Hypoglycaemia: Prevention and management

One of the most worrying short-term complications of diabetes, and one that often worries patients particularly, is hypoglycaemia. What steps can be taken to reduce the risk of hypoglycaemia and how should it be managed?

Hypoglycaemia is usually considered as plasma blood glucose less than 4 mmol/.l Most healthy adults develop symptoms around this level. A trio of criteria referred to as Whipple's triad - as they were first described by Whipple in association with insulin producing tumours - are needed to make a diagnosis of hypoglycaemia.^1,2 These are:

1. Symptoms known to be caused by hypoglycaemia

2. Low glucose at the time the symptoms occur

3. Reversal or improvement of symptoms or problems when the glucose is restored to normal

WHO GETS HYPOGLYCAEMIA?

Hypoglycaemia is mainly a feature of diabetes on treatment. It can also occur in individuals not on blood glucose lowering medication as a response to starvation or after eating highly sugary meals and exercising. It is also seen in some medical conditions such as insulinoma and renal disease. However, this article is confined to discussion of hypoglycaemia in diabetic patients.

HYPGLYCAEMIA IN DIABETES

Patients with type 1 diabetes (T1D) are the most likely to have hypoglycaemia events (hypos). Even during treatment with insulin, hypoglycaemia event rates in type 2 diabetes (T2D) are about one-third of those in T1D overall.³ However because T2D is roughly 20-fold more prevalent than T1D and many people with T2D ultimately require treatment with insulin, most episodes of hypoglycaemia, including those of severe hypoglycaemia, occur in individuals with T2D.

Most hypos are due to an imbalance between the medication the patient is using and the glucose needs of their body. This typically happens when a person does one or more of the following:^4,5

• Insulin (or insulin secretagogue) doses are excessive, ill-timed or of the wrong type.
• Exogenous glucose delivery is decreased (e.g. missed meals or during the overnight fast, or as a result of gastroparesis or coeliac disease).
• Glucose utilisation is increased (for example, during and shortly after exercise) without corresponding increase in food intake or decrease in insulin dose
• Endogenous glucose production is decreased (for example, following alcohol ingestion).
• Sensitivity to insulin is increased (in the middle of the night or following weight loss, improved fitness or improved glycaemic control).
• Insulin clearance is decreased (as in renal failure). CKD is a risk factor for hypos even in non diabetic patients.⁶

Hypo symptoms can be experienced at higher blood glucose levels than 4mmol/l often by poorly controlled diabetic patients. This is because they are accustomed to running a high blood glucose, and they are responding to the relative fall in glucose levels. The symptoms are real although the hypo is not a true one. This may lead to avoidance of normal blood sugar levels in the poorly controlled diabetic. Patients will need reassurance, in order to lower their readings to healthy levels and gradually adjust the body's response.

RISK FACTORS

There are some factors that identify patients as particularly at risk of hypo. These are:

• Absolute insulin deficiency i.e. type 1 diabetes or late type 2
• History of previous severe hypo, hypo unawareness or both
• Aggressive glycaemic therapy (studies with a control group treated to higher mean glycaemia consistently document higher rates of hypoglycaemia in the group treated to lower mean glycaemia)⁷

Remember, though, that hypoglycaemia can occur in individuals with any HbA1C level, and the fact that tight control is a risk factor does not mean that one cannot both tighten control and reduce the risk of hypoglycaemia in individual patients.

WHAT DOES A HYPO FEEL LIKE?

Box 1 lists typical symptoms experienced as part of hypos. A variety of symptoms can occur and some patients may have very few,¹ or indeed no warning symptoms prior to actually losing consciousness.

Hypoglycaemia can happen suddenly. It is usually initially mild and can be treated by eating or drinking a small amount of glucose-rich food. If left untreated, confusion, clumsiness, and loss of consciousness may result. Sometimes unconscious patients can look as though they have had a stroke, with facial asymmetry. Severe hypoglycaemia can lead to seizures, coma, and even death.

Hypoglycaemia unawareness

Hypoglycaemia unawareness is common,4 especially in those who have had type 1 diabetes for 10 years or more, and in type 2 diabetics on insulin. Excessive alcohol intake also makes it more likely, and some medications can cause hypoglycaemia unawareness, including some sulphonylureas and beta blockers.

Nocturnal hypoglycaemia

Hypos during sleep often go unrecognised as the patient may not wake. Thrashing around in bed or nightmares may result, but if there is nobody there to see it, the event will pass unnoticed. Nocturnal hypoglycaemia increases the risk of further hypoglycaemia unawareness in the subsequent 48 to 72 hours.⁴

CLASSIFICATION OF HYPOGLYCAEMIA⁷

Symptomatic hypoglycaemia can usefully be divided into 3 grades on the following clinical criteria:

Grade 1: when the patient is able to detect and treat hypoglycaemia himself/herself

Grade 2: when someone else has to go to the aid of the patient, but treatment is possible orally

Grade 3 or severe hypoglycaemia: when the patient is unconscious, or unable to take oral glucose because of extreme disorientation and therapy is either glucagon injection or intravenous glucose

WHICH MEDICATION MAKES THE BLOOD SUGAR FALL?

Some diabetes medications are more likely to cause hypos than others, as some medications work only in the presence of raised blood glucose (e.g. by prolonging the actions of the body's own insulin) whereas others lower blood sugar even if it is already low.

Box 2 lists drugs and drug combinations that carry a risk of hypoglycaemia.

Insulin pumps

It is increasingly common to see patients with type 1 diabetes using an insulin pump, a small battery powered device which pumps a constant supply of short acting insulin subcutaneously. These patients, who have no insulin of their own, depend on the pump to maintain normal blood glucose. It is important that these patients test their blood sugar regularly, and develop an awareness and understanding of how their body's insulin needs vary with exercise and varied food intake as they may be particularly prone to hypos.

MANAGEMENT OF HYPOS

The principle of hypo management is rapid carbohydrate replacement by the most easily absorbable but least invasive route.

The duration of a hypoglycaemic episode is a function of its cause. While a hypo caused by a short-acting insulin secretagogue or a rapid-acting insulin can be measured in hours, one that is caused by a long-acting insulin secretagogue or a slow-acting insulin can last for days, requiring hospitalisation for prolonged therapy.

Managing mild or moderate (grade 1 or 2) hypo

• Immediate oral rapidly absorbed simple carbohydrate e.g.
  • 5-15 g glucose or sucrose (tablets/sugar lumps) - See Box 3
  • 100 ml sweet drink (glucose/sucrose drinks, cola, etc)
• Wait 10-15 minutes. If no response...
• Repeat oral intake as above

As symptoms improve or normoglycaemia is restored, the next meal or oral complex carbohydrate should be ingested (e.g. fruit, bread, cereal, milk)

Managing Severe (grade 3) hypo

• Severe hypoglycaemia with loss of consciousness +/- convulsions (particularly if there is vomiting) is most safely and rapidly reversed by injection of Glucagon
  • 0.5 mg for age <12 years
  • 1mg for age 12+ years (or 0.1-0.2 mg/10 kg body weight) best given IM (or deep SC)

If glucagon is unavailable or recovery is inadequate...

• IV glucose should be administered slowly over several minutes
• If the hypoglycaemia is not associated with vomiting nor severe enough to remove the swallowing, spitting or gag reflexes, give concentrated sugar as glucose gel/syrup/honey/jam carefully by mouth

In the recovery phase close observation and blood glucose monitoring are essential because vomiting is common and recurrent hypoglycaemia may occur. The patient will usually require additional oral carbohydrate and/or IV infusion of glucose

RISKS ASSOCIATED WITH HYPOS

Hypoglycaemia is a serious event with significant health complications, including dizziness, disorientation, convulsions, and death. Hypoglycaemic episodes also impair defenses against subsequent hypoglycaemia.⁸

In addition to this, hypoglycaemia triggers a reactive surge in adrenergic activity, which can result in coronary ischemia, and serious cardiac arrhythmias, with consequent risk of sudden death.⁶ As many as 10% of patients with severe sulfonylurea-induced hypoglycaemia die.⁹ Importantly, an episode of severe hypoglycaemia was a significant predictor of death in the ACCORD trial.¹⁰

PREVENTION

Clearly hypos are to be avoided, as they represent a significant danger.

To minimise risk, the following four points are essential:¹¹

1. Acknowledge the problem - discuss hypoglycaemia at every patient contact

2. Apply the principles of aggressive glycaemic therapy. i.e.

• Patient education and empowerment.
• Frequent blood glucose monitoring - especially whenever hypo is suspected
• Flexible and appropriate insulin (and other) regimens.
• Individualised glycaemic goals.
• Ongoing professional guidance and support.

3. Consider the conventional risk factors in diabetes i.e. the risk factors that result in relative or absolute hyperinsulinemia. These include

• Reviewing the dose, timing and type of medication,
• Reviewing conditions in which exogenous glucose delivery or endogenous glucose production is decreased, glucose utilization or insulin sensitivity is increased or insulin clearance is decreased.

4. Consider the risk factors for hypo unawareness

• The degree of absolute endogenous insulin deficiency
• A history of severe hypoglycaemia, hypoglycaemia unawareness
• Relationship between iatrogenic hypoglycaemia and recent antecedent hypoglycaemia, prior exercise or sleep, and lower glycaemic goals.

PREPARING FOR HYPOS

It is important to be prepared. For patients at risk of hypo, particularly those with type 1 diabetes or type 2 diabetes on insulin, the following are recommended:⁶

• An immediate source of glucose or sucrose must always be available
• Equipment for BG measurement must be available for immediate confirmation and safe management of hypoglycaemia
• Children, adolescents, parents, and other care-givers should receive education on recognition and management of hypoglycaemia
• Glucagon should be readily accessible, especially when there is a high risk of severe hypoglycaemia. Education on administration is essential
• Children and adolescents with diabetes should wear some form of identification or warning of their diabetes

WHAT CAN PATIENTS DO TO HELP?

Diabetes treatment plans should be designed with the patient to match dose and timing of medication to the person's usual schedule of meals and activities.To help prevent hypoglycaemia, people with diabetes should always consider the following:

The meal plan A dietitian can help design a meal plan that works for the patient. People with diabetes should eat regular meals, have enough at each meal, and try not to skip meals or snacks. Snacks are important for some people before going to sleep or exercising.

Their daily activity To help prevent hypoglycaemia caused by physical activity, consider:

• Checking blood glucose before sports, exercise, or other physical activity and having a snack if the level is lower than expected
• Adjusting medication before physical activity
• Checking blood glucose at regular intervals during extended periods of physical activity and having snacks as needed
• Checking blood glucose periodically after physical activity

Physical activity is hugely beneficial, improving fitness and lowering blood glucose levels. However, physical activity can cause hypoglycaemia up to 24 hours afterward. For those who take insulin or one of the oral medications that increase insulin production, suggest having a snack if the glucose level is below 5.6mmol/l. It can also be useful to suggest extra blood glucose checks, especially after strenuous exercise.

Use of alcohol Alcohol, particularly on an empty stomach, can cause hypoglycaemia, even a day or two later. Heavy drinking can be particularly dangerous for people taking insulin or medications that increase insulin production. Alcoholic beverages should always be consumed with a snack or meal at the same time.

Diabetes management plan Those whose goal is tight control should talk with a health care provider about ways to prevent hypoglycaemia and how best to treat it if it occurs.

Advice about driving Hypoglycaemia is dangerous at the wheel, when it may affect concentration, vision, judgement and reaction times. People at risk of hypoglycaemia are advised to check their blood glucose level before driving. During longer trips, they should check their blood glucose level frequently and eat snacks as needed to keep the level at 4mmol/l or above. If necessary, they should stop for treatment.

TAKE HOME MESSAGES

• Hypoglyaemia is dangerous both in the short and long term.
• Prevention is via a good management plan and increased patient understanding of, and sharing of, that plan.
• When people with diabetes suspect their blood glucose level may be low, THEY SHOULD CHECK IT
• Treatment should be immediate. Blood sugar can fall fast.
• As treatment, people should have a serving of a quick-fix food, wait 15 minutes, and re-check their blood glucose. They should repeat the treatment until their blood glucose is at least 4mmol/l.
• People at risk should keep quick-fix food to hand.
• People at risk should take precautions when driving. They should check their blood glucose frequently and snack as needed to keep their level at 4mmol/l or above. Those on medication, including insulin, are obliged to inform the DVLA

REFERENCES

1. National Diabetes Information

Clearinghouse (NDIC) http://diabetes.niddk.nih.gov/dm/pubs/hypoglycaemia/

2. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ (March 2009). "Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 94 (3): 709-28.

3. Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, Band MM, Reekie G, Leese GP; DARTS/MEMO Collaboration 2005 Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 22:749-755

4. Hypoglycaemia in Wolters Kluwer health, online resource http://www.uptodate.com/contents/hypoglycaemia accessed 18/10/12

5. The Diabetes Control and Complications Trial Research Group 1995 The relationship of glycemic exposure (HbA1C) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 44:968-983

6. Moen MF, Zhan M, Hsu VD et al: Frequency of hypoglycaemia and its significance in Chrinoc Kidney Disease, Clinical Journal of the American Society of Nephrology June 2009 vol. 4 no. 6 1121-1127

7. ISPAD International Society for Paediatric and Adolescent Diabetes Consensus Guidelines 2000; classification of hypoglycaemia http://www.diabetesguidelines.com/health/dwk/pro/guidelines/ispad/13_03.asp accessed18/10/12

8. Cryer PE 2008 The barrier of hypoglycaemia in diabetes. Diabetes 57:3169-3176

9. Holstein A, Egberts EH 2003 Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes. Exp Clin Endocrinol Diabetes 111:405-414

10. ACCORD Study Group 2008 Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545-2559

11. Cryer PE, et al. Hypoglycaemia during therapy of diabetes. Endotext, 2011 http://www.endotext.org/diabetes/diabetes25/diabetesframe25.htm

12. ISPAD International Society for Paediatric and Adolescent Diabetes Consensus Guidelines 2000; Treatment of hypoglycaemia: http://www.diabetesguidelines.com/health/dwk/pro/guidelines/ispad/13_08.asp accessed 18/10/12

13. National Diabetes Information Clearinghouse's booklet What I need to know about Diabetes Medicines, available at www.diabetes.niddk.nih.gov/dm/pubs/medicines_ez accessed 18/10/12