Severe hypoglycemia is recognized to be one of the strongest predictors of macrovascular events, adverse clinical outcomes, and mortality in patients with type 2 diabetes. However, it is uncertain whether a direct pathophysiological link exists or whether hypoglycemia is primarily a marker of vulnerability to these events. Large clinical trials have reported an increased hazard ratio for all-cause mortality and cardiovascular events in patients with type 2 diabetes and severe hypoglycemia, but such an association has not been demonstrated in prospective trials of people with type 1 diabetes. Several cardiovascular effects occur during hypoglycemia either as a result of low blood glucose levels per se or through activation of the sympathoadrenal response: hemodynamic changes with an increase in cardiac work load and potential attenuation of myocardial perfusion, electrophysiological changes that may be arrhythmogenic, induction of a prothrombotic state, and release of inflammatory markers. Although the potential for a causal relationship has been demonstrated in mechanistic studies, the evidence from large prospective studies that hypoglycemia is a major causal contributor to cardiovascular events is limited to date. Other preexisting cardiovascular risk factors in addition to hypoglycemia may be the major link to the final cardiovascular event, but a low blood glucose level can trigger these events in patients with a high cardiovascular risk.

Hypoglycemia is a frequent adverse complication of glucose-lowering treatment of diabetes, particularly with insulin and sulfonylureas. Severe hypoglycemia has been identified to be one of the strongest predictors of macrovascular events, adverse clinical outcomes, and mortality in people with type 2 diabetes (14). The adjusted hazard ratios for total mortality of patients experiencing at least one episode of severe hypoglycemia (defined as requiring assistance for recovery) compared with those with no hypoglycemia in large prospective randomized trials have been found to be between 1.67 and 4.28; by contrast, nonsevere (self-treated) hypoglycemia was not associated with a significant increase in either total mortality or cardiovascular death (35). A meta-analysis of prospective and retrospective cohort studies in people with type 2 diabetes has supported this interpretation and reported a hazard ratio of 2.05 (95% CI 1.74, 2.42) for cardiovascular outcomes (i.e., death from cardiovascular causes, myocardial infarction, stroke, or surgical intervention for vascular disease) (6). In type 1 diabetes, large prospective studies such as the Diabetes Control and Complications Trial (DCCT) and the EURODIAB Prospective Complications Study have not demonstrated an increased risk of mortality or fatal cardiovascular disease related to hypoglycemia (7,8), but a recent retrospective cohort study using the Clinical Practice Research Datalink database reported a hazard ratio for all-cause mortality of 1.98 (1.25, 3.17) in patients with type 1 diabetes who had experienced at least one episode of severe hypoglycemia (9).

In large prospective studies in type 2 diabetes, the frequency of severe hypoglycemic events is much higher with intensification of glucose-lowering therapy compared with standard treatment by a factor of at least two to three, but the reported event rate differs considerably between the trials and is not exclusively associated with the HbA1c value but also depends on age, comorbidities, diabetes duration, and treatment regimens (3,8,1013). A high degree of underreporting of hypoglycemia is likely in these long-term trials, since many events occur during sleep and are not perceived by the patients, and continuous glucose monitoring was not undertaken (14). Despite the strong evidence for a relationship between hypoglycemia and both cardiovascular and all-cause mortality in large prospective outcome studies of patients with type 2 diabetes, it is unclear whether there is a direct pathophysiological link with hypoglycemia or whether hypoglycemia is primarily a marker of vulnerability to these events.

Cardiovascular Effects of Hypoglycemia

During hypoglycemia, the brain becomes neuroglycopenic and the central autonomic nervous system is stimulated as part of the counterregulatory response to hypoglycemia. With respect to the cardiovascular system, the most important response is sympathoadrenal activation with the release of catecholamines, but the parasympathetic division is also activated and will also influence cardiac responses. The autonomic neural stimulation, accompanied by the surge in plasma catecholamines and the diminished energy supply of glucose per se, has profound cardiovascular effects. In one hypoglycemia clamp study (plasma glucose 3.0 mmol/L [54 mg/dL]) in participants without diabetes, a 12-fold increase in plasma epinephrine concentration was observed that was associated with increased heart rate and cardiac stroke volume and decreased peripheral resistance (15). Acute hypoglycemia provokes a substantial rise in myocardial contractility (16) and cardiac output (17). These hemodynamic changes are accompanied by an increase in elasticity of large blood vessels and a fall in central arterial pressure, with both measures being diminished in young men with type 1 diabetes of long duration (>15 years) in whom arterial stiffness has developed (18). A recent analysis of coronary artery calcification scores in patients with type 1 diabetes suggested an association of higher scores—indicating a higher degree of calcification and hence arterial stiffness—with a higher rate of severe hypoglycemia (19). Progressive arterial stiffness in people with diabetes allows the reflected arterial pressure wave to return to the central aorta and heart more quickly, arriving during diastole instead of systole, which may compromise coronary filling. These hemodynamic responses to hypoglycemia may be detrimental for people with diabetes of longer duration, particularly patients with type 2 diabetes who have underlying cardiac disease including coronary heart disease, autonomic abnormalities, and dysfunction of cardiac muscle (20,21).

Evidence that hypoglycemia can cause myocardial ischemia is accumulating. In an American study of 19 patients with type 2 diabetes who had documented coronary heart disease, simultaneous continuous glucose monitoring and Holter ECG recording were applied; 10 episodes of hypoglycemia were associated with chest pain (out of 54 in total), and acute ischemic ECG abnormalities were present during 6 of these episodes (22). A surrogate measure of myocardial perfusion during hypoglycemia in young adults with and without type 1 diabetes has recorded lower values in the group with diabetes (23). How often severe hypoglycemia may cause myocardial infarction is unknown, as only a few anecdotal cases have been reported, while a large retrospective Japanese study of 414 subjects presenting with severe hypoglycemia revealed newly diagnosed vascular disease in five patients (with only 1 case of myocardial infarction and 4 cases of cerebrovascular disease) (24).

Even more important than the association between hypoglycemia and cardiac ischemia is the possible induction of serious cardiac arrhythmias, which can lead to sudden death, as has been documented in several case reports (2527). Epinephrine induces hypokalemia, which affects electrophysiological function and may predispose to the development of an arrhythmia (28). A very frequent finding during hypoglycemia is QT prolongation of the surface ECG. This has been demonstrated in both type 1 and type 2 diabetes (24,2931). QT prolongation is a strong risk factor for severe ventricular arrhythmia and sudden death (32) and has been suggested as an explanation for the “dead in bed” syndrome of patients with type 1 diabetes (29). Hypoglycemia can be proarrhythmogenic via different mechanisms: a low blood glucose has a direct effect on the ether-á-go-go–related gene (HERG) ion channel, and the catecholamine release causes hypokalemia and action potential prolongation and increases the risk of a dangerous ventricular arrhythmia (33,34).

Experimental animal studies of lethal hypoglycemia in rats have provided insight into disturbances of cardiac electrical stability, although these findings may not be directly applicable to humans. Profound biochemical hypoglycemia (blood glucose 0.6 mmol/L [12 mg/dL]) in rats initially induced sinus tachycardia and QT prolongation, followed by ventricular premature beat ventricular tachycardia and atrio-ventricular blockade. At the time of cardiorespiratory arrest, a markedly reduced heart rate (bradycardia) was the prominent finding (35). Interestingly, the reported ECG changes were significantly reduced after potassium supplementation or the administration of intracerebral glucose to prevent neuroglycopenia—both of these findings indicating a strong role for sympathoadrenal activation in the initiation of arrhythmias. Simultaneous recording of continuous interstitial glucose and ECG monitoring in humans with insulin-treated type 2 diabetes and cardiovascular disease demonstrated that a much higher incidence of bradycardia and atrial and ventricular premature beats was associated with spontaneous hypoglycemia, particularly during the night when the patients were asleep (36). In a comparable study population, our group in Germany observed a high number of complex ventricular arrhythmias but with no obvious synchronized occurrence of the cardiac arrhythmias with documented hypoglycemia (14,37). In this case-control study, the duration of severe hypoglycemia was the most important independent predictor of developing a serious ventricular arrhythmia. An example of a parallel recording is shown in Fig. 1. Finally, there are several case reports of hypoglycemia-induced cardiac arrhythmias, of which atrial fibrillation is one of the most commonly reported (29,38), though this has not been demonstrated by recent studies with parallel recording of ECG and continuous glucose monitoring.

Another mechanism that may link hypoglycemia with cardiovascular events is the prothrombotic effect of low blood glucose levels. Catecholamines and other hormones released during hypoglycemia increase blood viscosity and promote platelet aggregation and activation (21,3941). In addition, insulin-induced hypoglycemia in people with type 1 diabetes increases coagulation factors such as fibrinogen and factor VIII (42) and promotes the release of inflammatory cytokines to the circulation (41,43,44), which may remain elevated for several days after the hypoglycemia has resolved (40). Taken together, these proinflammatory and procoagulant effects could directly affect vascular flow, leave the affected individual vulnerable for some time after hypoglycemia, and potentially contribute to the occurrence of major vascular events. The major cardiovascular effects of hypoglycemia are shown in Table 1.

Clinical Implication of Hypoglycemia on Cardiovascular Events

The counterregulatory responses to hypoglycemia serve to restore euglycemia and protect the brain from protracted neuroglycopenia. However, some aspects of the counterregulatory mechanism, particularly the sympatho-adrenal response, can potentially promote a serious cardiovascular event, and the question remains whether there is a major link between low blood glucose level per se (or its related effects) and major cardiovascular and cerebrovascular events—myocardial infarction and sudden death from an arrhythmia or stroke. Despite the evident possibility of a causal relationship that has been clearly demonstrated by mechanistic studies, the evidence from large prospective studies that hypoglycemia is a major causal contributor to cardiovascular events is limited. The major limitation is the inability to assign the cause of death to hypoglycemia with absolute certainty, as many episodes are asymptomatic and are difficult to identify in clinical trials and the temporal relationship between hypoglycemia and a subsequent vascular outcome is often difficult to determine (14,20). Therefore, anecdotal case reports in which cardiac arrhythmia or sudden death is associated with documented hypoglycemia remain the principal source of evidence. Furthermore, most associations between hypoglycemia and cardiovascular events have been detected in patients with a high cardiovascular risk—defined by age, comorbidities, and concomitant medication. It is probable that preexisting cardiovascular risk factors other than the hypoglycemia per se were a major link to the cardiovascular events that were observed in these patients. This hypothesis is supported by additional analyses of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, and the Outcome Reduction With Initial Glargine Intervention (ORIGIN) study, which demonstrated indeed a higher rate of severe hypoglycemia but a lower rate of hypoglycemia-related mortality in the intensified treatment arm compared with the standard treatment (35).

In some mechanistic studies that focused on a high-risk population, the association between hypoglycemia and arrhythmias was influenced by covariates; for example, our group described a higher rate of ventricular tachycardia (VT) in patients with a hypoglycemic event, but VT occurred with the same frequency during daytime and sleep, whereas hypoglycemia was recorded twice as often at night than during daytime (14). This differs from the findings of Chow et al. (36), where bradycardia and ventricular ectopics were strongly associated with nocturnal rather than daytime hypoglycemia and may reflect the obtunded sympatho-adrenal response during sleep (43) allowing compensatory parasympathetic activity. Furthermore, the multivariate regression analyses of our data revealed—besides the duration of severe hypoglycemia—a low normal TSH level as an independent predictor for the occurrence of a VT (14). This would suggest that an interaction of risk factors, among them hypoglycemia, but not one factor alone may be a prerequisite for the final event.

So is hypoglycemia a major causal factor for cardiovascular events or is it a marker of vulnerability to these events? This question is not yet resolved. In conclusion, hypoglycemia can precipitate cardiac arrhythmias and may diminish myocardial perfusion, so leading to a major cardiovascular event (38) but probably in interaction with other risk factors. Through extrapolation of the evidence that is currently available, it would appear that severe hypoglycemia can trigger cardiovascular events in vulnerable patients who are at high cardiovascular risk and should therefore be avoided at all costs in people with known cardiac disease who require an individualized approach to diabetes care.

This publication is based on the presentations at the 5th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were made possible in part by unrestricted educational grants from AstraZeneca.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
Bedenis
R
,
Price
AH
,
Robertson
CM
, et al
.
Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study
.
Diabetes Care
2014
;
37
:
3301
3308
[PubMed]
2.
McCoy
RG
,
Van Houten
HK
,
Ziegenfuss
JY
,
Shah
ND
,
Wermers
RA
,
Smith
SA
.
Increased mortality of patients with diabetes reporting severe hypoglycemia
.
Diabetes Care
2012
;
35
:
1897
1901
[PubMed]
3.
Mellbin
LG
,
Rydén
L
,
Riddle
MC
, et al.;
ORIGIN Trial Investigators
.
Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial
.
Eur Heart J
2013
;
34
:
3137
3144
[PubMed]
4.
Zoungas
S
,
Patel
A
,
Chalmers
J
, et al.;
ADVANCE Collaborative Group
.
Severe hypoglycemia and risks of vascular events and death
.
N Engl J Med
2010
;
363
:
1410
1418
[PubMed]
5.
Bonds
DE
,
Miller
ME
,
Bergenstal
RM
, et al
.
The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study
.
BMJ
2010
;
340
:
b4909
[PubMed]
6.
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
[PubMed]
7.
Gruden
G
,
Barutta
F
,
Chaturvedi
N
, et al
.
Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study
.
Diabetes Care
2012
;
35
:
1598
1604
[PubMed]
8.
The Diabetes Control and Complications Trial Research Group
.
Hypoglycemia in the Diabetes Control and Complications Trial
.
Diabetes
1997
;
46
:
271
286
[PubMed]
9.
Khunti
K
,
Davies
M
,
Majeed
A
,
Thorsted
BL
,
Wolden
ML
,
Paul
SK
.
Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study
.
Diabetes Care
2015
;
38
:
316
322
[PubMed]
10.
Duckworth
W
,
Abraira
C
,
Moritz
T
, et al.;
VADT Investigators
.
Glucose control and vascular complications in veterans with type 2 diabetes
.
N Engl J Med
2009
;
360
:
129
139
[PubMed]
11.
Gerstein
HC
,
Miller
ME
,
Genuth
S
, et al.;
ACCORD Study Group
.
Long-term effects of intensive glucose lowering on cardiovascular outcomes
.
N Engl J Med
2011
;
364
:
818
828
[PubMed]
12.
Holman
RR
,
Paul
SK
,
Bethel
MA
,
Matthews
DR
,
Neil
HA
.
10-year follow-up of intensive glucose control in type 2 diabetes
.
N Engl J Med
2008
;
359
:
1577
1589
[PubMed]
13.
Patel
A
,
MacMahon
S
,
Chalmers
J
, et al.;
ADVANCE Collaborative Group
.
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes
.
N Engl J Med
2008
;
358
:
2560
2572
[PubMed]
14.
Pistrosch
F
,
Ganz
X
,
Bornstein
SR
,
Birkenfeld
AL
,
Henkel
E
,
Hanefeld
M
.
Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions
.
Acta Diabetol
2015
;
52
:
889
895
[PubMed]
15.
Laitinen
T
,
Huopio
H
,
Vauhkonen
I
, et al
.
Effects of euglycaemic and hypoglycaemic hyperinsulinaemia on sympathetic and parasympathetic regulation of haemodynamics in healthy subjects
.
Clin Sci (Lond)
2003
;
105
:
315
322
[PubMed]
16.
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
H1779
[PubMed]
17.
Hilsted
J
,
Bonde-Petersen
F
,
Nørgaard
MB
, et al
.
Haemodynamic changes in insulin-induced hypoglycaemia in normal man
.
Diabetologia
1984
;
26
:
328
332
[PubMed]
18.
Sommerfield
AJ
,
Wilkinson
IB
,
Webb
DJ
,
Frier
BM
.
Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia
.
Am J Physiol Endocrinol Metab
2007
;
293
:
E1274
E1279
[PubMed]
19.
Fährmann
ER
,
Adkins
L
,
Loader
CJ
, et al
.
Severe hypoglycemia and coronary artery calcification during the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study
.
Diabetes Res Clin Pract
2015
;
107
:
280
289
[PubMed]
20.
Hanefeld
M
,
Duetting
E
,
Bramlage
P
.
Cardiac implications of hypoglycaemia in patients with diabetes - a systematic review
.
Cardiovasc Diabetol
2013
;
12
:
135
[PubMed]
21.
Wright
RJ
,
Frier
BM
.
Vascular disease and diabetes: is hypoglycaemia an aggravating factor
?
Diabetes Metab Res Rev
2008
;
24
:
353
363
[PubMed]
22.
Desouza
C
,
Salazar
H
,
Cheong
B
,
Murgo
J
,
Fonseca
V
.
Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring
.
Diabetes Care
2003
;
26
:
1485
1489
[PubMed]
23.
Rana
O
,
Byrne
CD
,
Kerr
D
, et al
.
Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans
.
Circulation
2011
;
124
:
1548
1556
[PubMed]
24.
Tsujimoto
T
,
Yamamoto-Honda
R
,
Kajio
H
, 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
;
37
:
217
225
[PubMed]
25.
Leitch
A
.
Sudden death in insulin coma treatment for schizophrenia
.
J Nerv Ment Dis
1955
;
121
:
267
269
[PubMed]
26.
Tanenberg
RJ
,
Newton
CA
,
Drake
AJ
.
Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system
.
Endocr Pract
2010
;
16
:
244
248
[PubMed]
27.
Tattersall
RB
,
Gill
GV
.
Unexplained deaths of type 1 diabetic patients
.
Diabet Med
1991
;
8
:
49
58
[PubMed]
28.
Petersen
KG
,
Schlüter
KJ
,
Kerp
L
.
Regulation of serum potassium during insulin-induced hypoglycemia
.
Diabetes
1982
;
31
:
615
617
[PubMed]
29.
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
:
42
45
[PubMed]
30.
Landstedt-Hallin
L
,
Englund
A
,
Adamson
U
,
Lins
PE
.
Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus
.
J Intern Med
1999
;
246
:
299
307
[PubMed]
31.
Marques
JL
,
George
E
,
Peacey
SR
, et al
.
Altered ventricular repolarization during hypoglycaemia in patients with diabetes
.
Diabet Med
1997
;
14
:
648
654
[PubMed]
32.
Al-Khatib
SM
,
LaPointe
NM
,
Kramer
JM
,
Califf
RM
.
What clinicians should know about the QT interval
.
JAMA
2003
;
289
:
2120
2127
[PubMed]
33.
Nordin
C
.
The proarrhythmic effect of hypoglycemia: evidence for increased risk from ischemia and bradycardia
.
Acta Diabetol
2014
;
51
:
5
14
[PubMed]
34.
Zhang
Y
,
Han
H
,
Wang
J
,
Wang
H
,
Yang
B
,
Wang
Z
.
Impairment of human ether-à-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms
.
J Biol Chem
2003
;
278
:
10417
10426
[PubMed]
35.
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
;
62
:
3570
3581
[PubMed]
36.
Chow
E
,
Bernjak
A
,
Williams
S
, et al
.
Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk
.
Diabetes
2014
;
63
:
1738
1747
[PubMed]
37.
Stahn
A
,
Pistrosch
F
,
Ganz
X
, 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
:
516
520
[PubMed]
38.
Lindström
T
,
Jorfeldt
L
,
Tegler
L
,
Arnqvist
HJ
.
Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus
.
Diabet Med
1992
;
9
:
536
541
[PubMed]
39.
Frier
BM
.
Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications
.
Nat Rev Endocrinol
2014
;
10
:
711
722
[PubMed]
40.
Hutton
RA
,
Mikhailidis
D
,
Dormandy
KM
,
Ginsburg
J
.
Platelet aggregation studies during transient hypoglycaemia: a potential method for evaluating platelet function
.
J Clin Pathol
1979
;
32
:
434
438
[PubMed]
41.
Wright
RJ
,
Newby
DE
,
Stirling
D
,
Ludlam
CA
,
Macdonald
IA
,
Frier
BM
.
Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes
.
Diabetes Care
2010
;
33
:
1591
1597
[PubMed]
42.
Dalsgaard-Nielsen
J
,
Madsbad
S
,
Hilsted
J
.
Changes in platelet function, blood coagulation and fibrinolysis during insulin-induced hypoglycaemia in juvenile diabetics and normal subjects
.
Thromb Haemost
1982
;
47
:
254
258
[PubMed]
43.
Dandona
P
,
Chaudhuri
A
,
Dhindsa
S
.
Proinflammatory and prothrombotic effects of hypoglycemia
.
Diabetes Care
2010
;
33
:
1686
1687
[PubMed]
44.
Gogitidze Joy
N
,
Hedrington
MS
,
Briscoe
VJ
,
Tate
DB
,
Ertl
AC
,
Davis
SN
.
Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals
.
Diabetes Care
2010
;
33
:
1529
1535
[PubMed]