Section 1

Elizabeth, age 82, had seen her GP with a bitemporal headache, jaw claudication and lethargy, and been diagnosed as having giant cell (temporal) arteritis. Prednisolone 40 mg once daily was commenced on recommendation of the ophthalmology team, and blood tests revealed markedly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. HbA_1c was within normal range.

Elizabeth’s symptoms rapidly resolved but, at a review appointment a few days later, a capillary blood glucose level was raised at 25 mmol/L. She reported symptoms of increased thirst and micturition. There was no previous history of diabetes. Prior to this episode of giant cell arteritis, Elizabeth had been in good health, with her only medication being amlodipine 5 mg once daily for hypertension. Her weight was 51 kg.

What is your assessment of Elizabeth’s situation and how would you define this more clearly?

Section 2

Elizabeth was diagnosed with steroid-induced diabetes. In this situation HbA_1c is unhelpful as an indicator of current glycaemic control because the effects of the prednisolone have only recently arisen, although it was useful prior to treatment in excluding the possibility of previously undetected pre-existing type 2 diabetes.

Four-times-daily capillary blood glucose readings were 6–8 mmol/L pre-breakfast, 9–14 mmol/L pre-lunch, 20–25 mmol/L pre-evening meal and 12–20 mmol/L pre-bedtime. A random venous blood glucose reading was 18 mmol/L which, together with her symptoms, confirmed the diagnosis of steroid-induced diabetes.

What risk factors does Elizabeth have for developing steroid-induced diabetes?

Section 3

Elizabeth’s principal risk factors are age and the high dose of prednisolone used. The dose, potency and duration of steroid therapy will impact on the risk of inducing diabetes. Intrinsic risk factors for steroid-induced diabetes include (1–3):

• High BMI
• Increasing age
• Family history of type 2 diabetes
• Ethnicity – South-East Asian, Afro-Caribbean, Chinese
• Impaired glucose regulation (prediabetes): HbA_1c 42–47 mmol/mol
• Previous history of gestational diabetes or polycystic ovary syndrome.

For individuals with a high-risk profile taking more than a brief course of oral steroids, screening for hyperglycaemia with capillary glucose once daily (pre- or 1–2 hours post-lunch or evening meal) is warranted (4). Typically, hyperglycaemia is observed when supraphysiological doses of steroid are employed; in the case of prednisolone, this would equate to doses exceeding 5 mg daily (4).

Why is treating Elizabeth’s hyperglycaemia important?

Section 4

It is important to diagnose and manage steroid-induced diabetes as early as possible to reduce the risk of microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (cardiovascular) complications.

If blood glucose levels rise sufficiently in response to steroid therapy, then she may become symptomatic with thirst, polyuria, weight loss and fatigue. Under these circumstances, there is a risk of progression to hyperglycaemic hyperosmolar state (HHS; or, rarely, diabetic ketoacidosis) requiring hospital admission for rehydration and control of glucose levels (4).

Can you explain Elizabeth’s glucose profile induced by the prednisolone?

Section 5

The mechanism of action of glucocorticoids involves entry into the cell nucleus and subsequent gene transcription (2). This means that glucose levels will typically rise a few hours after taking oral steroids. Glucocorticoids have powerful effects on carbohydrate metabolism, interacting with insulin receptors on liver, muscle and adipose tissue to increase insulin resistance (5). Furthermore, it is understood that hyperglycaemia induced by steroids is manifested principally in rises in post-prandial blood glucose levels, rather than fasting blood glucose levels (6). These observations have important clinical implications.

The hyperglycaemia arising from a morning dose of prednisolone will, therefore, be most evident from lunchtime through to the evening, with glucose levels falling overnight. It is important to realise that a fasting blood glucose may underestimate prednisolone-induced hyperglycaemia (2,7).

The Joint British Diabetes Societies (JBDS) statement for inpatient care of individuals without prior diagnosis of diabetes receiving oral steroid therapy recommends once-daily capillary blood glucose monitoring for individuals judged to be at high risk of steroid-induced diabetes (4). In the case of a once-daily morning dose of corticosteroid, glucose monitoring is suggested prior to lunch or evening meal or, alternatively, 1–2 hours post-lunch or evening meal. Thus, to capture Elizabeth’s glucose rise, we should be capillary blood glucose (CBG) monitoring in the afternoon; this will also be the preferred time to judge response to treatments of hyperglycaemia.

Generally, if CBG levels are <12 mmol/L, then continue once-daily monitoring and, if they are consistently <10 mmol/L, then consider discontinuing monitoring. If, as in the case of Elizabeth, CBG levels are >12 mmol/L, then four-times-daily monitoring is advised (before meals and before bed). If CBG levels are consistently >12 mmol/L (typically 2 or more readings >12 mmol/L within 24 hours ), then treatment should be commenced (4,5).

What treatment would you choose to deal with Elizabeth’s hyperglycaemia?

Section 6

There is a lack of evidence to guide best-treatment pathways, but an important point is to match the glucose-lowering profile of medication to the hyperglycaemic excursions induced by the steroid regimen (8). Oral agents may be tried initially with persistent mild hyperglycaemia (2).

A sulfonylurea, specifically gliclazide, is first-choice oral treatment for hyperglycaemia arising from use of steroids because the impact on blood glucose lowering is immediate (4,5).

For Elizabeth, a reasonable starting point would be gliclazide 40 mg once daily with breakfast. If necessary, the dose could be up-titrated (every 48 hours or so) in 40 mg increments as far as 240 mg once daily, being guided by CBG readings which will need to be taken on multiple occasions during the day to identify hypo/hyperglycaemia. If this fails to achieve adequate glycaemic control, then an evening dose of 40–80 mg gliclazide could be added (4). Throughout this process, patients will need to be aware of the risk of hypoglycaemia, and how to identify and how to respond to it. A reasonable target CBG range for Elizabeth would be 6–12 mmol/L (4,5).

Mention should be made of the meglitinides, repaglinide and nateglinide, as an alternative to sulfonylureas. Like sulfonylureas, these agents are insulin secretagogues but have a quicker onset and shorter duration of action, and could be given with lunch and evening meal to target more specifically the post-prandial hyperglycaemia induced by steroids, possibly with a lower risk of hypoglycaemia (1).

Elizabeth did not have any specific lifestyle issues to address, but remember it may be appropriate to provide advice on diet, exercise and weight loss. Those maintained on oral corticosteroids should carry a steroid treatment card (counselling against abrupt withdrawal of treatment). Do not forget to address cardiovascular risk and, where necessary, smoking cessation, treatment of hypertension and use of statins should be instituted to prevent macrovascular complications.

Despite titrating the dose of gliclazide up to 240 mg with breakfast and 80 mg with her evening meal, afternoon CBGs were still above target, in the range 14–20 mmol/L.

Given that the gliclazide has proved insufficient in achieving satisfactory glycaemic control, what would you try next?

Section 7

There is limited evidence supporting the use of other non-insulin agents in steroid-induced diabetes (though these should be continued in pre-existing diabetes). Metformin may be useful in the longer term, but supporting evidence for use in acute steroid-induced hyperglycaemia is lacking. Pioglitazone once daily is suggested as a possible option, but evidence is weak and onset of action is slow compared to sulfonylureas. Also, you would need to exclude individuals with heart failure, predisposition to fracture and at risk of bladder cancer. DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors are not recommended on the currently available evidence (4,5).

If glucose targets are not reached on maximum doses of sulfonylurea (or meglitinides), with or without the use of other antidiabetes agents, then insulin should be considered (1,4,5). Indeed, if blood glucose levels are particularly high, then insulin may be the best initial option (2). Insulin therapy is increasingly likely the higher the dose and potency of the steroid. At this stage, it is likely that referral to the diabetes specialist team will be necessary for insulin initiation. Insulin has an immediate onset of action and up-titration to an effective dose is relatively easy. Clearly, patients will require education around blood glucose monitoring (multiple times daily), adjustment of insulin dose, and recognition and management of hypoglycaemia; advice on injection technique and sharps disposal; and discussion of insurance and driving regulations.

Human NPH (isophane) insulin (Humulin I, Insulatard, Insuman Basal) administered once daily in the morning would be the insulin of choice for Elizabeth because, as an intermediate-acting basal insulin, its activity profile (defined by half-life) matches the hyperglycaemic profile induced by a morning dose of oral prednisolone (4,5). Used in this manner, the risk of nocturnal hypoglycaemia is minimised. A typical starting dose for NPH insulin would be 10 units, although in a frail elderly person with low body mass, such as Elizabeth, this dose might be reduced (to, say, 6 units).

Subsequently, the insulin dose can be increased or decreased in 10–20% increments, according to capillary blood glucose readings, every 24–48 hours. Should CBG readings remain elevated throughout the day, then a longer-acting basal insulin (insulin detemir, insulin glargine, insulin degludec) would be preferred. If necessary, a more intense insulin regimen may be instituted, including a twice-daily pre-mixed insulin or a basal–bolus insulin regimen (4,5).

Because of her low body mass, Elizabeth was started on 6 units Humulin I in the morning. Subsequent up-titration to 14 units achieved satisfactory CBG readings.

What advice would you give Elizabeth regarding steroid dose reduction?

Section 8

Reducing glucocorticoid therapy

First, advise Elizabeth not to stop her prednisolone abruptly. With a prolonged course of steroids (>2 weeks) the dose must be tapered slowly to avoid the dangers associated with possible adrenal suppression (suppressing endogenous cortisol production).

When Elizabeth starts to reduce her prednisolone dose, a corresponding down-titration of doses of insulin or sulfonylurea will be necessary to avoid hypoglycaemia. Careful monitoring of blood glucose levels during this period is essential to achieve this safely. It may take a few days before the reduction in steroid dose translates into reduced blood glucose levels. JBDS suggests that for a weekly 5-mg reduction in prednisolone from a 20-mg daily regimen, a 20–25% reduction in insulin dose or a 40-mg reduction in gliclazide is appropriate (4).

Following cessation of steroid therapy (and corresponding reduction in glucose-lowering medication), blood glucose monitoring should continue in anticipation of a return to pre-steroid therapy blood glucose levels. Importantly, some will have had unrecognised type 2 diabetes prior to steroid treatment and will need continued treatment for hyperglycaemia. An HbA_1c 3 months following steroid therapy should be performed as a definitive test for diabetes status (4,5).

What other problems might arise through chronic steroid use?

Section 9

Aside from diabetes, other important side-effects from chronic use of steroids include:

• Hypertension
• Osteoporosis
• Muscle-wasting
• Weight gain
• Cushing’s syndrome
• Acne, skin thinning, striae
• Dyspepsia, peptic ulceration
• Candidiasis
• Hypothalamic–pituitary–adrenal suppression (see above)
• Mood disturbance
• Increased susceptibility to infection (risk of severe chickenpox and measles).

What monitoring and further treatment might you consider with these problems in mind?

Section 10

It is wise to monitor blood pressure and weight (in addition to capillary blood glucose). Use a tool, such as FRAX, to calculate long-term fracture risk, then initiate prophylactic treatment for osteoporosis, if recommended (bisphosphonates and calcium/vitamin D analogues). Where necessary, provide proton-pump inhibitor for gastroprotection.

Section 11

Frank, age 63, had recently been diagnosed with bronchial carcinoma. There was a history of smoking stretching back over 40 years and Frank was maintained on inhaled bronchodilator therapy for his COPD. Five years ago, Frank had been diagnosed with type 2 diabetes. This had always been well controlled with lifestyle measures and metformin (now 1000 mg twice daily). His most recent HbA_1c came back at 49 mmol/mol.

To relieve obstruction and oedema associated with the bronchial carcinoma, Frank was prescribed dexamethasone 4 mg once daily. At a medical examination prior to further investigations and treatment, Frank was found to have a fingerprick blood glucose reading of 22 mmol/L. Further management of his bronchial carcinoma was put on hold until blood glucose readings were adequately controlled.

What is your assessment of Frank’s situation? What differences in the effect on glucose levels are there between using dexamethasone and prednisolone as steroid therapy?

Section 12

In Frank’s situation, there is a steroid-induced hyperglycaemia exacerbating his pre-existing diabetes.

In this case, the more potent and longer-lasting steroid dexamethasone has been chosen. Blood glucose levels are likely to be elevated throughout a 24-hour period (certainly in the case of dexamethasone twice daily). Relative potencies of the corticosteroids are shown below (4).

Frank was asked to monitor CBG readings regularly, four times daily (pre-meals and pre-bed), and these were typically between 15 and 22 mmol/L. Additional treatment for hyperglycaemia was, therefore, indicated. He remained asymptomatic. The JBDS guideline and Diabetes UK position statement recommends that those with pre-existing diabetes taking corticosteroids should monitor CBG levels four times daily, irrespective of background diabetes control (4,5).

How would you manage Frank’s hyperglycaemia?

Section 13

Again, it would be worth trying gliclazide as a means of quickly lowering blood glucose levels, although we should bear in mind that his CBG readings were elevated throughout a 24-hour period.

Frank was commenced on 40 mg gliclazide twice daily. This was titrated up to 160 mg with breakfast and 80 mg with evening meal, which brought his CBG readings within the range 5–10 mmol/L.

If insulin had been required, then a single morning dose of a longer-acting insulin analogue could be added (e.g. insulin glargine 100 units/mL [Lantus], insulin detemir [Levemir]) (2,4,5). If basal insulin therapy proves insufficient (e.g. if the individual is already using a basal insulin), then a twice-daily pre-mixed biphasic insulin may be used (with an emphasis on increasing the morning dose in the case of once-daily prednisolone) or a basal–bolus insulin regimen emphasising upward titration of the lunch and evening meal boluses of rapid-acting insulin (4,5).

Section 14

Dev is a 53-year-old with type 2 diabetes for 6 years on maintenance treatments of metformin 1 g twice daily and empagliflozin 25 mg once daily. After developing a fever and cough, he tests positive for COVID-19 infection. With increasing breathing difficulty, Dev is admitted to hospital and, in the face of worsening hypoxaemia, is moved to ITU where he receives mechanical ventilation. In addition to oxygen therapy, fluid management and proning, Dev is commenced on dexamethasone 6 mg daily (9).

Dev’s condition steadily improves and, after completing 10 days’ treatment with dexamethasone, he is fit for discharge. During the admission, Dev’s metformin and empagliflozin were discontinued (to reduce the risk of lactic acidosis and diabetic ketoacidosis, respectively) and he was transferred to insulin therapy (sulfonylureas are not recommended in the situation of COVID-19 infection) (4,10). At discharge, Dev is receiving NovoMix 30 insulin injections, 22 units in the morning and 14 units in the evening.

Given the recent course of dexamethasone, what might be your concern in regulating Dev’s glucose levels on return to the community?

Section 15

COVID-19 infection and dexamethasone treatment are likely to induce insulin resistance. As the effects of the dexamethasone wear off and insulin resistance falls, Dev will be at risk of hypoglycaemia. In the case of COVID-19 infection, insulin sensitivity can be regained rapidly after discontinuation of dexamethasone (4,10).

Dev reports recurrent episodes of hypoglycaemia, with a lowest reading of 2.8 mmol/L during the day.

• This response will be awarded full points automatically, but it can be reviewed and adjusted after submission.

Section 16

You should advise cutting doses of his insulin by at least 25%. Dev needs to continue careful monitoring of his glucose levels and always have a supply of fast-acting carbohydrate to hand.

Dev’s NovoMix 30 doses are cut to 16 units with breakfast and 10 units with evening meal. He is referred urgently to the Community Diabetes Nurse for ongoing care.

Further cuts in insulin doses followed and, with the reintroduction of metformin and empagliflozin, insulin therapy was stopped.

Section 17 – Take-home messages

Elevated blood glucose readings as a consequence of receiving glucocorticoid (corticosteroid) treatment are a challenging problem. The cases of Elizabeth and Frank illustrate approaches to management of “steroid-induced diabetes” (a rise in glucose in people without a known diagnosis of diabetes) and steroid-induced hyperglycaemia (worsening of glucose control in people with pre-existing diabetes), respectively. The ideal target glucose range would be 6–10 mmol/L, with 6–12 mmol/L being acceptable depending on the individual situation. In end-of-life care, these targets may be eased to 6–15 mmol/L (4).

Prednisolone is the most commonly used corticosteroid in primary care, accounting for over 90% of cases of steroid usage in the UK, with respiratory conditions (asthma, COPD) responsible for around 40% of cases of steroid use within the community (4). Initiation of prednisolone for polymyalgia rheumatica (and less commonly temporal arteritis) is also a frequent requirement in primary care.

Whilst the majority of steroid courses are of short duration (e.g. rescue therapy for acute exacerbations of asthma and COPD), longer courses will require greater surveillance for hyperglycaemia and care with dose tapering to avoid the consequences of adrenal suppression. An estimated 22% of steroid use continues beyond 6 months (4).

When corticosteroid treatment is withdrawn, glucose levels should be carefully monitored. Treatments that induce hypoglycaemia (typically sulfonylureas and insulins) will need to be reduced to avoid hypoglycaemia, as illustrated in the cases of Elizabeth and Dev.

It is important to identify and manage hyperglycaemia in relation to steroid use in order to minimise the risk of acute and long-term complications, and prevent symptoms.