Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 791–794

Contents lists available at ScienceDirect

Diabetes & Metabolic Syndrome: Clinical Research &

Reviews
journal homepage: www.elsevier.com/locate/dsx

Hypoglycemia in Type 2 Diabetes Mellitus patients: A review article

Ayla M. Tourkmania,* , Turki J. Alharbia , Abdulaziz M. Bin Rsheeda ,
Abdulrhamn N. AlRasheeda , Saad M. AlBattala , Osama Abdelhaya , Mohamed A. Hassalib ,
Alian A. Alrasheedyc, Nouf G. Al Harbia , Abdulaziz Alqahtania
a
Family and Community Medicine Department, Chronic Diseases Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
b
Discipline of Social and Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
c
Department of Pharmacy Practice, Unaizah College of Pharmacy, Qassim University, Qassim Saudi Arabia

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

Keywords: Hypoglycemia is an essential issue for diabetic patients and considered a limiting factor in the glycemic
Diabetes management. Heterogeneity of the diseases in Type 2 Diabetes Mellitus can affect the frequency of
Hypoglycemia hypoglycemia, especially when the patient has cardiovascular diseases. There are several factors that lead
Frequency
to hypoglycemia including sulfonylurea therapy, insulin therapy, delaying or missing a meal, physical
Ramadan
exercise, or alcohol consumption. Long-term studies reported that repeated hypoglycemia could increase
Fasting
the risk of cardiovascular diseases. During Ramadan fasting, diabetic patients have high incidence of
hypoglycemia. Therefore, focused education about hypoglycemia in routine life of diabetic patients and
during fasting in Ramadan is important to reduce the complications.
© 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Contents

1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
2. The sequence of physiological mechanisms of Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
3. Classification of Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
4. Frequency of hypoglycemia in diabetic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
5. Risk factors for severe hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
6. Impact of hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
7. Prevention of hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
8. Recommendations for fasting with diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794

1. Definition physiological mechanisms are usually effective in preventing or

rapidly correcting hypoglycemia [2,3].
Hypoglycemia is defined among patients with diabetes as the
decrease of blood glucose level below 3.9 mmol/L (70 mg/dL). 2. The sequence of physiological mechanisms of Hypoglycemia
Hypoglycemia, usually iatrogenic, is considered the major limiting
factor in the glycemic control in T1D and to less extent T2D [1].  Decreased insulin secretion, which happens at a plasma glucose
In normal non-diabetic adults, the decrease of blood glucose concentration range of 72–108 mg/dl (4.0–6.0 mmol/l).
concentration normally stimulates a sequence of responses that  The release of counter-regulatory hormones including glucagon
are dependent on the levels of blood glucose (Fig. 1). These and epinephrine secretion, which happen at a plasma glucose
concentration range of 65–70 mg/dl (3.6–3.9 mmol/l). Glucagon
secretion stimulates glycogenolysis (breakdown of glycogen)
and stimulates gluconeogenesis (generation of glucose from
* Corresponding author. non-carbohydrate sources) in the liver. Epinephrine secretion
E-mail address: aylatourkmani@gmail.com (A.M. Tourkmani). stimulates hepatic glycogenolysis as well as hepatic and renal

https://doi.org/10.1016/j.dsx.2018.04.004
1871-4021/© 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.
792 A.M. Tourkmani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 791–794
Fig. 1. Glycemic thresholds for secretion of counter-regulatory hormones [5].
gluconeogenesis Onset of cognitive, physiological, and symp-
tomatic changes, which happen at a plasma glucose concentra-
tion range of 50–55 mg/dl (2.8–3.0 mmol/l). Hypoglycemia is
associated with acute short-term symptoms such as tachycardia
and sweating, irritability, confusion, and in severe cases stupor,
coma, and even death [4].
In diabetic patients, the counter-regulatory mechanisms that
aim to correct the hypoglycemia are intact early in the course of
T2D. However, in long-standing T2D, there are progressive insulin
deficiency and progressive increase in the frequency of iatrogenic
hypoglycemia. Thus, patients with T2D experience glucose
counter-regulatory defects similar to those experienced in T1D.
Among patients with T1D, the intake of excess insulin can cause
hypoglycemia and remove the first mechanism which is decreasing
insulin secretion. Additionally, the glucagon secretion as a
response to hypoglycemia is partially or fully lost among patients
with established T1D. Moreover, the epinephrine secretion as a
response to falling glucose levels is typically attenuated in T1D
[2,3,5].
The details of poor counter-regulatory mechanism in old
standing diabetes including the autonomic failure are shown in
Fig. 2.
Some studies examined the potential impact of aging on the
counter-regulatory and symptomatic responses to hypoglycemia. It
was shown that in healthy individuals the autonomic and neuro-
glycopenic symptoms are significantly lower in the older than
Fig. 2. Hypoglycemia-associated autonomic failure in diabetes [3].
younger adults. Additionally, in younger adults, higher blood glucose
levels initiate symptomatic responses to hypoglycemia, which allow
sufficient time for the body systems to take protective actions before
the start of more severe neuroglycopenic symptoms. However, the
effect of aging on the counter-regulatory and symptomatic responses
to hypoglycemia among patients with T2D was poorly studied, and
the results were conflicting [2]. This is probably caused by the wide
range of confounding factors expected in older population such the
number of comorbidities, hormonal imbalance, and intake of
multiple interacting medications [2].
3. Classification of Hypoglycemia
The American Diabetes Association workgroup suggests the
following classification of hypoglycemia in diabetes:
1) Severe Hypoglycemia. Severe hypoglycemia is an event requir-
ing the assistance of another person to actively administer
carbohydrates, glucagon, or take other corrective actions.
Plasma glucose concentrations may not be available during
an event, but neurological recovery following the return of
plasma glucose to normal is considered sufficient evidence that
the event was induced by a low plasma glucose concentration.
2) Documented symptomatic hypoglycemia. Documented symp-
tomatic hypoglycemia is an event during which typical
symptoms of hypoglycemia are accompanied by a measured
plasma glucose concentration #70 mg/dL (3.9 mmol/L).
3) Asymptomatic hypoglycemia. Asymptomatic hypoglycemia is
an event not accompanied by typical symptoms of hypoglyce-
mia but with a measured plasma glucose concentra-
tion 70 mg/dL (3.9 mmol/l)
4) Probable symptomatic hypoglycemia. Probable symptomatic
hypoglycemia is an event during which symptoms typical of
hypoglycemia are not accompanied by a plasma glucose
determination, but that was presumably caused by a plasma
glucose concentration#70 mg/dL (3.9 mmol/L).
5) Pseudo-hypoglycemia. Pseudohypoglycemia is an event during
which the person with diabetes reports any of the typical
symptoms of hypoglycemia with a measured plasma glucose
concentration. 70 mg/dL (.3.9 mmol/L) but approaching that
level.
4. Frequency of hypoglycemia in diabetic patients
The frequency of hypoglycemia is lower in T2D than T1D.
Additionally, the accuracy of determining the frequency of
hypoglycemia in T2D is lower due to the heterogeneity of the
disease. In fact, the frequency is lower in T2D patients due to the
relative deficiency in insulin level compared to the absolute
deficiency of insulin in T1D, and that it can affect people with wide
range of age. In the elderly people, the response of hypoglycemia is
lower due to the impairment of counter regulatory hormones
mechanism [6] Moreover; older people are aware of hypoglycemia
at a variable threshold between 5 mmol/L and nine mmol/L, which
is higher than the usually defined <4 mmol/L. Heterogeneity of the
diseases can affect the frequency of hypoglycemia, especially when
the patient has other comorbid diseases such as cardiovascular
diseases. However, the evidence of CV morbidity associated with
hypoglycemia has been hypothetical and anecdotal [2,6].
Also, the relative deficiency of insulin production in T2D is
variable between patients, unlike T1D which is characterized by an
absolute deficiency in insulin production. This risk might be
further confounded by the development of impaired awareness of
hypoglycemia particularly in patients with coexisting CV auto-
nomic neuropathy.
 A.M. Tourkmani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 791–794
Therefore, the lower frequency of hypoglycemia in T2D
compared with T1D may be explained by several reasons such
as the presence of some endogenous insulin production, insulin
resistance, better preserved counter-regulatory hormonal
response, and better-preserved hypoglycemia awareness [7].
The frequency of hypoglycemia varies depending on its degree
and the diabetes management. Mild hypoglycemia is defined as
hypoglycemia that can be self-treated, while severe hypoglycemia
is defined as episodes requiring external assistance [2].
In the U.S. Veterans Affairs T2D study, the frequency of mild
hypoglycemia among those who receive the standard diabetes
management was 1.5 episodes per patient per year, which was
significantly lower than the frequency in the intensively treated
patients, which was 16.5 episodes per patient per year [8].
The overall incidence of severe hypoglycemia in the same study
was 0.02 episodes per patient per year [8].
A review of 11 retrospective and prospective studies examining
the incidence of severe hypoglycemia was done [7]. It included
studies that examined patients with T2D treated with insulin and
followed for at least six months [7].
In the retrospective studies, between 1.4 and 15% of the patients
reported one or more episodes of hypoglycemia with the incidence
of severe hypoglycemia ranged from 15 to 73 episodes per 100
patient-year [7].
The frequency of hypoglycemia in T2D is different by the type of
treatment received [2].
Therefore, it is higher among those treated by insulin than oral
antidiabetic drugs. In a cross-sectional study among more than
1000 T2D in an outpatient diabetes clinic, it was found that the
prevalence of hypoglycemic symptoms was 12% in patients on a
diet alone, 16% in patients using oral antidiabetic drugs alone, and
30% among those using insulin [9].
Furthermore, severe hypoglycemic symptoms were observed
only among patients using insulin [9].
On the other hand, hypoglycemia seen among patient on oral
antidiabetic drugs is predominantly associated with sulfonylurea
which acts by stimulating the secretion of insulin (secretagogues).
The hypoglycemia associated with secretagogues is highest with
long-acting sulfonylureas such as (glibenclamide), chlorprop-
amide, and long-acting glipizide. On the other hand, hypoglycemia
is not common side effect among patients taking metformin and is
mainly seen in case of limited food intake. Similarly, hypoglycemia
is not a common side effect of thiazolidinediones and glucosidase
inhibitors [2].
5. Risk factors for severe hypoglycemia
On the other hand, Miller et al. did not find any relation between
severe hypoglycemia and several risk factors such as age, gender,
BMI, duration of diabetes, type of diabetes therapy, or increased
diabetic medication [9].
Contributing risk factors that were identified in literature
included sulfonylurea therapy, delayed or missed meal, physical
exercise, or drug or alcohol consumption [4].
Only a few studies examined the association of severe
hypoglycemia with patient risk factors. Henderson et al. 2003,
Reported the risk factors predispose to severe hypoglycemia in
patients with T2D treated with insulin. These included older age,
impaired hypoglycemia awareness, long duration of diabetes but
no association was found with HbA1c and insulin dose [10].
6. Impact of hypoglycemia
Hypoglycemia is a serious complication, and if not managed
promptly, it can be life-threatening. For example, it was shown that
severe hypoglycemia among patient with T2D treated with
793
sulfonylurea is associated with approximately 9% mortality rate
[11].
Additionally, There are several social and life style consequen-
ces of repeated episodes of hypoglycemia. These include difficulty
in getting or maintaining a job, reduced productivity, restricted
social interactions such as sport and leisure activities, disturbed
sleep rhythm, difficulty in getting or maintaining driving license,
liability to accidents such as fall and car accidents, lack of self-
confidence, and the fear of hypoglycemia [4].
Repeated hypoglycemia can be associated with weight gain due
to increased eating as self-defense against hypoglycemia. As
hypoglycemia needs more clinic and emergency visits, it can be
associated with higher healthcare utilization and spending [4].
Long-term studies reported that repeated hypoglycemia can be
associated with microvascular and macrovascular complication,
and increasing the risk of cardiovascular disease. The reasons could
be related to the weight gain and repeated exposure to catechol-
amines [4].
The fear of the occurrence of hypoglycemia can negatively affect
the ability to achieve glycemic control among patients with T2D
[5,12]. It was suggested that interventions that improved the
patient awareness of self-monitoring and cognitive behavioral
therapy could reduce levels of fear of hypoglycemia [12].
7. Prevention of hypoglycemia
To prevent hypoglycemic, the healthcare provider should set
individualized glycemic target while avoiding strict glycemic
control, particularly in elderly patients with complicated or
advanced T2D. In setting the treatment strategy, the physician
should aim to achieve the goals of treatment with minimal
development of adverse effects [5].
Healthcare providers should pay particular attention to a
patient's risk for hypoglycemia when initiating or intensifying the
pharmacological treatment regimen [13,14].
Some of these assessment factors include having unplanned
meal, practicing unusual exercise, alcohol ingestion, using multiple
medications, and associated comorbidity [5].
Diabetes education is a critical component for proper hypogly-
cemia prevention and management, particularly in patients with a
higher risk of hypoglycemia. It can improve the patient awareness
of hypoglycemia symptoms and increase his/her self-management
ability [5].
Other approaches include dietary and exercise modification and
medication adjustment. The later may include substitution of
sulfonylurea with other oral antidiabetic drugs with lower risk for
hypoglycemia, using long-acting basal analog insulin, using lowest
dose to achieve targeted glycemic control, and strict adherence to
medication [5].
During Ramadan fasting, diabetic patients have high incidence
of hypoglycemia In a large population-based cross-sectional study
conducted in 13 countries among more than 12,000 patients with
diabetes (epidemiology of diabetes and Ramadan "EPIDIAR"
study), the researchers found that the change in eating patterns
increased the risk of severe hypoglycemia during Ramadan by
4.7-times in type 1 diabetes (T1D) and 7.5-times in T2D.
Additionally, the incidence of severe hyperglycemia during
Ramadan increased five times in patients with T2D [15,16].
Moreover, according to a study from Pakistan, 21.7% of diabetic
patients who fast in Ramadan reported hypoglycemia while 19.8%
reported hyperglycemia. The study also found that 4% had major
hypoglycemic episodes and 8% had major hyperglycemic episodes
during Ramadan [17].
Education before fasting and encourage frequent monitoring of
the levels of blood glucose during Ramadan. Patients with diabetes
may face several challenges during Ramadan, these include:
794 A.M. Tourkmani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 791–794
 Diabetic patients may face the higher risk of developing severe
and sometimes life-threatening complications, such as hypogly-
cemia [13,15]. This risk may be even higher among those who
need to travel or exert more than usual physical activities.
 Diabetic patients who have inverted sleep and eating patterns
during Ramadan require major changes in the quality and timing
of diabetic management [18].
 Diabetic patients face long day-time fasting hours that may reach
16–17 h in several Islamic countries [19]. This may require
changes in the frequency of oral antidiabetic drugs.
 The traditional habits of having the breakfast outside home or
among groups or relatives, where a lot of high sugar and fat diets
are served [18,20], may represent an additional burden to keep
tight glycemic control.
 The majority of Muslim patients with diabetes are frequently
unaware of the risky symptoms or warning criteria that justify
immediate breaking of fasting [21].
 The majority of Muslim diabetic patients may have limited use of
intensive therapies.
8. Recommendations for fasting with diabetes
Impact of fasting on patients with diabetics Focused education
about hypoglycemia in routine life of diabetic patients and during
fasting in Ramadan is important to reduce complications, and it
could be recommended for T2D patients with increased risk of
hypoglycemia during Ramadan fasting Recently, in 2016, the IDF in
collaboration with the Diabetes and Ramadan (DAR) International
Alliance released updated clinical guidelines for diabetes in
Ramadan. The risk stratification of individuals with diabetes
before Ramadan and the recommendations are quite similar to
previous versions of three risk categories: very high, high, and
moderate/low [22]. However, the management of diabetes is more
detailed and it has more evaluations of individual antidiabetic
mediations using the recent literature and evidence. Additionally,
an updated guide for medications used to treat chronic diseases
during Ramadan such as diabetes, hypertension, and psychiatric
diseases had been published [23].
A recent study showed that Ramadan-specific diabetes self-
management education should be targeted to individuals with
prior episodes of hypoglycemia to reduce hypoglycemic events and
therapeutic management of diabetes during Ramadan should be
individualized [24].
9. Conclusion
Hypoglycemia is a common issue for diabetic patients and
considered a limiting factor in the glycemic control. There are
several factors that could lead to hypoglycemia such as sulfonyl-
urea therapy, insulin therapy, delayed or missed meal, physical
exercise, or drug or alcohol consumption. In literature, it is
reported that repeated hypoglycemia could increase the risk of
cardiovascular diseases. Focused education programs about
hypoglycemia is important to reduce the complications and
related consequences of hypoglycemia.
References
[1] Katon W.J., Young BA, Russo J, Lin EH, Ciechanowski P, Ludman EJ, et al.
Association of depression with increased risk of severe hypoglycemic episodes
in patients with diabetes. Ann Family Med 2013;11(3):245–50.
[2] Zammitt NN, Frier BM. Hypoglycemia in Type 2 diabetes. Diabetes Care
2005;28(12):2948–61.
[3] Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care
2003;26(6):1902–22.
[4] Ahrén B. Avoiding hypoglycemia: a key to success for glucose-lowering
therapy in Type 2 diabetes. Vasc Health Risk Manag 2013;9:155.
[5] Yun J-S, Ko S-H. Avoiding or coping with severe hypoglycemia in patients with
Type 2 diabetes. Korean J Intern Med 2015;30(1):6.
[6] Du Y-F Ou H-Y, Beverly EA, Chiu C-J. Achieving glycemic control in elderly
patients with type 2 diabetes: a critical comparison of current options. Clin
Intervent Aging 2014;9:1963.
[7] Akram K, Pedersen-Bjergaard U, Borch-Johnsen K, Thorsteinsson B. Frequency
and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a
literature survey. J Diab Complicat 2006;20(6):402–8.
[8] Abraira C, Colwell JA, Nuttall FQ, Sawin CT, Nagel NJ, Comstock JP, et al.
Veterans affairs cooperative study on glycemic control and complications in
type II diabetes (VA CSDM): results of the feasibility trial. Diabetes Care
1995;18(8):1113–23.
[9] Miller CD, Phillips LS, Ziemer DC, Gallina DL, Cook CB, El-Kebbi IM.
Hypoglycemia in patients with Type 2 diabetes mellitus. Arch Intern Med
2001;161(13):1653–2659.
[10] Henderson J, Allen K, Deary I, Frier B. Hypoglycaemia in insulin-treated Type 2
diabetes: frequency, symptoms and impaired awareness. Diabetic Med
2003;20(12):1016–21.
[11] Campbell I. Metformin and the sulphonylureas: the comparative risk.
Hormone Metab Res Supplement Ser 1985;15:105–11.
[12] Wild D, von Maltzahn R, Brohan E, Christensen T, Clauson P, Gonder-Frederick
L. A critical review of the literature on fear of hypoglycemia in diabetes:
implications for diabetes management and patient education. Patient Educ
Couns 2007;68(1):10–5.
[13] Ardigo S, Philippe J. Hypoglycémie et diabète. Revue médicale suisse
2008;160:1376.
[14] Moghissi E, Ismail-Beigi F, Devine R. Hypoglycemia: minimizing its impact in
Type 2 diabetes. Endocr Pract 2013;19(3):526–35.
[15] Salti I, Bénard E, Detournay B, Bianchi-Biscay M, Le Brigand C, Voinet C, et al. A
population-based study of diabetes and its characteristics during the fasting
month of Ramadan in 13 countries. Diabetes Care 2004;27(10):2306–11.
[16] Salti I, Benard E, Detournay B, Bianchi-Biscay M, Le Brigand C, Voinet C, et al. A
population-based study of diabetes and its characteristics during the fasting
month of Ramadan in 13 countries: results of the epidemiology of diabetes and
Ramadan 1422/2001 (EPIDIAR) study. Diabetes Care 2004;27(10):2306–11.
[17] Ahmadani M, Riaz M, Fawwad A, Hydrie M, Hakeem R, Basit A. Glycaemic trend
during Ramadan in fasting diabetic subjects: a study from Pakistan. Pak J Biol
Sci 2008;11(16):2044–7.
[18] Bahijri S, Borai A, Ajabnoor G, Khaliq AA, AlQassas I, Al-Shehri D, et al. Relative
metabolic stability, but disrupted circadian cortisol secretion during the
fasting month of Ramadan. PloS One 2013;8(4):e60917.
[19] Berbari AE, Mancia G. Special issues in hypertension. Springer; 2012.
[20] Bakhotmah BA. The puzzle of self-reported weight gain in a month of fasting
(Ramadan) among a cohort of Saudi families in Jeddah, Western Saudi Arabia.
Nutr J 2011;10(1):84.
[21] Bravis V, Hui E, Salih S, Mehar S, Hassanein M, Devendra D. Ramadan education
and awareness in diabetes (READ) programme for Muslims with Type 2
diabetes who fast during Ramadan. Diabetic Med 2010;27(3):327–31.
[22] International Diabetes Federation. Diabetes and Ramadan: Practical
Guidelines. April, 2016. URL: http://www.idf.org/sites/default/files/IDF-DAR-
Practical-Guidelines-Final-Low.pdf (Last Accessed August 10 2016). 2016.
[23] Y. Alomi, Update 2016- Drug Therapy during Holy Month of Ramadan Update
2016- Drug Therapy during Holy Month of Ramadan. URL: https://www.
researchgate.net/publication/303836239_Update_2016-
_Drug_Therapy_during_Holy_Month_of_Ramadan (Last Accessed on August
10 2016). 2016.
[24] Jabbar A, Hassanein M, Beshyah SA, Boye KS, Yu M, Babineaux SM. CREED
study: hypoglycaemia during Ramadan in individuals with Type 2 diabetes
mellitus from three continents. Diab Res Clin Pract 2017;132:19–26.