Risk of urogenital infections in non-diabetic patients treated with sodium glucose transporter 2 (SGLT2) inhibitors. Systematic review and meta-analysis

Published: June 13, 2023
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Although SGLT2 inhibitors have been initially employed in the treatment of type 2 diabetes, their clinical use was later extended to the treatment of other conditions such as heart failure, chronic kidney disease and obesity. In patients with type 2 diabetes, the administration of SGLT2 inhibitors has been associated with an increased incidence of urogenital infections, which may be linked to high glucose levels in the urine. The rate of urogenital side effects may be different in non-diabetic patients. The aim of this study was to review the risk of urogenital infections in non-diabetic patients taking SGLT2 inhibitors. Materials and methods: We conducted a systematic review and meta-analysis by searching PubMed and EMBASE for randomized controlled trials (RCTs) reporting urogenital adverse effects in non-diabetic patients treated with SGLT2 inhibitors. Odds ratios for urogenital infections were calculated using random effect Mantel-Haenszel statistics. Results: Out of 387 citations retrieved, 12 eligible RCTs were assessed for risk of bias and included in the meta-analysis. Compared to placebo, SGLT2 inhibitors were associated with increased odds of genital infections (OR 3.01, 95% CI: 1.93- 4.68, 9 series, 7326 participants, Z = 5.74, p < 0.0001, I2 = 0%) as well as urinary tract infections (OR 1.33, 95% CI: 1.13-1.57, 9 series, 7326 participants, Z = 4.05, p < 0.0001, I2 = 0%). When four trials investigating the effects of SGLT2 inhibitors in populations including both diabetic and non-diabetic patients were considered, administration of SGLT2 inhibitors in diabetic patients was associated with significantly higher odds of genital infections but not urinary tract infections compared to patients without type 2 diabetes. In patients taking placebo, the odds for urinary tract infections were significantly increased in diabetic patients compared to non-diabetic patients. Conclusions: The risk of genital infections is increased also in non-diabetic patients taking SGLT2 inhibitors although at a lesser extent that in diabetics. A careful assessment of the local anatomical conditions and of the history of previous urogenital infections is desirable to select those patients who need more intense follow-up, possibly combined with prophylactic measures of infections during treatment with SGLT2 inhibitors.

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Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014; 16:457-66. DOI: https://doi.org/10.1111/dom.12244
Butler J, Usman MS, Khan MS, et al. Efficacy and safety of SGLT2 inhibitors in heart failure: systematic review and meta-analysis. ESC Heart Fail. 2020; 7:3298-3309. DOI: https://doi.org/10.1002/ehf2.13169
Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018; 20:479-487. DOI: https://doi.org/10.1111/dom.13126
Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. DAPACKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020; 383:1436-1446. DOI: https://doi.org/10.1056/NEJMoa2024816
Zheng H, Liu M, Li S, et al. Sodium-Glucose Co-Transporter-2 Inhibitors in Non-Diabetic Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2021; 12:706914. DOI: https://doi.org/10.3389/fendo.2021.706914
Puckrin R, Saltiel MP, Reynier P, et al. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 2018; 55:503-514. DOI: https://doi.org/10.1007/s00592-018-1116-0
Li D, Wang T, Shen S, et al. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017; 19:348-355. DOI: https://doi.org/10.1111/dom.12825
Moher D, Liberati A, Tetzlaff J, et al. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009; 6:e1000097. DOI: https://doi.org/10.1371/journal.pmed.1000097
Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366:l4898. DOI: https://doi.org/10.1136/bmj.l4898
Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring). 2014; 22:1042-9. DOI: https://doi.org/10.1002/oby.20663
Hollander P, Bays HE, Rosenstock J, et al. Coadministration of Canagliflozin and Phentermine for Weight Management in Overweight and Obese Individuals Without Diabetes: A Randomized Clinical Trial. Diabetes Care. 2017; 40:632-639. DOI: https://doi.org/10.2337/dc16-2427
Lundkvist P, Pereira MJ, Katsogiannos , et al. Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes Obes Metab. 2017; 19:1276-1288. DOI: https://doi.org/10.1111/dom.12954
Cherney DZI, Dekkers CCJ, Barbour SJ, et al. DIAMOND investigators. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol. 2020; 8:582-593. DOI: https://doi.org/10.1016/S2213-8587(20)30162-5
Reis J, Teixeira AR, Gonçalves AV, et al. Dapagliflozin Impact on the Exercise Capacity of Non-Diabetic Heart Failure with Reduced Ejection Fraction Patients. J Clin Med. 2022; 11:2935. DOI: https://doi.org/10.3390/jcm11102935
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; 385:1451-1461 DOI: https://doi.org/10.1056/NEJMoa2107038
Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J. 2021; 42:700-710. DOI: https://doi.org/10.1093/eurheartj/ehaa943
The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023; 388:117-127. DOI: https://doi.org/10.1056/NEJMoa2204233
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. DOI: https://doi.org/10.1056/NEJMoa1911303
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; 383:1413-1424. DOI: https://doi.org/10.1056/NEJMoa2022190
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; 387:1089-1098. DOI: https://doi.org/10.1056/NEJMoa2206286
Wheeler DC, Stefánsson BV, Jongs N, et al. DAPA-CKD Trial Committees and Investigators. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021; 9:22-31. DOI: https://doi.org/10.1016/S2213-8587(20)30369-7
Anker SD, Butler J, Filippatos G, et al. Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial. Circulation. 2021; 143:337-349. DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.051824
https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/810/. Nutzenbewertungsverfahren zum Wirkstoff Empagliflozin (Neues Anwendungsgebiet: chronische Herzinsuffizienz mit linksventrikulärer Ejektionsfraktion LVEF > 40 %) - Gemeinsamer Bundesausschuss (g-ba.de)
Fünfstück R, Nicolle LE, Hanefeld M, Naber KG. Urinary tract infection in patients with diabetes mellitus. Clin Nephrol. 2012; 77:40-8. DOI: https://doi.org/10.5414/CN107216
Nicolle LE, Capuano G, Fung A, Usiskin K. Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad Med. 2014; 126:7-17.
Geerlings SE, Brouwer EC, Gaastra W, et al. Effect of glucose and pH on uropathogenic and non-uropathogenic Escherichia coli: studies with urine from diabetic and non-diabetic individuals. J Med Microbiol. 1999; 48:535-539. DOI: https://doi.org/10.1099/00222615-48-6-535
Turan H, Serefhanoglu K, Torun AN, et al. Frequency, risk factors, and responsible pathogenic microorganisms of asymptomatic bacteriuria in patients with type 2 diabetes mellitus. Jpn J Infect Dis. 2008; 61:236-8. DOI: https://doi.org/10.7883/yoken.JJID.2008.236
Geerlings SE, Stolk RP, Camps MJ, et al. Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group. Diabetes Care. 2000; 23:744-9. DOI: https://doi.org/10.2337/diacare.23.6.744
Geerlings SE, Stolk RP, Camps MJ, et al. Diabetes Women Asymptomatic Bacteriuria Utrecht Study Group. Risk factors for symptomatic urinary tract infection in women with diabetes. Diabetes Care. 2000; 23:1737-41. DOI: https://doi.org/10.2337/diacare.23.12.1737
Nicolle LE, Capuano G, Fung A, Usiskin K. Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad Med. 2014; 126:7-17. DOI: https://doi.org/10.3810/pgm.2014.01.2720
Gunther LS, Martins HP, Gimenes F, et al. Prevalence of Candida albicans and non-albicans isolates from vaginal secretions: comparative evaluation of colonization, vaginal candidiasis and recurrent vaginal candidiasis in diabetic and non-diabetic women. Sao Paulo Med J. 2014; 132:116-20. DOI: https://doi.org/10.1590/1516-3180.2014.1322640
Ciurea CN, Kosovski IB, Mare AD, et al. Candida and Candidiasis-Opportunism Versus Pathogenicity: A Review of the Virulence Traits. Microorganisms. 2020; 8:857. DOI: https://doi.org/10.3390/microorganisms8060857
Mukaremera L, Lee KK, Mora-Montes HM, Gow NAR. Candida albicans Yeast, Pseudohyphal, and Hyphal Morphogenesis Differentially Affects Immune Recognition. Front Immunol. 2017; 8:629. DOI: https://doi.org/10.3389/fimmu.2017.00629
Nikou SA, Kichik N, Brown R, et al. Candida albicans Interactions with Mucosal Surfaces during Health and Disease. Pathogens. 2019; 8:53. DOI: https://doi.org/10.3390/pathogens8020053
Rodrigues CF, Rodrigues ME, Henriques M. Candida sp. Infections in Patients with Diabetes Mellitus. J Clin Med. 2019; 8:76. DOI: https://doi.org/10.3390/jcm8010076
Van Ende M, Wijnants S, Van Dijck P. Sugar Sensing and Signaling in Candida albicans and Candida glabrata. Front Microbiol. 2019; 10:99. DOI: https://doi.org/10.3389/fmicb.2019.00099
Chandra J, Kuhn D, Mukherjee P, et al. Biofilm formation by the fungal pathogen Candida albicans: Development, architecture, and drug resistance. J. Bacteriol. 2001; 183:5385-5394. DOI: https://doi.org/10.1128/JB.183.18.5385-5394.2001
Talapko J, Meštrovic T, Škrlec I. Growing importance of urogenital candidiasis in individuals with diabetes: A narrative review. World J Diabetes. 2022; 13:809-821. DOI: https://doi.org/10.4239/wjd.v13.i10.809
Mikamo H, Yamagishi Y, Sugiyama H, et al. High glucose-mediated overexpression of ICAM-1 in human vaginal epithelial cells increases adhesion of Candida albicans. J Obstet Gynaecol. 2018; 38:226-230. DOI: https://doi.org/10.1080/01443615.2017.1343810
Calvet HM, Yoshikawa TT. Infections in diabetes. Infect. Dis. Clin. N. Am. 2001; 15:407-421. DOI: https://doi.org/10.1016/S0891-5520(05)70153-7
Alexander JT, Staab EM, Wan W, et al. Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis. J Gen Intern Med. 2022; 37:439-448. DOI: https://doi.org/10.1007/s11606-021-07227-0
Yokoyama H, Nagao A, Watanabe S, Honjo J. Incidence and risk of vaginal candidiasis associated with sodium-glucose cotransporter 2 inhibitors in real-world practice for women with type 2 diabetes. J Diabetes Investig. 2019; 10:439-445. DOI: https://doi.org/10.1111/jdi.12912
Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases
urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011; 13:669-672. DOI: https://doi.org/10.1111/j.1463-1326.2011.01406.x
Sarich T, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, increases 24-hour urinary glucose excretion and reduces body weight in obese subjects over 2 weeks of treatment. Diabetologia. 2010; 53(Suppl. 1):S349-S350.
Novak LM, Kruger DF. Bolstering your armamentarium with SGLT2 inhibitors. Nurse Pract. 2017; 42:28-34. DOI: https://doi.org/10.1097/01.NPR.0000524665.16846.63
Rieg T, Masuda T, Gerasimova M, et al. Increase in SGLT1- mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014; 306:F188-93. DOI: https://doi.org/10.1152/ajprenal.00518.2013
Nagata T, Fukazawa M, Honda K, et al. Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats. Am J Physiol Endocrinol Metab. 2013; 304:E414-23. DOI: https://doi.org/10.1152/ajpendo.00545.2012
Staplin N, Roddick AJ, Emberson J, et al. Net effects of sodiumglucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials. EClinicalMedicine. 2021; 41:101163. DOI: https://doi.org/10.1016/j.eclinm.2021.101163
McGovern AP, Hogg M, Shields BM, et al. MASTERMIND consortium. Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation. BMJ Open Diabetes Res Care. 2020; 8:e001238. DOI: https://doi.org/10.1136/bmjdrc-2020-001238
Cooke G, Watson C, Deckx L, et al. Treatment for recurrent vulvovaginal candidiasis (thrush) Cochrane Database Syst Rev. 2022; 1:CD009151. DOI: https://doi.org/10.1002/14651858.CD009151.pub2

How to Cite

Bapir, R., Bhatti, K. H., Eliwa, A., García-Perdomo, H. A., Gherabi, N., Hennessey, D., Magri, V., Mourmouris, P., Ouattara, A., Perletti, G., Philipraj, J., Stamatiou, K., Tolani, M. A., Tzelves, L., Anker, S. D., Trinchieri, A., & Buchholz, N. (2023). Risk of urogenital infections in non-diabetic patients treated with sodium glucose transporter 2 (SGLT2) inhibitors. Systematic review and meta-analysis. Archivio Italiano Di Urologia E Andrologia, 95(2). https://doi.org/10.4081/aiua.2023.11509