Published: 5 December 2024
Publications
Reminder: risk factors for ketoacidosis with SGLT-2 inhibitors
Prescriber Update 45(4): 73–76
December 2024
Ketoacidosis is a life-threatening condition that requires urgent hospitalisation.1
Ketoacidosis is a known adverse reaction of sodium-glucose co-transporter-2 (SGLT-2) inhibitor medicines, such as empagliflozin and dapagliflozin.1
This article is a reminder about ketoacidosis, in particular in patients being treated with SGLT-2 inhibitors. The article focuses on empagliflozin, the funded medicine in this class.
Ketoacidosis and SGLT-2 inhibitors
Mechanisms
SGLT-2 inhibitors predispose patients to ketoacidosis by multiple mechanisms that favour ketogenesis and lipolysis. These mechanisms include:2
- upregulation of glucagon
- glycosuria, which reduces blood glucose and allows for insulin dose reduction
- ketone reabsorption in the kidney
- osmotic diuresis.
Risk factors
Type 2 diabetes mellitus (T2DM) itself is a risk for ketoacidosis (diabetic ketoacidosis). However, there have also been reports of ketoacidosis in nondiabetic patients taking empagliflozin.1
Patients taking SGLT-2 inhibitors may also have other factors that predispose them to ketoacidosis, as shown in Table 1.
Table 1: Risk factors for ketoacidosis in patients taking SGLT-2 inhibitors
| Acute illness or infection |
| Surgery |
| Pancreatic disorders leading to insulin deficiency |
| Inappropriate insulin dose reduction (including via insulin pump failure) |
| Severe dehydration |
| Malnourished/Reduced caloric intake |
| Low carbohydrate or ketogenic diet |
| Heavy alcohol use |
| History of ketoacidosis |
Sources:
Boehringer Ingelheim (NZ) Limited. 2024. Jardiance New Zealand Data
Sheet 21 March 2024 URL:
medsafe.govt.nz/profs/Datasheet/j/jardiancetab.pdf (accessed 1 October
2024).
Musso G, Saba F, Cassader M, et al. 2020. Diabetic ketoacidosis with
SGLT2 inhibitors. British Medical Journal 371: m4147. DOI:
10.1136/bmj/m4147 (accessed 1 October 2024).
Chow E, Clement S, Garg R. 2023. Euglycemic diabetic ketoacidosis in
the era of SGLT-2 inhibitors. BMJ Open Diabetes Research & Care
11(5): e003666. DOI: 10.1136/ bmjdrc-2023-003666 (accessed 1 October
2024).
Prescribing considerations
Use caution when prescribing SGLT-2 inhibitors to patients with risk factors that may predispose them to ketoacidosis.1
Inform patients taking SGLT-2 inhibitors about ketoacidosis risk factors, signs and symptoms. Blood glucose levels may be normal or only mildly elevated. Symptoms may be non-specific and include nausea, vomiting, malaise, anorexia, abdominal pain, excessive thirst, shortness of breath, dizziness or confusion. Advise patients to seek medical attention immediately if they experience ketoacidosis symptoms, irrespective of blood glucose levels.1–3
Consider monitoring ketones and temporarily discontinuing SGLT-2 inhibitors in clinical situations known to predispose patients to ketoacidosis.1,3 Refer to local clinical guidelines for further advice, including management before surgery/procedures and during acute illness.
Ketoacidosis may be prolonged in patients with T2DM, despite stopping SGLT-2 inhibitors.4
New Zealand case reports: empagliflozin
Between January 2021 and 15 September 2024, there were 87 case reports of ketoacidosis in people who were taking empagliflozin.
All cases were reported as serious. The median onset time was 59 days (range 1 to 703 days). Table 2 shows the demographic distribution of the case reports.
In some cases, the reporter also included information to show that the patient had other risk factors, including:
- acute infection
- dietary changes
- dehydration
- weight loss
- insulin dose reduction or omission
- surgery/procedure
- high alcohol intake.
Table 2: Gender, age and ethnicity distibution of case reports of ketoacidosis* with empagliflozin, 1 January 2021 to 15 September 2024
| Demographic | Number (n=87) |
|---|---|
| Gender | |
| Male | 46 |
| Female | 40 |
| Not reported | 1 |
| Age (years) | |
| 18-44 | 13 |
| 45-64 | 33 |
| 65-74 | 12 |
| 75 and older | 8 |
| Not reported or unknown | 21 |
| Ethnicity | |
| Māori | 7 |
| Pacific Peoples | 3 |
| Asian | 2 |
| European/Other | 23 |
| Not reported or unknown | 52 |
* Includes MedDRA preferred terms: diabetic ketoacidosis (61), ketoacidosis (14), euglycaemic diabetic ketoacidosis (7), ketosis (3), blood ketone body increased (1), blood ketone body present (1).
Source: Suspected adverse reactions reported to the New Zealand Pharmacovigilance Database (accessed 15 September 2024).
Further information
Previous Prescriber Update articles
- Reminder: Flozins and the risk of diabetic ketoacidosis and Fournier’s gangrene (December 2022)
- Spotlight on empagliflozin (December 2020)
Resources
- Medsafe: Data sheet and consumer medicine information search
- New Zealand Society for the Study of Diabetes: Type 2 Diabetes Management Guidance
- bpacnz: Type 2 diabetes management toolbox: from lifestyle to insulin
- Healthify:
References
- Boehringer Ingelheim (NZ) Limited. 2024. Jardiance New Zealand Data Sheet21 March 2024 URL: medsafe.govt.nz/profs/Datasheet/j/jardiancetab.pdf (accessed 1 October 2024).
- Musso G, Saba F, Cassader M, et al. 2020. Diabetic ketoacidosis with SGLT2 inhibitors. British Medical Journal 371: m4147. DOI: 10.1136/bmj/m4147 (accessed 1 October 2024).
- Chow E, Clement S, Garg R. 2023. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Research & Care 11(5): e003666. DOI: 10.1136/ bmjdrc-2023-003666 (accessed 1 October 2024).
- Health Canada. 2024. Summary Safety Review – Sodium-glucose-co-transporter-2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) – Assessing the potential risks of prolonged or incident diabetic ketoacidosis despite stopping treatment in adult patients with type 2 diabetes 10 October 2024. URL: dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1724175682293 (accessed 4 October 2024).
