- Email: [email protected]
Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias?
Journal Pre-proofs Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias? Kelly Lainetti, João Pimenta, Marcio Faleiros Vendramini PII: DOI: Reference:
S0168-8227(19)30460-7 https://doi.org/10.1016/j.diabres.2019.107878 DIAB 107878
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
9 April 2019 31 July 2019 10 October 2019
Please cite this article as: K. Lainetti, J. Pimenta, M. Faleiros Vendramini, Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias?, Diabetes Research and Clinical Practice (2019), doi: https://doi.org/ 10.1016/j.diabres.2019.107878
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.
© 2019 Published by Elsevier B.V.
Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias? Kelly Lainetti, João Pimenta, Marcio Faleiros Vendramini
Corresponding Author: Kelly Lainetti Institution: Institute of medical assistance to public servants of the state (Iamspe) Address: Mirandinha Street, 755 City: Sao Paulo Postcode / ZIP Code: 03641000 Country: Brazil Telephone: +55 11998420467 E-mail: [email protected] Co-authors: First name: João Last name: Pimenta Institution: Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brasil. Email: [email protected] First name: Márcio Middle name: Faleiros Last name: Vendramini Institution: Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brasil. E-mail: [email protected]
1
SUMMARY Background: Sudden nocturnal death is a syndrome that usually affects patients with diabetes mellitus type 1 (DM1), being described mainly due to ventricular arrhythmias in response to nocturnal hypoglycemia. Objectives: Evaluate the relation between hypoglycemia and ventricular arrhythmias in patients with DM1 and normal structural heart. Method: Prospective, observational study with DM1 patients and normal structural heart on echocardiogram aged 18-60 years, of both sexes receiving insulin therapy for at least five years. Intermittent glucose reading device was implanted (iPro2 - Medtronic / USA) and 24hr ambulatory electrocardiographic recording by the Holter system (Cardios Systems - Brazil). Patients were monitored for hypoglycemia without any type of induction (interstitial glucose <70mg/dl) and cardiac arrhythmias within 24 hours. Results: Thirty-two patients were evaluated, with mean-age of 35 years, being 16 men. Eleven patients (34%) did not have hypoglycemia, other 3 (27.3%) also had no arrhythmia, while 8 (72.7%) had arrhythmias interpreted as irrelevant. The other 21 patients (66%) presented some hypoglycemic episodes and 10 (47.6%) did not present arrhythmias, whereas 11 (52.4%) presented arrhythmias considered not clinically significant, as also found in non-diabetic individuals. Conclusion: In patients with DM1 without structural heart disease there was no relationship between cardiac arrhythmia and episodes of hypoglycemia. Key-words: type 1 diabetes mellitus – hypoglycemia – continuous glucose monitoring · continuous ECG monitoring – arrhythmias. INTRODUCTION Diabetes is a chronic disease characterized by increased blood glucose levels (hyperglycemia), due to insufficient production (type 2 or DM2) or absence (type 1 or DM1) of insulin 1. Currently, nearly 500 million people in the world are living with diabetes and a third is over 65 years old 1. Hypoglycemia defined as blood glucose value less than 3,9 mmol/L (70mg/dL) accompanied by typical adrenergic symptoms such as sweating, palpitations, tremors and paresthesis by absence of regulatory response from the autonomical nervous system, eventually requiring medical intervention for corrective actions 2-3 is the most common side effect in diabetic patients who are treated with insulin due to inadequate use or by mistake in the dosages 4-6. Cardiac arrhythmias, such as conduction disturbances, ventricular tachyarrhythmias and sudden death have been described in patients with DM1 and is associated to acute episodes of hypoglycemia.
2
Large multicenter studies have shown that the increase of 1% in the level of glycated hemoglobin is associated with 18% increased risk of cardiovascular events and 12% to 14% increased risk of all-cause mortality 7-11. Some studies in humans showed that the heart is more likely to present electrophysiological changes and consequently the occurrence of arrhythmias when exposed to low concentration of blood glucose
12-15.
It has also been shown that severe hypoglycemia can
induce proarrhythmic effects such as ST-T segment abnormalities which is associated to the development of malignant ventricular arrhythmias as torsades de pointes, that might justify the mechanisms of sudden death described amongst young diabetic patients 8,16-21. Up to now, previous studies were unable to show hypoglycemia triggering cardiac arrhythmias. Then, the aim of this study is to demonstrate simultaneous relationship between episodes of hypoglycemia and arrhythmic events in DM1 patients with no structural heart disease. PATIENTS AND METHODS DM1 patients treated in a single Diabetes Clinic in a governmental tertiary hospital in São Paulo, Brazil were included. Patients older than 60 years, receiving insulin therapy less than 5 years were not included as well as patients with medical conditions associated to cardiac arrhythmias such as structural heart disease, thyroid disturbances and electrolyte imbalances were also not studied. Initial population had one hundred and eighty-seven individuals but 61 were older than 60 years, 42 showed some type of illness that made them ineligible, 49 did not accept to participate, remaining 35 patients that accepted and where eligible to participate. These patients were submitted to laboratory tests and TTE. At the beginning of the study, two individuals showed changes on their evaluations: one presented sequels of rheumatic fever with calcification of mitral ring and other acquired pulmonary tuberculosis, therefore not being able to participate in the study, remaining 32 patients. This study was approved by the Research Ethics Committee of the institution and all participants signed the informed consent. Continuous ambulatory Holter recording and blinded interstitial glucose monitoring (Medtronic iPro2) for 24 hours were installed. Data was analyzed each 5 minutes and the general picture was given by means of graphics as shown in figure 2. Patients were oriented to avoid the induction of hypoglycemia and not change any kind of daily activity, medicines or diet. After this recording period, all data was transferred and analyzed by specific software. Additional informations such as time of hypoglycemia and occurrence of arrhythmias were analyzed. Hypoglycemia was defined as glucose ≤3,9mmol/L, euglycemia 4,0mmol/L (72mg/dl) – 7,8mmol/L (140mg/dl) and hyperglycemia ≥7,9mmol/L (142mg/dl). Statistical analysis was not done because the results do not permit it. RESULTS Thirty-two patients were included in the study, the mean-age 33 (20-47) years and the median time of diagnosis was 21 years (5-37) (Table 1). Twenty-one (66%) patients presented
3
hypoglycemia within 24 hours and remained hypoglycemic for some period as shown in figure 1. Most of episodes of hyperglycaemia lasted less than 2 hours 40 minutes, 100% of episodes lasted more than 14 minutes, the shortest interval was 2%, corresponding to 28 minutes, and the highest, 68%, equivalent to 16 hours. Regarding glycemic values, the lowest level was 40 mg/dl (documented in 7 patients) and the highest was 400mg/dl (1 patient). In the Holter monitoring, 13 (40.6%) did not present arrhythmia and 19 (59.4%) presented arrhythmias without clinical relevance such as bradycardia, sinus tachycardia and isolated ventricular or supraventricular premature beats, as well as such as non-specific ST-T changes, all findings considered between normal limits, with no relationship with hypo or hyperglycemia (figure 3). Minimum heart rate documented was 40 bpm and the maximum, 209 bpm. Thus, 11 patients (34%) had no hypoglycemia, and 3 (27.3%) did not have arrhythmias, while 8 (72.7%) had arrhythmias interpreted as no clinical significance. The 21 (66%) were detected with a hypoglycemic episode (<70 mg/dL) in 24 hours, and in this group, 10 (47.6%) presented no arrhythmia while the other 11 (52.4%) had arrhythmia, but not significant, such as those found in non-diabetic individuals (figure 4). DISCUSSION This study demonstrates that episodes of hypoglycemia in DM1 individuals without structural heart disease there is no correlation with cardiac arrhythmias. Several investigations have shown controversial results to this communication and appear to be directly related to the study design. Thereby, a report with a methodology similar to this present study, with electrocardiographic Holter recording and interstitial glucose using iPro2, undergone in Australia by Lee et al
21,
did
not focus on arrhythmias, did not consider age limits, absence of cardiac abnormalities or time of evolution of diabetes, and there were only three patients with DM1. Other paper with similar methodology carried out in 2014 in the United Kingdom was conducted by Chow et al
22
but
included only patients with DM2, and patients with cardiac diseases, with risks for arrhythmias. Also, using the same monitoring methodology, Stahn et al
13
excluded DM1, emphasizing
ventricular arrhythmias in patients with DM2. The limits of the age considered in this study were an important delimitation, because none of the other studies have taken it into account, including multicenter studies. Thus, ADVANCE
11
and
ACCORD performed in different countries such Australia, Canada and United States, with over 7
10 thousand patients in each study (n 11.140 and 10.251, respectively), included elderly people that might have cardiac diseases related to senile stage, and a lower physiological response, due to lack of natural body responses, such as a release of growth hormone. In all available medical literature there has not been any study with the exclusion of patients that presented non cardiac diseases that potentially could lead to arrhythmias. It was realized that studies conducted with a higher number of patients showed different types of arrhythmias as those found in this study, certainly related to the lack of better selection of participants.
4
Strengths of this study include rigorous criteria to include only individuals with DM1, avoiding participants at increased risk to developing cardiac arrhythmias, for not to credit erroneously the episodes of hypoglycemia as possible causes of arrhythmias. Other factors that may have given warranty to these findings are the absence of arrhythmias associated with hypoglycemia is social attitudes, as users of illicit drugs. This fact directly influences the action of the metabolism of glucose due to an increase in the heart rate and the release of natural neurotransmitters by the action of the drug 23. This can also lead to the loss of the decision-making related to food consumption and insulin use correctly when it is under the effect of the drug. Limitations of the study – the first item to be considered would be related to the monitoring, since it would increase the chance to capture the occurrence of arrhythmias if the patient was supervised for more than 24 hours, which is not always feasible. In this way, longer follow-ups would require other analysis and extensive investigations as invasive interventions and devices, such as implantable looping recording (IRL), adding risks to the patients, procedures that could violate the ethical questions of the original protocol. Another aspect would be the sample size, small in this study due to characteristic of our hospital. So, if a larger number of patients with these same selection criteria were studied, better conclusions could be found. However, it is believed that the findings of this investigation can stimulate other researchers to confirm these results, as well as to aggregate new knowledge to this subject of extreme importance to daily clinical practice. So, it has been concluded that there were no arrhythmias considered significant during episodes of hypoglycemia up to a level of 40mg/dl in individuals with DM1 without structural heart disease. Funding statement: this study received financial support from the Instituto Cardios de Ensino e Pesquisa, São Paulo, SP - Brasil. No potential conflict of interest relevant to this article has been reported.
REFERENCES 1.
International Diabetes Federation. IDF Diabetes Atlas [journal in Internet]. 2017
[accessed in 2017 Ago 12]; 8th ed.150 p. Available from: http://diabetesatlas.org/resources/2017atlas.html 2.
Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018
Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018;42 Suppl 1:S1-325 3.
European Medicines Agency. Guideline on clinical investigation of medicinal products in
the treatment or prevention of diabetes mellitus [journal in Internet]. London, UK: EMA; 2012 [accessed
in
2017
Ago
13].
Available
from:
5
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC5001 29256.pdf 4.
Lalic NM. The Case for: hypoglycemia is of cardiovascular importance. Diabetes Care.
2013;36 Suppl 2:S264-6. 5.
Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes
Care. 2011;34 Suppl 2:S132-7. 6.
Wilson PW. Diabetes Mellitus and Cardiovascular Risk. In: Eckel RH, Antman E.
Metabolic Risk for Cardiovascular Disease. Massachussetts: Wiley; 2011. p.134-55. (AHA clinical series editor). 7.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Action to control
Cardiovascular Risk in Diabetes Study Group, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-59. 8.
Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-
analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141(6):421-31. 9.
Aronson D, Burger AJ. Diabetes and the occurrence of ventricular arrhythmic events in
patients with severe left ventricular dysfunction. Diabetologia. 2002;45(10):1440-5. 10.
McCoy RG, Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith S. Increased
mortality
of
patients
with
diabetes
reporting
severe
hypoglycemia.
Diabetes
Care.
2012;35(9):1897-901. 11.
Zoungas S, Patel A, Chalmers J, Bastiaan E, de Galan BE, Li Q, et al. Severe
hypoglycemia and risk of vascular events and death. N Engl J Med. 2010;363(15):1410-8. 12.
Mellbin LG, Rydén L, Riddle MC, Probstfield J, Rosenstock J, ORIGIN Trial Investigators,
et al. Does hypoglycaemia increase the risk of cardiovascular events? Eur Heart J. 2013;34(40):3137-44. 13.
Stahn A, Pistrosch F, Ganz X, Teige M, Koehler C, Bornstein S, et al. Relationship
between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases: silent hypoglycemias and silent arrhythmias. Diabetes Care. 2014;37(2):516-20. 14.
Tkác I. Cardiovascular importance of hyperglycemia and hypoglycemia. Diabetes Care.
2013;36 Suppl 2:S267-71. 15.
Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical
evidence. Diabetologia. 2010;53(8):1552-61. 16.
Frier BM, Barr S, Walker JD. Fatal cardiac arrest following acute hypoglycaemia in a
diabetic patient: case report. Pract Diabetes. 1995;12(6):284. 17.
Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal
hypoglycaemia in type 1 diabetes - the “dead in bed'’ syndrome revisited. Diabetologia. 2009;52(1):42-5.
6
18.
Robinson RTCE, Harris ND, Ireland RH, Macdonald IA, Heller SR. Changes in cardiac
repolarization during clinical episodes of nocturnal hypoglycaemia in adults with type 1 diabetes. Diabetologia. 2004;47(2):312-5. 19.
Lee SP, Harris ND, Robinson RT, Davis C, Ireland RH, Macdonald IA, et al. Effect of
atenolol on QTc interval lengthening during hypoglycaemia in type 1 diabetes. Diabetologia. 2005;48(7):1269-72. 20.
Koivikko ML, Karsikas M, Salmela PI, Tapanainen JS, Ruokonen A, Seppänen T, et al.
Effects of controlled hypoglycaemia on cardiac repolarization in patients with type 1 diabetes. Diabetologia. 2008;51(3):426-35. 21.
Lee AS, Brooks BA, Simmons L, Kilborn MJ, Wong J, Twigg SM, et al. Hypoglycaemia
and QT interval prolongation: Detection by simultaneous Holter and continuous glucose monitoring. Diabetes Res Clin Pract. 2016;113:211-4. 22.
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; 63(5):1738-47. 23.
Castro RA, Ruas RN, Abreu RC, Rocha RB, Ferreira RF, Lasmar RC et al. Crack:
pharmacokinetics, pharmacodynamics, and clinical and toxic effects. Rev Med Minas Gerais 2015; 25(2): 253-9.
7
Our reference: DIAB 107878 Article reference: DIAB_2019_421 Article title: Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias? To be published in: Diabetes Research and Clinical Practice Figure with legend
Figure 1. Percentage of interstitial glucose of total monitoring time (24h analysis). *1. From 1% (14 min.) to 5% (1h20min.) of the total time in hypoglycemia; * 2. From 6% (1h44min.) to 10% (2h40min.) of the total time in hypoglycemia; * 3. From 11% (2h54min.) to 15% (4h) of the total time in hypoglycemia; * 4. From 16% (4h24min.) to 20% (5h20min.) of the total time in hypoglycemia; * 5. From 21% (5h34min.) to 25% (6h) of the total time in hypoglycaemia; * 6. From 26% (6h24min.) To 30% (7h20min.) Of the total time in hypoglycemia; * 7. From 31% (7h34min.) to 35% (8h40min.) of the total time in hypoglycemia; * 8. From 36% (9h04min.) to 40% (10h) of the total time in hypoglycemia; * 9. From 41% (10h14min.) to 45% (11h20min.) of the total time in hypoglycemia; * 10. From 46% (11h34min.) to 50% (12h) of the total time in hypoglycemia; * 11. From 51% (12h14min.) to 55% (13h20min.) of the total time in hypoglycemia; * 12. From 56% (13h34min.) to 60% (14h40min.) of the total time in hypoglycemia; * 13. From 61% (14h54min.) to 65% (16h) of the total time in hypoglycemia; * 14. From 66% (16h14min.) to 70% (17h20min.) of the total time in hypoglycemia. There were no patients with a period greater than 70% of the total time in hypoglycemia.
Figure 2. Curve showing oscillation of the interstitial glucose level measured every 5 minutes for a period of 24h, showing a patient at the time of hypoglycemia. Green strip shows the normal range of glucose. * Interstitial glucose below 70 mg/dl ** Interstitial glucose between 70-140 mg/dl *** Interstitial glucose above 140 mg/dl
8
Figure 3. Electrocardiogram tracings obtained from Holter monitoring. In A, sinus tachycardia (approximately 125 bpm) recorded in periods with and without documented hypoglycemia; in B, isolated supraventricular premature beat (highlighted in green by Holter), found in several patients, with or without episodes of hypoglycemia; and in C, ventricular extrasystole (in red), also common in non-diabetic patients.
Figure 4. Follow-up of the interstitial glucose levels and the occurrence of arrhythmias.
9
S0168-8227(19)30460-7 https://doi.org/10.1016/j.diabres.2019.107878 DIAB 107878
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
9 April 2019 31 July 2019 10 October 2019
Please cite this article as: K. Lainetti, J. Pimenta, M. Faleiros Vendramini, Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias?, Diabetes Research and Clinical Practice (2019), doi: https://doi.org/ 10.1016/j.diabres.2019.107878
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.
© 2019 Published by Elsevier B.V.
Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias? Kelly Lainetti, João Pimenta, Marcio Faleiros Vendramini
Corresponding Author: Kelly Lainetti Institution: Institute of medical assistance to public servants of the state (Iamspe) Address: Mirandinha Street, 755 City: Sao Paulo Postcode / ZIP Code: 03641000 Country: Brazil Telephone: +55 11998420467 E-mail: [email protected] Co-authors: First name: João Last name: Pimenta Institution: Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brasil. Email: [email protected] First name: Márcio Middle name: Faleiros Last name: Vendramini Institution: Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brasil. E-mail: [email protected]
1
SUMMARY Background: Sudden nocturnal death is a syndrome that usually affects patients with diabetes mellitus type 1 (DM1), being described mainly due to ventricular arrhythmias in response to nocturnal hypoglycemia. Objectives: Evaluate the relation between hypoglycemia and ventricular arrhythmias in patients with DM1 and normal structural heart. Method: Prospective, observational study with DM1 patients and normal structural heart on echocardiogram aged 18-60 years, of both sexes receiving insulin therapy for at least five years. Intermittent glucose reading device was implanted (iPro2 - Medtronic / USA) and 24hr ambulatory electrocardiographic recording by the Holter system (Cardios Systems - Brazil). Patients were monitored for hypoglycemia without any type of induction (interstitial glucose <70mg/dl) and cardiac arrhythmias within 24 hours. Results: Thirty-two patients were evaluated, with mean-age of 35 years, being 16 men. Eleven patients (34%) did not have hypoglycemia, other 3 (27.3%) also had no arrhythmia, while 8 (72.7%) had arrhythmias interpreted as irrelevant. The other 21 patients (66%) presented some hypoglycemic episodes and 10 (47.6%) did not present arrhythmias, whereas 11 (52.4%) presented arrhythmias considered not clinically significant, as also found in non-diabetic individuals. Conclusion: In patients with DM1 without structural heart disease there was no relationship between cardiac arrhythmia and episodes of hypoglycemia. Key-words: type 1 diabetes mellitus – hypoglycemia – continuous glucose monitoring · continuous ECG monitoring – arrhythmias. INTRODUCTION Diabetes is a chronic disease characterized by increased blood glucose levels (hyperglycemia), due to insufficient production (type 2 or DM2) or absence (type 1 or DM1) of insulin 1. Currently, nearly 500 million people in the world are living with diabetes and a third is over 65 years old 1. Hypoglycemia defined as blood glucose value less than 3,9 mmol/L (70mg/dL) accompanied by typical adrenergic symptoms such as sweating, palpitations, tremors and paresthesis by absence of regulatory response from the autonomical nervous system, eventually requiring medical intervention for corrective actions 2-3 is the most common side effect in diabetic patients who are treated with insulin due to inadequate use or by mistake in the dosages 4-6. Cardiac arrhythmias, such as conduction disturbances, ventricular tachyarrhythmias and sudden death have been described in patients with DM1 and is associated to acute episodes of hypoglycemia.
2
Large multicenter studies have shown that the increase of 1% in the level of glycated hemoglobin is associated with 18% increased risk of cardiovascular events and 12% to 14% increased risk of all-cause mortality 7-11. Some studies in humans showed that the heart is more likely to present electrophysiological changes and consequently the occurrence of arrhythmias when exposed to low concentration of blood glucose
12-15.
It has also been shown that severe hypoglycemia can
induce proarrhythmic effects such as ST-T segment abnormalities which is associated to the development of malignant ventricular arrhythmias as torsades de pointes, that might justify the mechanisms of sudden death described amongst young diabetic patients 8,16-21. Up to now, previous studies were unable to show hypoglycemia triggering cardiac arrhythmias. Then, the aim of this study is to demonstrate simultaneous relationship between episodes of hypoglycemia and arrhythmic events in DM1 patients with no structural heart disease. PATIENTS AND METHODS DM1 patients treated in a single Diabetes Clinic in a governmental tertiary hospital in São Paulo, Brazil were included. Patients older than 60 years, receiving insulin therapy less than 5 years were not included as well as patients with medical conditions associated to cardiac arrhythmias such as structural heart disease, thyroid disturbances and electrolyte imbalances were also not studied. Initial population had one hundred and eighty-seven individuals but 61 were older than 60 years, 42 showed some type of illness that made them ineligible, 49 did not accept to participate, remaining 35 patients that accepted and where eligible to participate. These patients were submitted to laboratory tests and TTE. At the beginning of the study, two individuals showed changes on their evaluations: one presented sequels of rheumatic fever with calcification of mitral ring and other acquired pulmonary tuberculosis, therefore not being able to participate in the study, remaining 32 patients. This study was approved by the Research Ethics Committee of the institution and all participants signed the informed consent. Continuous ambulatory Holter recording and blinded interstitial glucose monitoring (Medtronic iPro2) for 24 hours were installed. Data was analyzed each 5 minutes and the general picture was given by means of graphics as shown in figure 2. Patients were oriented to avoid the induction of hypoglycemia and not change any kind of daily activity, medicines or diet. After this recording period, all data was transferred and analyzed by specific software. Additional informations such as time of hypoglycemia and occurrence of arrhythmias were analyzed. Hypoglycemia was defined as glucose ≤3,9mmol/L, euglycemia 4,0mmol/L (72mg/dl) – 7,8mmol/L (140mg/dl) and hyperglycemia ≥7,9mmol/L (142mg/dl). Statistical analysis was not done because the results do not permit it. RESULTS Thirty-two patients were included in the study, the mean-age 33 (20-47) years and the median time of diagnosis was 21 years (5-37) (Table 1). Twenty-one (66%) patients presented
3
hypoglycemia within 24 hours and remained hypoglycemic for some period as shown in figure 1. Most of episodes of hyperglycaemia lasted less than 2 hours 40 minutes, 100% of episodes lasted more than 14 minutes, the shortest interval was 2%, corresponding to 28 minutes, and the highest, 68%, equivalent to 16 hours. Regarding glycemic values, the lowest level was 40 mg/dl (documented in 7 patients) and the highest was 400mg/dl (1 patient). In the Holter monitoring, 13 (40.6%) did not present arrhythmia and 19 (59.4%) presented arrhythmias without clinical relevance such as bradycardia, sinus tachycardia and isolated ventricular or supraventricular premature beats, as well as such as non-specific ST-T changes, all findings considered between normal limits, with no relationship with hypo or hyperglycemia (figure 3). Minimum heart rate documented was 40 bpm and the maximum, 209 bpm. Thus, 11 patients (34%) had no hypoglycemia, and 3 (27.3%) did not have arrhythmias, while 8 (72.7%) had arrhythmias interpreted as no clinical significance. The 21 (66%) were detected with a hypoglycemic episode (<70 mg/dL) in 24 hours, and in this group, 10 (47.6%) presented no arrhythmia while the other 11 (52.4%) had arrhythmia, but not significant, such as those found in non-diabetic individuals (figure 4). DISCUSSION This study demonstrates that episodes of hypoglycemia in DM1 individuals without structural heart disease there is no correlation with cardiac arrhythmias. Several investigations have shown controversial results to this communication and appear to be directly related to the study design. Thereby, a report with a methodology similar to this present study, with electrocardiographic Holter recording and interstitial glucose using iPro2, undergone in Australia by Lee et al
21,
did
not focus on arrhythmias, did not consider age limits, absence of cardiac abnormalities or time of evolution of diabetes, and there were only three patients with DM1. Other paper with similar methodology carried out in 2014 in the United Kingdom was conducted by Chow et al
22
but
included only patients with DM2, and patients with cardiac diseases, with risks for arrhythmias. Also, using the same monitoring methodology, Stahn et al
13
excluded DM1, emphasizing
ventricular arrhythmias in patients with DM2. The limits of the age considered in this study were an important delimitation, because none of the other studies have taken it into account, including multicenter studies. Thus, ADVANCE
11
and
ACCORD performed in different countries such Australia, Canada and United States, with over 7
10 thousand patients in each study (n 11.140 and 10.251, respectively), included elderly people that might have cardiac diseases related to senile stage, and a lower physiological response, due to lack of natural body responses, such as a release of growth hormone. In all available medical literature there has not been any study with the exclusion of patients that presented non cardiac diseases that potentially could lead to arrhythmias. It was realized that studies conducted with a higher number of patients showed different types of arrhythmias as those found in this study, certainly related to the lack of better selection of participants.
4
Strengths of this study include rigorous criteria to include only individuals with DM1, avoiding participants at increased risk to developing cardiac arrhythmias, for not to credit erroneously the episodes of hypoglycemia as possible causes of arrhythmias. Other factors that may have given warranty to these findings are the absence of arrhythmias associated with hypoglycemia is social attitudes, as users of illicit drugs. This fact directly influences the action of the metabolism of glucose due to an increase in the heart rate and the release of natural neurotransmitters by the action of the drug 23. This can also lead to the loss of the decision-making related to food consumption and insulin use correctly when it is under the effect of the drug. Limitations of the study – the first item to be considered would be related to the monitoring, since it would increase the chance to capture the occurrence of arrhythmias if the patient was supervised for more than 24 hours, which is not always feasible. In this way, longer follow-ups would require other analysis and extensive investigations as invasive interventions and devices, such as implantable looping recording (IRL), adding risks to the patients, procedures that could violate the ethical questions of the original protocol. Another aspect would be the sample size, small in this study due to characteristic of our hospital. So, if a larger number of patients with these same selection criteria were studied, better conclusions could be found. However, it is believed that the findings of this investigation can stimulate other researchers to confirm these results, as well as to aggregate new knowledge to this subject of extreme importance to daily clinical practice. So, it has been concluded that there were no arrhythmias considered significant during episodes of hypoglycemia up to a level of 40mg/dl in individuals with DM1 without structural heart disease. Funding statement: this study received financial support from the Instituto Cardios de Ensino e Pesquisa, São Paulo, SP - Brasil. No potential conflict of interest relevant to this article has been reported.
REFERENCES 1.
International Diabetes Federation. IDF Diabetes Atlas [journal in Internet]. 2017
[accessed in 2017 Ago 12]; 8th ed.150 p. Available from: http://diabetesatlas.org/resources/2017atlas.html 2.
Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018
Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018;42 Suppl 1:S1-325 3.
European Medicines Agency. Guideline on clinical investigation of medicinal products in
the treatment or prevention of diabetes mellitus [journal in Internet]. London, UK: EMA; 2012 [accessed
in
2017
Ago
13].
Available
from:
5
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC5001 29256.pdf 4.
Lalic NM. The Case for: hypoglycemia is of cardiovascular importance. Diabetes Care.
2013;36 Suppl 2:S264-6. 5.
Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes
Care. 2011;34 Suppl 2:S132-7. 6.
Wilson PW. Diabetes Mellitus and Cardiovascular Risk. In: Eckel RH, Antman E.
Metabolic Risk for Cardiovascular Disease. Massachussetts: Wiley; 2011. p.134-55. (AHA clinical series editor). 7.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Action to control
Cardiovascular Risk in Diabetes Study Group, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-59. 8.
Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-
analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141(6):421-31. 9.
Aronson D, Burger AJ. Diabetes and the occurrence of ventricular arrhythmic events in
patients with severe left ventricular dysfunction. Diabetologia. 2002;45(10):1440-5. 10.
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Our reference: DIAB 107878 Article reference: DIAB_2019_421 Article title: Can hypoglycemic episodes in type 1 diabetics trigger cardiac arrhythmias? To be published in: Diabetes Research and Clinical Practice Figure with legend
Figure 1. Percentage of interstitial glucose of total monitoring time (24h analysis). *1. From 1% (14 min.) to 5% (1h20min.) of the total time in hypoglycemia; * 2. From 6% (1h44min.) to 10% (2h40min.) of the total time in hypoglycemia; * 3. From 11% (2h54min.) to 15% (4h) of the total time in hypoglycemia; * 4. From 16% (4h24min.) to 20% (5h20min.) of the total time in hypoglycemia; * 5. From 21% (5h34min.) to 25% (6h) of the total time in hypoglycaemia; * 6. From 26% (6h24min.) To 30% (7h20min.) Of the total time in hypoglycemia; * 7. From 31% (7h34min.) to 35% (8h40min.) of the total time in hypoglycemia; * 8. From 36% (9h04min.) to 40% (10h) of the total time in hypoglycemia; * 9. From 41% (10h14min.) to 45% (11h20min.) of the total time in hypoglycemia; * 10. From 46% (11h34min.) to 50% (12h) of the total time in hypoglycemia; * 11. From 51% (12h14min.) to 55% (13h20min.) of the total time in hypoglycemia; * 12. From 56% (13h34min.) to 60% (14h40min.) of the total time in hypoglycemia; * 13. From 61% (14h54min.) to 65% (16h) of the total time in hypoglycemia; * 14. From 66% (16h14min.) to 70% (17h20min.) of the total time in hypoglycemia. There were no patients with a period greater than 70% of the total time in hypoglycemia.
Figure 2. Curve showing oscillation of the interstitial glucose level measured every 5 minutes for a period of 24h, showing a patient at the time of hypoglycemia. Green strip shows the normal range of glucose. * Interstitial glucose below 70 mg/dl ** Interstitial glucose between 70-140 mg/dl *** Interstitial glucose above 140 mg/dl
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Figure 3. Electrocardiogram tracings obtained from Holter monitoring. In A, sinus tachycardia (approximately 125 bpm) recorded in periods with and without documented hypoglycemia; in B, isolated supraventricular premature beat (highlighted in green by Holter), found in several patients, with or without episodes of hypoglycemia; and in C, ventricular extrasystole (in red), also common in non-diabetic patients.
Figure 4. Follow-up of the interstitial glucose levels and the occurrence of arrhythmias.
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