Hypoglycaemia and the older patient

Hypoglycaemia in the elderly population is one of the most challenging complications encountered in the management of diabetes mellitus. The occurrence of hypoglycaemia, in particular when it is severe (ie. requiring third party assistance), often results in short and long-term consequences. In the ageing population, recurrent hypoglycaemia can affect physical and psychological wellbeing as well as being associated with premature mortality.

Definition of hypoglycaemia

Traditionally, hypoglycaemia was defined as the presence of the Whipples’ triad, which included low blood glucose; symptoms and signs associated with low blood glucose levels; and resolution of these symptoms and signs by carbohydrate ingestion.

More recently, hypoglycaemia has been classified according to its severity as mild or severe. Mild hypoglycaemia is where the individual can selftreat with oral carbohydrate. Severe hypoglycaemia occurs when third party assistance is required to administer carbohydrate or other glucose raising agents, eg. glucagon. Both definitions encompass the new definition advocated by the American Diabetes Association that states that hypoglycaemia is defined by ‘all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm.^‘1 An arbitrary value of ‰¤3.9mmol/L has been chosen as the definition of hypoglycemia for patients on insulin or oral hypoglycaemics, even though for those individuals who run high glucose levels symptoms can occur at much higher glucose concentrations.

Incidence and risk factors of hypoglycaemia

Hypoglycaemia occurs more frequently in people with type 1 diabetes. Population-based data indicate that the overall event rate for severe hypoglycaemia in insulin-treated type 2 diabetes is approximately 30% of that in type 1 diabetes (35 versus 115 episodes per 100 patient-years).^2,3 A recent consensus statement from the US showed that insulin-treated patients 80 years or older were more than twice as likely to visit the emergency room and nearly five times as likely to be subsequently hospitalised for insulin-related hypoglycaemia and errors than those 45 to 64 years.⁴

The risk of hypoglycaemia increases with advancing age for a number of reasons. These include the diminished visceral fat stores, which result in a reduction in insulin resistance that together with declining renal function leads to reduced insulin clearance. It also increases the duration of insulin action as well as increasing the glucose lowering effects.⁵ Table 1 lists a number of other factors that increase the risk of the more elderly patient developing hypoglycaemia.

Counter regulatory responses

The key physiological defences against falling plasma glucose concentrations are a decrease in pancreatic β-cell insulin secretion, an increase in pancreatic α-cell glucagon secretion and a sympatho-adrenal response that includes activation of the adrenal medulla to secrete epinephrine and norepinephrine as well as activation of the sympathetic nervous system to release norepinephrine and acetylcholine. Other hormones secreted in response to hypoglycaemia are growth hormone and cortisol, but their effects are delayed. With senescence these responses are altered, in particular there are reductions in glucagon, norepinephrine and acetylcholine secretion. This age-related attenuation of the counter-regulatory response is also further compromised by having diabetes.^6,7 This, together with frequent episodes of hypoglycaemia predispose the elderly to develop hypoglycaemia unawareness.⁸ Recurrent hypoglycaemia may itself then lead to hypoglycaemia associated autonomic failure, particularly in people with long standing diabetes.^9,10

As a consequence of these defective counter regulatory mechanisms the manifestation of hypoglycaemia may change in the elderly, with neuroglycopaenic symptoms predominating. These include weakness, blurred vision, impaired concentration, altered behaviour, loss of consciousness, and seizures rather than the symptoms of sympathetic overdrive such as hunger, sweating, shakiness, tremors, tachycardia, or anxiety. This change in the symptom complex of hypoglycaemia may lead to clinicians under reporting the true incidence of hypoglycaemia, but attributing them to alternative diagnoses, such as transient ischaemic attacks, infections, or delirium, thus delaying prompt treatment.^9,11

Consequences of hypoglycaemia

Hypoglycaemia in the elderly has major physical, psychological, cognitive, social and economic implications. Physical disability, functional decline, risk of falls and fractures as well as mortality is increased in the elderly with poor glycaemic control and recurrent hypoglycaemia.^{12,13,14,15,16,17,}

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, showed that severe hypoglycaemia was associated with increased risk of macro and microvascular complications as well as increased mortality.¹⁸ The study also showed an increased risk for a range of non-vascular outcomes, such as cancer and conditions affecting the respiratory system, the digestive system, and the skin.¹⁸ These findings were similar to those in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study that was stopped early due to an increased mortality in the intensive treatment arm.¹⁹ There have been other studies that have also shown a U-shaped relationship between HbA1c and mortality, with the lowest mortality risk in patients with modest glycaemic control (glucose levels of 5.5-8.3mmol/l or HbA1c of 54-75mmol/mol [7.1-9.0%]).^20,21,22

The brain relies on a constant supply of glucose as it main fuel to function, and severe or recurrent interruptions due to hypoglycaemia result in psychomotor retardation and cognitive impairment. These effects are particularly important in the elderly.

In a retrospective study of 16,667 people with diabetes and a mean age 65 years, the risk of dementia increased by 26% (HR 1.26, 95% CI 1.10 to 1.49), 80% (1.80, 1.37 to 2.36) and 94% (1.94, 1.42 to 2.64) in patients with a history of one, two and three or more severe hypoglycaemic episodes.²³ These were independent of overall glycaemic control, medications and comorbidities. However there seems to be a bidirectional association between hypoglycaemia and dementia where the presence of one predisposes to the other.²⁴

The psychological impact of hypoglycaemia can be marked, but remain hidden unless asked about. One study has shown that patients with symptomatic hypoglycaemia had significantly higher levels of fear of hypoglycaemia, lower psychological well-being, and higher diabetes-related distress (p<0.0001 for all). Furthermore, the experience of more than three episodes of hypoglycaemia was associated with a 13-fold risk of high fear of further hypoglycaemia (OR = 13.3; CI 95 % 8.4-21.0), an almost 60-fold higher risk of high diabetes-related distress (adjusted OR = 59.1; CI 95 % 29.2-119.8), and a higher risk of low psychological well-being (adjusted OR = 1.5; CI 95 % 0.9-2.4).²⁵

The socio-economic burden of hypoglycaemia has a major implication in the management of elderly patients with diabetes. Acute hypoglycaemic episodes result in frequent emergency department visits, hospital admissions, and increased length of stay in hospital. In turn, these can lead to increased frailty and loss of independence, resulting from frequent falls and fractures. Eventually these may necessitate nursing home placement. A recent retrospective cohort study in UK looked at the healthcare resource implications and length of stay in patients with diabetes and found that an episode of hypoglycaemia was associated with an average increase in costs of 40% compared to those who did not have hypoglycaemia.²⁶

Goals of treating hypoglycaemia

In elderly patients with diabetes glycaemic control has to be tailored on an individual basis to prevent hypoglycaemic complications. This should be based on pre-existing comorbidities, duration of diabetes and life expectancy because most complications of hyperglycaemia are duration dependant.²⁷ The aim should be to achieve a good quality of life with preservation of ability to self-treat. The glycaemic target should be to prevent symptomatic hypo or hyperglycaemia. Several international guidelines suggest that the target HbA1c should be 64mmol/mol (8%), with glucose values of 8.9 and 9.4mmol/L. However, in medication-treated frail older adults multiple comorbidities, with a predicted life expectancy of less than 10 years, the goal may be an HbA1c of 69mmol/l (8.5%). Individualised goals for the very old may be even higher (HbA1C between 58 and 75mmol/mol [7.5-9%]) to maximise benefits and minimise harms.^{4,28,29,30,31,32} Recent work has suggested that despite the evidence showing that tight glycaemic control is often unnecessary in older adults, there remains a ‘fixation’ on trying the achieve inappropriate low HbA1c values. This results in the likelihood that the harms of hypoglycaemia exceed the benefits of tight control, and that a substantial proportion of older adults are being over treated.³³

Conclusion

As individuals get older, they are at increased risk of hypoglycaemia because of physiological and pharmacological factors. Care givers need to be mindful of the changing circumstance of their patients and realise that one size does not fit all, and that individualising glycaemic targets is an ongoing process. Tight glycaemic control and polypharmacy is often inappropriate for the ageing adult and care should be taken to ensure they do not come to harm as a result of overzealous prescribing, or following guidelines too rigidly.

Dr Ketan Dhatariya, Consultant in Diabetes and Endocrinology

Shoib Ur Rehman, Specialist Registrar

Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich

Conflict of interest: none declared

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Dr Ketan Dhatariya

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