SGLT2 inhibitors: ketoacidosis, genital infections and foot care

SGLT2 inhibitors make the kidneys pass extra sugar into the urine. That lowers blood sugar, but it also means more sugar in the urinary and genital area, more fluid loss and a shift in how the body uses fuel. The NHS lists thrush, back pain, passing more urine and low blood sugar as common effects of dapagliflozin, and notes that vomiting, diarrhoea or a fever raise the risk of dehydration.

The MHRA has published a series of safety updates on the class. The rare reactions described below were identified after the medicines went on the market, and the advice is to know the warning signs rather than to avoid the medicines out of fear. Individual benefits and risks should be discussed with the diabetes team.

The MHRA says serious, life-threatening and fatal cases of diabetic ketoacidosis (DKA) have been reported with SGLT2 inhibitors, and a European review concluded the reaction is rare, affecting between 1 in 1,000 and 1 in 10,000 patients. In several UK Yellow Card cases blood glucose was only moderately elevated, for example below 14 mmol/L, which is an atypical presentation that can delay diagnosis. Clinicians are told to test for raised ketones in anyone with symptoms, even when glucose looks near normal.

Many cases occurred in the first 2 months of treatment and some soon after stopping. Dehydration, low food intake, weight loss, infection, surgery, vomiting, a drop in insulin dose and poor diabetes control were present in some cases. A substantial proportion involved off-label use in type 1 diabetes, and the MHRA reminds prescribers that SGLT2 inhibitors should not be used in type 1 diabetes. Treatment is stopped immediately if DKA is suspected and generally not restarted after a DKA episode unless another cause was found and resolved.

• Rapid weight loss, feeling or being sick, stomach pain

• Fast and deep breathing, sleepiness

• A sweet smell to the breath, or a sweet or metallic taste in the mouth

• A different odour to urine or sweat

In March 2020 the MHRA advised that SGLT2 inhibitor treatment should be interrupted in people hospitalised for major surgery or acute serious illness, that ketones should be monitored during this period, and that treatment can restart once ketone values are normal and the patient is stable. Blood ketone testing is preferred to urine testing, because SGLT2 inhibitors may reduce the excretion of ketones in the urine and make urine tests less reliable.

The NHS advice for dapagliflozin is to talk to a pharmacist or doctor if you become ill with vomiting, diarrhoea or fever, because of the risk of dehydration, and to avoid stopping suddenly without speaking to your doctor first, since blood sugar may rise. Tell any surgical or pre-assessment team that you take an SGLT2 inhibitor.

Thrush is a common effect, and the NHS also lists severe urinary tract infections with fever, shivering or burning when passing urine as serious effects needing medical advice. The rarest and most dangerous genital reaction is Fournier's gangrene, a necrotising infection of the genitals or perineum. The MHRA describes it as rare but potentially life-threatening and says a urogenital infection or perineal abscess may come before it.

Patients are advised to seek urgent medical attention for severe pain, tenderness, redness or swelling in the genital or perineal area with fever or malaise. If it is suspected, the SGLT2 inhibitor is stopped and treatment, including antibiotics and surgery if needed, begins urgently. The NHS describes the symptoms as severe pain, swelling, redness and blisters.

In 2017 the MHRA reported that canagliflozin may increase the risk of lower-limb amputation, mainly of the toes, in people with type 2 diabetes. Evidence did not show an increased risk for dapagliflozin and empagliflozin, but the risk may be a class effect. Clinicians are asked to monitor people on canagliflozin who have risk factors such as poor diabetes control or heart and blood vessel problems, and to consider stopping it if foot infection, skin ulcers, bone infection or gangrene develop.

Everyone with diabetes should have routine preventive foot care and stay adequately hydrated. Check your feet daily and report new sores, colour changes or pain early.

Suspected reactions can be reported through the MHRA Yellow Card scheme. At diabetes reviews, ask whether an SGLT2 inhibitor is still the right choice, particularly after any episode of ketoacidosis, recurrent genital infection or foot ulcer.