‘Flozins’ reduce diabetes complications, but beware of euglycaemic ketoacidosis

• Sodium-glucose cotransporter-2 inhibitors reduce renal, cardiovascular and heart failure complications of diabetes, while lowering blood glucose levels.
• It will be important to use a pro-equity approach to identify suitable candidates for empagliflozin.
• Euglycaemic ketoacidosis is an uncommon but serious adverse effect of SGLT2 inhibitors – patients should be made aware of precipitating factors, warning symptoms and signs.

Sodium-glucose cotransporter-2 inhibitors, or “flozins”, reduce blood glucose levels by inhibiting the SGLT2 system, which actively resorbs glucose in the kidneys. Inhibiting the system increases the excretion of glucose in the urine. It is now well established that this class of medicines also demonstrates benefits in cardiovascular disease, renal disease and heart failure, over and above glycaemic control in patients with type 2 diabetes.

These are unprecedented benefits that provide an opportunity to address long-standing inequities, importantly for Māori and Pacific peoples. It is important to note, however, that cardiovascular risk factors must still be assessed and addressed to maximise the additive benefits of flozins.

Similarly, SGLT2 inhibitors decrease serum urate, but they should only be viewed as an adjunct, not as a treatment, to achieve target serum urate in those with gout.

The American Diabetes Association, the European Association for the Study of Diabetes and the Royal Australian College of General Practitioners all recommend first-line availability, after metformin and lifestyle intervention, of both SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in their management guidelines for type 2 diabetes.

While Pharmac will also fund a GLP-1 receptor agonist once it is approved by Medsafe, flozins have superiority for heart failure (and gout with the above proviso) when compared with GLP1 receptor agonists. Both classes have cardiovascular disease and renal benefits.

Renal complications, including progression to end-stage renal disease in Māori and Pacific peoples, occur at higher rates than the increased prevalence of type 2 diabetes.

In people with established cardiovascular disease and chronic kidney disease, the benefits of empagliflozin are estimated to be a 29 per cent reduction in cardiovascular death, a 24 per cent reduction in all-cause mortality, and a 39 per cent reduction in hospitalisation with heart failure over approximately two and a half years. While reducing these complications, flozins also reduce HbA1c by about 8mmol/ mol and can result in 2–3kg of weight loss.

The following pro-equity approach is used to proactively identify suitable candidates for empagliflozin:

1. Code all patients with microalbuminuria.
2. Run a query to identify patients with diabetes and microalbuminuria.
3. Prioritise according to ethnicity (Māori and Pacific peoples).
4. Arrange an appointment for a consult, potentially a double consult and/or follow-up with the wider team.

John is identified and comes in to discuss starting empagliflozin. He is a 47-year-old Māori male who was diagnosed with type 2 diabetes six years ago. See the table for a list of his current medications. He is a non-smoker, consumes minimal alcohol and remains physically active, playing social rugby and swimming regularly.

Investigations reveal the following:

• BMI – 32.3kg/m²
• blood pressure – 132/82mmHg (average over last six months)
• HbA1c – 59mmol/mol
• estimated glomerular filtration rate – 87ml/min/1.73m²
• albumin:creatinine ratio – 11.2mg/mmol
• cardiovascular risk – 8 per cent
• electrolytes, complete blood count, liver function tests – unremarkable.

John is keen to start empagliflozin, understanding that:

• empagliflozin helps get rid of glucose by excreting it in the urine, so it has a different mechanism of action and works well with his other medicines
• his HbA1c may reduce by approximately 8mmol/mol
• the risk of hypoglycaemia is minimal as he is not on a sulphonylurea or insulin
• it will help reduce the chance of progressing to end-stage renal disease, and also help reduce his chance of a heart attack
• his blood pressure may reduce by 4–5mmHg, which would bring him within a target systolic blood pressure of <130mmHg
• he may experience 2–3kg of weight loss, though he still needs to maintain his diet and exercise regimens
• the initial dose is 10mg daily, which may be increased to 25mg daily if needed
• serum urate will likely decrease further and will be checked at the next lab test along with kidney function.

Possible adverse effects are discussed, and John is warned about:

• genital infections – occur at a rate of 4 to 5 per cent but do not usually require discontinuation of therapy
• urinary tract infections – occur commonly (approximately 8 per cent) but are generally mild
• pain, redness or swelling in the genital or perineal area, fever or malaise (Fournier gangrene – rare but can worsen quickly) – you might find it easier to cover these in one go by saying that these can occur, are usually mild and easily treated with medications, but rarely they can be severe, so any symptoms should be reported immediately
• possible increased urination
• rash
• the symptoms of euglycaemic ketoacidosis – although this is uncommon, John needs to immediately report any nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness, regardless of his blood glucose level; the risk is about 1 to 8 per 1000 person-years, and approximately three-quarters of these events occur in the first six months
• dehydration – it is important to make sure John maintains his fluid intake, especially over summer
• foot care and foot checks are important because, although there is conflicting evidence, there may be a very small risk of lower limb amputation.

John shares his blood glucose results through the long-term care nurse. Although his HbA1c level improves by 4mmol/ mol, the empagliflozin dose is increased to 25mg daily to maximise all benefit.

Ten weeks later, John rings, explaining that he just doesn’t feel right. He is lethargic, nauseated with some abdominal pain, very thirsty and urinating a lot. He remembers your advice and wonders if he has a urinary tract infection. His fasting blood glucose level is 10.1mmol/L. John says he has taken up jogging over the summer, and he is restricting his carbohydrates much more and having an “almost keto diet”.

John presents at the practice as requested. Using the practice dual blood glucose and ketone meter, it is found that he has high blood ketones. Because the euglycaemic ketoacidosis is a result of excretion of glucose in exchange for ketones, blood ketone testing is preferred over urine test strips (although not discounted if blood testing is unavailable) – it is more accurate for detecting onset and resolution of ketosis.

John is referred to secondary care for prompt insulin/dextrose infusion, hydration and normalisation of the anion gap. A blood test result eventually comes back with a sodium bicarbonate level <15mmol/L and a pH >7.3.

Risk factors for euglycaemic ketoacidosis include:

• SGLT2 inhibitor dose
• very-low carbohydrate or ketogenic diet (stop the SGLT2 inhibitor if the patient is on a very-low-calorie diet or fasting regimen)
• volume depletion – vigorous exercise, dehydration
• acute infections or serious medical illness – stop the SGLT2 inhibitor until resolved
• surgery – stop the SGLT2 inhibitor three days before surgery
• previous or high risk of pancreatitis
• excessive alcohol intake.

John’s empagliflozin is stopped. There are case reports of repeated episodes of euglycaemic ketoacidosis on rechallenge, so current evidence supports continued cessation. For John, the next option would be a GLP-1 receptor agonist.

Aside from the prohibitive cost of the dual blood glucose and ketone meter and testing strips, it is debated whether it is helpful for people to monitor for ketoacidosis during the first weeks of therapy. Some people may test unnecessarily and others not at all. Costs also compound inequity.

Leanne Te Karu is a pharmacist prescriber working in primary care; Linda Bryant is a clinical advisor and pharmacist prescriber at Newtown Union Health Service and Porirua Union and Community Health Service, Wellington

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