Skip to main content

Bittersweet: infective complications of drug-induced glycosuria in patients with diabetes mellitus on SGLT2-inhibitors: two case reports

Abstract

Background

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel hypoglycemic agents which reduce reabsorption of glucose at the renal proximal tubule, resulting in significant glycosuria and increased risk of genital mycotic infections (GMI). These infections are typically not severe as reported in large systematic reviews and meta-analyses of the medications. These reviews have also demonstrated significant cardiovascular benefits through other mechanisms of action, making them attractive options for the management of Type 2 diabetes mellitus (T2DM). We present two cases with underlying abnormalities of the urogenital tract in which the GMI were complicated and necessitated cessation of the SGLT2 inhibitor.

Case presentations

Both cases are patients with T2DM on empagliflozin, an SGLT2 inhibitor. The first case is a 64 year old man with Candida albicans balanitis and candidemia who was found to have an obstructing renal calculus and prostatic abscess requiring operative management. The second case describes a 72 year old man with Candida glabrata candidemia who was found to have prostatomegaly, balanitis xerotica obliterans with significant urethral stricture and bladder diverticulae. His treatment was more complex due to fluconazole resistance and concerns about urinary tract penetration of other antifungals. Both patients recovered following prolonged courses of antifungal therapy and in both cases the SGLT2 inhibitor was ceased.

Conclusions

Despite their cardiovascular benefits, SGLT2 inhibitors can be associated with complicated fungal infections including candidemia and patients with anatomical abnormalities of the urogenital tract may be more susceptible to these infections as demonstrated in these cases. Clinicians should be aware of their mechanism of action and associated risk of infection and prior to prescription, assessment of urogenital anatomical abnormalities should be performed to identify patients who may be at risk of complicated infection.

Peer Review reports

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel oral hypoglycemic agents which inhibit the re-uptake of filtered sodium and glucose at the proximal convoluted tubule. Large drug efficacy trials have found substantial improvement in glycemic control, weight loss, a reduction in blood pressure and cardiovascular mortality; so, are an attractive option for the management of Type 2 diabetes mellitus (T2DM) [1,2,3,4,5,6].

SGLT2 inhibitors cause significant glycosuria, associated with a nearly five-fold increased risk of genital mycotic infections (GMI; balanitis in men and vulvovaginitis in women) [4]. We describe two cases of candidemia secondary to GMI in patients on SGLT2 inhibitors, which led to significant morbidity and the subsequent discontinuation of the SGLT2 inhibitor.

Case presentations

A 64-year-old man with T2DM, managed with empagliflozin 10mg daily, which had been commenced 2 years prior, metformin and sitagliptin, presented to the emergency department with progressive lethargy, fevers and dysuria. The symptoms had progressed despite receiving 5 days of oral cephalexin a few weeks prior following collection of a urine sample which grew Candida albicans alone. On examination, he was febrile (39.6°C), tachycardic (108 beats per minute) and hypotensive (87/55 mmHg) and blood sugar level (BSL) was measured at 39mmol/L (702mg/dL). Examination revealed balanoposthitis but was otherwise unremarkable.

Initial investigations showed significantly raised inflammatory markers: C-reactive protein (CRP) of 287mg/L, total white blood cell count (WCC) of 32.1 × 109/L with a predominant neutrophilia of 28.2 × 109/L and acute kidney injury with serum creatinine 208μmol/L (CrCl 28ml/min). HbA1C was 11.0% (< 5.7%) and prostate specific antigen (PSA) 2.76mcg/L (< 4.51mcg/L).

He was transferred to the intensive care unit (ICU) for inotropic support; 24 h into his admission a yeast was identified from two sets of blood cultures and he was commenced on intravenous (IV) anidulafungin. Candida albicans was subsequently isolated from blood, urine and urethral swab cultures. The minimum inhibitory concentration (MIC) for fluconazole was < 0.05μg/L (susceptible) and he was changed to IV fluconazole 400mg daily.

An abdomino-pelvic computed tomography scan demonstrated right-sided emphysematous pyelonephritis, a 7mm non-obstructing calculus in the right renal pelvis, a large (57x43x65mm) bladder diverticulum and emphysematous prostatitis. As he remained candidemic, repeat imaging on day 7 demonstrated gas in the prostate and that the renal calculus had migrated to the proximal ureter causing acute obstruction necessitating the urgent insertion of a nephrostomy tube. On day 12 he underwent anterograde ureteric stent insertion. A transperineal ultrasound on day 13 confirmed the presence of a prostatic abscess requiring cystoscopy, transurethral drainage of the prostatic abscess and transurethral resection of the prostate. Culture of the abscess grew C. albicans (fluconazole MIC < 0.05μg/L). Transesophaegeal echocardiography and ophthalmological examination were normal. The SGLT2 inhibitor was ceased and he was discharged home on oral fluconazole 400mg daily with an indwelling urinary catheter (IDC).

Three weeks later whilst still on fluconazole, he had an episode of fever and right flank pain. The renal calculus, stent and catheter were removed. He received a total of 6 weeks of fluconazole and recovered.

A 72-year-old man presented emergently to hospital after having driven his car into a concrete barrier at low speed. He was febrile and confused. He had a history of T2DM, managed with metformin and empagliflozin 10mg daily; the latter prescribed only 2 months prior. Examination did not reveal any injury sustained from the collision; however, it was significant for balanitis with a tender prostate and he was in acute urinary retention. BSL was significantly raised at 22.2mmol/L (400mg/dL).

Investigations revealed a CRP of 261mg/L, total WCC of 14.4 × 109/L with a neutrophilia (13.4 × 109/L), acute kidney injury with serum creatinine 113μmol/L (CrCl 55mL/min). HbA1C was 9.0% (< 5.7%) and PSA was 8.8mcg/L (< 4.51mcg/L). Blood cultures grew a yeast at 36 h and the patient was commenced empirically on IV caspofungin. The yeast was identified as Candida glabrata; urine and urethral swab specimens were also culture positive for C. glabrata. For all isolates the same susceptibility profile was observed, with a fluconazole MIC of 128μg/L (resistant). Susceptibility was confirmed to caspofungin (MIC 0.06μg/L), 5- flucytosine (MIC ≤0.06μg/L) and amphotericin B (MIC 0.5μg/L). Blood culture clearance occurred after 48 h of caspofungin.

A renal tract ultrasound demonstrated prostatic enlargement, bladder diverticulae and an elevated post-void residual volume (>300mls). On day 5 of his admission, he underwent rigid cystoscopy and urethral dilatation with the significant findings of a pinpoint meatal urethral stricture, glandular adhesions and balanitis xerotica obliterans. During the procedure an IDC was inserted to relieve the bladder outlet obstruction. Transthoracic echocardiogram and ophthalmological examination were normal.

Caspofungin was changed to micafungin 100mg IV daily. Fluconazole was added and the dose was reduced from 1200mg (10mg/kg) to 800mg daily due to QTc prolongation. 5-flucytosine 25mg/kg QID was added. He received a total of 4 weeks treatment with clinical and microbiological cure. The SGLT2 inhibitor was ceased.

Discussion & Conclusions

SGLT2 inhibitors are selective membrane transport inhibitors which act on the proximal convoluted tubule and prevent glucose and sodium absorption back into the circulation resulting in glycosuria. In a randomised, placebo-controlled trial in patients taking varying doses of empagliflozin, urinary glucose excretion reached up to 90g/day [1]. The average daily volume of urine excreted by participants was 3 l equating to a urinary glucose concentration of 30g/L, roughly equivalent to that of Sabouraud agar, the preferred growth medium for optimal yeast culture including Candida species providing a biologically plausible explanation for the observed increased risk of GMI.

Patients with T2DM are more likely to have genital tract colonisation with Candida spp [7] and the risk of GMI is higher in patients with diabetes. In a population-based study, in the UK, diabetic women had a risk ratio of 1.81 (95% CI 1.64–2.0) for vaginitis and men had a risk ratio of 2.85 (2.84–4) for balanitis compared with those without diabetes [7]. A number of systematic reviews and meta-analyses, to date, have shown a 4- to 8-fold increased risk of GMI in patients taking SGLT2 inhibitors compared with placebo or other hypoglycemic agents [2,3,4,5,6, 8]. Mechanisms for this increased risk include increased adherence of Candida to the genital tract and reduced host immune response in patients with T2DM [9]. This, combined with the further increase in glycosuria in patients on SGLT2 inhibitor therapy and pre-existing anatomical abnormalities of the urogenital tract may predispose to complicated urinary tract infection (UTI).

The U.S. Food and Drug Administration (FDA) issued a warning about the risk of complicated UTI in patients taking SGLT2 inhibitors in 2015 after 19 cases of complicated UTI were reported from March 2013 through October 2014. In contrast, a large population-based cohort study found no increased risk of serious UTI in patients taking an SGLT2 inhibitor compared with other hypoglycemic agents. However, this study excluded patients with higher risk of UTI (including those with anatomical abnormalities such as prostatomegaly and obstructive defects of the renal pelvis and ureter including calculi) [10]. In patients with a higher predisposition for severe UTI, complications can include candidemia which is associated with up to 47% mortality, endophthalmitis and endocarditis [11].

Duration of therapy for fungal prostatic abscess and candidemia from a urinary tract source are not well-defined. These two cases were treated for 4–6 weeks. Case 1 had prolonged candidemia until source control (abscess drainage) was achieved. It has been reported that successful treatment of Candida prostatitis has been achieved with micafungin when paired with surgical drainage [12]. Case 2 highlights the potential challenges in treating fluconazole-resistant Candida spp infection from a urinary tract source.

Fluconazole is the usual drug of choice for Candida UTI [11, 13, 14]. It is mostly eliminated unchanged (80%) in the urine resulting in urinary concentrations that are 10–20 times that of plasma (levels >100μg/ml) [11, 13, 14]. Therefore, urinary concentrations are able to exceed MIC for susceptible but dose dependent (MIC 16-32μg/mL) and even resistant (MIC >64μg/mL) isolates. Higher dosing of fluconazole (12mg/kg) is often recommended for the treatment of susceptible C. glabrata infections; however, there are limited clinical data to support this advice [14,15,16]. Other azoles (e.g. posaconazole, voriconazole) are minimally excreted in the urine and therefore not recommended [11, 14]. Flucytosine has broad anti-fungal activity and excellent oral bioavailability, is mostly excreted unchanged in urine (97%) and similarly achieves high urinary concentrations (~ 60 times that of plasma) [11, 14, 16]. It is usually given in combination as resistance can develop when it is used as monotherapy; due to its short half-life it is dosed at 25mg/kg 4 times daily and therapeutic drug monitoring is recommended (as in case 2) [11, 14, 16]. There is emerging evidence that echinocandins, particularly micafungin, can achieve adequate clinical efficacy when correlated with PK/PD ratios [17]; and in the treatment of candidemia from a urinary tract source, similar outcomes have been achieved with echinocandins compared with fluconazole [18]. Case 2 was thus treated with a combination of high dose fluconazole plus flucytosine for optimal penetration into the urinary tract, with the addition of micafungin due to the severity of the infection.

SGLT2 inhibitors are prescribed more frequently in T2DM due to their favorable cardiovascular outcomes. However, as demonstrated in these cases, there appears to be an associated increased risk of complicated fungal infection in patients with underlying abnormalities of the urogenital tract. We suggest that prior to the prescription of SGLT2 inhibitors, urogenital abnormalities should be identified and treated. The risks and benefits of these medications should be discussed with the patient and alternate hypoglycemic agents considered if the risk of GMI is considered to outweigh the benefits.

Availability of data and materials

Not applicable.

Abbreviations

SGLT2:

Sodium-glucose co-transporter 2

GMI:

Genital mycotic infections

T2DM:

Type 2 diabetes mellitus

BSL:

Blood sugar level

CRP:

C-reactive protein

WCC:

White blood cell count

CrCl:

Creatinine clearance

HbA1c:

Glycated haemoglobin

PSA:

Prostate specific antigen

ICU:

Intensive care unit

IV:

Intravenous

MIC:

Minimum inhibitory concentration

IDC:

Indwelling catheter

QTc:

Corrected QT interval

UTI:

Urinary tract infection

References

  1. 1.

    Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, Woerle HJ. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(7):613–21. https://doi.org/10.1111/dom.12073.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    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(5):457–66. https://doi.org/10.1111/dom.12244.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783–94. https://doi.org/10.1111/dom.12670.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Storgaard H, Gluud LL, Bennett C, Grøndahl MF, Christensen MB, Knop FK, Vilsbøll T. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2016;11(11):e0166125. https://doi.org/10.1371/journal.pone.0166125.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319(15):1580–91. https://doi.org/10.1001/jama.2018.3024.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–306. https://doi.org/10.1056/NEJMoa1811744.

    CAS  Article  Google Scholar 

  7. 7.

    Hirji I, Andersson SW, Guo Z, Hammar N, Gomez-Caminero A. Incidence of genital infection among patients with type 2 diabetes in the UK general practice research database. J Diabetes Complicat. 2012;26(6):501–5. https://doi.org/10.1016/j.jdiacomp.2012.06.012.

    Article  Google Scholar 

  8. 8.

    Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin. 2012;28(7):1173–8. https://doi.org/10.1185/03007995.2012.697053.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A, Patorno E. Sodium-glucose cotransporter 2 inhibitors and the risk of severe urinary tract infection. Ann Intern Med. 2019;171(4):248–56. https://doi.org/10.7326/M18-3136.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Pappas PG, Kaufmann CA, Andes DR, et al. Clinical guideline for the Management of Candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50. https://doi.org/10.1093/cid/civ933.

    Article  PubMed  Google Scholar 

  12. 12.

    Gupta S, Liu-Young G, Mahnensmith R, Topal JE. Prostatic abscess with Candida glabrata treated with Micafungin. Infect Dis Clin Pract. 2008;16(6):387–9. https://doi.org/10.1097/IPC.0b013e31816613f1.

    Article  Google Scholar 

  13. 13.

    Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014;27(1):68–88. https://doi.org/10.1128/CMR.00046-13.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Fisher JF, Sobel JD, Kauffman CA, Newman CA. Candida urinary tract infections – treatment. Clin Infect Dis. 2011;52(suppl 6):457–66.

    Article  Google Scholar 

  15. 15.

    Walsh TJ, Foulds G, Pizzo PA. Pharmacokinetics and tissue penetration of fluconazole in rabbits. Antimicrob Agents Chemother. 1989;33(4):467–9. https://doi.org/10.1128/AAC.33.4.467.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Pfaller MA, Diekama DJ, Sheehan DJ. Interpretive breakpoints for fluconazole and Candida revisited: a blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev. 2006;19(2):435–47. https://doi.org/10.1128/CMR.19.2.435-447.2006.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Grau S, Luque S, Echeverria-Esnal D, et al. Urinary micafungin levels are sufficient to treat urinary tract infections caused by Candida spp. Int J Antimicrob Agents. 2016;48(2):212–4. https://doi.org/10.1016/j.ijantimicag.2016.05.010.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Cuervo G, Garcia-Vidal C, Puig-Asensio M, et al. Echinocandins compared to fluconazole for Candidemia of a urinary tract source: a propensity score analysis. Clin Infect Dis. 2017;64(10):1374–9.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The authors received no financial support for the research, authorship or publication of this article.

Author information

Affiliations

Authors

Contributions

CB, VH, & CL wrote the case presentations. CB, VH & NDF were the major contributors to the discussion. NDF & EA were involved in the clinical management of Case 1. AF and COM were involved in the clinical management of Case 2. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Caroline Bartolo or Victoria Hall.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Both patients have provided written consent for publication and this can be provided if requested by the editors.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bartolo, C., Hall, V., Friedman, N.D. et al. Bittersweet: infective complications of drug-induced glycosuria in patients with diabetes mellitus on SGLT2-inhibitors: two case reports. BMC Infect Dis 21, 284 (2021). https://doi.org/10.1186/s12879-021-05982-3

Download citation

Keywords

  • Candidemia
  • SGLT2 inhibitor
  • Glycosuria
  • Case report
  • Genital mycotic infection
  • Prostatic abscess