Terese presents to you today for repeat medication prescriptions and review of recent blood tests. Her HbA1c is 8.5% and has been above 8% for the past 9 months, despite increased physical activity and 2kg weight loss. Her eGFR is 62 and ACR 44 (microalbuminuria).
You are keen to add a second antihyperglycaemic medication and discuss with Terese using a SGLT2 inhibitor. You discuss common side effects, including genitourinary infections. Terese then asks about possible serious adverse events.
What is the risk of ketoacidosis in patients commencing SGLT2 inhibitors? And how can this risk be minimised?
Diabetic ketoacidosis is a rare but serious adverse effect of SGLT2 inhibitors1.
In 2020, a large cohort study of new users of SGLT2 inhibitors found that the relative risk of DKA was three times higher than matched controls taking a DPP-4 inhibitor, with an absolute risk of 1 in 500 cases per year2. A recent BMJ review paper stated that the risk is highest shortly after starting the drug, with 75% of cases occurring within 6 months3.
Patients usually present with typical symptoms of DKA, including polyuria, polydipsia, nausea, abdominal pain, vomiting, and drowsiness. However, up to one third of people with SGLT2i-related ketoacidosis present with normal or only mildly elevated glucose concentrations, so called 'euglycaemic DKA'. This is an important clinical point, as the absence of osmotic symptoms and hyperglycaemia may lead to a delay in diagnosis. As well, urinary ketone levels are unreliable and it is essential to check for capillary ketones to confirm the diagnosis.
The risk of SGLT2i-related ketoacidosis can be reduced in a number of ways. All patients commencing this class of medication should be informed of the risk, including symptoms and signs to look out for and advice around fasting and dehydrating illnesses. DKA risk is higher in people who are insulin deficient, and SGLT2 inhibitors should never be used in patients with T1DM, LADA, or diabetes secondary to pancreatic disease. Other higher risk patients include those with previous DKA, eating disorders, very low carbohydrate (ketogenic) diet, alcohol or drug misuse, and low BMI.
1. Markey AG, Scott TA, Killen JC, Venter JA. Sodium–glucose co-transporter 2 inhibitors: Think twice about diabetic ketoacidosis. Aust J Gen Pract. 2018 Apr;47(4):223-225. doi: 10.31128/AFP-09-17-4348. PIMD: 29621864.
2. Douros A, Lix LM, Fralick M, Dell'Aniello S, Shah BR, Ronksley PE, Tremblay É, Hu N, Alessi-Severini S, Fisher A, Bugden SC, Ernst P, Filion KB; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study. Ann Intern Med. 2020 Sep 15;173(6):417-425. doi: 10.7326/M20-0289. Epub 2020 Jul 28. PMID: 32716707.
3. Musso G, Saba F, Cassader M, Gambino R. Diabetic ketoacidosis with SGLT2 inhibitors BMJ 2020; 371 :m4147 doi:10.1136/bmj.m4147
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