It is estimated that over half of all those living with diabetes are over 65 years of age (Diabetes UK, 2010). Despite this, optimal glucose management remains poorly defined in this population, with many clinical trials routinely excluding people in this age group. The lack of heterogeneity in health status of older people, which ranges from active and otherwise healthy individuals, to those with frailty and multiple comorbidities makes diabetes management in older adults increasingly challenging (Kalyani et al, 2017). Many older people with diabetes will continue to live independently with good quality of life and life expectancy; however, others will suffer from progressive physical and/or mental health issues, frailty and cognitive decline, increasing their dependency and vulnerability (Hambling et al, 2019).
Whilst achieving an HbA1c target of 48 mmol/mol (6.5%) is the mainstay of treatment for those who are younger, with recent onset of diabetes and a low burden of co-morbidities, for those who are older and frail with complex comorbidities and/or limited life expectancy, the benefits of tight glycaemic control are often outweighed by the risk of harms (Du et al, 2014). A person centred holistic approach must be adapted, tailoring treatment targets and therapies on an individual basis.
Harms of overtreatment
Severe hypoglycaemia is the second most common cause of hospital admission for drug-related adverse events (Robson, 2017). Acute episodes of hypoglycaemia (generally defined as a blood glucose level below 4 mmol/L) can result in falls with consequences which can be mild such as bruising, to life threatening head injuries, fractures and cardiovascular events often leading to prolonged hospital admissions affecting quality of life (Hambling et al, 2017).
Hypoglycaemia is an under-appreciated problem. Signs and symptoms of hypoglycaemia can go unnoticed owing to non-specific presentation to include a feeling of unwell, weakness, unsteadiness, sleepiness and faintness (Hope et al, 2017). In older people, these non-specific symptoms may be misinterpreted as presentation of coexisting illness (Du et al, 2014). Often, neurological symptoms such as confusion, visual disturbances, drowsiness, restlessness and slurred speech tend to predominate in older people compared to the typical adrenergic symptoms such as palpitations, sweating and tremors. The loss of adrenergic warning signs in older people can mean they rapidly descend to dangerous neuroglycopenia. History of morning headache, vivid dreams or nightmares, and profuse sweating during sleep may also suggest nocturnal hypoglycaemia (Hambling et al, 2017).
The overtreatment of diabetes in older people with blood glucose lowering therapies known to cause hypoglycaemia is often under-recognised. Results from a Dutch study revealed that 20% (n=64) of people living with type 2 diabetes over the age of 70 years of age were over treated and frail (Abdelhafiz and Sinclair, 2018). Older people, particularly those with complex medical problems are more susceptible to hypoglycaemia and its consequences compared with those who are younger and healthier (Du et al, 2014). Older people are more susceptible to hypoglycaemia from antihyperglycaemic agents known to cause hypoglycaemia such as sulphonylureas and insulins owing to impaired drug metabolism and altered drug elimination, together with drug interactions from polypharmacy. Age related changes in pharmacokinetics (especially renal elimination) and pharmacodynamics (increased sensitivity) puts older people at an increased risk of adverse medicine-related events (Laubscher et al, 2012). It is also important to recognise that older people with diabetes and low HbA1c levels may be indicative of reduced food intake and malnutrition rather than good glycaemic control. These risks may be even more detrimental if the older person lives alone (Vischer et al, 2010).
With advancing age, older people are at significantly more risk of poor functional status, physical inactivity and malnutrition potentially leading to unintentional weight loss, depression and frailty. This makes them increasingly vulnerable to hypoglycaemia, particularly if they are taking blood glucose lowering therapies which have not been adjusted to reflect age associated changes in pathophysiology, drug metabolism and excretion (Du et al, 2014). The hypoglycaemic counter-regulatory mechanism is often defective in older people where response of glucagon to hypoglycaemia is lower compared to those who are younger (Ortiz-Alonso et al, 1994). Repeated episodes of hypoglycaemia can adversely affect defence mechanisms against falling blood glucose leading to hypoglycaemia unawareness resulting in morbidity and mortality, which is associated with a six-fold increase in death (Kalra et al, 2013).
Targets and individualised approaches
There is still some debate surrounding optimal glycaemic targets for older people living with diabetes. Organisations such as the National Institute for Health and Care Excellence (NICE), the European Association for the Study of Diabetes (EASD), and the American Diabetes Association (ADA) have developed guidelines acknowledging the need to individualise care, but often the glycaemic targets suggested are too tight for frail older individuals. Note, that for ‘biologically young’ older adults, a glycaemic target below 58 mmol/mol (7.5%) still remains the standard (Strain et al, 2018). In light of the current COVID-19 pandemic, those with diabetes, particularly those who are poorly controlled, may be at increased risk of poor outcomes. Treatment targets must be individualised and therapies reviewed where required (Zhu L et al, 2020).
NICE guideline (NG28) recommends considering relaxing HbA1c for people who are older or frail and unlikely to achieve longer term benefits but fails to define these relaxed targets (NICE, 2015). The European Diabetes Working Party for Older People, the ADA and the International Diabetes Federation (IDF) have all published position statements providing useful frameworks for managing diabetes in older people, albeit based predominantly on consensus and opinion. All recommend an HbA1c target of 53–58 mmol/mol (7.0–7.5%) for older people with type 2 diabetes without major comorbidities. For those who are frail, dependent, with multiple comorbidities and high risk of hypoglycaemia a relaxed HbA1c target of 59–70 mmol/mol (7.6–8.5%) is recommended (Strain et al, 2017).
In East Sussex, local guidance has been produced to assist diabetes teams in agreeing HbA1c targets as part of a project tackling the overtreatment of type 2 diabetes in frail older people through individualising care where it became apparent that clinicians lacked confidence in relaxing targets and de-escalating therapy (Syed, 2019). For frail older adults with diabetes, a consensus view is that very few people aged 70 years and over with diabetes benefit from intensive glucose control. A target range of 53–58 mmol/mol appears appropriate for people who are functioning well. For those with moderate to severe frailty, an HbA1c target of less than 64 mmol/mol is more appropriate. For people with severe frailty, the HbA1c target can be further increased to less than 70 mmol/mol.
Balancing harms and risks of treatment
Several studies including Dluhy and McMahon (2008) and Tsai et al (2011) have illustrated the clinical challenge of determining glycaemic targets where aiming for a too low HbA1c target in order to reduce the risk of long term diabetes complications has come at the cost of increased hypoglycaemia episodes. The UK Hypoglycaemia Study Group (2007) found that in people with type 2 diabetes treated with sulphonylureas, or on insulin for less than 2 years, the annual rate of severe hypoglycaemia requiring assistance from another person was 7%, this is significant given the potential severity of harm.
Effective management of diabetes in older people requires adapting an individualised approach based upon a comprehensive holistic evaluation of cognition, functional status and co-morbidities where the aim of treatment is to treat hyperglycaemia, reduce the risk of long term diabetes related complications while minimising the risk of hypoglycaemia. Glycaemic targets in those who are older and frail should be safe and appropriate where the aim of treatment is to keep the person free from adverse events and maintain functional status and quality of life.
A person centred approach which enables the person to participate in shared decision making with their healthcare team expressing their ideas, concerns and expectations for their diabetes care is fundamental in agreeing individualised glycaemia targets and enabling self-management. The NICE (2015) shared decision making tool is a useful resource in supporting these conversations. This tool helps people living with diabetes work with their healthcare professionals to decide the best HbA1c target for them and their options for controlling their blood glucose personalising their diabetes care.
How to de-escalate treatment
Pharmacological agents used in the treatment of diabetes should maintain optimal glycemic control while balancing the risk of hypoglycaemia through agreeing suitable and safe glycaemic targets which are person centred and individualised. As people become older and frailer, their needs change, making safety an increasing priority over potential long-term treatment benefits. Glycaemic targets should be periodically adjusted based upon cognitive function, functional status, treatment burden, quality of life and life expectancy (ADA, 2019).
All older adults with diabetes should have their medications regularly reviewed and be considered for a de-intensification approach where appropriate. The goal of deprescribing is to reduce and/or stop medicines that might be causing harm or are no longer of benefit while maintaining or improving quality of life through a planned and supervised process. A person-centred approach to managing polypharmacy and deprescribing can be achieved through the seven step model created by Barnett et al (2015) shown in Box 1, which incorporates the person's and clinician's priorities, promotes shared decision making and agreed goals, as well as good communication and follow up (Smith et al, 2019).
Box 1.A patient centred approach to managing polypharmacy
- Assess Patient
- Define goals and overall context
- Identify medicines with potential for risks
- Assess risks and benefits in context of individual patient
- Agree actions to stop, reduce dose continue or start
- Communicate actions with all relevant parties
(Barnett, 2015)
A pragmatic approach is necessary, targeting those who are at the highest risk of hypoglycaemia first, particularly those taking sulfonylureas or insulin. Reviewing those residing in care homes, recorded as severely frail or with very low HbA1c readings is a good place to start. Given the increasing likelihood of beta cell failure with sulphonylureas in older people, their usage should be limited. Similarly, although basal/bolus insulin regimens show improved control of glycaemia, changing to less intensive daily or twice daily regimens of insulin reduces risk of hypoglycaemia and the frequency of blood glucose testing (ADA, 2019). For most frail adults, once daily isophane insulin in the morning provides a modest peak in insulin after 4 hours with negligible activity overnight minimising the risk of nocturnal hypoglycaemia. Should nocturnal insulin be needed, once daily long acting analogue insulin may be associated with a lower nocturnal hypoglycaemia risk than twice daily isophane insulin (Strain et al, 2018).
In older adults at increased risk of hypoglycaemia, medication classes with low risk of hypoglycaemia are preferred (Table 1). Metformin remains the first-line agent for older adults with type 2 diabetes. However, it is contraindicated in patients with advanced renal insufficiency (eGFR less than 30 mL/min/1.73 m2). In people with moderate renal impairment (eGFR less than 45 mL/min/1.73 m2), a 50% dose reduction is recommended with renal function monitoring every 3 months. Metformin is only contraindicated in patients with advanced cirrhosis because it heightens the risk of developing lactic acidosis (Brackett, 2010). Pioglitazone should be avoided in those with, or at risk for, congestive heart failure and used cautiously in those at risk of falls or fractures.
Table 1. Antihyperglycemics and hypoglycaemia risk
| Drug | Causes hypoglycaemia |
|---|---|
| Insulin | Yes |
| Sulfonylureas | Yes |
| Metformin | No |
| DPP-4 Inhibitors | No |
| GLP-1 Mimetics | No |
| SGLT2 Inhibitors | No |
| Pioglitazone | No |
| Acarbose | No |
The use of sodium-glucose co-transporter-2 (SGLT2) inhibitors may be limited in older people owing to renal impairment (avoid initiation if eGFR below 60 mL/minute/1.73 m2) and concerns over volume depletion. However, for those older people with established atherosclerotic cardiovascular disease (ACVD), heart failure (HF) or chronic kidney disease (CKD) and where renal function allows, SGLT2 inhibitors with proven benefits may be useful in reducing disease progression. GLP-1 mimetics may be considered as an alternative for older people with established atherosclerotic cardiovascular disease (ACVD) and renal impairment as these agents can safety be used often down to end stage renal impairment (eGFR >15 ml/min/1.73 m2) if in line with NICE guidance. Both SGLT2 inhibitors and GLP-1 mimetics are not known to cause hypoglycaemia which makes them useful. Owing to causing weight loss, both classes should be used cautiously in those who are underweight. Dipeptidyl peptidase-4 (DPP-4) inhibitors have few side effects and minimal hypoglycaemia and hence may be a suitable option (ADA, 2019).
The National UK collaborative stakeholder group (Strain et al, 2018) and the Canadian Deprescribing Network (Farrell et al, 2017) have published frameworks to aid deprescribing of antihyperglycaemic agents in older people. The Canadian Deprescribing Network has also produced patient information to assist conversations about safe deprescribing which can be found here: https://deprescribing.org/wp-content/uploads/2018/08/deprescribing_pamphlet2018_AHG_v03.pdf. The main principles of de-escalation as shown in Table 2 are to reduce/stop agents most likely to contribute to hypoglycaemia, review renally eliminated antihyperglycaemics and monitor after each change for signs of hyperglycaemia. If symptoms of hyperglycaemia occur or blood glucose exceeds individualised target consider an alternative agent with less risk of hypoglycaemia.
Table 2. Recommended therapeutic targets and treatment de-escalation thresholds
| De-escalation threshold | Treatment target | ||
|---|---|---|---|
| Threshold | Suggested interventions | Targets | Interventions |
| Fit older Adult with diabetes 53 mmol/mol (7.0%) | Evaluate long-acting sulfonylurea and insulin therapy that may cause hypoglycaemia. Consider appropriate dosage in setting of renal function. | 58 mmol/mol (7.5%) | Avoid initiating new agents that may cause hypoglycaemia or exaggerate weight loss if person is underweight |
| Moderate to severe frailty 58 mmol/mol (7.5%) | Discontinue any sulfonylurea if HbA1c below threshold. Avoid pioglitazone because of risk of heart failure. Cautious use of insulin and metformin mindful of renal function. | 64 mmol/mol (8.0%) | DPP-4 inhibitors and longer-acting insulins have demonstrated safety. Pioglitazone may increase risk of heart failure. SGLT2 inhibitors and GLP 1 mimetics with proven benefits may be beneficial in people with established cardiovascular and renal disease |
| Very Severe frailty 64 mmol/mol (8.0%) | Withdraw sulfonylureas and short-acting insulins because of risk of hypoglycaemia. Review timings and suitability of NPH insulin with regard to risk of hypoglycaemia. | 70 mmol/mol (8.5%) | Consider DPP-4 inhibitors at renally appropriate dose for those close to target. Consider once-daily morning NPH insulin or analogue alternatives if symptomatic nocturnal hyperglycaemia/concerns of nocturnal hypoglycaemia. Educate carers and relatives regarding risk of hypoglycaemia |
Conclusion
Intensive treatment with insulin and sulfonylureas in older people can increase the risk of hypoglycaemia, morbidity and mortality. All older adults with diabetes should have their medications reviewed regularly, particularly those taking insulin and/or sulfonylureas to reduce risks of hypoglycaemia. A person-centred holistic approach to diabetes management must be adapted for older people living with diabetes.