In the February issue, we explored the assessment and management of diabetic ketoacidosis (DKA) (Mendes, 2025). DKA is a known complication previously of type 1 diabetes, but now more commonly seen in type 2 diabetes as well (Mendes, 2025). A primary reason for this spike in DKA cases among individuals living with type 2 diabetes is an increase in the prescription of sodium-glucose co-transporter-2 (SGLT-2) inhibitors (which are contraindicated in people with type 1 diabetes owing to their increased risk of developing DKA (Mendes, 2025).
The cause of DKA in patients taking SGLT2 inhibitors is unclear but possible theories surround the increased incidence of dehydration and infections (Ata et al, 2021).
SGLT-2 inhibitors are antihyperglycemic transporting agents that act upon the SGLT-2 proteins expressed in the proximal convoluted tubules in the nephron to pump filtered glucose from the kidneys back into the blood (Padda et al, 2023; Thain and Webster, 2025). As a result of this action, the amount of sodium and glucose absorbed by the blood is reduced, and excretion through the urine is encouraged (Kirwin and Cannon, 2025). This makes SGLT-2 inhibitors an effective treatment for choice for the management of type 2 diabetes, despite the increased risk of DKA (Mendes, 2025).
They are a popular drug of choice not only for type 2 diabetes, but are also approved for other conditions, and are prescribed off-label. However, as has been seen in the case of their use for type 2 diabetes and as with any drug, they are not without their risks. This article will therefore consider their various indications and cautions, and consider how their use can be continued effectively to benefit patients while minimising risks to optimise their prescribing.
Approved indications and off-label use
As an adjunct to diet and exercise, the following SGLT-2 inhibitors are approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK as well as the Food and Drug Administration (FDA) in the United States for the glycaemic management of adults with type 2 diabetes: canagliflozin, dapagliflozin, empagliflozin and ertugliflozin (UK Kidney Association, 2022; Padda et al, 2023). In addition to blood sugar control, however, SGLT-2 inhibitors also help to reduce the occurrence of major adverse cardiovascular events such as non-fatal myocardial infarction, non-fatal stroke and cardiovascular death in adult patients with type 2 diabetes and established cardiovascular disease (Zelniker et al, 2019; Padda et al, 2023).
Dapagliflozin and empagliflozin are the most commonly prescribed SGLT-2 inhibitors (Kirwin and Cannon, 2025) and are also approved for use in patients with heart failure, decreasing the risk of cardiovascular hospitalisation and death for patients with heart failure with reduced ejection fraction (HFrEF) in New York Heart Association (NYHA) classes II-IV (Monzo et al, 2021; UK Kidney Association, 2022; Padda et al, 2023) and, most recently approved to improve cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF) (Pabel et al, 2021; UK Kidney Association, 2022; Padda et al, 2023).
‘In patients with chronic kidney disease at risk of progressing, dapagliflozin is approved for use and has been shown to reduce the risk of estimated glomerular filtration rate (eGFR) decline, end-stage renal disease and associated hospitalisation; however, this recommendation does not apply to immunocompromised patients with a kidney transplant (Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group, 2022; UK Kidney Association, 2022; Padda et al, 2023).’
In terms of off-label use, SGLT-2 inhibitors are used for the management of obesity alongside glucagon-like peptide-1 receptor agonists (Pereira and Eriksson, 2019; Padda et al, 2023) and for non-alcoholic fatty liver disease as an adjunctive therapy in patients who also have type 2 diabetes (Cusi et al, 2022; Padda et al, 2023). However, worryingly, the use of SGLT-2 inhibitors to manage obesity, as well as their benefits for managing cardiovascular and renal complications, has to led to an increase in their use in individuals with type 1 diabetes, for whom their use increases an already high risk of DKA (Seery, 2024).
The use of SGLT-2 inhibitors to manage obesity, as well as their benefits for managing cardiovascular and renal complications, has to led to an increase in their use in individuals with type 1 diabetes
Cautions and contraindications for risk reduction
There are various cautions and contraindications associated with SGLT-2 inhibitors. Cautions include patients with a body mass index of more than 25 kg/m2 (or 23 kg/m2 in individuals of South Asian background); those who have experienced recent weight loss; those at risk of hypotension or hypovolaemia caused by diuretic and/or hypertensive medication; frailty; cognitive impairment or issues with compliance regarding sick day rules; long-term or recurrent steroids; raised haematocrit; severe hepatic impairment; and recurrent urinary tract or genital infections (Kirwin and Cannon, 2025).
In addition to taking such cautions, SGLT-2 inhibitors are also contraindicated for patients who (Kirwin and Cannon, 2025):
- Are aged under 18 years
- Are pregnant, likely to become pregnant, or breastfeeding
- Use excess alcohol consumption or intravenous drugs
- Are intolerant to SGLT-2 inhibitors or its excipients
- Are on dialysis or have had an organ transplant
- Have been diagnosed or suspected type 1 diabetes
- Are suspected to have latent autoimmune diabetes (a genetic cause of diabetes), pancreatic disease or injury or a rapid progression to insulin requirement within one year of diagnosis
- Have type 3c diabetes (develops as a result of damage to the pancreas)
- Have a history of DKA
- Have urosepsis or pyelonephritis
- Have recurrent pancreatitis.
Other considerations
The above cautions and contraindications should be taken into account when deciding whether or not to prescribe SGLT-2 inhibitors; a decision-making consideration process to follow during a patient's hospitalisation is included in Kirwin and Cannon (2025), based on Newcastle upon Tyne Hospitals NHS Foundation Trust's internal guideline, which will be of use to prescribers.
Kirwin and Cannon (2025) highlight that when a patient is admitted to hospital, a medication review should be conducted within the first 48 hours of admission and, subsequently, as often as clinically necessary. This review should consider the patient's primary complaint, laboratory test results, clinical observations, and potential drug interactions. Ongoing assessments – including repeat blood tests and evaluations of oral intake – should be performed at least every 48 hours to guide the decision on whether to continue or discontinue the SGLT2 inhibitor (Kirwin and Cannon, 2025).
Additional considerations when determining whether to prescribe or suspend an SGLT-2 inhibitor on a case-by-case patient basis, particularly in relation to their risk of developing DKA, include their ability to tolerate oral intake of SGLT2 inhibitor, as well as their potential to manage physiological stress such as surgery, infection, or gastrointestinal issues like vomiting and diarrhea (Kirwin and Cannon, 2025).
The internal guidelines of Newcastle upon Tyne Hospitals NHS Foundation Trust have been recently updated and were developed collaboratively by a multidisciplinary team (MDT) comprising renal, cardiology, and endocrinology specialists to mitigate potential risks and optimise patient outcomes. According to these guidelines, SGLT2 inhibitors should be withheld while awaiting medical review in the A&E department and the admissions assessment suite.
As with prescribing any medication, benefits should be weighed against risks, and contraindications should always be noted. Additionally, given the fact that patients receiving SGLT2 inhibitors may often be under the care of multiple specialties, MDT collaboration is essential to ensure the medication remains safe and effective across all indicated conditions (Kirwin and Cannon, 2025).