Hypoglycaemia

Definitions

Clinical implications of hypoglycaemia

Severe hypoglycaemia and cardiovascular disease

Risk factors for hypoglycaemia in the diabetic patient 

Management

Management of non-severe hypoglycaemia 

Management of severe hypoglycaemia

Education 

Recurrent hypoglycaemia 

Hypoglycaemia unawareness

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(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

SEMDSA 2017 Recommendations
In diabetes patients using insulin and insulin secretagogues (sulphonylureas and meglitinides), hypoglycaemia is an important limitation to achieving optimal glycaemic control in individuals with diabetes	A
Hypoglycaemia is defined as per the International Hypoglycaemia Study Group according to self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) values:   The glucose alert value for hypoglycaemia is less than 3.9 mmol/L Significant hypoglycaemia is a blood glucose value less than 3.0 mmol/L Severe hypoglycaemia is any low blood glucose value that is accompanied by cognitive dysfunction and a need for external assistance to correct the hypoglycaemia	C
Identify patients at high risk of hypoglycaemia; they include patients using insulin and/or insulin secretagogues, those on multiple glucose lowering drugs, the elderly, those with renal, hepatic or cognitive impairment, patients who exercise or skip meals, and those with excessive alcohol intake	A
Educate patients using insulin and/or secretagogues to be prepared for unexpected hypoglycaemia, to identify the symptoms of hypoglycaemia, to confirm the hypoglycaemia with SMBG whenever possible, and to correct the hypoglycaemia quickly; advise them that oral glucose (15-20g) is the preferred treatment for non-severe hypoglycaemia and offer them advice on alternative glucose sources	C
Use intravenous 50% dextrose water to correct severe hypoglycaemia; use 1mg subcutaneous or intra-muscular glucagon if there is no intravenous access	C
Severe hypoglycaemia is a strong associated risk factor for cardiovascular morbidity and mortality especially in people with pre-existing cardiovascular disease, and should be avoided by adjusting treatment or glycaemic targets	B
Individuals at risk for severe hypoglycaemia (e.g. those with a previous significant or severe hypoglycaemic episode, hypoglycaemia unawareness, cognitive impairment), must have a prescription for a glucagon kit and ensure adequate training of caregivers on how to store and use the glucagon kit	C
Attempt to establish the cause of each hypoglycaemic episode and take appropriate remedial action. Any episode of severe hypoglycaemia or hypoglycaemia unawareness must prompt a re-evaluation of the treatment regimen. Patients with recurrent severe hypoglycaemia and/or hypoglycaemia unawareness should be referred to an endocrinologist	C
Continuous glucose monitoring (CGM) can be used to evaluate patients with recurrent hypoglycaemic episodes and those with hypoglycaemic unawareness	B

Table I: Symptoms and signs of hypoglycaemia

Autonomic	Neuroglycopaenic
Sweating	Poor Concentration
Warmth	Drowsiness / Dizziness
Anxiety	Confusion
Tremor	Weakness
Nausea	Visual Disturbances
Palpitations	Speech Abnormalities
Tachycardia	Headache
Hunger	Seizures
--	Coma

Table II: Classification of hypoglycaemia³

Level	Glucose Criteria (SMBG)	Description
Glucose Alert Value (Level 1)	Less Than 3.9 mmol/L	Sufficiently low for treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy
Clinically significant hypoglycemic (Level 2)	Less than 3.0 mmol/L	Sufficiently low to indicate serious, clinically important hypoglycaemia
Severe Hypoglycaemic  (Level 3)	No specific glucose threshold	Hypoglycaemia associated with severe cognitive impairment requiring external assistance for recovery

DEFINITIONS

Hypoglycaemia in non-diabetic individuals is defined clinically by Whipple’s triad: symptoms of hypoglycaemia, a plasma glucose concentration < 3.0 mmol/l, and resolution of those symptoms after the plasma glucose concentration is raised.¹The symptoms are due to sympathoadrenergic activation (autonomic) and neuroglycopaenia, the symptoms of which are listed in Table I.

In diabetes, a single glucose value cannot be used to define hypoglycaemia based on the onset of symptoms, because the blood glucose level at which symptoms start varies in the same patient and between patients, depending on preceding glycaemic control; individuals with recurrent recent hypoglycaemia may only experience symptoms at much lower blood glucose levels (<3 mmol/L), and those with recent marked hyperglycaemia can have symptoms at blood glucose levels in the normal range (relative hypoglycaemia).² 

The American Diabetes Association (ADA) therefore defines diabetic hypoglycaemia as “all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm” without specifying a numerical value. However, the ADA and other groups also identified the need for a blood glucose value that draws the attention of both patients and caregivers to the harm associated with potentially impending hypoglycaemia. 

This glucose alert value has been defined as a self-monitored blood glucose (SMBG) less than 3.9 mmol/L for patients receiving treatment with insulin and/or insulin secretagogues.^2,3 Clinically significant hypoglycaemia is defined by blood glucose <3.0 mmol/L. Severe hypoglycaemia is any low blood glucose associated with cognitive impairment and requiring external assistance for recovery.³ (Table II)

CLINICAL IMPLICATIONS OF HYPOGLYCAEMIA

Hypoglycaemia is a common problem which is an important limitation to achieving optimal glycaemic control in individuals with diabetes who are treated with insulin and/or insulin secretagogues (viz. sulphonylureas and meglitinides). The short term implications range from unpleasant symptoms to severe cognitive impairment with the potential to cause harm to the individual with diabetes as well as to others. 

These episodes may result in falls, motor vehicle accidents or other injuries.⁴ Prolonged severe hypoglycaemia can cause transient neurological deficits such as paralysis, seizures, and coma. It may cause permanent neurological damage or brain death, and may be responsible for sudden death (the “dead in bed syndrome”). 

Potential long-term effects include reduced quality of life, fear of hypoglycaemia (which will impact glycaemic control) and weight gain. Hypoglycaemia has been associated with a greater risk of dementia:^5,6 However, it is not clear whether this is cause or effect. Clinicians should be aware of relative hypoglycaemia and patients should be encouraged to monitor their finger prick glucose whenever they develop symptoms suggestive of hypoglycaemia. 

Hypoglycaemic episodes can occur in the setting of patients with elevated HbA_1C levels, making the glucometer download of readings an important component of each consultation with a diabetic patient. Lipohypertrophy can result in erratic glucose readings, including hypoglycaemia. Therefore, all patients on insulin should have their injection sites inspected at each consultation.

SEVERE HYPOGLYCAEMIA AND CARDIOVASCULAR DISEASE

Cardiovascular disease is a major cause of mortality in type 2 diabetes and a reduction in cardiovascular outcomes has been the focus in 3 large glucose-lowering trials viz. ACCORD,ADVANCE, and VADT.^7,8,9 Not only did these studies not demonstrate any cardiovascular benefit, but the ACCORD study had to be prematurely halted because of an increased mortality in the intensively treated arm as compared to the standard arm. 

Although the rates of severe hypoglycaemia were higher in patients who were treated with intensive therapy, several post hoc analyses have failed to determine the underlying cause of the higher mortality associated with strict glycaemic control.^10,11,12,13 Irrespective of whether severe hypoglycaemia is causal or a consequence of vulnerability, it remains a strong predictor of cardiovascular morbidity and mortality and should be avoided. 

It is acknowledged that the consequences of hypoglycaemia are greatest in those with severe hypoglycaemia, the frail, and those with pre-existing cardiovascular disease.¹³ Putative mechanisms by which hypoglycaemia may increase cardiovascular disease and death, if it is indeed causal, include inflammation, endothelial dysfunction, blood coagulation abnormalities and an increased sympathoadrenal response causing haemodynamic changes and cardiac rhythm abnormalities.¹⁴

RISK FACTORS FOR HYPOGLYCEMIA  IN DIABETIC PATIENTS

These include:

• Exercise (common)
• Decreased food intake (common): missed or late meals, or small meals
• Inappropriate insulin or insulin secretagogue use/dose
• Intensive treatment with combination therapy
• Renal impairment
• Alcohol intake
• Lower cognitive function

MANAGEMENT 

In the long-term, management should be aimed at preventing or decreasing the frequency and severity of hypoglycaemic episodes in those who are at risk such as the elderly.

MANAGEMENT OF NON-SEVERE HYPOGLYCAEMIA  

Patients should be advised to check their SMBG level at the onset of hypoglycaemic symptoms, as this will avoid erroneous rapid correction of relative hypoglycaemia in those with hyperglycaemia/poor glycaemic control. SMBG confirmation, while preferable, should not delay corrective action. Patients who do not have hypoglycaemia unawareness should be able to correct the condition independently, quickly and early by ingesting 15 – 20 g glucose. This is equivalent to:

• 15-20 g of glucose powder or glucose tablets
• 3 to 4 teaspoons of sugar/sucrose (glucose + fructose) dissolved with a little water
• ¾ cup or ½ a can (175 ml) of fruit juice or soft-drink
• 6 to 8 Lifesavers or 2 to 3 Super C sweets
• 1 to 1½ tablespoons (15 to 20 ml) of honey

If necessary, this step should be repeated within 10-15 minutes. Thereafter, slowly digestible carbohydrates (e.g. bread) and protein (e.g. milk) must be taken for prolonged restoration of the blood glucose. Patients using insulin and/or insulin secretagogues should always carry glucose or sucrose for emergencies in their pockets/handbags/cars.

MANAGEMENT OF SEVERE HYPOGLYCAEMIA  

The patient should be treated immediately. Once the patient has recovered, he or she should be admitted to hospital.

The following steps should be taken on presentation of a suspected hypoglycaemic patient:

• Establish a large bore intravenous (IV) line
• Administer an immediate, rapid IV injection of 20 - 50 ml of 50% dextrose solution
• Assess the clinical and biochemical response over the next 5-10 minutes. If the blood glucose remains < 4.4 mmol/l, give a second IV injection of 20 - 50 ml 50% dextrose
• Continue the IV infusion of 10% dextrose in water, at a rate of about one litre over six hours, to prevent recurrent hypoglycaemia, particularly if induced by long acting insulin and/or a sulphonylurea. For patients that are alcoholic or malnourished, continue the IV infusion with 5% dextrose in water plus thiamine 100 mg intramuscular (IM) injection
• Once blood glucose is normal or has been elevated and the patient is awake, provide him or her with a snack
• If IV dextrose cannot be administered for any reason, inject 1 mg glucagon IM or subcutaneously. The blood glucose will take 10-15 minutes to rise. Importantly, glucagon should not be used in sulphonylurea-induced hypoglycaemia, as it may worsen the condition by further stimulating insulin release
• If the patient has not regained consciousness after 30 minutes, despite a normal or elevated blood glucose level, other causes of the coma will need to be considered (e.g.meningitis). Urgent referral to a specialist is indicated
• Refer all patients with severe hypoglycaemia to hospital for observation and education to prevent further hypoglycaemic episodes. In hospital, monitor the clinical state and blood glucose four hourly for 24-48 hours
• Always try to identify the underlying cause of the hypoglycaemic episode

Glucagon kits (GlucaGen HypoKit^®)

A glucagon emergency kit should be available in all emergency rooms. In addition, patients who experience recurrent severe hypoglycaemia, those at very high risk for hypoglycaemia and those who are hypoglycaemia unaware should be given one of these kits for home use. Family members will need to be trained to reconstitute the powder and solvent, and can be taught to safely administer glucagon by subcutaneous or intramuscular injection when oral glucose cannot be administered. Warn patients to always check that the glucagon kit is not expired.

Some important points to consider:

If hypoglycaemia was caused by a sulphonylurea drug, the patient may need hospitalisation and IV dextrose or glucose infusion for several days, particularly if glibenclamide was the cause or renal impairment is present. 

Honey or glucose syrup can be rubbed on the gums of patients who have lost consciousness if other medication is not readily at hand.

EDUCATION

It is essential that the cause of each hypoglycaemic episode is established, and the appropriate action is taken to prevent further episodes. All diabetic patients must be given education on the recognition and treatment of hypoglycaemia.

RECURRENT HYPOGLYCAEMIA 

All patients with recurrent hypoglycaemia should be referred to a specialist facility for assessment.

Consider the following in cases of recurrent hypoglycaemia:

• Inappropriate management
• Poor adherence to treatment
• Alcohol abuse
• Self-induced hypoglycaemia
• Renal impairment / failure
• Hypoglycaemia unawareness
• Drug interactions / herbal toxins
• Liver disease
• Non-diabetic causes of hypoglycaemia e.g. insulinoma

HYPOGLYCAEMIC UNAWARENESS

This complication occurs after recurrent episodes of hypoglycaemia, and is associated with hypoglycaemia associated autonomic failure. These patients do not exhibit the early (autonomic) symptoms of hypoglycaemia, and consequently present with neuroglycopaenia (i.e. confusion, seizures, and coma). Recurrent hypoglycaemia may be the cause or consequence of hypoglycaemic unawareness. 

Evidence exists that, in some of these individuals, scrupulous avoidance of hypoglycaemia for several weeks may reverse hypoglycaemic unawareness. Patients with hypoglycaemia unawareness should be referred to an endocrinologist and advised to raise their glycaemic targets to strictly avoid hypoglycaemia for at least several weeks. Continuous glucose monitoring is useful in monitoring and managing these patients.

Authors: Nasrin G Mahyoodeen and Kenneth RL Huddle
Editors: Aslam Amod and Joel A Dave

References and Further Reading

1. Desimone ME, Weinstock RS. Non-Diabetic Hypoglycemia. MDText.com, Inc.;2000.
2. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. J Clin Endocrinol Metab. 2013;98(5):1845-1859. doi:10.1210/jc.2012-4127.
3. 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: Table 1. Diabetes Care. 2017;40(1):155-157.doi:10.2337/dc16-2215.
4. Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10(12):711-722. doi:10.1038/nrendo.2014.170.
5. Whitmer RA. Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus. JAMA. 2009;301(15):1565. doi:10.1001/jama.2009.460.
6. Lin C-H, Sheu WH-H. Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study. J Intern Med. 2013;273(1):102-110. doi:10.1111/joim.12000.
7. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC,Miller ME, et al. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med. 2008;358(24):2545-2559. doi:10.1056/NEJMoa0802743.
8. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2008;358(24):2560-2572. doi:10.1056/NEJMoa0802987.
9. Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009;360(2):129-139. doi:10.1056/NEJMoa0808431.
10. Saremi A, Bahn GD, Reaven PD. A link between hypoglycemia and progression of atherosclerosis in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care.
    2016;39(3):448-454. doi:10.2337/dc15-2107.
11. Zoungas S, Patel A, Chalmers J, et al. Severe Hypoglycemia and Risks of Vascular Events and Death. N Engl J Med. 2010;363(15):1410-1418. doi:10.1056/NEJMoa1003795.
12. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340(jan08 1):b4909-b4909. doi:10.1136/bmj.b4909.
13. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology. Diabetes Care. 2009;32(1):187-192. doi:10.2337/dc08-9026.
14. Desouza C V., Bolli GB, Fonseca V. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care. 2010;33(6):1389-1394. doi:10.2337/dc09-2082.

Further Reading
Cryer PE, Axelrod L, Grosman AB, et al; Endocrine Society. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab. 2009;94:709-728.