CME INDIA Presentation by Dr. N.K. Singh, MD, FICP, Director, Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in.

Based on a presentation at ADC-Bengaluru on 27th May 2023.

• Genitourinary infections are quite common among diabetic patients.
• Some studies suggest that the use of SGLT2 inhibitors further increases this potential risk.
• As use of SGLT2i is expected to rise more and more in future, it is need of the time to be aware about GTI/UTI issues.

SGLT2 inhibitors results in glycosuria

• Urinary glucose excretion reaches up to 90g/day.
• The average daily volume of urine excreted equates to a urinary glucose concentration of 30g/L.
• It is roughly equivalent to that of Sabouraud agar, the preferred growth medium for optimal yeast culture including Candida species.
• So, it provides a biologically plausible explanation for the observed increased risk of GMI.
• It’s important to note that while the increased risk of GMI is a known side effect of SGLT2 inhibitors, there may be other factors contributing to this risk as well. For example, SGLT2 inhibitors can also cause changes in vaginal pH and the microbiome, which may further promote the growth of yeast.
• Overall, the increased urinary glucose excretion caused by SGLT2 inhibitors can provide a biologically plausible explanation for the increased risk of GMI, and other factors may also play a role in this observed association.

SGLT2 inhibitors can contribute to an increased risk of complicated urinary tract infections

• UTIs by SGLT2i, several mechanisms exist.
• Firstly, patients with type 2 diabetes mellitus (T2DM) already have a higher susceptibility to UTIs due to factors such as increased adherence of Candida (a type of yeast) to the genital tract and reduced host immune response.
• The combination of increased adherence of Candida to the genital tract, reduced host immune response in patients with T2DM, augmented glycosuria caused by SGLT2 inhibitors, and pre-existing anatomical abnormalities of the urogenital tract creates a situation that predisposes individuals to complicated UTIs.

How much is the Risk?

• Patients with T2DM are more likely to have genital tract colonization with Candida spp. The risk of GMI is higher in patients with diabetes.
• 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 as per one population-based study.
• 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.

The prevalence of genital infections in postmenopausal diabetic women on SGLT2i therapy

• It is still not clearly established due to scarcity of evidence.
• It has been hypothesized that hormonal changes during and post-menopause are related to diminished immunity in the female reproductive tract, which increases the chances of having genital infections.

Circumcision in men

• It is associated with maintenance of genital hygiene which is indirectly related to lower incidence of genital infection.

In 2015, the U.S. Food and Drug Administration (FDA) issued a warning

• FDS issued a warning about the risk of complicated urinary tract infections (UTIs) in patients using SGLT2 inhibitors. This action was taken following the reporting of 19 cases of complicated UTI between March 2013 and October 2014.

• An increased incidence of GTIs with SGLT2i versus placebo and active comparators has been reported.
• No differences have been demonstrated among SGLT2i.
• Post hoc analysis of data from Phase 3 studies of canagliflozin-treated patients with T2DM for the Indian subset has shown comparable incidence of GTIs in the Indian population vis-à-vis the overall population.
• Consistent results have been observed in studies from other Asian countries.

Predisposition to genital infections and urinary tract infections (UTIs) in type 2 diabetes mellitus (T2DM)

• It results from several factors such as glucosuria, adherence of bacteria to the uroepithelium and immune dysfunction.
• The precise role of glucosuria as a causative factor for these infections is yet to be fully elucidated.

Factors associated with genitourinary infection among Type 2 diabetics on SGLT2

• HbA1c of ≥7.0% signifying poorly controlled diabetes.
• Same factors have been linked with genital infection alone, along with
  • Diabetes duration of >10 years.
  • Overweight/obese BMI.
  • Factors associated with UTI alone include elevated Hba1c and eGFR of <60 ml/min.

Adding DPP4i with SGLT2i-Reality vs Hype

Simultaneous combination vs the sequential combination of SGLT2i and DPP4i

• The risk of genital infection has been found increased in the sequential combination subgroup (RR 5.57, 95% CI 2.33–13.333) but not in the simultaneous combination subgroup (RR 1.35, 95% CI 0.55–3.34).

• A systematic review and meta-analysis of seven RCTs involving 2082 participants with a duration of at least 12 weeks) investigated the effect of SGLT2i + DPP4i therapy in patients with T2DM.
• Overall, the results of this analysis suggest a possible lower risk of GTIs and nominal reduction in incidence of UTIs with simultaneous combination as opposed to sequential combination of SGLT-2i and DPP-4i
• Fadani et al:
  • In the five trials researchers retrieved, the pooled risk ratio for genital tract infections (GTIs) in patients on DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those on SGLT2 inhibitors alone was 0.51 (95% confidence interval [CI] 0.28-0.92).
  • They found that within the Food and Drug Administration AE Reporting System, the frequency of GUTIs among reports listing both SGLT2 and DPP-4 inhibitors as suspect or concomitant drugs was significantly lower than among reports listing SGLT2 inhibitors without DPP-4 inhibitors, with a proportional reporting ratio of 0.74 (95% CI 0.61-0.90).
  • In conclusion, in RCTs and in a large pharmacovigilance database, combination therapy with a DPP-4 inhibitor appears to reduce the frequency of G(U)TIs associated with SGLT2 inhibitors.

UTI-All Green

• Based on early reports of a limited number of cases, a concern for increased risk of urinary tract infections arose, which has become one of the main areas of concern for some clinicians.
• However, data from large randomized clinical trials and real-world population-based studies have not shown a significantly increased risk of UTI in patients on SGLT2 inhibitors.
• In one study, the incidence of UTI in patients with SGLT2 inhibitor treatment was 33.49%, compared with 11.72% in patients without SGLT2 inhibitor treatment.
• The results indicated that dapagliflozin and empagliflozin were associated with significant increases in UTI risk, by 3.79 and 3.64 times, respectively, compared with non-SGLT2 inhibitors.

Restarting SGLT2i after UTI / GTI

The South Asian Federation of Endocrine Societies (SAFES) consensus statement advocates

• The Perineal hygiene should be maintained to prevent GTIs and,
• After 3 months of GTI-free status, patients with T2DM can be prescribed with SGLT2i along with prophylactic antifungal coverage.
• SGLT2i should be avoided in the case of a previous history of upper UTIs, complicated GTIs, or refractory or resistant GTIs.

What to ask for while on SGLT2i

UTI- Ask for any history while especially on SGLT2I

1. If culture positive.
2. UTI symptoms with hospitalization.
3. No documented but symptoms suggestive.
4. These can be in comment section if you fill up UTI.

Vulvovaginitis

The symptoms of vulvovaginitis vary and depend on their cause. Questions can be asked accordingly.

1. Vulvar pruritus and burning – Primary symptoms of the disease.
2. Erythema and edema of the vestibule and of the labia majora and minora.
3. Thrush patches – Usually found loosely adherent to the vulva.
4. Thick, white, curd-like vaginal discharge.

Candida balanitis

Treatment of Candida balanitis

• Balanitis is usually associated with poor hygiene and hence frequent normal saline washes are recommended.
• Recommended regimen is clotrimazole cream 1% twice a day
  or 10 days. Miconazole cream 2% is also an alternative to
  clotrimazole cream. Relief is almost immediate, but treatment
  is to be continued for 10 days.
• Addition of topical steroids is not usually recommended in mild cases but where there is marked inflammation 1% hydrocortisone is used along with topical imidazoles. Topical therapy is usually sufficient in most of the cases of Candida balanitis.

How to treat Vulvovaginal Candidiasis

Knowing about Fluconazole

• Fluconazole is the usual drug of choice for Candida UTI. It is mostly eliminated unchanged (80%) in the urine resulting in urinary concentrations that are 10–20 times that of plasma (levels >100μg/ml). 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.
• Other azoles (e.g., posaconazole, voriconazole) are minimally excreted in the urine and therefore not recommended.

When to choose Flucytosine

• 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).
• 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.

There is emerging evidence that echinocandins

• Micafungin, can achieve adequate clinical efficacy when correlated with PK/PD ratios; and in the treatment of candidemia from a urinary tract source, similar outcomes have been achieved with echinocandins compared with fluconazole.

Ongoing GENIUS Study 2023

• At present no clear real-world data exists in India about the prevalence of GTI and UTI and its association with various factors like ethnicity, regionality, hygiene, circumcision, climate etc. Wide variation in prevalence of GTI and UTI with use of SGLT2-Inhibitors exists from single centre studies from India.
• 43 Pan-Indian centres are involved and retrospective data is being collected at present.

Primary objective of Genius Study

• To determine the prevalence of GTI and UTI in patients with Type 2 Diabetes Mellitus (T2DM) on SGLT-2 Inhibitors in India and to assess whether patients receiving SGLT-2 inhibitors were at increased risk for significant UTI/GTI events compared with those initiating use of dipeptidyl peptidase-4 (DPP-4) inhibitors.

Secondary Objectives of GENIUS Study

• To analyse demographic and clinical parameters associated with GTI/UTI on SGLT2-i
• To study whether those receiving both DPP-4 inhibitors and SGLT-2 Inhibitors in combination with other diabetic medications had less incidence of UTI compared to those on SGLT-2 Inhibitors alone with other diabetic medications.

CME INDIA Learning Edge

• In 2023, when concept of diabetes treatment has totally changed from gluco-centric to cardio-renal-metabolic-centric and encouraging data for primary prevention with SGLT2-inhibitors is on the door, a judicious use of SGLT2-inhibitors is the need of hour.
• Many fears like Acute kidney injury, hypovolemia and frailty issues are now in backyard. We do encounter UTI and GTI issues, but again these can be easily handled. If needed, stopping temporarily and restarting at appropriate juncture with proper hygiene related information is the answer.
• Both GTIs and UTIs are generally more common in females than males, mild to moderate in severity, rarely leading to treatment discontinuation and could be managed using standard treatment.
• Recurrent infections have been found rare in clinical studies, nevertheless caution needs to be exercised when recommending SGLT2i in patients with a history of recurrent UTIs or GTIs or those with anatomical obstruction to urinary tract.

What is needed MORE?

• Prospective studies with standardized follow-up period and method of assessment. Long-term follow-up periods are required to elucidate the trend in infection rates over time.
• Clinicians should closely monitor for signs and symptoms of genitourinary infection, especially those with known predisposing factors identified.
• Early identification of patients with infection can lead to earlier treatment, minimizing the possibility of drug discontinuation of patients who experienced these adverse events.

CME INDIA Tail-Piece

1. Remember this important point, presence of urinary ketone is not a contraindication to use SGLT2i.
2. Ketonuria on SGLT2i without Ketonemia is very common.

(Dr. A. K. Singh, DM, Endo, Kolkata)

Important Links

References:

1. Combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor in type 2 diabetes: a systematic review with meta-analysis. Sci Rep 8, 4466 (2018). https://doi.org/10.1038/s41598-018-22658-2
2. Min, S.H., Yoon, JH., Moon, S.J. et al. Combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor in type 2 diabetes: a systematic review with meta-analysis. Sci Rep 8, 4466 (2018). https://doi.org/10.1038/s41598-018-22658-2
3. Fadini  GP, Bonora BM, Mayur S, Rigato M, Avogaro A. Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2018;20:740-4. https://pubmed.ncbi.nlm.nih.gov/29053207
4. Wiegley, Nasim1; So, Paolo Nikolai2. Sodium-Glucose Cotransporter 2 Inhibitors and Urinary Tract Infection: Is There Room for Real Concern?. Kidney360 3(11):p 1991-1993, November 24, 2022. | DOI: 10.34067/KID.0005722022
5. Uitrakul, S.; Aksonnam, K.; Srivichai, P.; Wicheannarat, S.; Incomenoy, S. The Incidence and Risk Factors of Urinary Tract Infection in Patients with Type 2 Diabetes Mellitus Using SGLT2 Inhibitors: A Real-World Observational Study. Medicines 2022, 9, 59. https://doi.org/10.3390/medicines9120059
6. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA,Ostrosky‑Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:e1‑50.
7. Singh AK, Unnikrishnan AG, Zargar AH, Kumar A, Das AK, Saboo B, Sinha B, Gangopadhyay KK, Talwalkar PG, Ghosal S, Kalra S, Joshi S, Sharma SK, Sriram U, Mohan V. Evidence-Based Consensus on Positioning of SGLT2i in Type 2 Diabetes Mellitus in Indians. Diabetes Ther. 2019 Apr;10(2):393-428. doi: 10.1007/s13300-019-0562-1. Epub 2019 Jan 31. PMID: 30706366; PMCID: PMC6437257.

Discover CME INDIA

• Explore CME INDIA Repository
• Examine CME INDIA Case Study
• Read History Today in Medicine
• Register for Future CMEs

Get CME INDIA Highlights

Curated articles in your inbox.

SUBSCRIBE!

You have Successfully Subscribed!