The International Diabetes Federation currently estimates that there are 463 million people living in the world with diabetes, a number that is expected to grow to approximately 700 million by 2045.1 These figures, however, do not include people over the age of 80 years. In the UK, of the 4.9 million people registered with diabetes approximately 13% are over the age of 80, which equates to, one in five people over the age of 80 have type 2 diabetes.2

Both ageing and diabetes are recognised as important risk factors for the development of functional decline and disability (termed frailty), which are often compounded with impaired quality of life. In addition, diabetes has a high associated economic, social and health burden. Whereas in younger adults, macrovascular and microvascular complications account for the majority of morbidity and mortality of diabetes, in older adults, these account for less than half of the diabetes-related disability.

It is now acknowledged that cognitive decline, frailty and muscle loss (sarcopenia) are emerging as important new complications of diabetes and have the biggest impact on quality and quantity of life in these older adults.3

 

Further reading: Managing type 2 diabetes in the older patient

Further reading: Diabetes and severe mental illness

 

The physiological differences between these frail elderly patients and “young elderly” are substantial, due to their failing renal function, hepatic function, autonomic nervous system, incretin system (both production and sensitivity to the incretin hormones) and cognitive decline. Despite these physiological differences, elderly patients are systematically excluded from clinical trials, either based on an arbitrary age cut off, “multi-morbidities”, polypharmacy, cognitive impairment or reduced life expectancy. Indeed only 1.4% of clinical trials specifically include older adults.4 In practice, these differences result in exaggerated side effects from medications, notably the risk of a low blood sugar, termed hypoglycaemia.

Although hypoglycaemia in this older population is a problem, it is difficult to quantify due to under reporting, few clinical studies in this age group and the lack of standardisation of the measure of a hypoglycaemic event.5 However, observational work suggests hypoglycaemia is associated with significant increases in cardiovascular and cerebrovascular risks.

Pertinently a single hypoglycaemic episode is associated with an increased 26% risk of dementia, three or more hypoglycaemic attacks increase the incidence of dementia by 96% after adjustment for potential confounders.6 This has a significant impact not just on the individual and their family and carers, but also on the national health care budget.

Targeting a reduction in admissions for these vulnerable adults has become a national and political priority. As such, the UK guidelines for the management of older adults with diabetes have recently been updated to help minimise the risk of hypoglycaemia occurring.7 However, currently available treatment strategies and formularies are limited by a scant evidence base and, as a consequence, patients are often treated by extrapolating data from younger and physiologically distinct populations onto these vulnerable adults.8

Identification of hypoglycaemia

Hypoglycaemia has multiple different definitions. Often it is defined as a blood glucose of 3.9mmol/l (70mg/dL) or less for a person with diabetes. In other situations, a level of 3.2mmol/l (60mg/dL) or 2.8mmol/l (50mg/dL) is used. Each of these thresholds is based on a physiological response to dropping glucose.9

At 3.9mmol/dL glucagon and adrenaline are stimulated; at 3.2mmol/l brain glucose uptake starts to fall, triggering cortisol and growth hormone production, whilst at 2.8mmol/l neuroglycopaenia results in reduced cognition. These values are reproducible in physiologically fit adults however in the frail the neuroendocrine responses are blunted. Hepatic reserves are limited so that glucagon does not stimulate glycogenolysis or gluconeogenesis.10

Adrenergic response is not triggered until a glucose of <2.8mmol/l, after neuroglycopaenia has resulted in reduced cognition. As a result, the classic sympathetic symptoms of hypoglycaemia are often not present in older adults, particularly the frail population. Rather they present with vague non-specific symptoms of acute confusion state, loss of confidence, imbalance and falls, impaired sleep or nightmares, and cognitive decline. The issue with identification of these hypoglycaemic attacks, is that all of these symptoms are common in frail older adults therefore it is difficult to recognise them.11

In clinical practice, hypoglycaemia is often described as severe or mild, based on the person’s ability to self-manage their treatment. When third party assistance is required, then this is considered severe. In the frail older adult, this definition is limited by the ability of the older adult to seek assistance. The person with dementia can present with agitation or aggression, but these can also be signs or symptoms of hypoglycaemia, they may be unable to communicate their needs, so carers need to be made aware of this and be extra vigilant. Given the potential consequences of hypoglycaemia, notably falls, fractures and hospitalisations due to acute confusional states all hypoglycaemia in older adults should be regarded as severe.12

Prevalence of hypoglycaemia

In older people, hypoglycaemia is an under recognised disorder. Older people and those with dementia, are at an increased risk of hypoglycaemia because appetites are often poorer.6 Although ageing is generally associated with hyperglycaemic tendency due to the change in body composition with the accumulation of visceral fat increasing insulin resistance, in frail elderly there may be a tendency towards hypoglycaemia due to malnutrition, weight loss and comorbidities. 

Importantly, the weight loss triggers an “insulin resistance burnout” where loss of fat cells reduce insulin resistance and results in therapies that have maintained euglycaemia in the prior decades to be triggers of hypoglycaemia.13 This metabolic change towards hypoglycaemia rather than hyperglycaemia, has been supported by the evidence of successful withdrawal of diabetes medications in nursing homes in older patients, without deterioration in glycaemic control.

It is often under-reported, because the person, or their carers, do not recognise what is happening. This means that the actual number of people with diabetes who experience hypoglycaemia is largely unknown.14 Retrospective data suggest the frequency of hypoglycaemia is approximately 12.8%, 30% higher in people over 70 compared to those under 60 years of age.15 Prospective data, however, suggests approximately 39% of older adults treated with a sulphonylurea and 64% of people on insulin for five years or more will experience a hypoglycaemic attack in any 12 month period.12 In addition to ageing, dementia is a significant risk factor for hypoglycaemia, with a 4-fold increased risk.6

Consequences of hypoglycaemia

There is a bi-directional association between dementia and hypoglycaemia. After each hypoglycaemic episode, major cognitive changes occur leading to post-hypoglycaemic encephalopathy. Therefore, recurrent hypoglycaemia may be associated with impaired cognitive function and development of dementia. An American cohort demonstrated severe hypoglycaemic episode predisposes to a 26% increased risk of dementia.6 This excess risk increases to 96% if three or more events occur within a year, after adjustment for age, BMI, duration of diabetes, comorbidities, insulin use and glycaemic control.

Severe hypoglycaemia may also lead to serious acute vascular events such as stroke, myocardial infarction, acute cardiac failure, and ventricular arrhythmias.16,17 In the ACCORD study, mortality was three times higher for patients in either the conventional or intensive treatment groups who had severe hypoglycaemia than in those who did not have severe hypoglycaemia. Also, in the Veterans Affairs study, more than one episode of severe hypoglycaemia was associated with an 88% rise in the relative risk for sudden death.18

Further, there is a 45–70% increased risk of fall-related fracture in relation to hypoglycaemia in people >65 years.12 Indeed, each patient that experiences a hypoglycaemic attack results in a 36% increase in expenditure within the health service. In hospital, inpatient hypoglycaemia is associated with a 4-day increased length of hospital stay and increased risk of inpatient mortality.

The occurrence of inpatient hypoglycaemia is a marker for clinical deterioration and increased risk for adverse outcomes, although distinguishing between hypoglycaemia being an aetiopathogenic mechanistic step or being a marker of frailty has been a subject of considerable debate.19 It is agreed, however, that avoiding hypoglycaemia is a priority.

Treatment of hypoglycaemia

Whenever possible hypoglycaemia should be treated parentally. On the first detection of a blood glucose less than 4mmol/l, immediately treatment should ensue with 15-20g quick-acting glucose (For example, 200mls of smooth orange juice (small carton), 60mls glucojuice, five Glucotabs, six dextrose tablets or four standard jelly babies). For those with swallowing difficulties, two tubes of Glucogel (40% gel), can be put onto inner lower cheeks, gently rubbing out-side of cheeks to aid absorption. This should be followed by starchy food such as two plain biscuits, banana, piece of toast, or meal if due.

If consciousness is impaired, intravenous glucose (150mls of 10% glucose as a slow bolus over 10 minutes) is the treatment of choice. Alternatively, 50mls of 50% glucose may be given rectally with a similar absorption profile as mucosal glucose without the risk of aspiration. Intramuscular glucagon is recommended for the fit elderly, however, for the frail older adult, glucagon may not produce the same results due to the aforementioned impaired glycolysis and gluconeogenesis. In each case, this should be followed up with the starchy food as with those with less severe hypoglycaemia.

Prevention of hypoglycaemia

After each episode of hypoglycaemia, a thorough review of possible causes and identification of any new risk factors should be under-taken. When assessing for risk of recurrent hypoglycaemia, HbA1c should be evaluated in context. It must be remembered that many older people have medical conditions that interfere with HbA1c measurements.20

Anaemia can affect the level of HbA1c, with normochromic secondary anaemia leading to a falsely lower HbA1c, while iron deficiency anaemia artefactually elevates the HbA1c. Even without anaemia, it is known that the red cells of older adults survive marginally longer due to reduced red cell turnover. Additionally, the cell membranes of the frail older adults are more friable than a younger comparator. As a result, similar glucose exposure translates to higher HbA1c than a younger cohort, or conversely a similar glycated haemoglobin is associated with a lower glucose and higher risk of hypoglycaemia.

As previously discussed, the older person with diabetes, is less likely to benefit from the long-term protective effects of “good” glycaemic control, but are at marked increase in risk of adverse effects of treatments for diabetes, including admissions to hospital and hypoglycaemia. It is good practice to review all frail, older people and those with dementia who have type 2 diabetes. The aim should be for the best glycaemic control that can be achieved without increasing the risk of hypoglycaemia and without lowering quality of life through additional treatment burdens. Prescribed glucose-lowering medications should have a low (if any), risk of hypoglycaemia, minor side effect profile and be cost-effective.7

Sulfonylureas have a high risk of hypos and should be avoided in frail older adults due to consequences such as traumatic falls. However, although initiation of sulphonylureas is not recommended in the elderly, this is not the same as being contraindicated.21 If older patients are well controlled on sulphonylureas, without experiencing hypoglycaemia then they may be continued. As renal function and weight declines, however, perpetuating doses may result in over-treatment and an increased risk of future hypoglycaemia.

Insulin therapies suffer from the same risk as sulphonylureas, that as renal function declines, and weight (thereby insulin resistance) falls, doses that have been stable for a long time may become over-treatment. Suitable alternatives may be the DPP4 inhibitors which have a lower hypoglycaemic risk compared to other options. This class, at the appropriate dose, have been demonstrated to not to increase risk of hypoglycaemia or other complications of diabetes in older adults.

There are many other commonly used drugs that increase risk of hypoglycaemia, notably tramadol,22 beta-blockers,23 haloperidol,24 quinidine25 and quinine sulphate.26 Where possible these should be withdrawn.

Summary

Older adults with diabetes present unique challenges compared to their younger counterparts. Recognition of hypoglycaemia is challenging because the characteristic adrenergic symptoms do not occur due to attenuated counter-regulatory responses. They have reducing insulin resistance, thus long-term medications may become overtreatment. Further, HbA1c naturally rises in the older patient, thus treatment to similar targets require lower average glucose and heightened risk of hypoglycaemia. Hypoglycaemia should be treated acutely and there should be a focus on preventing future events by rationalising therapies.

For more diabetes articles go to our endocrinology section


Nicola Hewer, Community DSN, Cwm Taf Morgannwg UHB

David Strain, Diabetes and Vascular Medicine Research, University of Exeter, College of Medicine and Health, Royal Devon & Exeter Hospital

d.strain@exeter.ac.uk


References

  1. Saeedi, P., et al., Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract, 2019. 157: p. 107843.
  2. Sinclair, A., T. Dunning, and L. Rodriguez-Mañas, Diabetes in older people: new insights and remaining challenges. The Lancet Diabetes & Endocrinology. 3(4): p. 275-285.
  3. Sinclair, A.J., A.H. Abdelhafiz, and L. Rodríguez-Mañas, Frailty and sarcopenia - newly emerging and high impact complications of diabetes. Journal of Diabetes and Its Complications. 31(9): p. 1465-1473.
  4. Cruz-Jentoft, A.J., et al., Exclusion of older adults from ongoing clinical trials about type 2 diabetes mellitus. J Am Geriatr Soc, 2013. 61(5): p. 734-8.
  5. Abdelhafiz, A.H., et al., Hypoglycemia in older people - a less well recognized risk factor for frailty. Aging Dis, 2015. 6(2): p. 156-67.
  6. Whitmer, R.A., et al., Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA, 2009. 301(15): p. 1565-72.
  7. Strain, W.D., et al., Type 2 diabetes mellitus in older people: a brief statement of key principles of modern day management including the assessment of frailty. A national collaborative stakeholder initiative. Diabet Med, 2018. 35(7): p. 838-845.
  8. Lindley, R.I., Drug trials for older people. J Gerontol A Biol Sci Med Sci, 2012. 67(2): p. 152-7.
  9. O'Halloran, K.D., Counter-regulatory control of homeostasis during hypoglycaemia: adrenaline hits the sweet spot in the controversy concerning carotid body glucose sensing. J Physiol, 2016. 594(15): p. 4091-2.
  10. Perkisas, S. and M. Vandewoude, Where frailty meets diabetes. Diabetes Metab Res Rev, 2016. 32 Suppl 1: p. 261-7.
  11. Broz, J., J. Urbanova, and B.M. Frier, Hypoglycemia in the elderly: Watch for atypical symptoms. J Fam Pract, 2019. 68(2): p. 74.
  12. Johnston, S.S., et al., Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab, 2012. 14(7): p. 634-43.
  13. Abdelhafiz, A.H., L. Koay, and A.J. Sinclair, The Emergence of Frailty May Lead to a State of Burnt Out Type 2 Diabetes. J Frailty Aging, 2016. 5(3): p. 162-7.
  14. Hope, S.V., et al., Are we missing hypoglycaemia? Elderly patients with insulin-treated diabetes present to primary care frequently with non-specific symptoms associated with hypoglycaemia. Prim Care Diabetes, 2018. 12(2): p. 139-146.
  15. McCoy, R.G., et al., Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care, 2012. 35(9): p. 1897-901.
  16. Chow, E., et al., Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes, 2014. 63(5): p. 1738-47.
  17. Hanefeld, M., E. Duetting, and P. Bramlage, Cardiac implications of hypoglycaemia in patients with diabetes - a systematic review. Cardiovasc Diabetol, 2013. 12: p. 135.
  18. Group, A.S., et al., Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol, 2007. 99(12A): p. 21i-33i.
  19. Lake, A., et al., The effect of hypoglycaemia during hospital admission on health-related outcomes for people with diabetes: a systematic review and meta-analysis. Diabet Med, 2019. 36(11): p. 1349-1359.
  20. Masuch, A., et al., Preventing misdiagnosis of diabetes in the elderly: age-dependent HbA1c reference intervals derived from two population-based study cohorts. BMC Endocr Disord, 2019. 19(1): p. 20.
  21. Khunti, K., et al., Do sulphonylureas still have a place in clinical practice? Lancet Diabetes Endocrinol, 2018. 6(10): p. 821-832.
  22. Fournier, J.P., et al., Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med, 2015. 175(2): p. 186-93.
  23. Dungan, K., et al., Effect of beta blocker use and type on hypoglycemia risk among hospitalized insulin requiring patients. Cardiovasc Diabetol, 2019. 18(1): p. 163.
  24. Kojak, G., Jr., M.J. Barry, Jr., and C.F. Gastineau, Severe hypoglycemic reaction with haloperidol: report of a case. Am J Psychiatry, 1969. 126(4): p. 573-6.
  25. Phillips, R.E., et al., Hypoglycaemia and antimalarial drugs: quinidine and release of insulin. Br Med J (Clin Res Ed), 1986. 292(6531): p. 1319-21.
  26. Njomatchoua, A.C., et al., Glycemic effects of quinine infusion in healthy volunteers. BMC Res Notes, 2017. 10(1): p. 423.