Section 1

Jean is 76 years old and has had type 2 diabetes for nearly 20 years. She lives on her own, having recently been widowed, but remains physically and socially active. Following several hours of gardening, Jean experienced an episode of dizziness, confusion and speech slurring. She was spotted by a neighbour who called an emergency ambulance. Jean was found to have a capillary blood glucose reading of 2.3 mmol/L and was treated for hypoglycaemia.

An appointment was made for Jean to see her GP to review her diabetes management and medication. Her current treatment for hyperglycaemia consists of metformin MR 500 mg twice daily (previously troublesome gastrointestinal side-effects on higher doses) and gliclazide 80 mg twice daily. She also takes atorvastatin 20 mg once daily. Recent records show: BMI 26.7 kg/m²; HbA_1c 59 mmol/mol; eGFR 55 mL/min/1.73 m².

How would you respond to Jean’s episode of hypoglycaemia?

Section 2

The priority is to avoid future hypoglycaemia. It is important that Jean understands how to identify and treat hypoglycaemia, and it would also be helpful if this information is shared appropriately with family, friends or near neighbours. If gliclazide were to be continued, Jean should have access to capillary glucose monitoring and be reminded of DVLA requirements to drive safely (see later). If Jean is undertaking prolonged exercise, then a starchy carbohydrate snack (e.g. banana, cereal bar or sandwich) beforehand would help maintain glucose levels. However, it appears that Jean was unaware of her descent to hypoglycaemia and, with reduced symptom awareness, and newer drugs with fewer side effects and benefits beyond lowering glycaemia, the safest course of action would be to stop the gliclazide.

Hypoglycaemia can be defined biochemically as a plasma glucose concentration of less than or equal to 3.9 mmol/L (1,2) although this definition varies between sources. Symptomatic hypoglycaemia is an event when typical symptoms of hypoglycaemia accompany low plasma glucose concentrations. When symptoms are absent, this constitutes asymptomatic hypoglycaemia.

Jean’s gliclazide is discontinued. A few months later, a repeat HbA_1c returns at 68 mmol/mol.

What action would you now take following Jean’s latest HbA_1c result?

Section 3

Jean’s general health is good and her life expectancy could easily be 10 years or more. Whilst tight glycaemic control is less critical in a person of Jean’s age and duration of diabetes (3), it is worth improving glycaemic control, if this can be done safely.

Ideally, Jean’s gliclazide would have been replaced immediately, as we know it was working and the rise in HbA_1c was predictable. An SGLT2 inhibitor that could be initiated at her current eGFR was considered as per ADA/EASD guidance, but she had been intolerant previously and was unwilling to consider this class of drug again. Jean is prescribed a DPP-4 inhibitor at an appropriate dose for her eGFR, to add on to her metformin. The choice of a DPP-4 inhibitor is made on the grounds of safety (low risk of hypoglycaemia, safe to use in chronic kidney disease), favourable side-effect profile and ease of use.

Which treatments for diabetes carry a high risk of hypoglycaemia?

Section 4

The highest risk of hypoglycaemia lies with insulin therapy. However, we should also remember that the insulin secretagogues, namely sulfonylureas (SUs) and the less frequently used meglitinides (nateglinide and repaglinide), also carry a risk of hypoglycaemia.

For individuals with type 2 diabetes, and particularly the elderly and those with CKD who are at higher risk of hypoglycaemia, it is recommended that if SUs must be used, then the newer generation (including gliclazide, glimepiride and glipizide) be used to lower the risk of hypoglycaemia (4,5).

Basal insulins (especially the longer-acting basal insulin analogues) are less likely to induce hypoglycaemia than twice-daily mixed biphasic insulins and rapid-acting prandial insulins.

Agents that intrinsically carry a low risk of hypoglycaemia are listed below, although if these treatments are combined with insulin or insulin secretagogues the risk of hypoglycaemia returns.

• Metformin
• Pioglitazone
• DPP-4 inhibitors
• GLP-1 receptor agonists
• SGLT-2 inhibitors
• Acarbose

We have seen which diabetes medications predispose to hypoglycaemia. What other risk factors increase the likelihood of hypoglycaemia? How might you minimise risk of hypoglycaemia?

Section 5

In those taking medication predisposing to hypoglycaemia other risk factors for hypoglycaemia include (3):

• Incorrect dosing and timing of these drugs
• Aiming for intensive glycaemic control
• Increasing age
• Long duration of diabetes
• Renal impairment
• Recurrent episodes of hypoglycaemia
• Malabsorption (e.g. coeliac disease; more common in type 1 diabetes)
• Gastroparesis (an autonomic nerve complication of diabetes)
• Severe liver impairment
• Cognitive decline

Fasting, change in diet or an erratic lifestyle with missed or irregular meals present real challenges in avoiding hypoglycaemia. Regular meals with consumption of carbohydrates with a low glycaemic index can help to maintain glucose levels. Alcohol can lead to hypoglycaemia several hours after consumption, and binge drinking should be discouraged.

Prolonged exercise may also induce hypoglycaemia in insulin- or SU-treated diabetes. Taking on board additional starchy carbohydrate ahead of exercise can help mitigate falls in blood glucose levels. Alternatively, the dose of rapid-acting insulin or biphasic insulin may be reduced by around 20–25% (or higher, if necessary) with the meal preceding activity, with careful self-monitoring of blood glucose levels to assess individual’s response. Where hypoglycaemia is problematic, consider switching to diabetes medications that do not induce hypoglycaemia (as listed above) where possible.

Those people with type 2 diabetes on a reducing regimen of oral steroids are likely to experience falling plasma glucose levels and, in the presence of hypoglycaemic-inducing treatments, there should be careful monitoring for hypoglycaemia.

Finally, it is worth remembering that in the frail elderly (e.g. in a nursing home) hypoglycaemia should be considered as a possible cause in those individuals with episodic irritability, aggression, drowsiness or behavioural change that might otherwise be interpreted as depression or dementia.

Section 6

John is a 49-year-old HGV driver who has just joined your list and is maintained on metformin 1000 mg twice daily, gliclazide 160 mg twice daily and alogliptin 25 mg once daily for his type 2 diabetes, which he has had for 6 years. He is also taking rosuvastatin 10 mg once daily and lisinopril 20 mg once daily. BMI 34.6 kg/m²; HbA_1c 59 mmol/mol; eGFR 102 mL/min/1.73m².

On occasions, John experiences mild symptomatic hypoglycaemia (at capillary glucose readings between 3 and 4 mmol/L). With good warning symptoms, John is able to correct these episodes and is careful to always carry a supply of dextrose tablets. Because of the worry over hypoglycaemia, John frequently snacks on unhealthy food options whilst driving.

What do you think about the selection of antidiabetes medication for John? Would you make any changes?

Section 7

John’s current management, which does not include any of the newer diabetes therapies, is not appropriate for a person of his age. A better strategy for John would be to avoid antidiabetes medication that carries a risk of hypoglycaemia. Although he is managing his episodic mild hypoglycaemia adequately, there is always the concern that this might progress to severe hypoglycaemia (where assistance from another person is required). In addition to the personal health risks this poses, if John was driving at the time of a hypoglycaemic episode it could be catastrophic for others. A single occurrence of severe hypoglycaemia would be sufficient to cause a loss of his HGV licence (6). For these reasons, John should avoid SUs when there are safer alternatives available. Group 2 drivers must notify the DVLA of any medication for diabetes, although they only need to undertake regular testing (even on non-driving days) if on any oral treatment with a hypoglycaemia risk or insulin.

One option would be for John to discontinue the gliclazide and substitute an SGLT2 inhibitor, which would offer glycaemic benefit without the risk of hypoglycaemia associated with an SU. An additional benefit would be potential weight loss (in contrast with possible weight gain associated with an SU).

An alternative strategy would be to discontinue the SU and alogliptin in favour of a GLP-1 receptor agonist on your local formulary. This should enable good glycaemic control, with low risk of hypoglycaemia and the added benefit of potential weight loss. By reducing the risk of hypoglycaemia, John can have the confidence to avoid snacking, which would also benefit his weight and cardiovascular health.

Section 8

Chinua is a 58-year-old man of African ethnic origin, with type 2 diabetes for 13 years. His most recent HbA_1c was 73 mmol/mol, despite treatment with metformin 100 mg twice daily, empagliflozin 25 mg once daily and Levemir (insulin detemir) 36 units in the evening. Capillary glucose readings have been running at 6–9 mmol/L pre-breakfast, rising to 10–16 mmol/L during the day. In response to these results, Chinua is switched from Levemir to twice-daily pre-mix insulin in the hospital diabetes clinic.

Chinua has been warned about the possible increased risk of hypoglycaemia, and comes to see you asking for more information on how he might spot this and what he should do about it.

What are the symptoms of hypoglycaemia that Chinua should be looking out for?

Section 9

Generally, the first symptoms of hypoglycaemia to be experienced are autonomic (see below), generated following activation of the sympatho-adrenal system and mediated through the effects of catecholamines, such as adrenalin. Typically, they start to take effect when plasma glucose levels fall below 4 mmol/L, although this will vary between individuals. This autonomic response is protective against the development of severe hypoglycaemia in that it acts as an early warning system, allowing a corrective response from the person, and, in itself, stimulates glucose release from the liver (7).

The second set of symptoms arise from an inadequate supply of glucose to the brain (neuroglycopaenia). These typically appear with blood glucose levels <3 mmol/L (7,8).

These signals of hypoglycaemia, and the need to act on them, should be explained to Chinua.

What does Chinua need to know about treating hypoglycaemia?

Section 10

Advise Chinua that, if he experiences symptoms of hypoglycaemia, he should take a rapid-acting carbohydrate (15–20 g), examples of which are shown below (7,8). If hypoglycaemia is suspected, it is good practice to check a plasma glucose level but, if testing equipment is not to hand, then treatment must not be delayed.

Oral treatments for hypoglycaemia

• 3 glucose or dextrose tablets
• 5 jelly babies
• Small glass (150–200 mL) of sugary (non-diet) drink
• Small carton (200 mL) pure orange juice
• 2 tubes of glucose gel (e.g. GlucoGel)

Clinical improvement and restoration of blood glucose levels should be anticipated within 10 minutes of treatment but, if this is not apparent or blood glucose levels remain <4 mmol/L, then treatment should be repeated.

If a meal is not due, then a more complex (starchy) carbohydrate should also be consumed to maintain blood glucose levels (banana, cereal bar, sandwich, fruit). Glucose levels should be carefully monitored in the aftermath of hypoglycaemia and, if it is more than a mild episode (either in terms of symptoms or glucose levels), the individual with diabetes should not be left alone.

Chinua then asks about hypoglycaemia in regard of driving. How can you advise him?

Section 11

Chinua (in common with all drivers who use insulin) should be reminded of the need to inform the DVLA and his insurer. He should also be advised to check blood glucose levels less than 2 hours before driving and at least every 2 hours on longer journeys (6). “Don’t drive below five” is a useful reminder that blood glucose levels should not be <5 mmol/L before driving and that, if necessary, a snack containing longer-acting carbohydrates should be taken to raise glucose levels. Driving must be avoided if there are symptoms of hypoglycaemia or glucose levels are <4 mmol/L. A fast-acting carbohydrate and glucose-testing kit should be carried at all times when driving, in case of hypoglycaemia. Driving must not resume until 45 minutes after an episode of hypoglycaemia has resolved.

There is a strong argument that the above advice should extend to those people with type 2 diabetes using SUs or meglitinides, and this is mandatory in the case of drivers holding a Group 2 licence (for heavy goods vehicles and passenger-carrying vehicles) who must notify the DVLA if they are taking any antidiabetes medication.

Should Chinua experience hypoglycaemia whilst driving, he should follow the DVLA guidance (6):

• Pull over and stop car in safe location
• Remove keys from ignition and move out of driver’s seat
• Treat hypoglycaemia
• Do not drive for 45 minutes after glucose levels have returned to normal (at least 5 mmol/L)

A fast-acting carbohydrate should be used to restore blood glucose level, followed by a longer-acting carbohydrate to maintain it. The delay before driving again after correction of hypoglycaemia is necessary because cognitive recovery may be incomplete until this amount of time has passed.

Section 12

Candice, 65 years old, is treated with metformin and a basal bolus insulin regimen (once-daily Lantus plus NovoRapid with three main meals) for her type 2 diabetes. She has an appointment to see the Practice Nurse but, shortly after arrival at the surgery, reports feeling unwell and then becomes semi-conscious. A finger-prick glucose reading is 1.7 mmol/L.

How can you manage this episode of severe hypoglycaemia?

Section 13

With impaired consciousness swallowing is unsafe, so Candice should not be given oral treatments for hypoglycaemia. If available, Candice can be given 1 mg glucagon by intramuscular injection, place her in the recovery position and call for an emergency ambulance.

It is important to try and discover the specific reason for severe hypoglycaemia. In this case, Candice had administered her morning NovoRapid dose but, in a rush to attend the surgery, had eaten very little breakfast; the result was an episode of severe hypoglycaemia.

It transpires that Candice has been experiencing fairly frequent episodes of hypoglycaemia that she does not identify until glucose readings fall below 3 mmol/L.

What problem is Candice exhibiting and how can this problem be addressed?

Section 14

Candice would seem to have impaired awareness of hypoglycaemia. This dangerous situation arises when the autonomic (adrenalin-mediated) response to hypoglycaemia is blunted, and there can be rapid progression to neuroglycopaenia and loss of consciousness. The seriousness of this situation may be aggravated by a sluggish glucagon response (glucagon being the major counter-regulatory hormone to insulin that stimulates glucose synthesis and release from the liver) (9).

Thus, in long-standing diabetes, notably in the elderly, a deficient adrenalin response, against a background of glucagon inadequacy, can lead to warning symptoms not arising until blood glucose levels fall to around 2 mmol/L by which time severe hypoglycaemia with cognitive dysfunction has taken hold.

A further contributing factor to hypoglycaemia is recurrent hypoglycaemia itself. Such episodes can reset the triggering of the sympatho-adrenal response to a lower level of plasma glucose, again narrowing the window between these protective symptoms and neuroglycopaenia (9).

Candice’s insulin doses should be reduced immediately based on her glucose monitoring values by around 20% and adjusted according to self-monitoring of blood glucose. She should be reminded to monitor regularly her capillary glucose levels and to always carry a supply of fast-acting carbohydrate. She should avoid missing meals and, if this is unavoidable, she should also omit her dose of prandial insulin. If she is due to engage in prolonged exercise, then she should take on board a starchy carbohydrate snack and/or cut her prandial insulin dose with the meal prior to exercise (10).

Given her hypoglycaemic unawareness, Candice needs to avoid hypoglycaemia. Target finger-prick glucose readings should be raised, perhaps to 7–12 mmol/L. After a period of weeks in which hypoglycaemia is avoided, then Candice may regain better awareness of hypoglycaemia (9). A higher HbA_1c target for Candice would be appropriate, bearing in mind the risks and consequences of hypoglycaemia.

For those whose diabetes treatment places them at risk of hypoglycaemia, it is appropriate to relax glycaemic targets. This includes those with hypoglycaemic unawareness, longer duration diabetes and with increased comorbidity (renal impairment, cardiovascular disease), and the frail elderly (3).

What are the potential consequences of hypoglycaemia?

Section 15

Hypoglycaemia causes distressing symptoms for the person with diabetes during the episode and often for many hours afterwards, and causes considerable anxiety for their families and carers. Quality of life is diminished not only by the episodes of hypoglycaemia (which are likely to result in the person feeling unwell for at least 24 hours), but also by the fear of them. Fear of hypoglycaemia is negatively associated with good glycaemic control and diabetes management, although this may be ameliorated by using cognitive behavioural therapy (11).

Severe episodes of hypoglycaemia may lead to convulsions, coma and fatalities. There is an association with cardiac arrhythmias and cardiovascular events (myocardial infarction and stroke), and an increased risk of fracture from falls (12).  Hypoglycaemia is associated with road traffic accidents, including fatalities.

Costs to the NHS resulting from hypoglycaemia are vast. Up to 100 000 emergency calls for hypoglycaemia are made in the UK each year (13).