Glycaemic targets
Hypoglycaemia, the elderly and cognitive impairment
Important considerations about therapeutic agents in the elderly
DPP4-inhibitors and GLP-1 analogues







The last few years have seen the emergence of an increased number of therapeutic agents available to treat hyperglycaemia. The purpose of this article is to broadly review the management of older patients with a particular focus on prescribing. Avoidance of hypoglycaemia is of huge clinical importance in older patients. Some general considerations for managing diabetes in the elderly are laid out throughout this article and although such principles broadly apply to the management of diabetes in any patient they are of particular pertinence in older patients. Data soon to be published from the National Diabetes Audit shows that the highest prevalence (13%) of all patients with diabetes is in the 75-79 age range with a prevalence of 12.5% in the 80-84 age range, just over 10% in the 85-90 age range and 7.5% in patients aged 90 or above.1


Glycaemic targets

NICE clinical guidelines for the management of type 2 diabetes2 advocate an HbA1c target of 48mmol/mol (6.5%) at step 1 and 2 of the treatment algorithm with a target of 58mmol/mol (7.5%) suggested beyond this. It is, however, important to set agreed, practical and safe glycaemic targets in any patient but this is even more relevant in older patients. Tight control in younger individuals is beneficial as long as hypoglycaemia can be avoided or minimised, but with increasing age and in the presence of more macrovascular pathology glycaemic targets should be set higher.


Hypoglycaemia, the elderly and cognitive impairment

There is a significant burden of hypoglycaemia in patients with type 2 diabetes. A study published in 20033 sought to determine the incidence, predisposing factors, and costs of emergency treatment of severe hypoglycemia in people with type 1 and type 2 diabetes. This involved a one-year population-based study (of 367,051 people including 8,655 people with diabetes) to measure the incidence of severe hypoglycaemia, which required treatment by the emergency services.

Emergency treatment was required for 7.1% of people with type 1 diabetes, 7.3% of those with insulin-treated type 2 diabetes and 0.8% of people taking oral agents. Increasing age, duration of diabetes and socioeconomic status were identified as risk factors for severe hypoglycaemia. Hypoglycemia requiring emergency assistance was as common in people with type 2 diabetes treated with insulin as in people with type 1 diabetes.

Another study that followed patients with either type 1 or insulin treated type 2 diabetes for one month4 demonstrated that patients with type 2 diabetes require the assistance of emergency services to treat hypoglycaemia at least as often as those with type 1 diabetes despite the fact that their overall risk of hypoglycaemia is less. One suggestion is that this could be accounted for by increasing numbers of elderly frail patients with type 2 diabetes treated with insulin.

Older patients are more vulnerable to hypoglycaemia due to a lower intensity of autonomic and neuroglycopaemic symptoms5 with autonomic dysfunction being as a result of ageing rather than diabetes.6 In older patients hypoglycaemic symptoms and cognitive dysfunction develop at a similar level of blood glucose (approximately 3mmol±0.2mmol/L) which in turn affects an individual's ability to self-manage.7 It also follows that cognitive impairment itself could also prevent the prompt and appropriate treatment of hypoglycaemia. More than one-fifth of patients with type 2 diabetes over the age of 75 years have cognitive impairment (defined as a MMSE score of 26 or less).8 30% of patients with dementia made errors when asked about the use of carbohydrate to treat hypoglycaemia (compares with 7% for normal cognitive function) and 51% were unsure how to adjust treatment following an episode of hypoglycaemia (compared with 22% for those with normal cognitive function).8

Consequences of hypoglycaemia include falls, injuries and fractures etc. There are also strong economic reasons to minimise hypoglycaemia. A study published in 20129 reported on the estimated costs of emergency care for severe hypoglycaemia in the UK. The average cost per emergency call for an episode of hypoglycaemia was £263 and the estimated annual cost of emergency calls for severe hypoglycaemia is £13.6 million for England alone. Anecdotally many older patients with type 2 diabetes and their relatives and carers have a poor understanding of the symptoms and treatment of hypoglycaemia coupled with a poor understanding of the mechanism of action of their medication, a particular concern if such medication can cause hypoglycaemia.


Important considerations about therapeutic agents in the elderly


Metformin acts predominantly by reducing hepatic glucose production mainly through a reduction in hepatic gluconeogenesis. It also increases insulin sensitivity, enhances peripheral glucose uptake and reduces glucose absorption from the gut.10 It is licensed for the treatment of type 2 diabetes especially in overweight individuals when dietary and physical activity alone doesn't improve glycaemic control. It is first line therapy in all guidelines. It can be used as monotherapy or in combination with the other oral hypoglycaemic agents, GLP-1s and insulin.

The commonest side effects of metformin are gastrointestinal, resulting in diarrhoea, bloating and cramps. Consideration should be given to the use of the modified release preparation to simply reduce a patient's tablet burden and this preparation can also reduce gastrointestinal side effects. Metformin is excreted in the urine and there is a rare risk of lactic acidosis in renal impairment. NICE suggests reviewing the dose of metformin if the serum creatinine exceeds 130µmol/L (eGFR < 45ml/min) and practically the maximum daily dose should probably not exceed 1g. Metformin should be stopped if creatinine rises above 150µmol/L (eGFR < 30ml/min). It is worth advising patients, especially the elderly, to temporarily withhold metformin if they have an inter-current illness especially where they are at risk of dehydration. It should also be stopped prior to the use of IV contrast in radiological procedures. The issue of prescribing in patients with renal impairment often co-exists in elderly patients. Box 1 provides a summary of various agents and how their dose should be modified according to eGFR.



Sulphonylureas bind to the SUR1 receptor, which is the regulatory subunit of the ATP sensitive potassium channels on the surface of b-cells. This in turn leads to insulin secretion through membrane depolarisation even when there is no increase in metabolic rate.10 The various sulphonylureas have a variable affinity for the SUR1 receptor and can result in hypoglycaemia as they stimulate glucose secretion in a non-glucose dependant fashion. The UK Hypoglycaemia Study Group11 showed that rates of hypoglycaemia in patients treated with sulphonylureas were comparable to patients with type 2 diabetes in the first two to three years of treatment with insulin. An increased risk of hypoglycaemia exists in patients with renal impairment. Sulphonylureas with a long duration of action such as glibenclamide and chlorpropamide are certainly best avoided especially in the elderly.

Some debate exists as to whether these agents increase cardiovascular risk. Any increased risk could result from weight gain (1-4kgs in the first six months) or hypoglycaemia which can promote arrhythmias resulting from prolongation of the QT interval and cardiac repolarisation.12



Glinides bind to potassium channels on the surface of b-cells but not at the same site as sulphonylureas. They have a short duration of action and are recommended to be taken no more than 30 minutes before a main meal. They require frequent daily dosing, are associated with hypoglycaemia and are not a good option for elderly patients.


Thiazolidinediones (glitazones or TZD drugs)

Rosiglitazone (and combination therapy containing rosiglitazone) was withdrawn in the UK in 2010 following concerns in relation to its cardiovascular safety.13 A meta-analysis published in 2007 showed a significant 43% increase in myocardial infarction and a borderline significant 64% increase in mortality for patients taking rosiglitazone.13 This leaves pioglitazone as the only TZD now licensed in the UK. It can be used as monotherapy or as part of dual or triple therapy in combination with metformin and sulphonylurea. It can also be used with insulin. These agents work by activating the nuclear transcription factor peroxisome proliferator-activated (PPAR) gamma, which leads to the up-regulation of insulin sensitive genes.14

Fluid retention and subsequent weight gain are the most common side effects especially when used in combination with insulin. Any degree of heart failure is an absolute contraindication to using pioglitazone as the increase in oedema can precipitate new or worsen pre-existing failure. Anaemia is quite common in people using pioglitazone and reflects a dilutional effect from fluid retention. Long-term use of TZDs has been associated with an increase in fractures in women with type 2 diabetes and careful consideration needs to be given when using pioglitazone in post-menopausal women and patients with risk factors for osteoporosis. There is also some evidence to suggest a slightly higher risk of bladder cancer in patients taking pioglitazone.15 A patient with a previous history of a bladder carcinoma or undiagnosed haematuria should not be prescribed pioglitazone.

There is also the concern of an increase in diabetic macular oedema with the use of these agents, especially where patients also have peripheral oedema. One study reported a 2.6 fold increase in the risk of developing diabetic macular oedema (95% CI, 2.4-3.0) with TZDs.16


DPP4-inhibitors and GLP-1 analogues

Incretin effect

Incretin hormones are peptides released from the gut in response to mixed meals and contribute to glucose homeostasis. Glucose-dependant insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the two main incretin hormones. Both are rapidly degraded by a ubiquitous enzyme DPP4 (Dipeptidyl-peptidase 4) resulting in a circulating half-life of GLP-1 of only two to three minutes. Very simply the incretin effect is the greater insulin response observed when glucose is given orally compared with an equivalent dose given intravenously. However in patients with type 2 diabetes the incretin response is diminished.17 There are two ways of influencing the incretin system, either through the administration of exogenous GLP-1, which is resistant to breakdown by DPP4 or to block/inhibit DPP4 so to prevent the degradation of endogenous GLP-1 (the response to GIP is lost in type 2 diabetes). These agents can lead to weight loss and there is a low risk of hypoglycaemia although this risk is increased when they are used with sulphonylureas or insulin. They should not be given to patients with a previous history of pancreatitis or indeed to patients with risk factors such as excess alcohol consumption, significantly elevated triglycerides or known gall stone disease.



These agents were shown to result in an average reduction of HbA1c of 0.7% when used as a second line therapy in addition to metformin and they don't result in weight gain.18 NICE recommends their use as a second line agent where hypoglycaemia or weight gain is undesirable and therefore represent a useful tool in the therapeutic armamentarium especially when managing elderly patients. These agents are well tolerated.



Dapagliflozin (Forxiga) is the first SGLT-2 inhibitor to market and inhibits the reabsorption of glucose from the proximal renal tubule. Because the glucose lowering properties of dapagliflozin are obviously dependant on renal function it follows that it will not be as effective in patients with moderate renal impairment and therefore shouldn't be used in patients with an eGFR <60.

An increased risk of urinary tract infections, vulvovaginitis and balanitis is also seen with dapagliflozin with infections being more common in females than males. Adverse reactions in relation to hypovolaemia such as dehydration have also been observed and are particularly important considerations in the elderly.



A detailed review of the use of insulin in older patients is beyond the scope of this review. The updated NICE guidance on newer therapies for blood glucose lowering in type 2 diabetes positioned insulin as a third line agent. It is recommended to begin with human neutral protamine (NPH) insulin injected at bed time or according to need. A common debate surrounds the issue of whether human insulin leads to more hypoglycaemia than analogue insulin. Basal insulin analogues provoke fewer episodes of hypoglycaemia overall and fewer nocturnal episodes of hypoglycaemia. However, they are not associated with lower rates of severe hypoglycaemia.19 A long acting insulin analogue can be considered if: the person needs assistance to inject and the use of a long acting analogue would reduce the frequency of injections from twice to once daily, the person's lifestyle is restricted by recurrent symptomatic hypoglycaemia, the person would need twice daily NPH insulin in combination with OHAs or the person can't use the device to inject NPH insulin.


Dr Paul Downie

Conflict of interest: Dr Downie has attended advisory boards for Novonordisk and MSD. He has received speaker fees from Novonordisk, Eli-Lilly, Sanofi-Aventis, Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim and Takeda.



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