Dear Sirs,
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors (dapagliflozin, empagliflozin, canagliflozin) are increasingly being prescribed in the primary-care setting for cardiovascular indications. SGLT2 inhibitors have been found to reduce the risk of all-cause mortality, heart failure (HF) hospitalisations and cardiovascular death in a wide range of HF patients.1
Many randomised-controlled clinical trials (RCTs), such as DAPA-HF, DELIVER, EMPEROR-Preserved, EMPEROR-Reduced and CREDENCE trials have been conducted, using the different SGLT2 inhibitors, and have reported increased positive outcomes in the HF population.1–6
The mechanism(s) behind the cardiovascular protective effects by SGLT2 inhibitors remains unclear. Pleiotropic effects have been suggested; other plausible mechanisms include improved glycaemic control, reduced albuminuria, reduced blood pressure and amelioration of fluid overload.7 However, the increased use of this class of medications should be undertaken with awareness of the potential safety issues.
Medicines and Healthcare products Regulatory Agency (MHRA) have highlighted potential safety issues associated with prescribing SGLT2 inhibitors.8-10 The following is a brief summary of the safety issues:
- Risk of diabetic ketoacidosis (DKA): the European Medicines Agency reported that fatal cases of DKA have been reported, albeit rarely, in patients taking SGLT2 inhibitors. The presentation was atypical with blood glucose levels ranging from normal to moderately elevated.
- Risk of lower limb amputations (mainly toes): MHRA advises to stop canagliflozin in patients who develop lower limb ulcers or gangrene, and carefully monitor patients who have risk factors for amputation. This is currently not identified as a risk in dapagliflozin and empagliflozin.
- Risk of Fournier’s gangrene (necrotising fasciitis of genitalia or perineum): a rare, potentially life-threatening infection in patients taking SGLT2 inhibitors. If suspected, immediately discontinue the medication.
Other common reported side effects include: balanoposthitis, dyslipidaemia, hypoglycaemia (in combination with insulin or sulfonylurea), increased risk of infection, urinary disorders, vulvovaginal disorders and transient decline in renal function (reversible after stopping treatment).11,12
Despite RCT data on safety and tolerability of SGLT2 inhibitor use being reassuring in HF, we strongly feel that awareness of the possible adverse effects (including the risk of lower limb amputation and renal adverse events) is useful for physicians in primary and secondary care settings. Overall, SGLT2 inhibitors are promising drugs to consider in HF management. But we strongly recommend physicians take into account possible safety issues when prescribing SGLT2 inhibitors with appropriate patient discussion prior to initiation.
Ismail Sooltan
Internal Medicine Trainee
([email protected])
Sudantha Bulugahapitiya
Cardiology Consultant
Bradford Teaching Hospitals NHS Foundation Trust, Bradford, Duckworth Lane, BD9 6RJ
Firuza Dzhakhangirli
Internal Medicine Trainee
Leeds Teaching Hospitals NHS Trust, Beckett Street, LS9 7TF
Rajib Haque
Foundation Year 2 Trainee
Calderdale and Huddersfield NHS Foundation Trust, Acre Street, Huddersfield, HD3 3EA
Conflicts of interest
None declared.
Funding
None.
References
1. Cardoso R, Graffunder FP, Ternes CMP et al. SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: a systematic review and meta-analysis. EClinicalMedicine 2021;36:100933. https://doi.org/10.1016/j.eclinm.2021.100933
2. McMurray JJV, Solomon SD, Inzucchi SE et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303
3. Solomon SD, McMurray JJV, Claggett B et al.; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089–98. https://doi.org/10.1056/NEJMoa2206286
4. Anker SD, Butler J, Filippatos G et al.; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038
5. Packer M, Anker SD, Butler J et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190
6. Perkovic V, Jardine MJ, Neal B et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744
7. Lee S. Renal effects of SGLT2 inhibitors and potential clinical implications: beyond the heart. Int J Heart Fail 2022;4:177–9. https://doi.org/10.36628/ijhf.2022.0017
8. UK Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis. London: MHRA, 2016. Available from: https://www.gov.uk/drug-safety-update/sglt2-inhibitors-updated-advice-on-the-risk-of-diabetic-ketoacidosis [accessed November 2023].
9. UK Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors: updated advice on increased risk of lower-limb amputation (mainly toes). London: MHRA, 2017. Available from: https://www.gov.uk/drug-safety-update/sglt2-inhibitors-updated-advice-on-increased-risk-of-lower-limb-amputation-mainly-toes [accessed November 2023].
10. UK Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum). London: MHRA, 2019. Available from: https://www.gov.uk/drug-safety-update/sglt2-inhibitors-reports-of-fournier-s-gangrene-necrotising-fasciitis-of-the-genitalia-or-perineum [accessed November 2023].
11. McGill JB, Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors. Am J Cardiol 2019;124(suppl 1):S45–S52. https://doi.org/10.1016/j.amjcard.2019.10.029
12. Halimi S, Vergès B. Adverse effects and safety of SGLT-2 inhibitors. Diabetes Metab 2014;40(6 suppl 1):S28–S34. https://doi.org/10.1016/S1262-3636(14)72693-X
