diabetes research and clinical practice 158 (2019) 107878

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Diabetes Research
and Clinical Practice
journal homepage: www.elsevier.com/locat e/dia bre s

Can hypoglycemic episodes in type 1 diabetics

trigger cardiac arrhythmias?

Kelly Regina Lainetti a,*, João Pimenta b, Marcio Faleiros Vendramini b

a
Institute of Medical Assistance to Public Servants of the State (IAMSPE), Mirandinha Street, 755, Sao Paulo 03641000, Brazil
b
Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, SP, Brazil

A R T I C L E I N F O A B S T R A C T

Article history: Background: Sudden nocturnal death is a syndrome that usually affects patients with
Received 9 April 2019 diabetes mellitus type 1 (DM1), being described mainly due to ventricular arrhythmias in
Received in revised form response to nocturnal hypoglycemia.
31 July 2019 Objectives: Evaluate the relation between hypoglycemia and ventricular arrhythmias in
Accepted 10 October 2019 patients with DM1 and normal structural heart.
Available online 24 October 2019 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
Keywords:
24hr ambulatory electrocardiographic recording by the Holter system (Cardios
Type 1 diabetes mellitus
Systems – Brazil). Patients were monitored for hypoglycemia without any type of induction
Hypoglycemia
(interstitial glucose <70 mg/dl) and cardiac arrhythmias within 24 h.
Continuous glucose monitoring
Results: Thirty-two patients were evaluated, with mean-age of 35 years, being 16 men.
Continuous ECG monitoring
Eleven patients (34%) did not have hypoglycemia, other 3 (27.3%) also had no arrhythmia,
Arrhythmias
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.
Ó 2019 Elsevier B.V. All rights reserved.

1. Introduction 3,9 mmol/L (70 mg/dL) accompanied by typical adrenergic

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
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].

* Corresponding author.
E-mail addresses: klainetti@hotmail.com (K.R. Lainetti), pimenta@cardiol.br (J. Pimenta).
https://doi.org/10.1016/j.diabres.2019.107878
0168-8227/Ó 2019 Elsevier B.V. All rights reserved.
2 diabetes research and clinical practice 158 (2019) 107878

Cardiac arrhythmias, such as conduction disturbances,
ventricular tachyarrhythmias and sudden death have been
described in patients with DM1 and is associated to acute epi-
sodes of hypoglycemia.
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 1214% increased
risk of all-cause mortality [7–11]. Some studies in humans
showed that the heart is more likely to present electrophysi-
ological changes and consequently the occurrence of arrhyth-
mias 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 hypo-
glycemia 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.
2. Patients and methods
DM1 patients treated in a single Diabetes Clinic in a govern-
mental 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 med-
ical 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 inel-
igible, 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 pul-
monary 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 h were
installed. Data was analyzed each 5 min and the general pic-
ture was given by means of graphics as shown in Fig. 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 ana-
lyzed by specific software. Additional informations such as
time of hypoglycemia and occurrence of arrhythmias were
analyzed. Hypoglycemia was defined as glucose 3,9
mmol/L, euglycemia 4,0 mmol/L (72 mg/dl) – 7,8 mmol/L
(140 mg/dl) and hyperglycemia 7,9 mmol/L (142 mg/dl). Statis-
tical analysis was not done because the results do not permit it.
3. 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). Twenty-one (66%) patients presented hypo-
glycemia within 24 h and remained hypoglycemic for some

Fig. 1 – Percentage of interstitial glucose of total monitoring time (24 h 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% (4 h) 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% (6 h) 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% (10 h) 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% (12 h) 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% (16 h) 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.
 diabetes research and clinical practice
Fig. 2 – Curve showing oscillation of the interstitial glucose level measured every 5 min for a period of 24 h, 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 and 140 mg/dl, *** Interstitial glucose above 140 mg/dl.
period as shown in Fig. 1. Most of episodes of hyperglycaemia
lasted less than 2 h 40 min, 100% of episodes lasted more than
14 min, the shortest interval was 2%, corresponding to
28 min, and the highest, 68%, equivalent to 16 h. Regarding
glycemic values, the lowest level was 40 mg/dl (documented
in 7 patients) and the highest was 400 mg/dl (1 patient). In
the Holter monitoring, 13 (40.6%) did not present arrhythmia
and 19 (59.4%) presented arrhythmias without clinical rele-
vance 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 (Fig. 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 h, 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 (Fig. 4).
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 dia-
betes, 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.
158 (2019) 107878 3
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 [7] performed in different
countries such Australia, Canada and United States, with over
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.
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 erro-
neously the episodes of hypoglycemia as possible causes of
arrhythmias.
Other factors that may have given warranty to these find-
ings are the absence of arrhythmias associated with hypo-
glycemia is social attitudes, as users of illicit drugs. This
fact directly influences the action of the metabolism of glu-
cose 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 h, 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
4 diabetes research and clinical practice 158 (2019) 107878

Fig. 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.

found. However, it is believed that the findings of this investiga- So, it has been concluded that there were no arrhythmias
tion can stimulate other researchers to confirm these results, as considered significant during episodes of hypoglycemia up to
well as to aggregate new knowledge to this subject of extreme a level of 40 mg/dl in individuals with DM1 without structural
importance to daily clinical practice. heart disease.
 diabetes research and clinical practice
Fig. 4 – Follow-up of the interstitial glucose levels and the occurrence of arrhythmias.
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.
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