Section 1 – Margaret

Margaret is a 78-year-old lady with type 2 diabetes taking metformin and linagliptin. You are called by a neighbour to see her because she is confused, “off her legs” and has lost control of her micturition. Margaret appears pale, drowsy and disorientated. She feels thirsty and nauseous. Her mouth is dry.

Margaret’s pulse rate is 122 bpm, blood pressure is 116/58 mmHg, temperature is 38.2°C. A capillary blood glucose reading is High (above 30 mmol/L) but blood ketones are negative. A urine dipstick tests positive for leucocytes, blood and nitrites.

What is your assessment of Margaret and what acute diabetes complication is she likely to have?

Section 2

Margaret has a urinary tract infection. Her glycaemia is uncontrolled and she looks to have possibly progressed to hyperosmolar hyperglycaemic state (HHS).

How would you manage this situation?

Section 3

Hyperosmolar hyperglycaemic state (HHS) is a medical emergency requiring urgent rehydration and stabilisation of glucose levels.

HHS is a hyperglycaemic crisis (typically with blood glucose levels exceeding 30 mmol/L) with profound hypovolaemia that is characterised by thirst, polyuria, confusion, drowsiness and, ultimately, loss of consciousness. Unlike diabetic ketoacidosis (DKA), the most common hyperglycaemic crisis in people with type 1 diabetes, HHS presents without ketosis or acidosis, and most often occurs in elderly people with type 2 diabetes. In fact, HHS carries a higher risk of mortality than DKA.

Urgent rehydration, correction of electrolyte imbalance and reduction of glucose levels is required, along with thromboprophylaxis and correction of the underlying cause (Joint British Diabetes Societies for Inpatient Care, 2022).

Urgent hospital admission is arranged for Margaret.

Section 4 – Rajeshri

Rajeshri, a 47-year-old lady of Indian ethnic origin with a diagnosis of type 2 diabetes, has developed a productive cough with fever and is breathless on exertion. She feels lethargic and nauseous, and is struggling to take food on board.

Rajeshri takes metformin 1 g twice daily, gliclazide 80 mg twice daily and atorvastatin 20 mg once daily. A recent HbA_1c of 54 mmol/mol (7.1%) confirmed close-to-target glycaemic control. She has no known diabetes complications. She has asthma, for which she takes a regular combined corticosteroid/LABA inhaler and a SABA inhaler when required.

When Rajeshri is seen later at the surgery, she is alert and well perfused, and is passing urine reasonably. Pulse rate is 84 bpm, blood pressure 128/82 mmHg with no significant postural drop, O₂ saturation 96%, peak expiratory flow rate 260 L/min,  temperature 37.9°C. She has moist mucosal membranes and is not tachypnoeic. There is good air entry to the chest in all areas but with some scattered inspiratory crackles and a widespread expiratory wheeze.

Rajeshri is diagnosed with acute bronchitis with exacerbation of her asthma. She is prescribed amoxicillin and prednisolone, advised on her inhaler use and asked to monitor her peak flow readings.

What is likely to happen to Rajeshri’s blood glucose levels during this acute illness?

Section 5

Any type of acute illness in type 2 diabetes can lead to elevated glucose levels as concentrations of cortisol, catecholamines (adrenaline and noradrenaline) and glucagon rise. These, together with pro-inflammatory cytokines, drive hyperglycaemia by stimulating hepatic gluconeogenesis and glycogenolysis, and inhibiting glucose uptake in peripheral tissues such as skeletal muscle by increasing insulin resistance (Marik and Bellomo, 2013).

Rajeshri has a capillary blood glucose of 12.7 mmol/L. The initiation of prednisolone is likely to further aggravate her hyperglycaemia.

How would you advise Rajeshri in regard of managing her diabetes?

Section 6

Rajeshri should follow normal sick day rules for her diabetes (see How to advise on sick day rules; Down, 2020). She is advised to maintain a good fluid intake (aiming for 4–6 pints daily of sugar-free fluids) and encouraged to eat a light diet such as soup, milk, fruit juice, toast and plain biscuits.

Rajeshri is given a glucose monitor to keep a check on her readings and advised to ask for help if she develops persistent vomiting and inability to keep fluids down, or if glucose readings continue to rise. If glucose levels are significantly raised then Rajeshri may need to increase her morning dose of gliclazide to counter the hyperglycaemic effects of her morning dose of prednisolone (Joint British Diabetes Societies for Inpatient Care, 2023).

Section 7 – Tim

Tim, a 63-year-old gentleman with type 2 diabetes, makes an appointment to see you at the surgery after developing diarrhoea and vomiting after eating out the evening before. He has cramping abdominal pains but no blood in the stool and no fever. Tim tells you that he is feeling very fatigued, thirsty and nauseous. Urine output has been reduced.

Tim is maintained on modified-release metformin 1g twice daily, dapagliflozin 10 mg once daily, ramipril 10 mg once daily and atorvastatin 20 mg once daily. Recent results include an HbA_1c of 55 mmol/mol (7.2%) and an eGFR of 53 mL/min/1.73 m².

When examined, Tim is judged to have mild dehydration but not sufficient to require hospital admission.

What immediate tests might you check in the surgery?

Section 8

You should check a blood glucose level and, crucially, a blood ketone level, as Tim is taking dapagliflozin. SGLT2 inhibitors carry a risk of inducing diabetic ketoacidosis (DKA) in situations of acute illness. Blood ketone testing is preferable to urinary ketone testing because blood ketone levels are more contemporaneous and detect beta-hydroxybutyrate, which is the important ketone body in DKA (Laffel, 1999; Diggle, 2020).

Tim’s fingerprick glucose reading is 13.8 mmol/L. Blood ketones are 0.3 mmol/L.

How would you interpret Tim’s blood ketone result?

Section 9

Tim’s blood ketone level is not significantly raised.

The table below outlines interpretation of blood (and urine) ketone results (Morris, 2019).

At what level of hyperglycaemia can DKA occur in people taking SGLT2 inhibitors?

Section 10

In the situation of hypovolaemia, SGLT2 inhibitors can predispose to DKA even with only moderately elevated blood glucose levels (<14 mmol/L); this is referred to as euglycaemic DKA (Peters et al, 2015; Fralick et al, 2017).

What symptoms might alert you to DKA?

Section 11

Symptoms of DKA include lethargy, thirst, increased urination, nausea and vomiting, abdominal pain and shortness of breath. A fruity smell on the breath would be consistent with ketosis. Look out for any signs of mental confusion or disorientation.

A problem in Tim’s case is that there is symptom overlap between DKA and gastroenteritis –abdominal pain, vomiting, thirst and lethargy could be expected in both conditions.

How would you manage Tim’s situation? What advice would you give in terms of his medication?

Section 12

Tim should be reminded of the sick day rules (see Section 6). He should aim for a fluid intake of at least 100 mL/hour (frequent sips). Because of the features of dehydration, it is advisable to temporarily stop his ramipril to reduce the risk of acute kidney injury (AKI), which he is already at increased risk of due to his chronic kidney disease. He should also be advised to pause dapagliflozin to reduce the risks of AKI (SGLT2 inhibitors have a diuretic action) and DKA. Tim’s dose of metformin is halved to reduce the risk of lactic acidosis.

Tim is advised to get back in touch if vomiting persists and he is unable to keep down fluids, if blood glucose readings are persistently >20 mmol/L or if he has symptoms suggestive of DKA.

What options do you have if Tim’s blood glucose levels need to be stabilised?

Section 13

There is certainly a risk of worsening hyperglycaemia by withholding the metformin and dapagliflozin. If necessary, gliclazide could be used as a rescue treatment for hyperglycaemia because its glucose-lowering actions are immediate (see How to: Rescue therapy in the management of type 2 diabetes; Alabraba, 2024). Beyond this, bolus doses of a rapid-acting insulin could be used to control hyperglycaemia, but hospital admission may need to be considered by this stage.

Conversely, there is a risk of hypoglycaemia if Tim is not eating. If blood glucose levels do fall towards 4 mmol/L then Tim should drink sugary fluids and subsequently recheck blood glucose levels to ensure an adequate response.

The diabetes medications can be resumed at normal dose when the risk of hypovolaemia has receded.

In the situation of hypovolaemia in type 2 diabetes, which medications should you consider pausing?

Section 14

At times of volume depletion, consider temporarily stopping the SADMAN drugs listed below (NICE, 2024; Down, 2020). The decision to pause these drugs will be a clinical judgement based on the degree of dehydration and individual risk factors. Bear in mind that stopping glucose-lowering drugs (metformin and SGLT2 inhibitors) may aggravate hyperglycaemia.

• SGLT2 inhibitors – risk of DKA and AKI.
• ACE inhibitors – risk of AKI and electrolyte imbalance.
• Diuretics – risk of AKI and electrolyte imbalance.
• Metformin – risk of lactic acidosis.
• Angiotensin receptor blockers – risk of AKI and electrolyte imbalance.
• Non-steroidal anti-inflammatory drugs – risk of AKI.

We have considered the need to stop metformin and SGLT2 inhibitors in situations of hypovolaemia. What about other medications for hyperglycaemia?

Section 15

As discussed, consideration should be given to stopping metformin and SGLT2 inhibitors if acute illness is severe enough to lead to hypovolaemia. Otherwise, in general, oral medications for type 2 diabetes should be continued during acute illness. DPP-4 inhibitors and pioglitazone may be continued, as can sulfonylureas (although bear in mind the risk of hypoglycaemia if food is not being eaten). GLP-1 receptor agonists may need to be discontinued in the situation of vomiting and abdominal pain – medical advice should be sought.

If a basal insulin or a “mixed” biphasic insulin is being taken, this should be continued; if a rapid-acting insulin is being used then the dose will need to be varied according to blood glucose readings.

Additional rescue doses of insulin will be needed for raised glucose readings (say, >11 mmol/L). As a guide, advice from Trend Diabetes (2022) can be followed:

• Blood glucose 11–17 mmol/L: add 2 units to each dose.
• Blood glucose 17–22 mmol/L: add 4 units to each dose.
• Blood glucose >22 mmol/L: add 6 units to each dose.

If the total daily dose of insulin were to exceed 50 units then double the rescue doses and, conversely, if the individual is taking less than 25 units per day then halve the rescue doses.

How would you advise Tim with a view to reducing risk of DKA in the future?

Section 16

Tim needs to be aware of how to recognise DKA (see symptoms earlier) and what action to take if DKA is suspected. When taking an SGLT2 inhibitor, Tim should maintain a good fluid intake and avoid a very-low-carbohydrate diet (which predisposes to ketosis) (Rosenstock and Ferrannini, 2015).

Tim should temporarily stop the SGLT2 inhibitor in the situation of acute illness, vomiting and diarrhoea, inability to eat and drink, or 48 hours prior to planned major surgery (to reduce risk of DKA and AKI). If he suspects he may have DKA, he should stop the SGLT2 inhibitor and urgently seek medical advice (even if blood glucose levels are not unduly raised) (Morris, 2019).

Section 17: SGLT2 inhibitors and DKA

As usage of SGLT2 inhibitors has become more widespread, it has become apparent that they are associated with a small increased risk of DKA, a potentially life-threatening complication. A significant proportion of cases were associated with ketosis-prone diabetes (type 1 diabetes, latent autoimmune diabetes in adults and pancreatogenic diabetes) (Rosenstock and Ferrannini, 2015; Peters et al, 2015; Fralick et al, 2017).

Regulatory bodies in the UK and Europe have issued warnings over the risk of DKA when using SGLT2 inhibitors (MHRA, 2016; EMA, 2016). The European Medicines Agency, however, concluded that the benefits of SGLT2 inhibitors continue to outweigh the risks in treatment of type 2 diabetes.

Situations predisposing to DKA in people taking SGLT2 inhibitors are listed below – typically where there is a relative insulin deficiency (Wilding et al, 2018; Morris, 2019):

• Type 1 diabetes, latent autoimmune diabetes in adults, pancreatogenic diabetes.
• Sudden reduction in insulin dose.
• Acute illness/infection.
• Dehydration.
• Surgery.
• Alcohol excess.
• Fasting (carbohydrate restriction, ketogenic diet).
• Corticosteroid therapy.