Published: 1 December 2022
Amended:  23 December 2022

Publications

Reminder: Flozins and the risks of diabetic ketoacidosis and Fournier’s gangrene

Prescriber Update 43(4): 48–50
December 2022

Introduction

The Centre for Adverse Reactions Monitoring (CARM) has received reports of diabetic ketoacidosis (DKA) and Fournier’s gangrene (FG) in patients taking empagliflozin. Medsafe is reminding health professionals about the risk of these serious and sometimes life-threatening conditions in patients taking sodium-glucose co-transporter 2 (SGLT-2) inhibitors.^1,2

Empagliflozin and dapagliflozin are SGLT-2 inhibitors indicated for the treatment of type 2 diabetes mellitus and heart failure.^1,2 Both medicines are available as single-substance formulations (Jardiance, Forxiga) or in combination with metformin (Jardiamet, Xigduo XR). In addition to improving glycaemic control in patients with type 2 diabetes, SGLT-2 inhibitors slow kidney function decline and reduce the risk of cardiovascular death and hospitalisation in patients with heart failure.^1,2

Medsafe has requested updates to the empagliflozin and dapagliflozin data sheets.

The benefits of SGLT-2 inhibitors continue to outweigh the risks of harm.

Patients taking SGLT-2 inhibitors are at increased risk of diabetic ketoacidosis

DKA is a complication of diabetes and develops when insulin levels are insufficient to meet the body’s metabolic requirements.³ It is more common in patients with type 1 diabetes, but DKA can occur in patients with type 2 diabetes.³

DKA has also been reported as a rare adverse reaction to SGLT-2 inhibitors.^1,2 Individuals with SGLT-2 inhibitor-associated DKA may have normal or mildly elevated blood glucose (euglycaemic DKA).⁴

Advise patients to seek medical attention immediately if they are experiencing signs and symptoms of DKA, regardless of their blood glucose level.⁴ Symptoms may include nausea, vomiting, excessive thirst, abdominal pain and difficulty breathing.⁴

Discontinue SGLT-2 inhibitor treatment if DKA is suspected and follow local protocols for DKA treatment.⁴ If the patient developed DKA while taking an SGLT-2 inhibitor, do not restart treatment unless another clear precipitating factor is identified and resolved.⁵

Interrupt treatment with SGLT-2 inhibitors if patients have diabetic ketoacidosis risk factors

Factors that increase the risk of DKA in patients taking SGLT-2 inhibitors include a low carbohydrate diet, dehydration, acute illness, surgery, insulin deficiency from any cause, reduced caloric intake or increased insulin requirements.⁵

If patients taking SGLT-2 inhibitors also have DKA risk factors, consider monitoring for DKA and temporarily discontinuing treatment. Consider ketone monitoring, even if treatment has been interrupted, and follow local protocols.⁵

Interrupt treatment with SGLT-2 inhibitors in patients who are hospitalised for major surgical procedures.^5,6 During this time, patients may require increased doses of other glucose-lowering agents, plus ketone monitoring.^5-7 Restart treatment with SGLT-2 inhibitors only when the ketone values are normal, and the patient's condition has stabilised.⁷

Fournier’s gangrene and SGLT-2 inhibitors

FG is a rapidly progressive infection of the deep soft tissues, affecting the fascia planes in the perineal, perianal or genital areas. FG is also known as ‘necrotising fasciitis of the perineum and genitalia’.⁸

SGLT-2 inhibitors lower blood glucose by inhibiting glucose reabsorption in the renal tubule.^1,2 Subsequent glycosuria (glucose in the urine) can favour the growth of microorganisms,⁸ increasing the risk of urinary tract infections.⁵

Residual bacteria from ineffective cleaning of the anogenital area, coupled with high glucose content of the urine, can promote both urinary tract infections and localised infections. If the infection is not appropriately treated, the bacteria may infect the deeper soft tissues by breaching mucosal barriers or a break in the skin. Infection of these deep soft tissues may then progress to FG.⁸

Diabetes and SGLT-2 inhibitors are risk factors for Fournier’s gangrene 

FG typically affects males, but cases have been reported in females. Patients with comorbidities that affect cellular immunity or microcirculation are at increased risk of FG. Patients with diabetes are also at increased risk of FG, with diabetes present in 60% of FG cases.⁸

FG has also been reported with SGLT-2 inhibitors.^1,8 Patients treated with SGLT-2 inhibitors who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever or malaise should be evaluated promptly for FG.¹

Discontinue SGLT-2 inhibitor treatment immediately if FG is suspected.¹

Advise patients to watch out for Fournier’s gangrene

Advise patients to check the genital area regularly for signs or symptoms of FG and seek medical attention immediately if symptoms occur.^7,9 Encourage patients to maintain good genital hygiene.⁹

Consider managing other FG risk factors, such as smoking and obesity, and maintaining diabetes control.¹⁰

Medsafe recently published a consumer information leaflet (PDF, 248 KB, 2 pages) with information for patients about FG.

New Zealand case reports

As of 30 September 2022, CARM had received a total of 24 reports of DKA with empagliflozin. Of these, 22 reports were for empagliflozin, and 2 were for empagliflozin + metformin. The reports indicate that DKA can happen at any point during treatment. Euglycemic DKA was reported in several cases.

As of 30 September 2022, CARM had received a total of 6 reports of Fournier’s gangrene with empagliflozin. Of these reports, 4 were in males and 2 in females.

More information

See the sponsors’ data sheets and consumer medicine information (CMI) leaflets published on the Medsafe website.

• Search for a data sheet or CMI

For prescribers

• Prescriber Update December 2020: Spotlight on empagliflozin
• Prescriber Update September 2021: Empagliflozin: advise patients on the risk of ketoacidosis and Fournier’s gangrene

For patients

• Medsafe consumer information leaflet: Watch out for Fournier’s gangrene (infection) when taking SGLT2 inhibitors like empagliflozin (PDF, 248 KB, 2 pages).  Leaflets are also available in te reo Māori (PDF 193 KB, 2 pages) and Samoan (PDF 203 KB, 2 pages).
• Health Navigator medicine information: Empagliflozin . Factsheets are available in English, te reo Māori, Samoan, Tongan, Chinese (simplified), Chinese (traditional), Cook Islands Māori, Hindi, Niuean, Tokelauan and Tuvaluan. A video is also available in English, te reo Māori and New Zealand Sign Language (NZSL). 

References

1. Boehringer Ingelheim (NZ) Limited. 2022. Jardiance New Zealand Data Sheet 29 August 2022. URL: medsafe.govt.nz/profs/Datasheet/j/jardiancetab.pdf (accessed 31 October 2022).
2. AstraZeneca Limited. 2022. Forxiga New Zealand Data Sheet 18 July 2022. URL: medsafe.govt.nz/profs/Datasheet/f/forxigatab.pdf (accesssed 6 October 2022).
3. Hirsch IB and Emmett M. 2022. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: epidemiology and pathogenesis. In: UpToDate 18 July 2022. URL: uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-epidemiology-and-pathogenesis (accessed 5 October 2022).
4. New Zealand Formulary (NZF). 2022. NZF v124: Antidiabetic drugs 1 October 2022. URL: nzf.org.nz/nzf_3689 (accessed 6 October 2022).
5. Boehringer Ingelheim Pty Limited. 2022. Jardiance Australian Product Information 9 September 2022. URL: ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2014-PI-01783-1&d=20221017172310101 (accessed 4 October 2022).
6. New Zealand Society for the Study of Diabetes. 2020. Periprocedural diabetic Ketoacidosis (DKA) with SGLT2 inhibitor use January 2020. URL: diabetessociety.com.au/documents/ADS_DKA_SGLT2i_Alert_update_2020.pdf (accessed 4 October 2022).
7. Boehringer Ingelheim International GmbH. 2022. Jardiance EPAR Product Information – Annex I: Summary of Product Characteristics 9 September 2022. URL: ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_en.pdf (accessed 5 October 2022).
8. Singh A and Oakley A. 2022. Fournier gangrene. In: DermNet March 2022. URL: dermnetnz.org/topics/fournier-gangrene (accessed 5 October 2022).
9. Health Navigator New Zealand. 2022. Empagliflozin 12 October 2022. URL: healthnavigator.org.nz/medicines/e/empagliflozin/ (accessed 31 October 2022).
10. Ellegård L and Prytz M. 2020. Fournier's gangrene under SGLT-2 inhibitor therapy: a literature review and case report. International Journal of Surgery Case Reports 77: 692-4. DOI: 10.1016/j.ijscr.2020.11.100 (accessed 6 October 2022).