was demonstrated that the mean length of the QTc interval was significantly prolonged in patients with diabetes presenting at the emergency department of tertiary hospitals during or soon after a severe hypoglycaemic episode, as compared to nonhypoglycaemic diabetic patients of similar age, sex and duration of diabetes. In addition, the prevalence of abnormal arrhythmic or proarrhythmic ECG manifestations during or soon after hypoglycaemia was higher than in control individuals. The association between the occurrence of severe hypoglycaemia and increased short and long-term morbidity/mortality has been repeatedly observed in the past and has been an issue of controversial interpretation. [15] The core of the controversy lies on whether the association is causal or hypoglycaemia is simply a marker of frailty, which mediates the association. Although the latter hypothesis is undoubtedly true, it has been shown that it may not fully explain this association, strongly supporting a possible direct detrimental
7 effect of hypoglycaemia.[16] A proarrhythmic effect has been implicated as a major mechanism linking hypoglycaemia to adverse outcomes.[17] Low blood glucose causes action potential prolongation by blocking repolarising K+ channels[18], a mechanism commonly observed with proarrhythmic medications.[19] In addition, the catecholamine flood following a hypoglycaemic episode may cause longer QT intervals in experimental animals and in humans, mainly through an increase in intracellular Ca++.[20] Moreover, hypokalemia which may be induced by hyperinsulinaemic hypoglycaemia may also contribute to QTc prolongation and increase the incidence of arrhythmic events.[21] Some studies have suggested that sulphonylureas may affect QTc independently of hypoglycaemia, in relation with the closing of K+ channels [26,27]. In the present study, patients treated with a sulphonylurea had a numerically (but not statistically significant) lower QTc interval length compared to non-sulphonylurea treated patients, a difference that was attenuated after adjustment for blood glucose value (p=0.1). Our results are in accordance with a recent study using continuous glucose monitoring and simultaneous ambulatory electrocardiography in sulphonylurea and insulin-treated patients, which suggested that increased QTc was associated with iatrogenic hypoglycemia rather than sulfonylurea treatment specifically [28]. It has to be noted though that in our study patients were taking several combinations of hypoglycaemic drugs, rendering the investigation of any drug-specific effect on QTc length very difficult. To our knowledge, there is only one previous study that investigated QTc length in patients with diabetes presenting with severe iatrogenic hypoglycaemia. In that study, the investigators retrospectively examined 59,602 cases that presented at the emergency room of a single hospital and identified 414 cases with hypoglycaemia. A QTc measurement was available in 199 cases. Very similarly to our study, they found that 58% of patients (versus 49.4% in the present study) had an abnormally prolonged QTc interval (>440 msec) and 14.4% (versus 10.4% in the present study) a very prolonged one (>500 msec). In the present multicentre study, all cases were identified prospectively, according to a prespecified protocol.[13] This procedure allowed for a proper adjudication of cases with regards to diagnosis, cause(s) and consequences of hypoglycaemia. In addition, in the present study, the ECG findings of hypoglycaemic patients were compared to those of a control group. The latter consisted of patients with diabetes matched for age, gender and duration of disease and the population was recruited from the outpatient clinics of the participating hospitals during a routine visit, when no symptoms or signs of hypoglycaemia were present. Since diabetes itself is a proarrhythmic condition, frequently associated with
8 QTc prolongation and other arrhythmic events[22],[23], the inclusion of non-hypoglycaemic patients with diabetes as controls allowed to account for this confounding factor. The exclusion of patients presenting with low potassium levels might underestimate the role of hypoglycaemia-induced QTc prolongation in this analysis. However, since we aimed to isolate -as much as possible- the role of low blood glucose levels in inducing QTc prolongation, we preferred to exclude this confounder. In this way, the potassiumindependent QTc prolongation that was observed in the present analysis further enhances the notion of causality between severe hypoglycaemia and QTc prolongation. To this direction, the statistically significant correlation between the degree of low blood glucose levels and the extent of QTc interval length which was observed in the present analysis, although relatively weak, leaves little doubt about a causal effect of hypoglycaemia on QTc prolongation. Importantly, to our knowledge, it is the first time that this observation is described in humans under real-life conditions. The clear difference in QTc interval length between severely hypoglycaemic patients and controls is of great clinical significance. Previous studies in patients with type 2 diabetes, during continuous and simultaneous recordings of ECG and subcutaneous glucose levels have shown that QTc length was prolonged during periods of low glucose levels, with mean values ranging substantially and depending on type of diabetes, time of day and study [9– 11]. In those studies, arrhythmias were detected more frequently during low-glucose than during normal-glucose periods. Most low-glucose periods were asymptomatic and literal hypoglycaemia was actually not confirmed, since glucose was measured in the subcutaneous tissue. The present study differs substantially from the above-mentioned observations in that all cases of hypoglycaemia were symptomatic and patients sought hospital assistance for an emergency condition. Several arrhythmic disorders were detected in the qualitative ECG assessment of the present analysis. Of note, sinus bradycardia was detected in 13 patients (8.5%), a proportion similar to that in controls (7.4%). Although sinus bradycardia was a prominent finding during hypoglycaemia in studies of simultaneous ECG/interstitial glucose monitoring, it was mainly detected during night periods of asymptomatic drops in interstitial glucose levels. The investigators hypothesized that such bradycardic episodes might be attributed to increased vagal counteraction [9,24]. However, it has to be noted that apart from a few case reports, bradycardia is an uncommonly reported manifestation of severe hypoglycaemia.[25] On the other hand, we found several cases of ventricular premature beats (VPC) (10.4% of patients), a number clearly higher than in controls (2.1%), but without any episodes of ventricular
9 tachycardia in either patients or controls. Since VPCs are more likely to occur in older individuals and patients with comorbidities, their more frequent presence in the hypoglycemic cohort might be, apart from a result of increased epinephrine load, simply a marker of frailty. One hypoglycaemic patient presented with third degree atrioventricular block. One patient died from prolonged hypoglycaemia (asystole). The main strengths of the present study include its prospective and multicentre design, the opportunity to analyze ECGs from severely hypoglycaemic individuals under real-life conditions and the possibility to compare the ECG findings to those of matched diabetic patients without hypoglycaemia who served as controls. Nevertheless, our study has some limitations: first, some important clinical aspects of the hypoglycaemic cases are missing, such as a detailed medical history, socioeconomic status and HbA1c value; second, the exact timing of the ECG recordings in relation to the diagnosis and management of hypoglycaemia is not available; third, the ECG recordings are those that are usually obtained in routine clinical practice of an emergency department, hence they are of short duration and not suitable for a thorough study of heart rhythm; and fourth, ECGs after recovery from hypoglycaemia are not available. The study protocol was based on standard clinical practice applied in emergency departments of the participating hospitals, which did not generally perform additional ECGs, unless specifically indicated. In conclusion, the present study has demonstrated that patients with diabetes presenting with iatrogenic hypoglycaemia at the emergency department of tertiary hospitals have a clinically and statistically prolonged QTc interval while, at the same time, the degree of QTc prolongation is associated with the profoundness of hypoglycaemia. Although not many cases with arrhythmic disorders were detected in the present analysis, the proarrhythmic nature of severe hypoglycaemia in patients with diabetes has been confirmed under real-life conditions, a fact emphasizing the importance of preventive measures against hypoglycaemia in this population.
Acknowledgements Stavroula Kalopita, Athanasia Papazafiropoulou, Spyros Karamagkiolis, Andreas Melidonis, Apostolos Xilomenos, Ioannis Ioannidis, Gregory Kaltsas, Leonidas Lanaras, Christos Basagiannis, Stavros Pappas, Kanellina Zerva, Konstantinos Tsakalis. The abovementioned investigators are acknowledged for their contribution in the study conduction, collection and transfer of the data at each participating hospital.
10 Conflict of interest and funding The authors declare no conflict of interest or funding from any source.
References [1]
Liatis S, Katsilambros N. Hypoglycemia caused by Insulin. 2011. https://doi.org/10.1002/9781119971825.ch4.
[2]
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: A report of aworkgroup of the American diabetes association and the endocrine society. Diabetes Care 2013;36:1384–95. https://doi.org/10.2337/dc122480.
[3]
Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: Retrospective epidemiological analysis of the ACCORD study. BMJ 2010. https://doi.org/10.1136/bmj.b4909.
[4]
Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010. https://doi.org/10.1056/NEJMoa1003795.
[5]
Pieber TR, Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, et al. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia 2018. https://doi.org/10.1007/s00125-017-4422-0.
[6]
Misra-Hebert AD, Pantalone KM, Ji X, Milinovich A, Dey T, Chagin KM, et al. Patient characteristics associated with severe hypoglycemia in a type 2 diabetes cohort in a large, integrated health care system from 2006 to 2015. Diabetes Care 2018. https://doi.org/10.2337/dc17-1834.
[7]
Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes 2013. https://doi.org/10.2337/db13-0216.
[8]
Marques JLB, George E, Peacey SR, Harris ND, Macdonald IA, Cochrane T, et al. Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med 1997. https://doi.org/10.1002/(SICI)1096-9136(199708)14:8<648::AIDDIA418>3.0.CO;2-1.
11 [9]
Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014. https://doi.org/10.2337/db13-0468.
[10]
Makrilakis K, Stathi C, Vlahodimitris I, Kalopita S, Thomakos P, Konstantopoulos P, et al. Hypoglycaemia causes both daytime and nighttime QTc interval prolongation in patients with type 2 diabetes receiving insulin treatment. Diabetes Metab 2017. https://doi.org/10.1016/j.diabet.2017.08.005.
[11]
Gill G V., Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes-the “dead in bed” syndrome revisited. Diabetologia 2009. https://doi.org/10.1007/s00125-008-1177-7.
[12]
Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care 2014. https://doi.org/10.2337/dc13-0701.
[13]
Liatis S, Mylona M, Kalopita S, Papazafiropoulou A, Karamagkiolis S, Melidonis A, et al. Hypoglycaemia requiring medical assistance in patients with diabetes: A prospective multicentre survey in tertiary hospitals. Diabetes Metab 2015;41. https://doi.org/10.1016/j.diabet.2014.10.006.
[14]
Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings: A scientific statement from the American heart association and the American college of cardiology foundation. Circulation 2010. https://doi.org/10.1161/CIRCULATIONAHA.109.192704.
[15]
Amiel SA, Aschner P, Childs B, Cryer PE, de Galan BE, Frier BM, et al. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019. https://doi.org/10.1016/S22138587(18)30315-2.
[16]
Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013;347:f4533–f4533. https://doi.org/10.1136/bmj.f4533.
[17]
Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010;53:1552–61. https://doi.org/10.1007/s00125-010-17526.
12 [18]
Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z. Impairment of Human Ether-à-GoGo-related Gene (HERG) K + Channel Function by Hypoglycemia and Hyperglycemia. J Biol Chem 2003;278:10417–26. https://doi.org/10.1074/jbc.M211044200.
[19]
Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med 2004;350:1013–22. https://doi.org/10.1056/NEJMra032426.
[20]
Darbar D, Smith M, Mörike K, Roden DM. Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem. Am J Cardiol 1996;77:1351–5. https://doi.org/10.1016/S00029149(96)00204-4.
[21]
Chvilicek JP, Hurlbert BJ, Hill GE. Diuretic-induced hypokalaemia inducing torsades de pointes. Can J Anaesth 1995;42:1137–9. https://doi.org/10.1007/BF03015102.
[22]
Festa A, D’Agostino R, Rautaharju P, Mykkänen L, Haffner SM. Relation of systemic blood pressure, left ventricular mass, insulin sensitivity, and coronary artery disease to QT interval duration in nondiabetic and type 2 diabetic subjects. Am J Cardiol 2000;86:1117–22. https://doi.org/10.1016/S0002-9149(00)01170-X.
[23]
Hancox JC. A basis for human QT interval prolongation and arrhythmia risk in type 2 diabetes? Exp Physiol 2017;102:1395–6. https://doi.org/10.1113/EP086618.
[24]
Fisher BM, Gillen G, Hepburn DA, Dargie HJ, Frier BM. Cardiac responses to acute insulin-induced hypoglycemia in humans. Am J Physiol 1990;258:H1775-9. https://doi.org/10.1152/ajpheart.1990.258.6.H1775.
[25]
Bolognesi R, Tsialtas D, Bolognesi MG, Giumelli C. Marked sinus bradycardia and QT prolongation in a diabetic patient with severe hypoglycemia. J Diabetes Complications 2011;25:349–51. https://doi.org/10.1016/j.jdiacomp.2011.01.001.
[26]
Najeed SA, Khan IA, Molnar J, Somberg JC. Differential effect of glyburide (glibenclamide) and metformin on qt dispersion: A potential adenosine triphosphate sensitive k+ channel effect. Am J Cardiol 2002;90:1103–6. https://doi.org/10.1016/S0002-9149(02)02776-5.
[27]
Floyd JS, Sitlani CM, Avery CL, Noordam R, Li X, Smith A V, et al. Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. Pharmacogenomics J 2018;18:127–35. https://doi.org/10.1038/tpj.2016.90.
[28]
Middleton TL, Wong J, Molyneaux L, Brooks BA, Yue DK, Twigg SM, et al. Cardiac
13 effects of sulfonylurea-related hypoglycemia. Diabetes Care, vol. 40, American Diabetes Association Inc.; 2017, p. 663–70. https://doi.org/10.2337/dc16-1972.
14
Figure 1. QTc dispersion chart in hypoglycaemic patients and in controls
15 Table 1. Reasons for patient exclusion Hypoglycaemic events ECGs not provided from Tzaneio Hospital (due to hospital confidentiality policy) ECGs performed at a late time (>30 min after admission) Patients under medication affecting QT interval Patients with a pacemaker Patients with atrial fibrillation Patients with hypokalemia Total ECGs available for analysis
295 34 41 15 5 15 31 154
Table 2. Main characteristics of patients and controls
Type of diabetes T1D T2D
Patients (n=154)
Controls (n=95)
17 (11.0%) 135 (87.7%)
4 (4.2) 91 (95.8%)
2 (1.3%) 73.2 (16.2)
0 70.7 (10.4)
74 (48.1%) 80 (51.9%) 15.1 (13.6-17.4) 38.5 (13.2)
51 (53.7%) 44 (46.3%) 15.0 (9.8-22.3) NA
73(47.4%) 85 (55.6%) 67 (43.8%) 15 (9.7%) 6 (3.9%) 2 (1.3%)
45 (47.6%) 13 (13.7%) 59 (62.1%) 34 (35.8%) 2 (2.1%) 1 (1.1%)
p 0.12
Unclassified Age (years) Gender Females Males Duration of diabetes (years) Plasma glucose (mg/dl) Type of medication (Yes) Insulin SUs Metformin DPP-4-i TZD GLP-1RA
0.08 0.23
0.79
0.99 <0.001 <0.001 <0.001 ΝΑ ΝΑ
Data are presented as n(%), mean (SD) for normally distributed variables or median (interquartile range) for skewed variables. T1D: Type 1 diabetes, T2D: Type 2 diabetes, NA: Chi-square not Applicable, SU: Sulphonylureas, DPP-4-i: Dipeptidyl peptidase-4 inhibitors, TZD: Thiazolidinediones, GLP-1RA: Glucagon-like peptide-1 receptor agonists Table 3. QTc interval in hypoglycaemic patients and controls QTc (mean±SD) QTc (median-IQ range) QTc >440 msec (n[%]) QTc >500 msec
Patients 441.9±48.2 msec 438.4 (409.4-473.0) msec 76 (49.4) 16 (10.4)
* Independent two-sided t-test ** Mann-Whitney U test
Controls 401.0±29.6 msec 400.0 (378.0-425.0) msec 11 (11.6) 0 (0)
p <0.001* <0.001** <0.001 <0.001
16 Table 4. Qualitative assessment of the ECGs
ECG Findings Sinus tachycardia Sinus bradycardia 1st degree AV Block 3rddegree AV Block VPB SVPB Bigeminy RBBB LBBB
Patients 6 13 6 1 16 3 2 5 3
Controls 2 7 3 0 2 5 0 0 0