Sodium–glucose cotransporter-2 inhibitors in patients without diabetes
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* Elise Fryml
* Matthew B. Lanktree

## In patients without diabetes, sodium–glucose cotransporter-2 (SGLT2) inhibitors (or “flozins”) should be considered for moderate chronic kidney disease or clinical heart failure regardless of ejection fraction

Moderate chronic kidney disease includes an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2, regardless of urinary albumin-to-creatinine ratio (uACR) or eGFR of 45–90 mL/min/1.73 m2 with uACR higher than 25 mg/mmol.1–3 Sodium–glucose cotransporter-2 inhibitors reduce the relative risk of kidney disease progression by 37% and cardiovascular death or hospital admission for heart failure by 23%, with similar effects in patients with or without diabetes.3

## Benefits of SGLT2 inhibitors include improved blood pressure, albuminuria and weight loss

Within 12 weeks, systolic blood pressure is reduced by 5 mm Hg, uACR by 30% and weight by 2 kg.4

## Testing eGFR is not required after starting SGLT2 inhibitors except in patients at risk of volume depletion (i.e., orthostatic hypotension, high-dose diuretics)5

An acute 10%–30% reduction in eGFR occurs in the first month after starting SGLT2 inhibitors and is not cause for concern.5 Study patients who were prescribed SGLT2 inhibitors were also taking standard-of-care medications including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

## Women are 2–3 times more likely than men to have a genital mycotic infection while taking SGLT2 inhibitors

Mycotic (yeast) infection affects 3%–7% of women who take these agents. A previous yeast infection or development of one during treatment are not contraindications to SGLT2 inhibitors. Counselling regarding symptoms, personal hygiene and prescription of single-dose oral fluconazole is recommended.1,2

## No cases of severe hypoglycemia or euglycemic diabetic ketoacidosis were reported in SGLT2 inhibitor clinical trials that included 5877 patients without diabetes2

Despite initial concerns, a meta-analysis of 10 trials also did not identify an increase in serious urinary tract infections, Fournier gangrene or lower limb amputations.2 Withholding of SGLT2 inhibitors is recommended if the patient is fasting or unwell.

## Footnotes

*   **Competing interests:** Matthew Lanktree has received speaking fees from Otsuka and advisory board fees from Bayer, Otsuka, Reata and Sanofi. Speaking and advisory board fees were unrelated to SGLT2 inhibitors. No other competing interests were declared.

*   This article has been peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: [https://creativecommons.org/licenses/by-nc-nd/4.0/](https://creativecommons.org/licenses/by-nc-nd/4.0/)

## References

1.  Mancini GBJ, O’Meara E, Zieroth S, et al. 2022 Canadian Cardiovascular Society guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults. Can J Cardiol 2022;38:1153–67.
    
    

2.  Herrington WG, Frankel AH, Wonnacott A, et al. UK kidney association clinical practice guideline: sodium-glucose cotransporter-2 (SGLT-2) inhibition in adults with kidney disease. Bristol (UK): UK Kidney Association; 2021. Available: [https://ukkidney.org/sites/renal.org/files/UKKA%20guideline_SGLT2i%20in%20adults%20with%20kidney%20disease%20v1%2020.10.21.pdf](https://ukkidney.org/sites/renal.org/files/UKKA%20guideline_SGLT2i%20in%20adults%20with%20kidney%20disease%20v1%2020.10.21.pdf) (accessed 2023 March 20).
    
    

3.  Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 2022;400:1788–801.
    
    

4.  Teo YH, Teo YN, Syn NL, et al. Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus: a systematic review and meta-analysis of randomized-controlled trials. J Am Heart Assoc 2021;10:e019463.
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fcmaj%2F195%2F17%2FE619.atom) 

5.  Heerspink HJL, Cherney DZI. Clinical implications of an acute dip in eGFR after SGLT2 inhibitor initiation. Clin J Am Soc Nephrol 2021;16:1278–80.
    
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