A 56-year old man presented with a one week history of feeling out of sorts - tired, thirsty and unwell. He had an extensive past medical history and polypharmacy.
He had type 2 diabetes for which he was on insulin, had ischaemic heart disease with a recent angioplasty and stenting, chronic back pain and spinal stenosis and essential hypertension.
The patient’s symptoms for the last week included being tired, thirsty and feeling ill. There were no symptoms to indicate a chest or urinary infection, and there had been no recent changes to his medication, which consisted of:
- metformin M/R 1g BD, dapaglifozin 10mg, insulin aspart 20u morning/22u evening, insulin glargine 80u night
- clopidogrel 75mg, amlodipine 10mg, bisoprolol 10mg, nicorandil 10mg BD , pravastatin 40mg, aspirin 75mg, lisinopril 20mg
- lansoprazole 30mg
- morphine sulfate 10mg at night, tramadol 50mg PRN, nefopam 30mg 2 TDS
Of note he had to double his insulin requirements over the week, going to insulin aspart 42u/40u+ and insulin glargine 120u to maintain normal blood sugar readings.
Clinical examination was unremarkable. He was apyrexial. A urine dip showed a trace of ketones and nothing else. Bloods were requested , which showed normal white cell count and inflammatory markers. He had a small drop in his haemoglobin, but not enough to expect him to be symptomatically tired. There were no signs of underlying infection.
The reason for his symptoms and rapid and significant increase in Insulin requirements were a puzzle. It was our practice nurse lead for diabetes who came upon the answer. She had read of a drug safety update regarding SGLT2 inhibitors and the risk of diabetic ketoacidosis.1 The patient had been taking dapaglifozin since March 2014 and we advised him to stop his dapagliflozin immediately.
Within two days he was back to normal, both symptomatically and with regard to his insulin needs. The incident was reported via the yellow card scheme.
SGLT2 (sodium glucose co-transporter 2) inhibitors are licensed for use in adults with type 2 diabetes. They include canaglifozin, dapagliflozin and empagliflozin. They work by blocking SGLT2 in the proximal tubule of the kidney.
SGLT2 is responsible for 90% of the glucose reabsorption from the proximal convoluted tubule, although a SGLT2 inhibitor inhibits 30-50% of glucose absorption in people with diabetes. Hence they promote glucose excretion. They have potential benefits of weight loss and blood pressure control as well as improved glycaemic control. Genital mycotic infection and increased urination are the most common side effects.
Serious cases of diabetic ketoacidosis (DKA) have been reported in patients taking this class of medication. Blood glucose levels may be only moderately elevated, although symptoms may fit with DKA and they may have ketones in the urine. Half of cases occurred within two months of starting the medication, but a small number occurred after stopping it. SGLT2 inhibitors are not licensed for use in Type 1 diabetes and cases have been reported in this group of individuals.
Advice for patients
Patients who start on this type of medication could be given ketosticks and a patient information leaflet on the signs and symptoms of DKA. These would include nausea and vomiting, anorexia, abdominal pain, confusion, unusual fatigue and excess thirst. If DKA is suspected, patients should be advised to stop SGLT2 inhibitor treatment, test for ketones and to seek medical help.
Factors which may predispose patients on this medication to developing DKA include alcohol misuse, surgery, increased insulin need due to acute illness, a low beta cell function reserve and severe dehydration.
Practices may opportunistically advise patients on SGLT2 inhibitors about the risk of DKA and provide ketone testing strips. Practices may wish to run searches to see how many of their patients are on this medication and investigate the feasibility of calling them in to talk about the complication.
Management of DKA is detailed in useful web pages such as NICE clinical knowledge summaries2 or the Diabetes UK website.3
- Dr Simon Gowda is a GP in Cheshire
- Medicines and Healthcare products Regulatory Agency (2015) SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin): risk of diabetic ketoacidosis.
- CKS (2015) Insulin therapy in type 2 diabetes
- Diabetes UK (2016) Diabetic ketoacidosis