Hypoglycemia: Causes

#### **Chapter 3**

### Causes of Hypoglycemia

*Ala' Abu-Odeh, Dalal Alnatour and Leen Fino*

#### **Abstract**

Blood glucose levels may vary during the day, when this variation goes below a specific limit, hypoglycemia occurs. Hypoglycemia is often associated with reductions in quality of life and even the risk of death. Moreover, hypoglycemia is correlated with physical and/or psychological morbidity. It is usually a result of the complex interaction between hyperinsulinemia and the compromised physiological and behavioral responses attempting to reduce glucose levels. Nevertheless, several conditions can cause hypoglycemia, both in diabetic and non-diabetic patients. Mutually, diabetic and non-diabetic hypoglycemia is common in terms of several medications, alcohol ingestion, critical illnesses, and non-B cell tumors.

**Keywords:** hypoglycemia, diabetes, drug-induced hypoglycemia, nondiabetic hypoglycemia

#### **1. Introduction**

Glucose is the main source of energy for your body and brain. It can be synthesized de novo or taken from food. Insulin helps to keep blood glucose at normal levels, so your body can work efficiently. Insulin's task is to help glucose to enter your cells and produce energy. If your glucose level is too low, hypoglycemia may occur [1].

Hypoglycemia is defined as a low plasma glucose level of less than 50 mg/dL, thus exposing the subject to potential harm. It is associated with several signs—palpitation, sweating, tremors (adrenergic response), dysarthria, confusion, epilepsy, visual disturbances, and coma (neuroglycopenic response) [2–4]. These affect patients' quality of life and can even increase the risk of death, particularly in diabetic patients. Furthermore, hypoglycemia is often associated with physical and psychological morbidity (such as generalized worry and mood disturbance) [3, 5]. In diabetic patients, the complex interaction between hyperinsulinemia and the compromised physiological and behavioral responses to reduced glucose levels can lead to hypoglycemia [6].

Diabetes—particularly with the use of insulin or sulfonylurea, that is, insulin secretagogue treatment, is the classical cause of hypoglycemia. Moreover, diverse causes are also common, such as medications, alcoholism, critical illness, cachectic state, cortisol insufficiency, gastric or bariatric surgery, pancreas transplantation, glucagon deficiency, dietary toxins, and various conditions (sepsis, starvation, severe excessive exercise), and insulinoma [3, 7, 8]. Not to mention the non-classical causes that may include congenital hyperinsulinism, insulin receptor mutation, inborn errors of metabolism, and non-islet-cell tumor [9].

#### **Figure 1.**

*Physiologic and behavioral defenses against hypoglycemia in humans.*

The primary cause of hypoglycemia is a complex interaction between hyperinsulinemia and compromised physiologic and behavioral responses to reducing glucose levels (**Figure 1**).

### **2. Diabetic hypoglycemia**

Diabetic hypoglycemia is both a physiologic and a clinical condition that is associated with increased mortality and morbidity in both type 1 and type 2 diabetes. Hypoglycemia has proven to have detrimental complications for diabetic patients in both the short and long term [10]. There are several causes of hypoglycemia in diabetic patients, including age, renal insufficiency or end-stage renal disease, pregnancy, and polypharmacy of diabetic medications [10, 11], as shown in (**Table 1**).

#### **2.1 Etiology**

#### *2.1.1 Drug induced*

As mentioned before, hypoglycemia is well known to be associated with diabetes. The risk of hypoglycemia is manifested as a limiting factor and a barrier to optimal treatment and glucose control of type 1 and type 2 diabetes. Although the risk of


#### **Table 1.**

*Causes of hypoglycemia in diabetic patients.*

hypoglycemia is more common in type 1 diabetes, it is prominent in type 2 diabetes with the use of an insulin secretagogue (such as sulfonylurea and glinides) and insulin [6, 10, 12]. Other types of antidiabetic medications have a low incidence of hypoglycemia.

Drug-induced hypoglycemia is not limited to antidiabetic medication use; other medications can also induce hypoglycemia. The most common non-antihyperglycemic medications that are correlated with hypoglycemia are angiotensin-converting enzyme inhibitors (ACEi), beta-blockers (BB), non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials, antiarrhythmics (such as quinine and quinidine), psychotropic medications antibiotics, for example, (cotrimoxazole, ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin). In addition, Clarithromycin has also been implicated in many hypoglycemia cases, and the risk of hypoglycemia is exceptionally high in the concomitant use of repaglinide [3, 11, 13]. A systematic review conducted in 2008 and included 448 references assessed 164 drugs associated with hypoglycemia [14], the most commonly mentioned drugs to be linked with hypoglycemia were—quinolones, pentamidine, quinine, beta-blockers, angiotensinconverting enzyme inhibitors (ACEI), and IGF.

#### *2.1.2 Insulin-related causes*

#### *2.1.2.1 Absolute insulin excess*

Both absolute and relative insulin excess is a major cause of hypoglycemia. Absolute insulin excess occurs due to excessive insulin doses, wrong time of injection, wrong insulin type, and decreased insulin clearance as in renal failure and ill-timed.

Therefore, the antidiabetic regimen should be adjusted according to a review of blood glucose patterns. In addition, understanding the pharmacokinetic profile of different types of insulin is a key to dosing insulin safely [6, 8, 10, 15].

#### *2.1.2.2 Relative insulin excess*

The relative insulin excess occurs due to:

a.Decreased exogenous glucose delivery

The risk of hypoglycemia is increased during overnight fasting and with exercise. A new exercise routine, duration, intensity, and inadequate energy intake can increase insulin sensitivity and glucose utilization. The glucose utilization/ insulin dose mismatch can increase the risk of hypoglycemia. It is worth mentioning that insulin doses on days of planned exercise should be well-controlled. Patients need to associate the meal with inulin injection and need to understand how the carbohydrates in their diet affect blood glucose [9, 12, 16]. Inherently, delayed meals, inadequate carbohydrate intake, and skipping meals or snacks can increase the risk of hypoglycemia [17].

b.Increased insulin sensitivity

The body's insulin sensitivity following weight loss or improved glycemic control often increases during midnight [6, 8].

#### c.Decreased endogenous glucose production

The effects of alcohol on blood glucose levels depend on the amount of alcohol consumption and the fed status of the individual. Acute alcohol intake after a fasting state (3–4 days) can induce severe hypoglycemia even in a healthy individual. Alcohol intake has an inhibitory effect on gluconeogenesis [13].

#### *2.1.3 Diabetic complications (gastroparesis, neuropathy)*

Gastroparesis, that is, delayed gastric emptying, is common autonomic neuropathy in patients with long-standing diabetes. It results in poor glycemic control and poor nutrition, and dehydration, resulting in frequent hypoglycemia episodes, hospitalizations, and poor quality of life [18, 19]. Neuropathy is also associated with hypoglycemia, particularly hypoglycemia-associated autonomic failure (HAAF). HAAF is a situation in which there is an absence or reduction of insulin secretion, enhancement of glucagon secretion, and/or a defective glucose counter-regulation by epinephrine. These factors induce hypoglycemia by reducing sympathetic neural activity and neurogenic symptoms [20].

#### *2.1.4 Malabsorption (Celiac disease, pancreatic exocrine insufficiency)*

Celiac disease is a chronic autoimmune disorder that destructs the small intestine, so the patient is unable to take nutrients in. It is prevalent in type 1 diabetes and causes episodes of hypoglycemia. Pancreatic exocrine insufficiency, which is characterized by a deficiency of exocrine pancreatic enzymes, is also associated with type I and II diabetes.

#### *2.1.5 Hormone deficiency (cortisol, growth hormone, hypopituitarism, glucagon, and epinephrine deficiency in insulin-deficient diabetes)*

The hormonal deficiency was found to be associated with hypoglycemia. Cortisol and growth hormone deficiencies, for instance, cause a reduction in gluconeogenesis and increased glucose utilization leading to hypoglycemia. Moreover, isolated glucagon deficiency can also result in hypoglycemia if insulin secretion is not suppressed and the counter-regulatory hormone epinephrine secretion is decreased. Studies also found that hypopituitarism may present with life-threatening hypoglycemia [21].

#### *2.1.6 Concurrent illness (renal, hepatic, or cardiac failure, sepsis)*

Hypoglycemia developing secondary to an underlying illness is associated with increased nutritional body demand due to increased metabolic response in critically ill patients. Endogenous glucose production is rapidly reduced in hepatic diseases and liver cirrhosis [22].

As kidneys play a major role in metabolizing insulin, reabsorption and synthesizing glucose, and excretion of different metabolites of hypoglycemic medications. Therefore, kidney impairment will prohibit all these processes leading to hypoglycemia. On the other hand, the counter-regulatory response to hypoglycemia may be defective due to uremia and associated anorexia [21]. On the other hand, in uremia, gluconeogenesis from the kidney and liver is reduced. Hypoglycemia can also occur in acute renal failure and end-stage renal disease (ESR), this is due to reduced renal insulinase-mediated insulin clearance.

Furthermore, severe cardiac failure and hepatic congestion may contribute to lower glucose output from the liver and reduce its intestinal absorption. While hypoglycemia in sepsis and adrenal insufficiency develops due to increased serum cortisol levels [4]. In literature, hypoglycemia in sepsis is often related to strict glycemic control protocols for stress hyperglycemia [23–27].

#### *2.1.7 Psychological*

#### *2.1.7.1 Fear of hypoglycemia*

The fear of hypoglycemia is common in patients with diabetes. It influences the quality and health outcomes. It can also increase the risk of poor metabolic control [28].

#### *2.1.7.2 Depression*

In diabetic patients with depression, hypoglycemia can occur frequently as a result of poor adherence to medications, diet, physical activity, smoking cessation, poor self-care, and blood glucose monitoring [29].

#### *2.1.7.3 Cognitive impairment*

Cognitive dysfunction and dementia may increase the risk of hypoglycemia, especially in elderly patients [30]. Although the association remains unclear, it is thought that person with cognitive disabilities will have errors in taking his medication [21].

#### **3. Non-diabetic hypoglycemia**

#### **3.1 Non-diabetic hypoglycemia: overview**

Non-diabetic hypoglycemia (hypoglycemia without diabetes) is a rare condition, it comes from having too much insulin in the blood, leading to low blood glucose levels. It can occur in pre-diabetes, sepsis, and critical organ failure including renal or hepatic failure. It also rarely occurs in cortisol deficiency [8], and β-cell tumors due to endogenous hyperinsulinism [8, 31–33]. Moreover, hypoglycemia can be accidental, surreptitious, or even malicious [34].

Hypoglycemia can occur post-bariatric surgery, that is, gastric bypass surgery, or even due to an autoimmune disease [8, 32, 33]. **Table 2** demonstrates the causes of hypoglycemia in nondiabetic patients.

#### **3.2 Differential diagnosis**

Whipple's triad (low plasma glucose level, clinical signs or symptoms of hypoglycemia, and resolution of signs or symptoms when the plasma glucose level increases) should be documented prior to initiating an evaluation [35].

When the patient is either looking ill or medicated, the initial diagnosis should focus on the possibility of drug involvement, critical conditions, hormone deficiency, or non-islet cell tumor hypoglycemia. If the patient seems well in the absence of any of the fore-mentioned etiologies, the focus should be on the possibility of having endogenous hyperinsulinism due to insulinomas, functional β-cell disorders, or insulin autoimmune conditions. In addition to the possibility of accidental, surreptitious,


#### **Table 2.**

*Causes of hypoglycemia in nondiabetic patients.*

or malicious hypoglycemia [35, 36]. Hypoglycemia in patients post-bariatric surgery is increasingly recognized as the frequency of these operations has grown in the last few decades [36].

#### **3.3 Etiology**

#### *3.3.1 Drug-induced*

Fasting hypoglycemia is found to be associated with several medications, such as salicylates pain killers, antibiotic sulfa drugs, pentamidine, and quinine antimalarial medications [1].

#### *3.3.2 Critical illnesses*

Dysglycemia, in the form of hyperglycemia, hypoglycemia, and/or marked glucose variability, is a characteristic feature of critical illness in both diabetic and nondiabetic patients [37]. It can increase morbidity and mortality [38]. Among hospitalized patients, serious illnesses, such as renal, hepatic, or cardiac failure; sepsis; and inanition are the only drugs to cause hypoglycemia.

#### *3.3.2.1 Sepsis*

Sepsis is one of the main causes of death across the world and is considered the most familiar cause of death among intensive care unit (ICU) patients [39]. The mortality rate due to sepsis ranges from 15 to 56% [40]. Not to mention that patients with sepsis usually report variable types of dysglycemia due to the changes in endocrine metabolism in sepsis, which affects the stability of the internal environment and worsens their general condition [41].

Sepsis patients are often complicated by hypoglycemia as has been approved by multiple large-scale randomized controlled trials (RCTs). Although such protocols have not been approved to improve patient mortality, rather they possibly increase the risk of hypoglycemia [41]. While there is a dearth of studies on the effects of spontaneous hypoglycemia in patients with sepsis, its occurrence leads to increased mortality and elevated lactate levels in patients with sepsis [41].

In septic patients, increased glucose utilization is induced by cytokine production in macrophage-rich tissues, such as the liver, spleen, and lung. Hypoglycemia develops if glucose production fails to keep pace. Cytokine-induced inhibition of gluconeogenesis in the setting of nutritional glycogen depletion, in combination with hepatic and renal hypoperfusion, may also contribute to hypoglycemia.

#### *3.3.2.2 Hepatic failure*

The liver as a metabolic organ plays an important role in glucose metabolism. It regulates the blood glucose level mainly through glycogenolysis and gluconeogenesis. Hepatic impairment is well known to correlate with poor blood glucose regulation [42]. The presence of liver impairment or hepatocellular damage can lead to a disturbance of the metabolic function of the liver causing an imbalance in blood glucose levels. Rapid and extensive hepatic destruction, such as toxic hepatitis, for example, causes fasting hypoglycemia due to the lack of endogenous glucose production.

#### *3.3.2.3 Renal failure*

Patients with end-stage kidney disease frequently experience variable glycemic disturbances, with the common incidence of both hypoglycemia and hyperglycemia. The risk of hypoglycemia is increased in critically ill renal patients and having chronic kidney disease is a known risk factor for developing hypoglycemia [43, 44]. Multiple mechanisms are involved in hypoglycemia development in kidney disease patients, including impaired gluconeogenesis process run by the kidney, impaired insulin clearance by the kidney, and impaired insulin degradation due to uremia.

Other mechanisms of developing hypoglycemia in kidney disease also include increased erythrocyte glucose uptake during hemodialysis, impaired counter-regulatory hormone responses (cortisol, growth hormone), and nutritional deprivation [45–49]. Moreover, insulin sensitivity may improve in uremic patients after starting renal replacement therapy increases the risk of hypoglycemia in renal replacement patients [50]. In contrast, the risk of hypoglycemia is reduced with starting hemodialysis due to the addition of glucose to the dialysis solution [51].

#### *3.3.2.4 Cardiac failure*

Severe heart failure is sometimes associated with hypoglycemia. However, the exact mechanism is yet to be determined. Several mechanisms have been suggested including impaired gluconeogenesis due to hepatic congestion and the reduced glycogen stores from either inadequate intake or reduced gastrointestinal absorption [52–54].

#### *3.3.2.5 Inanition*

Inanition is a well-known cause of hypoglycemia. During starvation, a catabolic state occurs when the body shifts from predominately carbohydrate metabolism to that of fat and protein, the brain then starts conversing and utilizing alternative substrates, such as lactate, pyruvate, and ketone bodies with only a modest counterregulatory neuroendocrine and autonomic nervous system response.

The refeeding syndrome (RFS) can occur after starvation and energy replenishment. This can be defined as severe electrolyte and metabolic abnormalities in undernourished patients after the introduction of nutrients [55–57]. Multiple organ systems including cardiac, respiratory, neurologic, and hematologic can be affected by the RFS and are occasionally associated with postprandial hypoglycemia [55, 58].

#### *3.3.3 Hormone deficiencies*

Increased cortisol and growth hormone (GH) secretion are involved in the defense mechanism against prolonged hypoglycemia. When these defenses fail to refute the hypoglycemia episode, plasma glucose levels will continue to fall [35].

Chronic cortisol deficiency is typically associated with anorexia and weight loss, likely leading to glycogen depletion. Cortisol deficiency is also associated with impaired gluconeogenesis and low levels of gluconeogenic precursors causing

#### *Causes of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.105061*

the substrate limited gluconeogenesis, in the setting of glycogen depletion, which leads to hypoglycemia.

Growth hormone deficiency can cause hypoglycemia in young children. In addition to extended fasting, high rates of glucose utilization, such as during exercise and in pregnancy, or low rates of glucose production, such as post-alcohol consumption, can precipitate hypoglycemia in adults with previously undiagnosed hypopituitarism [59].

#### *3.3.4 Non-islet cell tumor hypoglycemia (NICTH)*

Hypoglycemia due to non-islet cell tumors abbreviated as NICTH is considered to be rare [8, 31–33]; it is a rare paraneoplastic syndrome encountered in the setting of a wide variety of tumors and is most common in tumors of mesenchymal or hepatic origin [60]. Hypoglycemia in this realm is initially attributed to glucose consumption by the tumor and to tumor secretion of an "insulin-like" factor afterward, this factor is a precursor of IGF-2, called Big-IGF-2. While secretion of Big-IGF2 is the most common cause of NICTH, secretion of somatostatin or IGF1 may also be responsible [61]. Usually, IGF-2 related hypoglycemia manifests when the tumor turns quite large [62, 63].

#### *3.3.5 Endogenous hyperinsulinism*

Endogenous hyperinsulinism is a clinical condition that involves excessive insulin secretion and is related in 55% of cases to insulinoma [64]. Nesidioblastosis and insulinoma represent the main cause of endogenous hyperinsulinemic hypoglycemia in infants and apparently healthy adults, respectively [35]. The main pathophysiological feature of endogenous hyperinsulinism is the failure of insulin secretion to fall to very low levels when plasma glucose concentrations fall to hypoglycemic levels; hypoglycemia in this case is a result of low rates of glucose production, rather than high rates of glucose utilization [65]. Nesidioblastosis is a rare cause of persistent hyperinsulinemic hypoglycemia in adults. The hypoglycemia in the case of nesidioblastosis is attributed to β-cell hypertrophy and hyperfunction [66–68].

Post-prandial hypoglycemia can also be observed after bariatric surgeries, especially the procedures that divert nutrients into the mid-small bowel, such as Roux-en-Y gastric bypass surgery (RYGB), and not fully restrictive procedures like adjustable gastric banding [69]. Post-RYGB surgery hypoglycemia (PGBH) usually occurs between 1 and 8 years after the procedure [70], this might be due to several causes including late dumping syndrome, nesidioblastosis, and insulinoma [71].

#### *3.3.6 Insulin autoimmune hypoglycemia*

Hypoglycemia can also be caused by an antibody to insulin or its receptors, a condition known as insulin autoimmune syndrome (IAS) and also known as Hirata's disease or insulin autoimmune hypoglycemia (IAH). It is essentially a rare autoimmune disorder caused by the spontaneous production of anti-insulin and anti-insulin receptor antibodies which bind insulin/proinsulin and/or insulin receptors and work as insulin-mimetic leading to predominantly postprandial hyperinsulinemic hypoglycemia [9, 72]. Graves' disease is frequently present in Hirata syndrome and appears to be particularly prevalent in Japan [73].

#### *3.3.7 Intentional/accidental*

Hypoglycemia can also happen accidentally and can be surreptitious, malicious, or sometimes fictitious [74]. Pharmacy errors (e.g., substitution of a hypoglycemic drug for another medication) and medical treatment errors can stand behind some accidental intake cases [75].

Intentional hypoglycemia can be surreptitious and this is most commonly seen in people with knowledge of and access to glucose-lowering medications. It can be malicious which is usually accomplished by the administration of insulin or an insulin secretagogue [74]. It also can be fictitious in some cases.

#### *3.3.8 Infancy and childhood*

Hyperinsulinemic hypoglycemia (HH), which is characterized by unregulated insulin release, is the most common cause of persistent and severe hypoglycemia in infants and children [76]. This can be transient (associated with risk factors), or permanent (linked to genetic mutations). In the majority of cases (60–70%) hypoglycemia occurs in the first week of life [77, 78], and it carries a considerable risk of neurological damage and developmental delays if diagnosis and treatment were delayed [76].

HH is also classified as primary and secondary HH. The primary HH, which is also known as congenital HH (CHH), where the hypoglycemia is associated with variants in several genes involved in pancreatic development and function. The secondary HH, where hypoglycemia is associated with syndromes, such as intrauterine growth restriction, maternal diabetes, and birth asphyxia [79].

CHI can be classified according to etiology into two types—acquired and genetic. In neonates, acquired forms are usually associated with some conditions, such as perinatal stress or maternal gestational diabetes, and are often transient [80]. Genetic CHI can be caused by single-gene mutations in the insulin secretory pathway or genes causing syndromes with multiple associated factors, such as Beckwith-Wiedemann syndrome or Kabuki syndrome [78].

Hypoglycemia in infants can also be caused by counter-regulatory hormone deficiencies, such as adrenal insufficiency or GH deficiency [80]. In such cases, replacement of the deficient hormones yields a complete resolution of hypoglycemia. Some metabolic disorders, such as fatty acid oxidation disorders and certain glycogen storage disease types, are additional causes of hypoglycemia in infants and children [81].

*Causes of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.105061*

#### **Author details**

Ala' Abu-Odeh\*, Dalal Alnatour and Leen Fino Applied Science Private University, Amman, Jordan

\*Address all correspondence to: a\_abuodeh@asu.edu.jo

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Desimone ME, Weinstock RS. Nondiabetic hypoglycemia. The Journal of Clinical Endocrinology and Metabolism. 2016;**98**(10):39A

[2] Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: A report of a workgroup of the American Diabetes Association and the Endocrine Society. The Journal of Clinical Endocrinology and Metabolism. 2013;**98**(5):1845-1859

[3] Kalra S, Mukherjee JJ, Venkataraman S, Bantwal G, Shaikh S, Saboo B, et al. Hypoglycemia: The neglected complication. Indian Journal of Endocrinology and Metabolism. 2013;**17**(5):819

[4] Toor A, Toor A, Krishnamurthy M. Critical illness associated fatal hypoglycemia in a nondiabetic male. Case Reports in Critical Care. USA 2019;**2019**:1-3

[5] Cryer PE. Hypoglycemia. In: Endocrine Emergencies. USA: Springer; 2021. pp. 27-35

[6] Oyer DS. The science of hypoglycemia in patients with diabetes. Current Diabetes Reviews. 2013;**9**(3):195-208

[7] Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism. Elsevier, Amsterdam 2009;**94**(3):709-728

[8] Cryer PE, Polonsky K. Glucose homeostasis and hypoglycemia. In: Williams Textbook of Endocrinology. Vol. 88. Amsterdam: Elsevier; 2008. pp. 1589-1590

[9] Douillard C, Jannin A, Vantyghem MC. Rare causes of hypoglycemia in adults. 2020 [2213-3941 (Electronic)]

[10] Evans Kreider K, Pereira K, Padilla BI. Practical approaches to diagnosing, treating and preventing hypoglycemia in diabetes. Diabetes Therapy. 2017;**8**(6):1427-1435

[11] Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, et al. Drug-induced hypoglycemia: A systematic review. The Journal of Clinical Endocrinology and Metabolism. 2009;**94**(3):741-745

[12] Lamounier RN, Geloneze B, Leite SO, Montenegro R, Zajdenverg L, Fernandes M, et al. Hypoglycemia incidence and awareness among insulintreated patients with diabetes: The HAT study in Brazil. Diabetology and Metabolic Syndrome. 2018;**10**(1):1-10

[13] Kalaria T, Ko YL, Issuree KKJ. Literature review: Drug and alcoholinduced hypoglycaemia. Journal of Laboratory and Precision Medicine. 2021:1-16

[14] Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, Erwin PJ, et al. Clinical review: Drug-induced hypoglycemia: A systematic review [1945-7197 (Electronic)], USA

[15] Vanek C, Loriaux L. Endocrine Emergencies: Recognition and Treatment. USA: Springer; 2021

[16] Cryer P. Hypoglycemia in Diabetes: Pathophysiology, Prevalence, and Prevention. USA: American Diabetes Association; 2016

*Causes of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.105061*

[17] Silbert R, Salcido-Montenegro A, Rodriguez-Gutierrez R, Katabi A, McCoy RG. Hypoglycemia among patients with type 2 diabetes: Epidemiology, risk factors, and prevention strategies. Current Diabetes Reports. 2018;**18**(8):1-16

[18] Krishnasamy S, Abell TL. Diabetic gastroparesis: Principles and current trends in management. Diabetes Therapy. 2018;**9**(1):1-42

[19] Homko C, Siraj ES, Parkman HP. The impact of gastroparesis on diabetes control: Patient perceptions. Journal of Diabetes and its Complications. 2016;**30**(5):826-829

[20] Yanai H, Adachi H, Katsuyama H, Moriyama S, Hamasaki H, Sako A. Causative anti-diabetic drugs and the underlying clinical factors for hypoglycemia in patients with diabetes. World Journal of Diabetes. 2015;**6**(1):30

[21] Martín-Timón I, del Cañizo-Gómez FJ. Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World Journal of Diabetes. 2015;**6**(7):912

[22] Narla RR, Hashimoto T, Kelly K, Heaney A. Hypoglycemia: A tale of three causes. Journal of Clinical and Translational Endocrinology: Case Reports. 2016;**2**:4-6

[23] Metzger S, Nusair S, Planer D, Barash V, Pappo O, Shilyansky J, et al. Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1βsecreting tumor. Endocrinology. 2004;**145**(11):5150-5156

[24] Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. New England Journal of Medicine. 2008;**358**(2):125-139

[25] Kalfon P, Giraudeau B, Ichai C, Guerrini A, Brechot N, Cinotti R, et al. Tight computerized versus conventional glucose control in the ICU: A randomized controlled trial. Intensive Care Medicine. 2014;**40**(2):171-181

[26] Tanner O. Intensive versus conventional glucose control in critically ill patients. New England Journal of Medicine. 2009;**360**(13):1283-1297

[27] Maitra SR, Wojnar MM, Lang CH. Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis. Shock. 2000;**13**(5):379-385

[28] Anderbro T, Gonder-Frederick L, Bolinder J, Lins P-E, Wredling R, Moberg E, et al. Fear of hypoglycemia: Relationship to hypoglycemic risk and psychological factors. Acta Diabetologica. 2015;**52**(3):581-589

[29] Katon WJ, 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. Annals of Family Medicine. 2013;**11**(3):245-250

[30] Yun J-S, Ko S-H. Risk factors and adverse outcomes of severe hypoglycemia in type 2 diabetes mellitus. Diabetes and Metabolism Journal. 2016;**40**(6):423-432

[31] Service F. Hypoglycemic disorders. New England Journal of Medicine. 1995;**332**(17):1144-1152

[32] Service FJ. Classification of hypoglycemic disorders. Endocrinology and Metabolism Clinics of North America. 1999;**28**(3):501-517

[33] Guettier J-M, Gorden P. Hypoglycemia. Endocrinology and Metabolism Clinics. 2006;**35**(4):753-766

[34] Marks V, Teale JD. Drug-induced hypoglycemia. Endocrinology and Metabolism Clinics. 1999;**28**(3):555-577

[35] Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ, et al. Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline [1945-7197 (Electronic)]

[36] Madunić J, Madunić IV, Gajski G, Popić J, Garaj-Vrhovac V. Apigenin: A dietary flavonoid with diverse anticancer properties. Cancer Letters. 2018;**413**:11-22

[37] Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? [0021-9738 (Print)]

[38] Pérez-Calatayud ÁA, Guillén-Vidaña A, Fraire-Félix IS, Anica-Malagón ED, Briones Garduño JC, Carrillo-Esper R. Metabolic control in the critically ill patient an update: Hyperglycemia, glucose variability hypoglycemia and relative hypoglycemia [2444-054X (Electronic)]

[39] Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current Estimates and Limitations [1535-4970 (Electronic)]

[40] Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019—Results from a systematic review and meta-analysis. Critical Care. 2020;**24**(1):239

[41] Wang J, Zhu CK, Yu JQ, Tan R, Yang PL. Hypoglycemia and mortality in sepsis patients: A systematic review and meta-analysis [1527-3288 (Electronic)]

[42] Kumar R. Hepatogenous diabetes: An underestimated problem of liver cirrhosis [2230-8210 (Print)]

[43] Fischer KF, Lees JA, Newman JH. Hypoglycemia in hospitalized patients. Causes and Outcomes [0028-4793 (Print)]

[44] Arem R. Hypoglycemia associated with renal failure [0889-8529 (Print)]

[45] Sobngwi E, Enoru S, Ashuntantang G, Azabji-Kenfack M, Dehayem M, Onana A, et al. Day-today variation of insulin requirements of patients with type 2 diabetes and end-stage renal disease undergoing maintenance hemodialysis. Diabetes Care. 2010;**33**(7):1409-1412

[46] Rahhal M-N, Gharaibeh NE, Rahimi L, Ismail-Beigi F. Disturbances in insulin-glucose metabolism in patients with advanced renal disease with and without diabetes. The Journal of Clinical Endocrinology and Metabolism. 2019;**104**(11):4949-4966

[47] Gianchandani RY, Neupane S, Iyengar JJ, Heung M. Pathophysiology and management of hypoglycemiain end-stage renal disease patients: A review. Endocrine Practice. 2017;**23**(3):353-362

[48] Mak RH, De Fronzo RA. Glucose and insulin metabolism in uremia. Nephron. 1992;**61**(4):377-382

[49] Tuttle KR, Bakris GL, Bilous RW, Chiang JL, De Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: A report from an ADA Consensus Conference. Diabetes Care. 2014;**37**(10):2864-2883

*Causes of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.105061*

[50] DeFronzo RA, Tobin JD, Rowe JW, Andres R. Glucose intolerance in uremia. Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin [0021-9738 (Print)]

[51] Burmeister JE, Scapini A, da Rosa Miltersteiner D, da Costa MG, Campos BM. Glucose-added dialysis fluid prevents asymptomatic hypoglycaemia in regular haemodialysis [0931-0509 (Print)]

[52] Kittah NE, Vella A. Management of endocrine disease: Pathogenesis and management of hypoglycemia [1479- 683X (Electronic)]

[53] Sako A, Yasunaga H, Matsui H, Fushimi K, Hamasaki H, Katsuyama H, Tsujimoto T, et al. Hospitalization with hypoglycemia in patients without diabetes mellitus: A retrospective study using a national inpatient database in Japan. 2008-2012 [1536-5964 (Electronic)]

[54] Mellinkoff SM, Tumulty PA. Hepatic hypoglycemia; its occurrence in congestive heart failure [0028-4793 (Print)]

[55] Boateng AA, Sriram K, Meguid MM, Crook M. Refeeding syndrome: Treatment considerations based on collective analysis of literature case reports [1873- 1244 (Electronic)]

[56] Solomon SM, Kirby DF. The refeeding syndrome: A review [0148- 6071 (Print)]

[57] Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome [0899-9007 (Print)]

[58] Heruc GA, Little TJ, Kohn MR, Madden S, Clarke SD, Horowitz M, et al. Effects of starvation and shortterm refeeding on gastric emptying and postprandial blood glucose regulation in adolescent girls with anorexia nervosa [1522-1555 (Electronic)]

[59] Reznik Y, Barat P, Bertherat J, Bouvattier C, Castinetti F, Chabre O, et al. SFE/SFEDP adrenal insufficiency French consensus: Introduction and handbook [Consensus sur l'insuffisance surrénale de la SFE/SFEDP: introduction et guide]. Annales d'Endocrinologie. 2018;**79**(1):1-22

[60] Teale JD, Marks V. Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH). Clinical Endocrinology. 1998;**49**(4):491-498

[61] Daughaday WH. Hypoglycemia due to paraneoplastic secretion of insulinlike growth factor-I. The Journal of Clinical Endocrinology and Metabolism. 2007;**92**(5):1616

[62] Phillips LS, Robertson DG. Insulinlike growth factors and non-islet cell tumor hypoglycemia. Metabolism. 1993;**42**(9):1093-1101

[63] Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL, et al. Tumors, IGF-2, and hypoglycemia: Insights from the clinic, the laboratory, and the historical archive. Endocrine Reviews. 2013;**34**(6):798-826

[64] Phan GQ, Yeo CJ, Hruban RH, Littemoe KD, Pitt HA, Cameron JL. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: Review of 125 patients. Journal of Gastrointestinal Surgery. 1998;**2**(5):473-482

[65] Rizza RA, Haymond MW, Verdonk CA, Mandarino LJ, Miles JM, Service FJ, et al. Pathogenesis of hypoglycemia in insulinoma patients: Suppression of

hepatic glucose production by insulin. Diabetes. 1981;**30**(5):377-381

[66] Dravecka I, Lazurova I. Nesidioblastosis in adults. Neoplasma. 2014;**61**(3):252-256

[67] Jabri A, Bayard C. Nesidioblastosis associated with hyperinsulinemic hypoglycemia in adults: Review of the literature. European Journal of Internal Medicine. 2004;**15**(7):407-410

[68] Anlauf M, Wieben D, Perren A, Sipos B, Komminoth P, Raffel A, et al. Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: Diagnostic criteria, incidence, and characterization of β-cell changes. The American Journal of Surgical Pathology. 2005;**29**(4):524-533

[69] Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycemia after gastric bypass surgery: Current concepts and controversies. The Journal of Clinical Endocrinology and Metabolism. 2018;**103**(8):2815-2826

[70] Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. The New England Journal of Medicine. 2005;**353**(3):249-254

[71] Moreira RO, Moreira RB, Machado NA, Gonçalves TB, Coutinho WF. Post-prandial hypoglycemia after bariatric surgery: Pharmacological treatment with verapamil and acarbose. Obesity Surgery. 2008;**18**(12):1618-1621

[72] Ismail AA. The insulin autoimmune syndrome (IAS) as a cause of hypoglycaemia: An update on the pathophysiology, biochemical investigations and diagnosis. Clinical Chemistry and Laboratory Medicine. 2016;**54**(11):1715-1724

[73] Paudyal B, Shakya M, Basnyat B. Spontaneous hypoglycaemia in a patient with Graves' disease. BMJ Case Reports 2016;2016:bcr2016214801

[74] Marks V, Teale JD. Hypoglycemia: Factitious and felonious. Endocrinology and Metabolism Clinics of North America. 1999;**28**(3):579-601

[75] Bates DW. Unexpected hypoglycemia in a critically ill patient. Annals of Internal Medicine. 2002;**137**(2):110-116

[76] Banerjee I, Raskin J, Arnoux JB, De Leon DD, Weinzimer SA, Hammer M, et al. Congenital hyperinsulinism in infancy and childhood: Challenges, unmet needs and the perspective of patients and families. Orphanet Journal of Rare Diseases. 2022;**17**(1):61

[77] Arnoux J-B, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, et al. Congenital hyperinsulinism: Current trends in diagnosis and therapy. Orphanet Journal of Rare Diseases. 2011;**6**(1):63

[78] Banerjee I, Salomon-Estebanez M, Shah P, Nicholson J, Cosgrove KE, Dunne MJ. Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia. Diabetic Medicine. 2019;**36**(1):9-21

[79] Gϋemes M, Rahman SA, Kapoor RR, Flanagan S, Houghton JAL, Misra S, et al. Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management. Reviews in Endocrine & Metabolic Disorders. 2020;**21**(4):577-597

[80] Halaby LP, Steinkrauss L. Hypoglycemia: Symptom or diagnosis? *Causes of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.105061*

Journal of Pediatric Nursing. 2012;**27**(1):97-99

[81] Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. The Journal of Pediatrics. 2015;**167**(2):238-245

Section 3

## Diagnosis and Treatment of Hypoglycemia

### **Chapter 4** Blood Glucose Monitoring

*Anujka Selea Zivojinovic*

#### **Abstract**

Glucose monitoring is the integral part of diabetes management. We have over the years moved from qualifying sugars in urine to identifying glucose alone in the interstitial tissue. Even more we are anow able to identify and use minute to minuet glucose fluctuations and use them to avoid the dangers and unpleasantries of hypoglycemia. We look at the development of glucose monitoring methods. The development of classic basic glucose monitors as well as the development of continuous glucose monitors. Basic principles of function, advantages, and disadvantages, as well as areas of actual and projected use are mentioned. We name some of the patient groups that have proven to get most advantage of glucose monitoring. He need for individual approach an patient activation as well as for alert diabetes health care provided is necessary for optimal use of technology for glucose monitoring.

**Keywords:** glucose, glucose monitor, continuous glucose monitoring (CGM), intensified insulin treatment, hypoglycemia

#### **1. Introduction**

Diabetes mellitus is group of metabolic diseases, resulting from absent or defective insulin secretion and/or action and manifested by high blood glucose levels. We think of diabetes as of a chronic long and progressive disease that requires a complex multifaceted treatment.

At the time of insulin discovery, identification, and quantification of glucose was a demanding laboratory task. Today, glucose in blood is the most frequently analyzed parameter in a clinical chemistry laboratory. The value of global blood glucose monitoring systems market size in 2021. in the US was estimated at 14.78 billion dollars and with a projected to grow to over 31 billion dollars by 2029.

While it was the discovery of insulin, 100 years ago, that most profoundly shifted the perspective of diabetes form a lethal, relatively quickly progressive disease to a chronic progressive disease which increases risk for micro- and/or macrovascular complications, it was the availability of simple, easy to use, reliable glucose testing that has made diabetes, with its acute and chronic events (mostly hyperglycemia but also hypoglycemia), closer to every patient and living with diabetes more predictable. Glucose monitoring has, together with development of diabetes education programs, contributed to aiming the complex diabetes patient at being a "patient centered care" where "… patient values guide all clinical decisions".

It is the development of glucose monitoring systems that has made the health care providers and researchers focus again to the fact that glucose control is a

continuum- diabetes with glucose swings and inappropriate glucose control is a disease of deviant homeostasis, where insulin plays the main, but not the only role. It may be that our approach to hyperglycemia and hypoglycemia will be changed in future, again, due to the observations got through glucose monitoring systems and our interventions.

The way to modern glucose monitoring equipment was not short and was not easy.

It was necessary with development of basal natural sciences to get form the intuitive to the quantitative and beyond…

#### **1.1 The glucose molecule**

The first glucose molecule was isolated from raisins in 1747 by Andreaas Marggraf. The name (glycos- sweet) was established and used in 1838 by Jean Baptiste Dumas.

Glucose is classified as a monosaccharide- simple sugar. The molecular formula C6H12 O2.

Glucose qualifies as a hexose, because it contains 6 carbon atoms. It an aldosemeaning that it contains an aldehyde group that is easily oxidized [1].

Friederich August Kekule proposed also the name dextrose, being aware of the ability of glucose water solution to turn the plane of polarized light to the right. The metabolically active glucose is D (+) glucose.

In 1902 the Nobel Prize for chemistry was given to Emil Fisher who explained the cyclic structure of glucose: Biologically active glucose is mostly in cyclic structure.

A few chemical properties are of significance when defining glucose, but the most important is borne by the aldehyde group. That redox capacity can translate in a subset of reactions leading to formation of colored substrates or electrochemical reaction.

#### **1.2 Glucose, laboratory identification**

It was in 1838, that George Rees, a physician at Guy's Hospital, London, isolated sugar and in excess from blood of a diabetic patient [2].

Monitoring of glucose was at first done through monitoring of glucose in the urine. That was not an easy task and it was of little clinical significance: the finding of glucose in the urine signified advanced disease. Hypoglycemia could not be verified. The technique was complicated. The method was at most semiquantitative. Basis for use lies in the classical Fehling and Benedict reaction:

In 1848. The German chemist Herman Von Fehling developed a test that was able to differentiate reducing (sugars with aldehyde group) from nonreducing (sugars with keto group). Reducing sugar (such as glucose is) would be reducing a cuprous ion that than changes color and precipitates. The reaction requires a temperature of almost 60°C.

Stanley Benedict developed a modified copper reagent urine glucose test in 1908. The test uses the same principle as Fehling `s test but was easier to perform. The test was the basic glucose-monitoring test for almost 50 years. Urinary test based on Benedict reaction was introduced for home use in 1925. Test tube was given at the doctor's office, with the required reagents measured and dispensed by the physician. But it was basically the first test that the patients could use at home [3].

Benedict test, as a semiquantitative method, was a cornerstone of glucose monitoring in over 50 years and can be thought of the ground self-monitoring test.

In 1925, 26-year-old Danish botanist Detlev Muller discovered glucose oxidase [4]. The discovery was overshadowed by the work of Otto Warburg og Christian Walter who in 1932–1933 discovered glucose 6 phosphate dehydrogenase, the first discovered flavoenzyme. That the reaction produces color is of significance for further development of analytics. Warburg got, else, the Nobel prize for discovery of the nature and mode of action of respiratory enzyme).

Today's glucose monitoring techniques, quantitative, are mostly based on enzymatic reactions- glucose oxidase, hexokinase, or glucose dehydrogenase. The enzyme changes (oxidizes) glucose, and the transfer of electrons causes chromogenic reaction. The change in color is detected photometrically. The electron flow can also be measured electrochemically [5]. The methods are quantitative.

None of these methods, that we, regardless of many analytical problems, think of as an acceptable and reliable (also accurate and precise) reflection of blood glucose [6], would be in use had it not been for the basic chemical and physicochemical research done from the 1800.

#### **2. Glucose monitoring: moving towards the patient**

Benedict's reaction was developed in 1908. In 1925. we had a test for elf testing of glucose in the urine. It was a test that could be done home, but it was long from practical and it was necessary that the doctor gives the necessary equipment. In 1945, Ames (Elkhart, IN) developed a tablet with modified copper reagent, Clinitest. The method was also based on Benedicts reaction, but it was easier to perform. The method was semiquantitative and estimated the level of urinary glucose by comparison to the color chart.

By the late e1940 ies Hellen Fee (Mile's laboratories – which was known for producing Alca Selzer) developed the "dip and read" urine test – known as Clinistix. This was a huge step forward in clinical laboratory – the reagents for complete oxidative chain of reactions were set on a filter paper strip and could instantly identify glucose.

In 1957 Kohn showed that Clinistix could also give approximate results for blood glucose [7].

Dry chemistry came in to stay. In 1964, Boehringer Ingelheim introduced first Combur test that could identify glucose, protein, pH in the urine, and later Ketostix that could also identify ketones.

The first test strip for blood glucose was introduced in 1964: Ames -Mile's laboratories presented Dextrostix. Earnest C Adams was the developer. The test was based on glucose oxidase reaction. It included a semipermeable membrane that allowed glucose, but not the red blood cells to get to the reagent. The method was semiquantitative. It was meant for use at the doctor's office. The strips were widely used by the health care personnel at different points of health care, regardless that there were too many steps in the procedure ant too many steps that could lead to an inaccurate result. Stix limitations have been the trigger to develop automatic electronic glucose test strip reader, with standardized precision and quantitative results.

#### **2.1 Glucose monitoring- glucometers come**

Therefore, the first glucometer came. It was in 1970. It used Dextrostix. High cost, weight *at* 1,2 kg and only available at the doctor's office. Even the lighter and improved version produced by the Japanese in 1972, was a long way from what we think of as glucometer. It required repeated calibration, operator training and continuing practice, but with imminent insecurity about precision and variability.

It was developed further to a Glucometer 1, that came in 1981, as a first portable lightweight glucometer. It used again Dextrostix, and it was recommended for bedside monitoring of blood glucose. Glucometer 1 used a hexokinase-based glucose method.

In 1987. Came also the first blood glucose biosensor system. It used glucose oxidase strip. The electron transfer, stepwise, generated a current detected by amperometic sensor. It was the third generation of blood glucose monitoring systems. This was the final step that enabled the development of improved and easily used precise blood glucose monitoring instruments.

By the 1990 we have so moved from large instruments that required many analytical steps and the required blood volume for analysis was significantly reduced. Analytical time was reduced. High requirements for accuracy and precision are well met - while the first tests had variability of up to 40%, todays requirements today are less than 5% between meters and laboratory methods [8]. The development of software allows for keeping the measurements and eventually can make them available for analysis.

As much as chemistry and technology advanced, it is also the knowledge about diabetes that was pushing to test that would be reliable easy to use and available.

#### **3. Continuous glucose monitoring (CGM): the principle**

Continuous glucose measurement systems measure glucose in the interstitial fluid by a device that is inserted subcutaneously. The CGM system contains the sensor, a transmitter and a receiver or monitor.

The components have undergone significant changes from the first presented CGM system.

The first ever CGM system was approved by the FDA in 1999. It was produced by Medtronic (Medtronic guardian RT).

The device was measuring glucose in the interstitial fluid every 5 minutes. Glucose sensing electrode was inserted subcutaneously in the abdomen or in the arm. Glucose was measured electrochemically. The sensor lasted for 3 days. The results were stored and could be analyzed at the doctor's office. The data was not real time data ant the patient did not have access to data self. The patient could not get information about imminent hypoglycemia/hyperglycemia. The system needed calibration by fingerstick glucose measurements every 6–12 hours. The sensor and the receiver were physically connected by a cable that transmitted the measurements. The CGM could collect data in a three-day period [9]. Also, far away from the CGM systems that we know today.

The revolutionary, however, was that the glucose was measured often (1–5 minutes). The number of fingerstick was reduced – to calibration and eventually to check the results. The first generations of CGMS were basically only for professional use: the patients did not have insight into the glucose levels in the observation period. The first CGMs had an exceptionally large glucose variability, something that, naturally, was not wanted.

#### **3.1 Continuous glucose monitoring (CGM): some important steps**

The first real time CGM was the Glucowatch biographer (Cygnos, Redwood CA), The device used reversed iontophoresis for measuring interstitial glucose. It was

noninvasive, worn as a wristwatch. However, it caused a lot of local irritation and was not a commercial success.

In 2004, Medtronic introduced wireless transmitting from sensor to receiver. It was possible to give alerts on high low glucose: that was significant improvement and became industry standard.

In 2006 Medtronic comes with Guardian REAL time CGM system with alerts on high and low glucose. By 2006 integrated pump and sensor was released.

Dexcom introduced its first real time sensor STS in 2006. The device needs calibration. The device needed calibration. The sensor lasted for 72 hours. It could be programmed to alert high and low values. The results could, however, not be used for clinical decisions- dvs that every result had to be checked by usual SBGM before change In insulin dosage.

In 2008 Abbott came with Free Style Navigator. The main advantage was longevity of the sensor – up to 5 days. But the equilibration (warm-up) time was up to 10 hours. The receiver had also a function as a glucometer: it was again necessary to check the result before changing the treatment.

In 2012 Dexcom G4 was available, now with a 7-day wear period. In 2015 it got FDA approval for use as aa CGM in patients ages 2–17. The same year A Dexcom G5 mobile platform was launched. That allowed for the CGM data to be transmitted to a compatible mobile device – users cell phone.

The last generation Dexcom G6 is a device that does not need calibration, lasts for 10 days and requires no confirmatory finger sticks. In 2018. Dexcom 6 became the first CGM to be approved by the FDA for integration in automated insulin dosing systems.

In 2016, Abbott introduced a new GCM device, Free Style Libre Pro Flash CGM, the first that does not require calibration. Initially, the system was indicated only for use by health care professionals and for use in the adult patients. The sensor could store the glucose data for up to 14 days. Glucose measurements were registered at 15 min intervals. But the system could not give real time data. The system was further upgraded to Free Style Libre 1 and 2, such that the patient can scan and get to know glucose levels. The system is allowed fro use in children older tah 4 years and in pregnant women.

In May 2016, Eversense introduced a CGM that included the only implantable glucose sensor with a 90 day lifespan. In 2017, Eversense XL was launched – with a lifespan of 180 days. To this day it is the CGM with the long- lasting glucose sensor available on the market.

Medtronic works in this period more on the integration of glucose sensor and insulin pump. In 2013 came MiniMed 530G sensor, the first pump with threshold suspends for hypoglycemia. Integration of CGM and insulin pump required also significant advantage in software, insulin algorithms and mobile technology. Today, integration of CGM with insulin infusion pumps includes both threshold and predictive low glucose suspend, as well as hybrid- and fully automated closed loop systems using either insulin alone or insulin and glucagon. The goal is to make an insulin pump that delivers insulin in accordance to sensed glucose, with truly little need for manual control of the device.

#### **4. Glucose monitoring - what we do**

Glucose monitoring is of proven clinical benefit in diabetes patients and it is the standard of diabetes medical care [10–12]. The possibility to move to capillary glucose measurement was significant for patient understanding of glucose variations, response to daily activities and effect of choices they make.

To summarize, we have several options that the health care provider and, more important, the patient can choose to follow with blood glucose levels.


We are aware of the classic glucose laboratory test is also in use and most used tests in modern laboratory medicine and are reference to accuracy, reproducibility and reliability of other methods.

It is also good to remember of some laboratory finesses that can be of significance if not observant in diagnosing diabetes.

Glucose can be measured in the whole blood, plasma or serum samples. Concentration of glucose is approximately 15% lower than in plasma or serum. Blood glucose cannot be decided accurately on postmortem specimens. Glucometers use capillary blood – also full blood that has a lower concentration of glucose than plasma. However, capillary blood has a higher concentration (up to 20%) than venous blood. Glucose concentration in samples that wait long for analysis are lower -because of glycolysis (and of course if not properly stored).

None of the devices is perfect and we must be aware of their limits. Not all the new devices are appropriate for all diabetes patients.

#### **4.1 Blood glucose monitoring (BMG): self-blood glucose monitoring (SBGM)**

Self-blood glucose monitoring is performed buy a glucometer. Capillary blood glucose is analyzed, using glucose oxidase or hexokinase methods.

It is the standard recommended glucose monitoring for most diabetes patients today.

Regular blood glucose monitoring (BGM) has been associated with improved glycemic control in T1D patients [10, 13]. Higher frequency of measurements is associated with lower HbA1c [14]. Evidence on the role of BGM in achieving optimal glucose control in patients with type 2 diabetes (especially the patients that are not using insulin) is limited [15–17]. It does, however, give BGM a significant new role in empowering the patient to live with diabetes.

#### **4.2 Blood glucose monitoring: glucometers - glucose monitors**

Glucose measuring devices analyze capillary blood glucose. The devices we use today give a reliable insight in glucose levels. Although great improvements since the first one that was in use, one must be aware that there are some analytical limitations of the devices (and not being sensitive enough in the low glucose range, is one of the most significant).

The accuracy of a glucometer is the parameter that is most important when deciding which ne to recommend and use. The question of accuracy and standardization is ongoing [18].

The highest standards are given by ISO and FDA. Standards vary depending on whether the device will be used by a professional or at home.

Marketed monitors in Europe must meet the following standard to be certified as accurate (dvs that the results can be used to make a therapeutic decision):

95% of the results must be within 15% of the reference method for blood glucose >100 mg/dl.

95% must be within 15 mg/dl for blood glucose <100 mg/dl.

For a glucometer to be certified by FDA, for use in diabetes patients, it is necessary that 95% of the results should be within 15% of the comparator method and 99% of results should be within +/−20% of the comparator across the entire claimed measuring range.

It is also necessary to perform adequately in the low glucose range: professional devices (used in the hospital) should achieve 95% of results within +/−12% of the comparator method for blood glucose levels >75 mg/dl (4,1 mmol/l) and within +/−12 mg/dl for levels under 75 mg/dl, they should achieve 98% of values within +/−15% of the comparator method for blood glucose levels >75 mg/dl and +/−15 mg/ dl for levels <75 mg/dl across the entire claimed measuring range [19, 20].

BGM today is performed through a few simple steps. No matter how easy the steps may seem and no matter how accurate the system is, it is still possible to get a result that is inaccurate, because of the pre- or postanalytical errors. Some of the preanalytical errors are – poor skin preparation (having lotion or food rests on the skin, feks) or use of test strips that are incorrectly stored or expired. Postanalytical errors are mostly connected to registration of results, missing the values in the log, use of incorrect glucose units etc.

It is also estimated that only 7–13% of errors may occur during the analytical phase – if the patient is taking ascorbic acid or acetaminophen that will influence the results. Monitors that use glucose oxidase strips can give unreliable results when used bedside in patients that have oxygenation problems: low oxygen saturation will lead to false higher glycemia, while higher oxygen tensions in pat using oxygen may result I false ow glycemia. Monitors have also optimal range of working temperature. Test strips are most sensitive (again) to oxidation during improper or too long storage.

#### **4.3 Blood glucose monitoring: the patient**

One of the great changes in modern medicine, is moving from doctor- and medicine centered follow up of chronic diseases, towards patient empowered and disease mastering patient treatment. BGM is essential in such treatment concept in diabetes.

BGM is a standard of care and basic necessity for all patients with diabetes [21–23].

The significance of BGM is different in different groups of diabetes patients.

Also, the significance that BGM has for a patient is completely individual and are depending mostly on patient's motivation to integrate BGM in diabetes treatment plan.

#### *4.3.1 Insulin treated diabetes type 1 patients*

T1D patients on intensified insulin (multiple daily injections or CSII) treatment have, as previously mentioned, the greatest use of BGM based on their insulin regimen. It is recommended with monitoring in context of insulin dosage, postprandial, in mistaken hypoglycemia or hypoglycemia unawareness, after treating hypoglycemia, prior to exercise, prior to activity that requires normoglycemia (such as driving) or in the context of acute illness.

BGM with multiple daily monitoring in children and adolescents has special significance [24].

#### *4.3.2 Gestational diabetes mellitus*

Pregestational and gestational BGM is reduces HbA1c, but also the complications of diabetes pregnancies [25]. The recommendations ad requirements here are high:

Patients with known diabetes should plan pregnancy. In the pregestational period it is recommended that glucose monitoring be intense: pre breakfast, 2 h after all meals and at Bedtime.

Insulin dose should be titrated to achieve blood glucose.

4,0–5,8 mmol/l before breakfast.

>7,8 mmol/l post meal.

And 6-8 mmol/l at bedtime.

Once pregnancy is diagnosed intensive blood glucose monitoring is started, with the same glucose levels wanted): treatment is changed accordingly.

Pregnancy is surely the only glucose monitoring chapter with low tolerance for inconsistency.

How many times a day and in what order glucose should be monitored, is variable and has to be individualized also depending on what the goal is. In T1D patients on intensified insulin regime it is mainly insulin dosage that is the result of such monitoring. The intensity of BGM can also differ at different times, depending on patients specific needs at the time and patients goals at the time.

#### *4.3.3 Diabetes type 2*

Recommendations for patients that have T2D are a bit different: patients that use intensified insulin treatment should follow the recommendations as T1D patients.

Patients that use conventional treatment with basal insulin only can use BGM to titrate insulin dosage, but do, generally, not need intensified BGM.

Patients that do not use hypoglycemic drugs can have some help av. BGM, especially when adjusting diet, medications, level of activity or as a part of (introductory) diabetes treatment program.

Patients with prediabetes do not require self-blood glucose monitoring.

#### *4.3.4 High accuracy*

It is important to insist on devices with high accuracy (point of care requirements) glucose monitor in patients who [26].

1.Have a history of severe hypoglycemia or hypoglycemia unawareness

#### 2.Are pregnant

3.Receive insulin therapy


Its is necessary that all patients get god information and be educated to optimally use glucose meters, having in mind the major causes o eventually unreliable result.

#### **4.4 Glucose monitoring: glucose monitors: what more is needed**

Individual approach to every patient is important so that the recommendation on BGM (most of all structure of the measurements) leads to improved glucose control, but also improved feeling of diabetes control in patient self. It is important that the glucose value can be related to insulin dosage, meals, activity, illness, stress, new condition and that the patient/health care provider can get insight in glucose/diabetes dynamics, but also that they be able to conclude with a reasonable change. All the diabetes associations give some guidelines on number of necessary glucose measurements. But the number of required measurements must be in relation to patients needs. Gestational diabetes is maybe the only type of diabetes where the demand for BGM must be uncompromised.

But we must mention that it is often that the patient cannot follow with the requirements with BGM- it is not unusual to have patients that do not check blood glucose or do inconsequently. There are also patients who are not able to take appropriate self-management actions based on acquired data.

To motivate the patient for use of BGM can be a very complex and not always a successful job: although finger sticking can be the most intuitive hinder to multiple daily glucose measurements, it is not the main problem- BGM is a behavior and behavior is difficult to change without a structured plan and motivation [27–29].

BGM is the cornerstone of optimal diabetes management. It is important because it gives the patient direct insight into glycemia. It helps relate the symptoms to the number (hyper or hypoglycemia). It helps identifies hypoglycemia. The patterns and effects of different daily choices is obvious for the patient and health care provider. But, BGM gives us at discontinuous glycemic picture- there are periods of time that we do know nothing about blood glucose movements, periods with hypoglycemia or short postprandial hyperglycemia etc. That is an obstacle and hidden reason for patients' symptoms, daily function and obviously parameters of glucose control.

We hope that that is overcome today by the continuous glucose monitors.

#### **5. Continuous glucose monitoring (CGM): significance**

Continuous glucose monitor is, as previously mentioned, a device that can register interstitial glucose at short intervals. The results are sent o the receiver and are further used – stored or/and displayed for the patient. The device is a system of glucose sensor, transmitter, and receiver.

The use of CGM has brought the (patho) physiological glucose continuum in focus there where it belongs. CGM today can provide real time glucose data 24 h/day, give

alerts on imminent hypo- and hyperglycemia, show the rate of glucose level change. With help av. different algorithms the glucose levels can be used to show glucose change dynamics, periods with hypoglycemia TIR and so on.

From the first study where real time CGM was proved to reduce HbA1c and time spent in hypoglycemia [30], data is consistent. The use of CGM in patients on intensified insulin regime (with MII or insulin pumps) is associated with better HbA1, less time spent in hypoglycemia, less acute hypoglycemic events, and generally better satisfaction of patients. That covers many patient groups, also including diabetes type, gender, and age differences [30–35].

From the basic concept of CGM and first study it was clear that the CGM is most sensitive and useful in detecting and preventing hypoglycemia and time in hypoglycemic/ near hypoglycemic range.

#### **5.1 Continuous glucose monitoring - types**

CGM devices can display real time data (CGM measures in short periods of time, presents real time data on the monitor, but also continuously stores data). Or CGM can continuously measure and store data, but gives the glucose level upon request, dvs when scanning the sensor.

CGM can be owned/used continuously by the patient intended for personal use. CGM can also be used by a professional- meaning that the CGM system is owned by the health care institution/provider: the patient gets the CGM over a period of time (7–14 days). The results may or may not be available for the patient at the time of use: the data are sent and stored at the doctor's office and analyzed retrospectively. Such short CGM periods can be useful for detecting daily patterns, vulnerable periods with hyper−/hypoglycemia.

The CGM measures glucose in the interstitial fluid. That means that the results we get are estimates- the numbers we get are somewhat "late" compared to the blood glucose. The greater rate of glucose level change in the circulation the greater "time lag", meaning also greater difference I the glucose level we get from CGM and BGM taken at the same time. That discrepancy is ameliorated by calibration or by integrated CGM algorithm. Not all the systems require calibration. But still, all the patients that have and use CGM, should have a blood glucose monitor available at all times- for eventual check on the CGM results (warm up periods, suspect hypoglycemia, lack of clinical correlation to hypo- alarm, fast change in glucose levels, lack of contact with the sensor etc..).

Some of the CGM (Dexcom G6- real time CGM and Free style Libre 2 - intermittently scanned CGM) can be integrated into insulin pumps. These CGM require no calibration.

#### **5.2 Continuous glucose monitoring: some technicalities we have to consider**

The sensitivity and accuracy of the CGMs is the subject of continuous improving. The mean absolute relative difference (MARD) is currently the most common metric used to assess the performance of CGM systems. MARD is the average of the absolute error between all CGM values and matched reference values. A small percentage indicates that the CGM readings are close to the reference glucose value, whereas a larger MARD percentage indicates greater discrepancies between the CGM and reference glucose values. MARD of <10% is considered sufficient to allow for therapeutic decision (insulin dose change).

#### *Blood Glucose Monitoring DOI: http://dx.doi.org/10.5772/intechopen.105605*

CGM systems are sophisticated but it is not only the technical part that is responsible for eventual dysfunction. We are aware that the CGM is a foreign material that can cause allergic reactions. CGM must be inserter into the connective tissue. The actual connective tissue can be of different biological quality, variably circulated, the insertion is rarely the same etc. A sensor/glucose electrode can cause host response - irritation, immune reaction or inflammatory reaction or infection – the local process, no matter how complex, can change the sensitivity of the sensor. Sometimes it is only press on the sensor while sleeping that can provoke false alarm/ unreliable result.

Clinical situations that are associated with large body fluid shifts – dehydration, hypotension, hyperosmolality states, ketosis are not good ground for CGM function.

One must also be observant on substances that influence the glucose oxidase/ dehydrogenase systems.

The use of CGM should also be registered before major radiographic diagnostics.

CGM are expensive instruments and not evenly reimbursed. Optimal use of CGM requires a good educated health provider, a motivated and good educated patient and that of course implies a lot of time, not always available at the local doctor's office. Technical support, analyzing av. stored data (the need for compatible software, problems with personal safety when transmitting data etc. can also be a challenge [36, 37].

Patient motivation to understand the benefits and accept to wear CGM is also one of the critical factors for optimal use of CGM.

All this maybe explains that high quality CGMs are in use in about 50–75 pediatric endocrine practices and 35–50% in adult endocrine practices for individuals with T1DM [38].

#### **5.3 CGM: The patient "who is capable of using devices safely"**

The amount of data gathered on CGM was such that the ADA, in its Standards of care I 2020. states:

"when used properly, real time and intermittently scanned continuous glucose monitors in conjunction with insulin therapy are useful tools to lower A1c level and/or reduce hypoglycemia in adults with T1D who are not meeting glycemic targets, have hypoglycemia unawareness, and/or have episodes of hypoglycemia—and in conjunction to insulin therapy .. to lower A1C levels and/or reduce hypoglycemia in adults with type 2 diabetes who are not meeting glycemic targets" [39].

The 2022. Standards of Care recommend the use of real time continuous glucose monitoring (evidence level A) intermittently scanned continuous glucose monitoring (B) should be offered for diabetes management


CGM, real time can be used for diabetes management in adults with diabetes on basal insulin who are capable on using the device safely.

Continuous glucose monitoring in adjunct to pre- and postprandial glucose monitoring can help achieve HBA1c targets in gestational diabetes.

Real time CGM should be used "as close to daily as possible" in patients using multiple daily injections or CSII for maximal benefit. Intermittent scanned CGMs should be scanned frequently, at least every 8 h.

The choice of CGM should be made based on patents "circumstances, desires and needs".

#### *5.3.1 Gestational diabetes*

The latest NICE guidelines do not differ significantly [40]. However, realtimeCGM should be offered to all pregnant women with type 1 diabetes, to help them meet pregnancy glucose targets an improve neonatal outcomes.

RT CGM should be considered for pregnant women that are on insulin therapy, not diabetes type 1, but have sever hypoglycemia (with or without impaired awareness of hypoglycemia). Or if they have unstable blood glucose levels. If CGM is already in use furthermore education and support should be provided by the antenatal/diabetes team [41].

As previously mentioned, the patient using CGM should always have a BGM available.

A large group of diabetes patients that have the need and desire for better glucose control can benefit for CGM. The patients who are, because of comorbidities, age etc., at increased risk for hypoglycemia or have poorly managed diabetes are candidates for real time or intermittent CGM, even periodically. But both the patient and the health care provider should be educated in use of CGM and both must be clear about the goals of CGM use. The patient (or, as nicely defined by the standards of care, caregiver) must be motivated to follow the message that CGM is sending and be able to respond properly. That would be the basis of GCM safety [42].

Of notice when considering safety is that the most advanced CGM are approved for use in children older than 2 years (Dexcom G6).

#### **5.4 Continuous glucose monitoring: new glucose control parameters**

Traditional methods of describing glucose control (HbA1c, BGM) are, now that we have a large amount of data from CGMs, not quite enough to fully describe glucose control and in most patients on intensified insulin regimes [43], not always enough to choose a proper therapeutic strategy.

#### *5.4.1 Hypoglycemia*

Hypoglycemia prevention and reduction of hypoglycemic episodes is one of the main advantages CGM can provide. But hypoglycemia in diabetes patient is sometimes difficult to define. The level of glucose, the rate of glucose level change and the duration of event is of significance. Originating form, the classic definition of hypoglycemia, CGMs register hypoglycemic events through two major intervals:


#### *Blood Glucose Monitoring DOI: http://dx.doi.org/10.5772/intechopen.105605*

When defining hypoglycemia under CGM use, one should register the percentage of values below the named threshold (dvs percent of time with glycemia <3,9 mmol/l and percent of time spent under 3 mmol/, the later weighing heavier for the estimate); or the number of minutes/hours below the threshold. The number of such event should be reported. A significant event must last at least 15 minutes. Time spent in hypoglycemia should not exceed 1% for levels <3 mmol/l in adults with T1D, 4% for levels under 3,9 mmol/l.

In older adults time with hypoglycemia under 3,9 mmol/l should not exceed 1%.

#### *5.4.2 Glucose variability*

CGM has given us insight into different glucose patterns. Glycemic variability which reflects the amplitude frequency and duration of glucose fluctuation, is also a parameter that indicates the level of glucose control and is associated also with increased mortality in the ICU [44–46].

#### *5.4.3 Time in range*

Time in range is the time glucose measurements are in individual's target ("wanted") glucose range. TIR is giving some orientation about the time in eventual significant hyperglycemia or hypoglycemia. Such periods cannot be seen through HbA1c and discontinued capillary blood glucose measurements. Acceptable TIR for adults with type 1 diabetes is >70%, in older and high-risk patients >50%. Clinical benefits come with every 5% increment in TIR [47].

So, for complete insight in level of glucose control, optimal use av. data from CGM and right therapeutic decision we need to analyze far more parameters than HbA1c and the results of self-blood glucose monitoring, if any presented. Sufficient data is the data is 70–80% of possible CGM readings obtained for 2 weeks.

Here is a consensus on the parameters we should be aware of/analyze when analyzing CGM data.

(From: Battelino T, DanneT, Begenstal RM et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international Consensus on time in range: Diabetes care 2019; 42 [8]:1593–1603)

Standardized CGM metrics


6.Time > 250 mg/dL (>13.9 mmol/L)


9.Time < 70 mg/dL (<3.9 mmol/L)

10.Time < 54 mg/dL (<3.0 mmol/L)

11.LBGI and HBGI (risk indices)

12.Episodes (hypoglycemia and hyperglycemia) 15 min

13. Area under the curve

14.Time blocks (24-h, day, night)

Use of Ambulatory Glucose Profile (AGP) for CGM report.

CV, coefficient of variation; LBGI, low blood glucose index; HBGI, high blood glucose index.

We believe that with such range of data to be considered, will the estimate of glucose control in diabetes patient is more adequate. If such analysis and, consequently estimate will be easier to get a therapeutic decision on, it is something that has to be seen. It is probably on the the next important mission, on GCMs integration with insulin pumps that the answer awaits.

#### **6. Conclusion**

It is difficult to imagine modern diabetes management without glucose monitoring. A number of devices help us get insight into diabetes of each and every patient and makes us intervene accordingly, for the short term and long-term benefit of the patient. It is only to expect that with constant improvement, glucose monitoring will continue to connect the patient, diabetes health care provider, but also the army of researchers, hardware and software developers, investors and people with great courage and ideas.

Although the advantages of glucose monitoring are beyond doubt, and are recommended clinical practice, there are still some obstacles to the broad and universal use of the different devices (lately the CGM devices). One of the main obstacles is certainly the cost of the devices. The reimbursement is variable. Availability is different in different parts of the world. The cost benefit is probably not considered from all levels of healthcare.

To optimally use glucose monitoring is not enough only to have the newest device. The educated health care provider (the choice and performances of devices, the analysis of data feks) and motivated and educated patient are also necessary to choose optimal way to use glucose monitoring. Enough time to educate, to obtain the data, to do the adequate analysis can be difficult to find in a busy practice and with an impatient patient.

Blood glucose monitoring is a daily task: although the devices and necessary routines are trending towards small, simple to use, easy to wear, easy to manipulate, easy to understand, "does it itself", it is necessary that the patient possesses a certain level of literacy and numeracy as well as knowledge on the method, so that the message on the monitor is understood and applied. Training in understanding and using the results to optimize glycemic management is necessary.

But, despite these impediments, the fact is that glucose monitoring has evolved and so has our understanding of diabetes and diabetes treatment. Technical advances are impressive.

There is a large diabetes population that expects to become free from multiple daily injections, bolus insulin dosage, fear for hypoglycemia and hypoglycemia. Integrating CGM in fully automated closed loop system, with insulin or combination with glucagon is maybe a way to open a new chapter in diabetes understanding and treatment. The high initial cost of implementing technology in everyday life of a diabetes patient and diabetes healthcare provider is still incomparable to the liberty such technology can give to the patient and to the satisfaction precisely tailored individualized successful treatment gives to both.

#### **Author details**

Anujka Selea Zivojinovic Internal Medicine, Endocrinology, Medical Department, Aalesund Hospital, More og Romsdal HF, Norway

\*Address all correspondence to: seleanujka@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Roberts JD, Caserio MC. The Structure and Properties of D-Glucose. Pasadena, CA: California Institute of Technology; 2021

[2] Clarke SF, Foster JR. A history of blood glucose meters and their role in self- monitoring of diabetes mellitus. British Journal of Biomedical Science. 2012;**69**(2):83-93

[3] Olczuk D, Priefer R. A history of continuous glucose monitors (CGMs) in self –monitoring of diabetes mellitus. Diabetes and Metabolic Syndrome-Clinical Research and Reviews. 2018;**12**:181-187

[4] Heller A, Ulstrup J. Detlev Muller's discovery of glucose oxidase in 1925. Analytical Chemistry. 2021;**93**(18):7148-7149

[5] Howell JO, Kaufman AD, Yeh HJ. Glucose test strips and electroanalytical chemistry in the undergraduate laboratory. Available from: https://www. basinc.com/assets/library/presentations/ pdf/JOH-01.pdf

[6] Kohn J. A rapid method of estimating blood glucose ranges. Lancet. 1957;**273**(6986):119-121

[7] ADA Diabetes technology. Standards of care. Diabetes Care. 2021;**44**(Supplement-1):S85-S99

[8] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;**352**:837-853

[9] Didyuk O, Econom N, Gaurdia A, et al. Continuous glucose monitoring devices: past present and future, focus on the history and technological innovation. Journal of Diabetes Science and Technology. 2021;**15**(3):676-683

[10] The Diabetes Control and Complications Trial Research Group. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine. 1993;**329**:977-986

[11] Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care. Feb 1995;**18**(2):258-268

[12] American Diabetes Association. Consensus statement on self-monitoring of blood glucose. Diabetes Care. 1987;**10**(1):95-99

[13] Newton EJM, Ruta DA, et al. Frequency of blood glucose monitoring in relation to glycemic control: observational study with diabetes database. BMJ. 1999;**319**:83-86

[14] Miller KM, Beck RW, Bergenstal RM, et al. Evidence of a strong association between frequency of self -monitoring of blood glucose and HbA1c levels in T1D exchange clinic registry participants. Diabetes Care. 2013;**36**:209-214

[15] Farmer A, Wade A, Goyder E, et al. Impact of self-monitoring on blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomized trial. BMI. 2007;**336**:1174-1177

[16] Simon J, Gray A, Clarke P, Wade A, Neil A, Diabetes Glycemic Education and Monitoring Trial Group. Cost

#### *Blood Glucose Monitoring DOI: http://dx.doi.org/10.5772/intechopen.105605*

effectiveness of self-monitoring of blood glucose in patients with noninsulin treated type 2 diabetes: economic evaluation of data from the DIGEM trial. BMJ. 2008;**336**:1177-1180

[17] Schwedes U, Siebold's M, Martes G. meal related structured self -monitoring of blood glucose: effect on diabetes control in nn-insulin treated type 2 diabetes patients. Diabetes Care. 2002;**25**:1928-1932

[18] US Food and Drug Administration. Self-Monitoring Blood Glucose Test Systems for Over the Counter Use: Guidance for the Industry and Food and Drug Administration Staff, US Food and Drug Administration. Available from: www.fda.god/regulatory-information/ search-fda-guidance-documents/selfmonitoring-blood-glucose-test-systemsover-counter-use-0

[19] US Food and Drug Administration. Blood Glucose Monitoring Test Systems for Prescription Point-of Care Use: Guidance by Industry and Food and Drug Administration Staff. US Food and Drug Administration. Available from: www.fdagod/regulatiry-information/ search-fda-guidance-documents/ blood-glucose-monitoring -test-systemsprescription-point-care -use

[20] Hagvik J. Glucose measurement: time for a gold standard. Journal of Diabetes Science and Technology. 2007;**1**(2):169-172

[21] Diabetes Technology. Standards of medical care in diabetes −2022. Diabetes Care. 2022;**45**(Suppl 1):S97-S112

[22] www.diabetes.ca/health-care providers/clinical-practice-guidelines/ chapter-9

[23] www.niddk.nih.god/ health-information/diabets 7 overview/managing-diabetes/ continuous-glucose-monitoring [24] Ziegler R, Heidtmann B, Hilgard D, Hofer S, et al. DPV-Wiss-Initiative. frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatric Diabetes. 2011;**12**:11-17

[25] Siega-Riz AM, Viswanathan M, Moos MK, et al. A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. American Journal of Obstetrics & Gynecology. 2009;**201**(339):e1-339.e14

[26] Bailey TS, Grunberger G, Bode BW, et al. 2016 outpatient glucose monitoring consensus statement. Endocrine Practice. 2016;**22**:231-261

[27] Weinstock RS, Aleppo G, Bailey TS, Bergenstal RM, Fisher WA, Greenwood DA, et al. The Role of Blood glucose Monitoring in Diabetes Management. Arlington (VA): American Diabetes Association;

[28] Centers for Disease Control and Prevention. Diabetes Self-Management Education and Support (DSMES toolkit). Centers for Disease Control and Prevention; Available from: www.cdc. goc/diabetes/dsmes\_toolkit/background/ benefits.htlm

[29] Fisher WA, Kohut T, Stegner P, Schachner H. Understanding selfmonitoring of blood glucose among individuals with type 1 and type 2 diabetes: an Information-Motivation-Behavioral Skills analysis. Diabetes Education. 2011;**37**:85-94

[30] Wv T, Beck RW, Bode BW, et al. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study group. continuous glucose monitoring and intensive treatment of type 2 diabetes. New England Journal of Medicine. 2008;**359**:1464-1476

[31] Beck RW, Hirsch IB, Laffel L, et al. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes Care. 2009;**32**:1378-1383

[32] Vigersky RA. The benefits, limitations, and cost-effectiveness of advanced technologies in the management of patients with diabetes mellitus. Journal of Diabetes Science and Technology. 2015;**9**:320-330

[33] Klonoff DC, Buckingham B, Christiansen JS, et al. Endocrine Society: Continuous glucose monitoring: an Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism. 2011;**96**:2968-2979

[34] Ehrhardt NM, Chellappa M, Walker MS, Fonda SJ, Vigersky RA. The effect of real-time continuous glucosemonitoring on glycemic control in patients with type 2 diabetes mellitus. Journal of Diabetes Science Technology. 2011;**5**:668-67532

[35] Baretlino T, Conget I, Olsen B, et al. SWITCH Study group te use and efficacy of continuous glucose monitoring in type 1 diabetes treated with insulin pump therapy: a randomized controlled trial. Diabetologia. 2012;**55**:3155-3162

[36] Beck RW, Riddelsworth T, Ruedy K, et al. Effects of continuous glucose monitoring on glycemic control in patients with type 1 diabets using insulin injections: the DIAMOND randomized clinical trial. JAMA. 2017;**317**:379-387

[37] Rodbard D. Continuous glucose monitoring: A review of success, challenges and opportunities. Diabetes Technology & Therapeutics. 2016;**18**(2):S2-3-S2-13

[38] Foster NC, Brown SA, LUmJW, Kovatchev BP. State of type 1 diabetes management and outcomes from the T1DExchange in 2016-2018. Diabetes Technology & Therapeutics. 2019;**21**:66-72

[39] American Diabetes Association. 7. Diabetes technology: standards of medical care in diabetes −2020. Diabetes Care. 2020;**43**(Suppl. 1):S77-S88

[40] www.nice.org. uk/guidance/ng17

[41] www.nice org.uk/guidance ng 3

[42] Miller EM. Using continuous glucose monitoring in clinical practice. Clinical Diabetes. 2020;**38**(5):429-438

[43] Danne T, Nimri R, Battelino T, et al. International consensus on use of continuous glucose monitoring. Diabetes Care. 2017;**40**(12):1631-1640

[44] Eslami S, Taherzadeh Z, Schultz MJ, Abu-Hanna A. Glucose variability measures and their effect on mortality: a systematic review. Intensive Care Medicine. 2011;**37**:583-593

[45] Battelino T, Danne T, Begenstal RM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the International Consensus on time in range. Diabetes Care. 2019;**42**(8):1593-1603

[46] Vigersky RA, McMahon C. The relationship of hemoglobin A1C to time-in-range in patients with diabetes. Diabetes Technology & Therapeutics. 2019;**21**:81-85

[47] Roy W. Beck, Richard M. Bergenst MD et al. The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c al, Journal of Diabetes Science and Technology 2019 13(4): 614-626

#### **Chapter 5**

## Hypoglycemia Detection in Diabetes

*James M. Richardson and Rimma Shaginian*

#### **Abstract**

Hypoglycemia, once detected in a timely manner, is commonly treated by administration of glucose or glucagon in accordance with HCP advice, however, identifying the hypoglycemic event or need to treat is of initial paramount importance. The definition of hypoglycemia is provided, together with the implications of such an event on clinical and economic outcomes. The current accuracy standards are discussed and how they are applied to the low blood glucose range and current technologies.

**Keywords:** accuracy standards, blood glucose monitoring, continuous glucose monitoring, diabetes, hypoglycemia

#### **1. Introduction**

Diabetes is a lifelong, chronic disease characterized by episodes of hyperglycemia [1, 2]. Treatment of diabetes, in order to be effective, must lower glucose concentration to a euglycemic level, however, the key barrier to optimal glycemic control is hypoglycemia (low blood glucose levels) despite ongoing improvements in therapies and technology [3].

Hypoglycemia is one of the most impactful adverse events in diabetes and is a common problem for people with both type one (T1D) and type two (T2D) diabetes [4]. Too much insulin or, insulin-producing medications are commonly related to a hypoglycemic event, however other factors such as delayed, missed, or reduced meals other than what was planned, unanticipated strenuous exercise, alcohol consumption or interactions with other drugs are also known contributors. Additionally, individual patient factors such as older age, nutritional status, duration of diabetes, renal or hepatic disease, history of hypoglycemic episodes [5], and hypoglycemic unawareness may increase the risk of events [6].

#### **2. The size of the problem**

#### **2.1 Hypoglycemia is the key problem in diabetes management**

Despite recent advances in diabetes technology, hypoglycemia remains a key obstacle to achieving adequate glycemic control [3, 7, 8]. Even though the issue is well accepted, the size of the issue varies depending on how hypoglycemia is defined,

measured, and reported. The incidence of hypoglycemia reported between randomized controlled trials vs. observational studies vs. patient-reported outcomes was found to differ by a factor of over 100 in one review [9].

#### **2.2 Hypoglycemia is common problem for both T1D and T2D**

The frequency of hypoglycemia varies from 42 to 91 events per patient year for adults with Type 1 diabetes (T1D) and from 20.3–44.4 events per patient year for adults with Type 2 diabetes (T2D) [10]. Severe hypoglycemia is not only a problem for insulin-treated patients but is also common among older adults with T2D across all levels of glycemic control. The risk tends to be higher in patients with either nearnormal glycemia or very poor glycemic control [4]. Additionally, frequent episodes of mild hypoglycemia may compromise the hormonal counterregulatory response to produce adrenaline and subsequent autonomic warning symptoms such as trembling and sweating leading to hypo-unawareness increasing the risk of severe hypoglycemia further [6].

#### **2.3 Clinical consequences of hypoglycemia are significant**

With the general exception of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS), the clinical consequences of prolonged hyperglycemia are long-term. These long-term risks were demonstrated in the Diabetes Control and Complications Trial (DCCT) [11] and the United Kingdom Prospective Diabetes Study (UKPDS) [12] for T1 and T2 diabetes respectively and are the result of neuropathy, retinopathy, and/or nephropathic complications.

The clinical consequences of severe hypoglycemia on the other hand can be immediately associated with the event and include acute cerebrovascular disease, myocardial infarction, neurocognitive dysfunction, and loss of vision [13]. If left untreated, severe hypoglycemia can result in significant morbidity and mortality [14, 15].

#### **2.4 Economic consequences and human impact of hypoglycemia are significant**

All levels of hypoglycemia are associated with significant indirect costs, not only on employers but also on individuals with diabetes [16]. A recent study showed a clear link between severe hypoglycemia and the costs of lost productivity, with the highest loss in productivity attributed to non-severe nocturnal hypoglycemic events [17]. Numerous studies have shown that hypoglycemia negatively impacts patients' ability to concentrate and participate in daily activities, thereby negatively impacting the quality of life (QoL) [17]. Even non-severe hypoglycemia, which occurs in 24–60% of patients with diabetes, can adversely affect QoL [18]. The greatest reductions in QoL are seen among those participants reporting a higher frequency of non-severe hypoglycemia [18]. As reported by Geelhoed-Duijvestijn et al., it takes an average of 50.4 min to return to normal functioning following a daytime non-severe hypoglycemic event, but negative feelings persisted for an average of 5.4 hours [19]. Following a nocturnal non-severe hypoglycemic event, functionality was diminished for an average of 80.5 min while negative feelings persisted for 12.2 hours [19].

Severe hypoglycemic episodes not only significantly affect the individual but are associated with long-term cost implications to the health system. One cohort study assessed the costs between a population requiring hospitalization due to severe hypoglycemia and a matched control. The results demonstrated that the group suffering

#### *Hypoglycemia Detection in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.103137*

from the severe hypoglycemic episode incurred an additional \$10,873 (p < 0.001) in direct and indirect costs vs. the control for that event year [20].

Hypoglycemia detection and management remain the cornerstone of modern diabetes management and it is important that patients and their healthcare providers (HCPs) understand the strengths and limitations of various blood glucose monitoring systems (BGMS) in order to select the most appropriate system that meets their individual needs [13].

#### **3. Hypoglycemia definition and current threshold**

#### **3.1 Current classification of hypoglycemia**

A joint position statement of the International Hypoglycemia Study Group of ADA and EASD has proposed three glucose severity levels when reporting hypoglycemia in clinical trials of glucose-lowering drugs for the treatment of diabetes (**Table 1**). The Group recommends that the frequency of detection of a glucose concentration < 3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycemia, should be included in clinical trial reports [21]. These levels are further aligned by the most recent version of the ADA's Standards of Medical Care in Diabetes 2022 (**Table 1**).


#### **Table 1.**

*Levels of hypoglycemia proposed when reporting in clinical trials and as defined by the ADA.*

#### **4. Benefits and limitations of diabetes technologies assessing glucose levels**

#### **4.1 BGMS**

*4.1.1 Limitations of current ISO 2013 and FDA 2020 accuracy requirements for blood glucose monitoring systems in diabetes management*

According to current ISO 15197:2013 accuracy requirements, ≥95% of BG results should be demonstrated to be within ±15% of the reference method for samples

with BG concentrations ≥100 mg/dL, and ± 15 mg/dL when BG concentrations are <100 mg/dL. (International Organization for Standardization.)

The FDA guidance 2020 recommends that ≥95% of all BGMS results should be within ±15%, and ≥ 99% of all BGMS results should be within ±20% of the reference laboratory method across the entire claimed to measure range of the BGMS. (US Department of Health and Human Services [22]. Food and Drug Administration.)

These more stringent guidelines recognized the limitations of evaluating BG samples at the extreme ends of the measuring range, especially in the low range where very few samples are available [23]. Recognizing the clinical importance of the accuracy of BG measurements for hypo- and hyperglycemic blood samples, both European and US authorities have requested that accuracy data be reported separately for low, normal, and high BG ranges [23]. This issue is however complicated by system accuracy requirements being applied to measurement results from the whole glycemic range. If a BGMS shows 100% accurate results at BG concentrations ≥80 mg/dL (4.44 mmol/L) (80% of results, following ISO 15197:2013) [24], this results in 25% of the samples in the low-glucose range being allowed outside the accuracy limits (5% "results outside of accuracy limits" divided by 20% "results <80 mg/dL [4.44 mmol/L]") [23].

#### *4.1.2 Difference of accuracy in hypoglycemic range of BGMS compliant with ISO 2013 standards and/or FDA 2020 guidelines*

Despite the boundaries of ISO 2013 standards and/or FDA 2020 guidance, (International Organization for Standardization., US Department of Health and Human Services [22]. Food and Drug Administration) considerable differences exist in the performance of commercially available BGMS [25]. Such error patterns over the operating range of BGMS may lead to relevant differences in clinical and economic outcomes. These differences can potentially increase the risk of not detecting hypoglycemic events when they occur, and, therefore, inadequately identifying and treating them [25].

Thus, if a patient's true BG concentration is 60 mg/dL (3.33 mmol/L), acceptably accurate results range from 45 to 75 mg/dL (2.50 to 4.16 mmol/L) according to the ISO limits and from 51 to 69 mg/dL (2.83 to 3.83 mmol/L) according to FDA criteria. This can make it difficult for a patient to detect and manage their hypoglycemia. If a BGMS cannot reliably differentiate between 50, 60, and 70 mg/dL (2.77, 3.33, and 3.88 mmol/L), the utility of predefined hypoglycemia thresholds comes into question [23].

#### *4.1.3 Evidence shows that the accuracy of different BGMS (compliant with ISO 2013) is not the same in the low-BG range*

Multiple post-market studies of BGMS have failed to replicate the accuracy normally required to gain market approval by the regulatory authorities [26–30]. Many of these products remain on the market today.

Whilst it is not difficult to obtain BG samples in the normal range it is more of a challenge to obtain and subsequently assess the accuracy of devices outside of this range. It may be unethical and potentially dangerous to purposefully cause hypoglycemia in a patient simply for the purposes of testing device accuracy. The remaining choices to assess accuracy at this level is either to accept the smaller

*Hypoglycemia Detection in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.103137*

sample size, modify the sample prior to testing, or to create a statistical model. These concepts have further been explored in the low blood glucose range and evidence shows that the accuracy of different BGMS (that were approved under ISO 2013 standards) are not the same at these critical levels and some would appear non-compliant [29, 31]. Recently a methodology was developed to demonstrate the differences in accuracy in the low blood glucose range among several BGMSs as demonstrated in **Figure 1** [32–35]. The differences in accuracy between devices was clinically meaningful.

#### **4.2 Continuous glucose monitoring technologies**

Continuous glucose monitoring (CGM) devices have become more widespread over the past decade. They generally fall into two categories, real-time (rt-CGM) and intermittently scanned (is-CGM) devices. rt-CGM has shown positive improvements in improving HbA1c and reducing hypoglycemia in insulin users in RCTs [36–38] whereas is-CGM generally relies on observational data to support its use [39]. They predominantly differ from BGMS by measuring glucose concentration in the interstitial fluid, several times per hour, whereas BGMS measure blood (normally capillary) glucose once per test, up to around 10 times per day, depending on individual patient needs [1].

Unlike BGMS that have well-defined FDA and ISO accuracy criteria that must be met prior to obtaining marketing authorization, there remains no such standardized metrics for CGM accuracy requirements. In spite of this, it is commonplace for manufacturers to describe the accuracy of a CGM using Mean Absolute Relative Difference (MARD). This is calculated by averaging the absolute values of relative difference from the comparison method and does not account for positive or negative bias, i.e. all differences are made positive [40]. The MARD of some CGM systems has been reported to be in the 10–12% range whereas some BGMS has demonstrated to be below 5% [40].

One reason for the difference in MARD between some CGMs and BGMS could be attributed to measuring glucose in different compartments of the body. There is an inherent delay between glucose levels in each compartment with one study suggesting that to be between 6 and 10 minutes [41]. This makes it very difficult for a CGM to be as accurate, particularly at times of rapid glucose change. A further study demonstrated that MARD could change considerably throughout the day, approximately doubling between fasting periods and after food (8.0–16.3% and 9.1–16.3% depending on the device) [42]. This brings into question the value of such a metric if it can vary so much. **Table 2** provides some examples of when BGM is needed in CGM users.

Additionally, the detection of hypoglycemia by a CGM device is dependent on the duration of the hypoglycemic event. A recent study showed that two-thirds of all patients reported hypoglycemic events required minimum duration of 15 minutes in order to be by the CGM device [43].

A low ISF glucose reading below 3.9 mmol/L can prompt corrective actions that may be unnecessary if actual blood glucose, as measured by SMBG, is significantly higher. For instance, a user may develop hypoglycemia and take corrective action. Due to the time lag between blood glucose and ISF glucose, if the user continues to rely only on ISF glucose readings, there may be a lag in the rise of ISF over blood glucose, resulting in further and unnecessary treatment of hypoglycemia.

**Figure 1.** *Probability curves for real-world BGMSs (all meeting ISO 15197:2013 criteria) (adapted from [32]).*


*ISF: interstitial fluid; CGM: continuous glucose monitoring; EU: European Union; and UK: United Kingdom.*

#### **Table 2.**

*Some examples for adjunct blood glucose testing in CGM users.*

Similarly, experienced users may become less concerned with ISF low glucose readings than they would be with SMBG readings and take no immediate action. Each of these scenarios potentially creates unwanted risks [44].

The use of a CGM, particularly for the management of T1D, is preferred; however, all patients should learn how to use a BGMS for backup and monitoring if CGM is not available and/or desired [39]. This was further confirmed by the American Diabetes Association [1] which stated, "Every patient using a CGM must have a BGM." The reasoning for using a BGM when using a CGM includes whenever there is suspicion that the CGM is inaccurate, while waiting for warm-up, for calibration (some sensors) or if a warning message appears, and in any clinical setting where glucose levels are changing rapidly (>2 mg/dL/min), which could cause a discrepancy between CGM and BGM readings.

The definition of hypoglycemia is based on blood glucose readings, therefore the use of BGM in CGM users remains an essential part of their diabetes management.

#### **5. Implications of hypoglycemia**

#### **5.1 Which diabetes patient needs the most accurate technology for hypoglycemia detection?**

The American Association of Clinical Endocrinologists and American College of Endocrinology 2016 outpatient glucose monitoring consensus statement provided clinical situations and patients groups requiring the highest possible accuracy in glucose monitoring for detection of hypoglycemia [45]. These include those with a history of severe hypoglycemia; hypoglycemia unawareness; infants and children receiving insulin therapy; patients at risk for hypoglycemia, including patients receiving basal insulin or basal/bolus insulin therapy, patients with irregular schedules, skipped or small meals, vigorous exercise, travel between time zones, disrupted sleep schedules, shift work, and people with occupational risks that enhance possible risk from hypoglycemia (e.g., driving or operating hazardous machinery) [45].

Other patient groups include those receiving sulfonylurea or glinides [46], and people with diabetes with comorbidities such as hyperlipidemia or chronic renal disease who may also be taking multiple medications [47]. Age is also an important factor, as risk factors for hypoglycemia such as renal impairment, cardiovascular disease, and polypharmacy all increase with advancing age in adults with T2D [48–50].

The high accuracy in the low blood glucose range is also necessary for diabetes management during pregnancy, therefore CGM use in this patient population remains adjunctive use only [45, 51]. Blood glucose monitoring remains a cornerstone of glucose management during pregnancy [1].

### **6. Conclusions**

In order to make correct therapy decisions, a correct glucose reading is essential [52]. In order to obtain a correct glucose reading, the correct device must be used. This selection spans both device types, i.e. CGM/BGM, and also specific device within the type. Accuracy variation within both system types is proven to be significant, therefore understanding the importance of education for HCP and patients to make an informed choice based on individual needs.

### **Acknowledgements**

Medical writing was supported by Madano.

### **Conflict of interest**

RS and JR are employees of Ascensia Diabetes Care Holdings AG.

### **Author details**

James M. Richardson and Rimma Shaginian\* Ascensia Diabetes Care Holdings AG, Basel, Switzerland

\*Address all correspondence to: rimma.shaginian@ascensia.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] American Diabetes Association Professional Practice Comittee. 6. Glycemic Targets: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022;**45**(Supplement\_1):S83-S96

[2] Schnell O, Hanefeld M, Monnier L. Self-monitoring of blood glucose: A prerequisite for diabetes management in outcome trials. Journal of Diabetes Science and Technology. 2014;**8**:609-614

[3] Cryer PE. Hypoglycemia: Still the limiting factor in the glycemic management of diabetes. Endocrine Practice. 2008;**14**:750-756

[4] Lipska KJ, Warton EM, Huang ES, Moffet HH, Inzucchi SE, Krumholz HM, et al. HbA1c and risk of severe hypoglycemia in type 2 diabetes: The Diabetes and aging study. Diabetes Care. 2013;**36**:3535-3542

[5] Anderson M, Powell J, Campbell KM, Taylor JR. Optimal management of type 2 diabetes in patients with increased risk of hypoglycemia. Diabetes Metab Syndr Obes. 2014;**2014**(7):85-94. Published 2014 Mar 6

[6] Clarke WL, Cox DJ, Gonder-Frederick L, Julian D, Kovatchev B, Young-Hyman D. Biopsychobehavioral model of risk of severe hypoglycemia. Self-Management Behaviors. Diabetes Care. 1999;**22**(4):580-584

[7] Cariou B, Fontaine P, Eschwege E, Lievre M, Gouet D, Huet D, et al. Frequency and predictors of confirmed hypoglycaemia in type 1 and insulintreated type 2 diabetes mellitus patients in a real-life setting: Results from the dialog study. Diabetes & Metabolism. 2015;**41**:116-125

[8] Giorda CB, Ozzello A, Gentile S, Aglialoro A, Chiambretti A, Baccetti F, et al. Incidence and risk factors for severe and symptomatic hypoglycemia in type 1 diabetes. Results of the HYPOS-1 study. Acta Diabetologica. 2015;**52**:845-853

[9] Silbert R, Salcido-Montenegro A, Rodriguez-Gutierrez R, Katabi A, Mc Coy RG. Hypoglycemia among patients with type 2 Diabetes: Epidemiology, risk factors, and prevention strategies. Current Diabetes Reports. 2018;**18**(8):53

[10] Khunti K, Alsifri S, Aronson R, Cigrovski Berkovic M, Enters-Weijnen C, Forsen T, et al. Impact of hypoglycaemia on patient-reported outcomes from a global, 24-country study of 27,585 people with type 1 and insulin-treated type 2 diabetes. Diabetes Research and Clinical Practice. 2017;**130**:121-129

[11] Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The New England Journal of Medicine. 1993;**329**(14):977-986

[12] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). [published correction appears in Lancet 1999 Aug 14;354(9178):602]. Lancet. 1998;**352**(9131):837-853

[13] Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, Devries JH, et al. International consensus on use of continuous glucose monitoring. Diabetes Care. 2017;**40**:1631-1640

[14] Griesdale DE, De Souza RJ, Van Dam RM, Heyland DK, Cook DJ, Malhotra A, et al. Intensive insulin therapy and mortality among critically ill patients: A meta-analysis including Nice-sugar study data. CMAJ. 2009;**180**:821-827

[15] Noh RM, Graveling AJ, Frier BM. Medically minimising the impact of hypoglycaemia in type 2 diabetes: A review. Expert Opinion on Pharmacotherapy. 2011;**12**:2161-2175

[16] Pawaskar M, Iglay K, Witt EA, Engel SS, Rajpathak S. Impact of the severity of hypoglycemia on health— Related quality of life, productivity, resource use, and costs among US patients with type 2 diabetes. Journal of Diabetes and its Complications. 2018;**32**:451-457

[17] Brod M, Christensen T, Thomsen TL, Bushnell DM. The impact of nonsevere hypoglycemic events on work productivity and diabetes management. Value in Health. 2011;**14**:665-671

[18] Polonsky WH, Fisher L, Hessler D. The impact of non-severe hypoglycemia on quality of life in patients with type 2 diabetes. Journal of Diabetes and its Complications. 2018;**32**:373-378

[19] Geelhoed-Duijvestijn PH, Pedersen-Bjergaard U, Weitgasser R, Lahtela J, Jensen MM, Ostenson CG. Effects of patient-reported non-severe hypoglycemia on healthcare resource use, work-time loss, and wellbeing in insulintreated patients with diabetes in seven European countries. Journal of Medical Economics. 2013;**16**:1453-1461

[20] Wong CKH, Tong T, Cheng GHL, et al. Direct medical costs in the preceding, event and subsequent years of a first severe hypoglycaemia episode requiring hospitalization:

A population-based cohort study. Diabetes, Obesity & Metabolism. 2019;**21**(6):1330-1339

[21] International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: A joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2017;**60**:3-6

[22] US Department of Health and Human Services. Food and Drug Administration. Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use – Guidance for Industry and Food and Drug Administration Staff. 2020. Available from: https://www.fda. gov/media/87721/download [Accessed: January 2022]

[23] Heinemann L, Zijlstra E, Pleus S, Freckmann G. Performance of blood glucose meters in the low-glucose range: Current evaluations indicate that it is not sufficient from a clinical point of view. Diabetes Care. 2015;**38**:e139-e140

[24] International Organization for Standardization. In Vitro Diagnostic Test Systems—Requirements for Blood-Glucose Monitoring Systems for Self-Testing in Managing Diabetes Mellitus. ISO 15197. Geneva: International Organization for Standardization; 2013

[25] Budiman ES, Samant N, Resch A. Clinical implications and economic impact of accuracy differences among commercially available blood glucose monitoring systems. Journal of Diabetes Science and Technology. 2013;**7**:365-380

[26] Freckmann G, Baumstark A, Jendrike N, Zschornack E, Kocher S, Tshiananga J, et al. System accuracy evaluation of 27 blood glucose

*Hypoglycemia Detection in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.103137*

monitoring systems according to DIN EN ISO 15197. Diabetes Technology & Therapeutics. 2010;**12**:221-231

[27] Freckmann G, Schmid C, Baumstark A, Pleus S, Link M, Haug C. System accuracy evaluation of 43 blood glucose monitoring systems for selfmonitoring of blood glucose according to DIN EN ISO 15197. Journal of Diabetes Science and Technology. 2012;**6**:1060-1075

[28] Hasslacher C, Kulozik F, Platten I. Analytical performance of glucose monitoring systems at different blood glucose ranges and analysis of outliers in a clinical setting. Journal of Diabetes Science and Technology. 2014;**8**:466-472

[29] Klonoff DC. Postmarket surveillance of blood glucose monitor systems is needed for safety of subjects and accurate determination of effectiveness in clinical trials of Diabetes drugs and devices. Journal of Diabetes Science and Technology. 2019;**13**:419-423

[30] Pleus S, Baumstark A, Jendrike N, Mende J, Link M, Zschornack E, et al. System accuracy evaluation of 18 CE-marked current-generation blood glucose monitoring systems based on EN ISO 15197:2015. BMJ Open Diabetes Research & Care. 2020;**8**:e001067

[31] Freckmann G, Pleus S, Link M, Baumstark A, Schmid C, Hogel J, et al. Accuracy evaluation of four blood glucose monitoring Systems in Unaltered Blood Samples in the low glycemic range and blood samples in the concentration range defined by ISO 15197. Diabetes Technology & Therapeutics. 2015; **17**:625-634

[32] Pardo S, Shaginian RM, Simmons DA. Accuracy beyond ISO: Introducing a new method for distinguishing differences between blood glucose monitoring systems meeting ISO 15197:2013 accuracy requirements. Journal of Diabetes Science and Technology. 2018;**12**:650-656

[33] Richardson JM, Stuhr A, Pardo S, Shaginian RM. Challenges of hypoglycemia management using mobile applications. Oral presentation session 05. Diabetes Technology & Therapeutics. 2020:A-1-A-250

[34] Shaginian R, Richardson J, Pardo S, Stuhr A. Blood glucose monitoring systems' in the low blood glucose range and its clinical implications. Diabetes Technology & Therapeutics. No. S1A bstracts February 19-22, Madrid, Spain: The Official Journal of ATTD Advanced Technologies & Treatments for Diabetes Conference; 2020;**22**:A-1-A-250

[35] Stuhr A, Richardson JM, Pardo S, Shaginian RM. Accuracy of the contour®next one blood glucose monitoring system in the low blood glucose range using probability methodology. Diabetes Technology & Therapeutics. 2020;**22**:A-1-A-250. DOI: 10.1089/ dia.2020.2525.abstracts [Published Online: 18 Feb 2020]

[36] Bolinder J, Antuna R, Geelhoed-Duijvestin P, Kröger J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: A multicentre, non-masked, randomised controlled trial. Lancet. 2016;**388**(10057):2254-2263

[37] The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. The New England Journal of Medicine. 2008;**359**(14):1464-1476

[38] Van Beers CAJ, Devries JH, Kleijer SJ, Smits MM, Geelhoed-Duijvestijn PH, Kramer MHH. Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (In control): A randomised, open-label, crossover trial. The Lancet Diabetes and Endocrinology. 2016;**4**(11):893-902

[39] Holt RIG, Devries JH, Hess-Fischl A, Hirsch IB, Kirkman MS, Klupa T, et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2021;**64**:2609-2652

[40] Freckmann G, Pleus S, Grady M, Setford S, Levy B. Measures of accuracy for continuous glucose monitoring and blood glucose monitoring devices. Journal of Diabetes Science and Technology. 2019;**13**(3):575-583

[41] Basu A, Dube S, Veettil S, Slama M, Kudva YC, Peyser T, et al. Time lag of glucose from intravascular to interstitial compartment in type 1 Diabetes. Journal of Diabetes Science and Technology. 2015;**9**(1):63-68

[42] Pleus S, Stuhr A, Link M, Haug C, Freckmann G. Variation of mean absolute relative differences of continuous glucose monitoring systems throughout the day. Journal of Diabetes Science and Technology. 20 Feb 2021;1932296821992373. DOI: 10.1177/1932296821992373. [Online ahead of print]

[43] Svensson CH, Henriksen MM, Thorsteinsson B, Pedersen-Bjergaard U. Continuous Glucose Monitoring (CGM) Readings during Patient-Reported Symptomatic. Hypoglycemia: Assessment of the Advanced Technologies and Treatments for

Diabetes Consensus Definition of CGM-Recorded Hypoglycemia. Diabetes Technology & Therapeutics. Ahead of print; 2021. DOI: 10.1089/dia.2021.0216

[44] Ajjan RA, Cummings MH, Jennings P, Leelarathna L, Rayman G, Wilmot EG. Accuracy of flash glucose monitoring and continuous glucose monitoring technologies: Implications for clinical practice. Diabetes & Vascular Disease Research. 2018;**15**:175-184

[45] Bailey TS, Grunberger G, Bode BW, Handelsman Y, Hirsch IB, Jovanovic L, et al. American association of clinical endocrinologists and American college of endocrinology 2016 outpatient glucose monitoring consensus statement. Endocrine Practice. 2016;**22**:231-261

[46] Dunkley AJ, Fitzpatrick C, Gray LJ, Waheed G, Heller SR, Frier BM, et al. Incidence and severity of hypoglycaemia in type 2 diabetes by treatment regimen: A UK multisite 12-month prospective observational study. Diabetes, Obesity & Metabolism. 2019;**21**:1585-1595

[47] Alsahli M, Gerich JE. Hypoglycemia in patients with Diabetes and renal disease. Journal of Clinical Medicine. 2015;**4**:948-964

[48] Freeman J. Management of hypoglycemia in older adults with type 2 diabetes. Postgraduate Medicine. 2019;**131**:241-250

[49] Prinz N, Stingl J, Dapp A, Denkinger MD, Fasching P, Jehle PM, et al. High rate of hypoglycemia in 6770 type 2 diabetes patients with comorbid dementia: A multicenter cohort study on 215,932 patients from the German/Austrian diabetes registry. Diabetes Research and Clinical Practice. 2016;**112**:73-81

[50] Sinclair A, Dunning T, Rodriguez-Manas L. Diabetes in older *Hypoglycemia Detection in Diabetes DOI: http://dx.doi.org/10.5772/intechopen.103137*

people: New insights and remaining challenges. The Lancet Diabetes and Endocrinology. 2015;**3**:275-285

[51] Immanuel J, Simmons D. A perspective on the accuracy of blood glucose meters during pregnancy. Diabetes Care. 2018;**41**:2053-2058

[52] Klonoff DC, Alexander Fleming G, Muchmore DB, Frier BM. Hypoglycemia evaluation and reporting in diabetes: Importance for the development of new therapies. Diabetes/Metabolism Research and Reviews. 2017;**33**:2883

#### **Chapter 6**

## Treatment of Hypoglycemia

*Yasin Simsek and Emre Urhan*

#### **Abstract**

Hypoglycemia is an important condition that can be seen in everyone, more often in those with diabetes mellitus, and can sometimes be life-threatening. Hypoglycemia is a condition that can be prevented with simple precautions. It is a simple procedure that can be done mostly by ordinary people when the treatment is known. The most important step in the treatment is the education of those at risk of hypoglycemia and their relatives. The first step in treatment is to measure blood glucose, if possible. If blood sugar is below 70 mg/dl, hypoglycemia is diagnosed; if it is below 50 mg/dl, it is called severe hypoglycemia. The first approach in a conscious patient is to give the patient 15 mg of carbohydrate and measure the blood glucose again after 15 minutes. If the measured value is <70 mg/dl, the procedure should be repeated. If possible, glucagon should be administered to unconscious, out-of-hospital hypoglycemic patients until emergency help arrives. If glucagon is not available, glucose gel can be applied to the buccal mucosa. 50 ml of 50% glucose IV is administered to an unconscious hypoglycemic patient in the hospital. If the blood sugar does not rise above 70 mg/dl, the procedure is repeated.

**Keywords:** hypoglycemia, glucagon, glucose gel

#### **1. Introduction**

Hypoglycemia is generally considered to be a plasma blood glucose level of less than 4 mmol/L (70 mg/dL) in patients with diabetes mellitus. In general, the 'Whipple triad' (glycemia <50 mg/dL, symptoms suitable with low glycemia and these symptoms improve with a treatment that increases low glycemia) is sufficient for the diagnosis of hypoglycemia in persons with nondiabetics, although the plasma glucose level is above 50 mg/dL, most diabetic patients need treatment because of the symptoms of hypoglycemia [1].

#### **2. Symptoms of acute hypoglycemia**

It is divided into two main groups: adrenergic (neurogenic, autonomic) and neuroglycopenic [2]:

#### **2.1 Adrenergic signs and symptoms**

It develops due to the activation of the autonomic nervous system and the adrenal medulla.


#### **2.2 Neuroglycopenic signs and symptoms**

It develops due to decreased glucose delivery to the cerebral cortex.


### **3. Classification of hypoglycemia**

Dividing symptomatic hypoglycemia into three according to the following clinical criteria is beneficial in terms of managing hypoglycemia;

#### **3.1 Mild hypoglycemia**

A condition in which the patient can detect and treat hypoglycemia ownself. Blood glucose is less than 70 mg/dL but is 54 mg/dL or higher.

#### **Symptoms:**

#### **3.2 Moderate hypoglycemia**

It is the situation when the patient has to go to someone else's aid, but treatment is possible orally. Blood glucose is less than 54 mg/dL.

#### **Symptoms:**

Difficulty concentrating or speaking. Confusion. Weakness. Vision changes. Mood swings.

#### **3.3 Severe hypoglycemia**

When the patient is unconscious or unable to take oral glucose due to excessive disorientation and the treatment has to be administered parenterally as glucagon injection or intravenous glucose [3, 4].

#### **Symptoms:**

Confusion. Dizziness. Nausea or vomiting. Shortness of breath. Tremors or chills. Extreme anxiety. Irritability and changes in behavior. Profuse sweating. Pale, clammy skin. Rapid heartbeat. Extreme fatigue or sleepiness. Loss of consciousness. Seizures.

#### **4. Treatment of hypoglycemia**

#### **4.1 Mild and moderate hypoglycemia**

Mild hypoglycemic episodes can be prevented if a patient maintains a healthy diet and blood sugar levels are monitored regularly. For example, eating frequent small meals and having a few small snacks throughout the day will work in preventing hypoglycemia and keeping the patient's blood sugar under control. A good general rule is to eat six small meals each day, enough to meet your total daily carbohydrate needs. You should also drink plenty of water throughout the day. Treatment of mild hypoglycemia usually involves taking glucose tablets and/or foods containing simple sugars in case of hypoglycemia. However, this type of treatment is usually only necessary when you have no other choice. If patients continue to experience hypoglycemia despite following appropriate treatment and a healthy lifestyle, they should talk to their physician to revisal of their treatment [5].

Studies have shown that the glycemic response to oral glucose is transient, typically less than 2 hours. It was concluded that in the case of persistent or recurrent hypoglycemia, although oral glucose is effective, this is a temporary measure and may require a more substantial snack or meal followed by a meal. There is a "rules of 15" that recommends treating blood sugar <70 mg/dL by eating or drinking, a popular treatment strategy for mild hypoglycemia. 15 g carbs and repeat this treatment if symptoms persist after 15 minutes [6].

#### **4.2 Severe hypoglycemia**

Out of hospital: It is recommended that immediate administration of glucagon, if available, for the treatment of hypoglycemia in an unconscious person and in whom IV treatment is not possible. Administration of glucagon (subcutaneous, intramuscular, or nasal) will usually result in recovery of consciousness within about 15 minutes, although this may be followed by marked nausea and even vomiting. Therefore, the dose of glucagon should be followed by oral intake of concentrated carbohydrates just before the patient regains consciousness and nausea develops [7]. In the absence of glucagon, there are no conclusive data to guide the management of severe hypoglycaemia in patients with impaired consciousness who

**Figure 1.** *Treatment of Hypoglycemia.*

#### *Treatment of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.103112*

do not have immediate access to glucagon or intravenously (IV) dextrose (while emergency personnel are waiting). In a study on normoglycemic volunteers, buccal absorption of glucose was shown to be minimal. However, due to the lack of other options for such patients, some authors suggest that while awaiting emergency personnel, family members may apply a glucose gel (e.g., teeth and buccal mucosa) with the patient's head tilted slightly to the side [8]. If a glucose gel or pastry cream is not available There is some data showing that sprinkling table sugar under the tongue may be effective [9].

In hospital: Patients currently in the hospital can usually be treated quickly by administering 25 g of 50% glucose (dextrose) IV. Capillary blood glucose measurement must be repeated after 10 minutes. If it is still less than 70 mg/dL repeat IV glucose administration (**Figure 1**) [7].

#### **5. Glucagon therapy**

Glucagon exerts its hyperglycemic effects mainly by stimulating hepatic glycogenolysis. Unlike insulin, glucagon promotes catabolism and releases glucose [10]. Unlike other peptide hormones (e.g., insulin), glucagon does not show a clear doseresponse relationship, suggesting that the glycemic response to glucagon is saturable. Increasing doses of glucagon do not result in a dose-dependent increase in glucose. Therefore, fixed doses are usually used. This situation has recently paved the way for the use of mini-doses of glucagon administered in doses of 100–150 μg instead of 1 mg to prevent or treat mild hypoglycemia [11].

#### **5.1 Intranasal glucagon**

Intranasal glucagon is a simple system that inserts the tip of the device into one nostril and empties the powder into the nostril. In a randomized trial comparing intranasal (3 mg) and intramuscular (1 mg) glucagon in patients with type 1 diabetes (T1DM) and hypoglycemia, hypoglycemia was successfully corrected in 98.7% and 100% of patients. The time taken for glucose values to rise above 70 mg/dL was 16 min for intranasal administration and 13 min for intramuscular administration [12].

#### **5.2 Stable, liquid glucagon**

Glucagon (or its glucagon analog) can be administered using a syringe kit as a pre-filled syringe containing a single-dose vial, all containing a fixed-dose, stable liquid glucagon preparation (dilution is not required) [13]. In studies in patients with type 1 diabetes, the improvement effects of hypoglycemia were similar in patients receiving 1 mg of stable liquid glucagon, 1 mg of reconstituted glucagon, or 0.6 mg of a glucagon receptor agonist (daciglucagon) [14].

#### **5.3 Reconstituted glucagon**

Glucagon lyophilized powder requires reconstitution just before use. It is administered subcutaneously or intramuscularly (1 mg). In an emergency, the dilution work may force the helpers into the environment [15].

### **6. Treatment of hypoglycemia in special cases**

#### **6.1 Strick glycemic control**

In the treatment of diabetes, tight control is an important strategy in the prevention of microvascular complications. However, the morbidity and potential mortality of hypoglycemia are proven downsides of intensive glycemic management of diabetes [16]. There is strong evidence that tight glycemic control with insulin, sulfonylurea and glinide increases hypoglycemic morbidity and mortality in T1DM and type 2 diabetes (T2DM) [17, 18]. Therefore, alternative drugs with low hypoglycemic effect should be preferred if regulation can be achieved.

#### **6.2 Lipohyperthyrophy at injection sites**

Lipohyperthyrophy is an area of thickened subcutaneous fat tissue which is become due to the administering of continuous injection of insulin to the same area and incorrect rotation. When injecting insulin into the lipohypertrophic area, absorption is irregular, the rate of absorption is unpredictable and may cause glycemic fluctuations such as hypoglycemia [19]. Development of lipohypertrophy is preventable by changing the injection site (rotation) and not using insulin needles more than once [20].

#### **6.3 Hypoglycaemia unawareness**

Hypoglycemia unawareness (HU) refers to the occurrence of neuroglycopenia before the onset of warning symptoms in response to hypoglycemia. It is a condition that prevents strict diabetes regulation and reduces the quality of life, occurs in approximately 40% of people with T1DM and less frequently in T2DM [21]. Blood glucose monitoring, individualized goals and educational programs are important for the prevention and management of HU. Glycemic targets should be individualized, targeting less stringent regulation, especially for patients with long-standing diabetes, patients at high risk of HU and severe hypoglycemia, and/or patients with multiple comorbidities [22].

#### **6.4 Severe hepatic dysfunctions**

Hypoglycemia occurs when gluconeogenesis fails, especially in severe conditions such as liver failure where liver glycogen stores are reduced. The liver is one of the most important organs of glucose balance. Any disorders of its metabolism, structural integrity, or cellular functioning may impair the liver's ability to maintain normal glucose homeostasis. If such a disruption affects hepatic glucose output and gluconeogenesis, hypoglycemia may be occurred [23]. For patients with active liver disease, restrictive diets can often worsen protein-calorie malnutrition [24]. Most oral antidiabetic drugs are metabolized in the liver, and decreased glycogen stores are a risk factor for insulin-induced hypoglycemia, therefore strict monitoring of blood glucose levels should be performed during treatment in diabetic patients [25].

#### **6.5 Impaired renal functions**

Chronic kidney disease (CKD) can increase the risk of hypoglycemia. Decreased GFR is associated with decreased renal gluconeogenesis and clearance of insulin and other glucose-lowering drugs, and attenuation of the efficacy of regulatory

mechanisms against hypoglycemia. Therefore, an individualized approach to diabetes management is essential, especially for patients with advanced CKD [26].

#### **7. Prevention of hypoglycemia**

Patient education, appropriate diet and exercise regimens, blood glucose monitoring, appropriate antidiabetic drug selection, and close clinical follow-up are necessary to prevent hypoglycemia [7].

#### **7.1 Patient education**

Patients and those around them should be educated about recognizing the symptoms of hypoglycemia and giving appropriate treatment for hypoglycemia as soon as possible. It is important to explain to patients the potential dangers of hypoglycemia and how it should be treated in patients treated with insulin, a sulfonylurea or glinide. Any documented hypoglycemia should be investigated with the patient to try to identify the causes, e.g., skipped meals/prolonged fasting, physical exertion, alcohol consumption, and injection of high insulin dose.

Diabetic patients at high risk of hypoglycemia are instructed to always carry glucagon with them. Family members and people around the patients with diabetes should be educated about the administration of glucagon to the patient; they also need to know where the glucagon is being held. There are subcutaneous, intramuscular injections, and intranasal forms of glucagon in the market.

#### **7.2 Diet regulation**

Dietary adjustment includes information about the amount of carbohydrates in meals and its effect on blood sugar concentration, and creating a personalized regular meal plan. The importance of administering insulin with the appropriate dose and timing regarding meals should be emphasized in patients receiving insulin therapy. Patients at risk of hypoglycemia should be advised to keep foods containing glucose or carbohydrates with them or in an accessible place. In some patients, especially those with T1DM or at high risk of nocturnal hypoglycemia, a bedtime snack may be recommended to prevent nocturnal hypoglycemia.

#### **7.3 Recommendations on physical exercise**

Physical exercise increases the risk of hypoglycemia by increasing glucose consumption. If necessary, early action can be taken to prevent hypoglycemia by measuring blood glucose before and after physical exercise. If there is a decrease in glucose level to the level of hypoglycemia, small meals should be eaten before physical exercise. Patients should be carried fast-acting carbohydrates with them during physical exercise. When planning physical exercise, it is important to adjust the insulin dose according to the exercise. Insulin doses should be reduced, more in heavy exercise and less in light exercise.

#### **7.4 Medication adjustment**

In patients receiving diabetes treatment, episodes of hypoglycemia may be associated with the treatment itself; therefore, it is important to use drugs with the low risk of hypoglycemia in such patients. Metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and pioglitazone are drugs with a low risk of hypoglycemia. In contrast, sulfonylureas and glinides are associated with a higher risk of hypoglycemia; Therefore, if treatment-related hypoglycemia occurs, it is recommended to consider reducing or discontinuing the dose of these drugs and switching to a different treatment [27].

With the transition to the use of long-acting basal insulin analogues (such as Detemir and Glargine U100), a significant reduction in nocturnal hypoglycemia attacks was achieved compared to Neutral Protamine Hagedorn (NPH) insulin [28]. The new ultra-long basal insulins Glargine U300 and Degludec have recently led to a significant additional reduction in the rate of nocturnal hypoglycemia [29]. The use of short-acting insulin analogs has resulted in a significant reduction in the rates of severe hypoglycemia compared to conventional human insulin [30].

#### **Author details**

Yasin Simsek1 \* and Emre Urhan<sup>2</sup>

1 Endocrinology and Metabolism Department, Acibadem Hospital, Kayseri, Turkey

2 Endocrinology and Metabolism Department, Erciyes University, Kayseri, Turkey

\*Address all correspondence to: yasinsimsek79@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Cryer PE, Axelrod L, Grossman AB, et al. Endocrine Society. Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism. 2009;**94**(3):709-728

[2] Slama G, Traynard PY, Desplanque N, et al. The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Archives of Internal Medicine. 1990;**150**(3):589-593

[3] ISPAD International Society for Paediatric and Adolescent Diabetes Consensus Guidelines 2000; Classification of Hypoglycaemia. Available from: http://www. diabetesguidelines.com/health/dwk/pro/ guidelines/ispad/13\_03.asp [Accessed: October 18, 2012]

[4] Sua YJ, Liao CJ. Hypoglycemia in emergency department. Journal of Acute Disease. 2015;**4**(1):59-62

[5] Delahanty LM, Halford BN. The role of diet behaviors in achieving improved glycemic control in intensively treated patients in the Diabetes Control and Complications Trial. Diabetes Care. 1993;**16**(11):1453-14588

[6] Wiethop BV, Cryer PE. Alanine and terbutaline in treatment of hypoglycemia in IDDM. Diabetes Care. 1993;**16**(8):1131-11366

[7] Diabetes Canada Clinical Practice Guidelines Expert Committee, Yale JF, Paty B, Senior PA. Hypoglycemia. Canadian Journal of Diabetes. 2018;**42**(1):104-108

[8] Gunning RR, Garber AJ. Bioactivity of instant glucose. Failure of absorption through oral mucosa. Journal of the American Medical Association. 1978;**240**(15):1611-1612

[9] Barennes H, Valea I, Nagot N, et al. Sublingual sugar administration as an alternative to intravenous dextrose administration to correct hypoglycemia among children in the tropics. Pediatrics. 2005;**116**(5):648-653

[10] Kulina GR, Rayfield EJ. The role of glucagon in the pathophysıology and management of diabetes. Endocrine Practice. 2016;**22**(5):612-621

[11] Blauw H, Wendell DVJH, et al. PCDIAB consortium. Pharmacokinetics and pharmacodynamics of various glucagon dosages at different blood glucose levels. Diabetes, Obesity & Metabolism. 2016;**18**(1):34-39

[12] Rickels MR, Ruedy KJ, Foster NC, et al. Intranasal glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: A randomized crossover noninferiority study. Diabetes Care. 2016;**39**(2):264-270

[13] Valentine V, Newswanger B, Prestrelski S, et al. Human factors usability and validation studies of a glucagon autoinjector in a simulated severe hypoglycemia rescue situation. Diabetes Technology & Therapeutics. 2019;**21**(9):522-530

[14] Beato-Vibora PI, Arroyo-Diez FJ. New uses and formulations of glucagon for hypoglycemia. Drugs Context. 2019;**8**:212599

[15] Isaacs D, Clements J, Turco N, Hartman R. Glucagon: Its evolving role in the management of hypoglycemia. Pharmacotherapy. 2021;**41**(7):623-633

[16] Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: Systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ. 2011;**343**:d6898

[17] ORIGIN Trial Investigators, Mellbin LG, Ryden L, Riddle MC, et al. Does hypoglycemia increase the risk of cardiovascular events? A report from the ORIGIN trial. European Heart Journal. 2013;**34**(40):3137-3144

[18] McCoy RG, Van Houten HK, Ziegenfuss JY, et al. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;**35**(9):1897-1901

[19] Omar MA, El-Kafoury AA, El-Araby RI. Lipohypertrophy in children and adolescents with type 1 diabetes and the associated factors. BMC Research Notes. 2011;**12**(4):290

[20] Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Research and Clinical Practice. 2018;**138**:271-281

[21] Vignesh JP, Mohan V. Hypoglycaemia unawareness. The Journal of the Association of Physicians of India. 2004;**52**:727-732

[22] Martin-Timon I, Del Cazzo-Gomez FJ. Mechanisms of unawareness of hypoglycemia and implications in diabetic patients. World Journal of Diabetes. 2015;**6**(7):912-926

[23] Norris ML, Harrison ME, Isserlin L, et al. Gastrointestinal complications associated with anorexia nervosa:

A systematic review. The International Journal of Eating Disorders. 2016;**49**(3): 216-237

[24] Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;**30**(3):734-743

[25] Garcia-Champion D, Gonzalez-Gonzalez JA, Lavalle-Gonzalez FJ, et al. The treatment of diabetes mellitus of patients with chronic liver disease. Annals of Hepatology. 2015;**14**(6):780-788

[26] Ahmad I, Zelnick LR, Batacchi Z, et al. Hypoglycemia in people with type 2 diabetes and CKD. Clinical Journal of the American Society of Nephrology. 2019;**14**(6):844-853

[27] American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2021. Diabetes Care. 2021;**44**(1):111-124

[28] Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: A meta-analysis. Diabetes Research and Clinical Practice. 2008;**81**(2):184-189

[29] Gerber AJ, King AB, Del Prato S, et al. NN1250-3582 (BEGIN BB T2D) Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): A phase 3, randomised, open-label, treatto-target non-inferiority trial. Lancet. 2012;**379**(9825):1498-1507

[30] Pedersen-Bjergaard U, Kristensen PL, et al. Effect of insulin analogues on risk

*Treatment of Hypoglycemia DOI: http://dx.doi.org/10.5772/intechopen.103112*

of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): A prospective, randomised, open-label, blinded-endpoint crossover trial. The Lancet Diabetes and Endocrinology. 2014;**2**(7):553-561

### *Edited by Alok Raghav*

Management of hypoglycemia in diabetes mellitus is a landmark achievement, especially in patients who take insulin. This book provides a comprehensive overview of hypoglycemia, including its pathophysiology, causes, clinical manifestations, management, and screening. It presents recent findings and research in the field and discusses new advancements in hypoglycemic control, including recently developed point-of-care devices for the home and the clinic.

Published in London, UK © 2022 IntechOpen © tussik13 / iStock

Basics of Hypoglycemia

Basics of Hypoglycemia

*Edited by Alok Raghav*