Prevalence of genitourinary infection in diabetic patients treated with SGLT 2 inhibitors

Introduction Genitourinary infections are common in Diabetes patients compared to the general population more so in patients with Sodium glucose co transporter 2 inhibitors (SGLT2i) treatment , So, we did a study to find the prevalence of genitourinary infection in T2DM patients treated with SGLT2i. Methods One hundred and twenty patients receiving SGLT2i, who had signs and symptoms indicative of genitourinary infections were enrolled into the study. Results The mean age of presentation was 54.4 ± 7.7 years and percentage of males were 62 (51.66%). In this cohort, 72(60%) were treated with empagliflozin, 34(28.33%) with dapagliflozin and 14(11.66%) with canagliflozin. Twenty patients had genital mycotic infection and 4 had urinary tract infection. Female patients had higher incidence of infections than male patients with no statistically significant difference (P = ns). We did not find any significant correlation between age of the patient, gender, duration of disease and treatment, HbA1c, different types and dose of SGLT2i used with the incidence of genital mycotic infections (P = ns). Conclusion We need to counsel the patients before starting SGLT2i regarding possible chance of getting genitourinary infection, proper genital hygiene, drinking plenty of water and consulting the doctor if any symptoms at the earliest.


Introduction
Diabetes mellitus (DM) is a chronic metabolic disorder, due to either an absolute or relative insufficiency of insulin, its action or both. This leads to uncontrolled hyperglycaemia. Infection is one of the important health challenges in patients with DM increasing morbidity and mortality. Diabetic patients are more prone to develop infections compared to non-diabetic, usually twice likely as non-diabetics 1 . We know that there is greater risk of genitourinary infections in DM patients. Microbial agents responsible are fungi, viruses, bacteria, and parasites. There is usually overlap of genital and urinary infections in DM patients. Males usually develop balanoposthitis and females develop vulvovaginal infections 2 . According to the literature Indian diabetic women are most likely to de-velop vulvovaginal candidiasis (VVC) 3 . In diabetic men Candida balanitis is the most common infection reported especially if they are uncircumcised 4 . According to a US study on management of risk factors for infection, women and men with T2DM were 2.3-and 1.9-times more prone to develop genitourinary infection than women and men without diabetes 5 . C. albicans is the frequent causative organism causing balanitis in men, and C. glabrata is the main pathogen in women with genital mycotic infections 6,7 . Because of high sugar concentration in urine in uncontrolled DM patients, the urinary tract becomes a favoured area for multiplication of bacteria and fungi. The main symptoms of infections are itching, burning micturition, yellow white discharge, and dyspareunia. Management involves strict control of blood glucose and local application of antifungal ointments and/ or oral antifungal and antibiotics 8 . Sodium glucose co transporter 2 inhibitors (SGLT2i) are a new group of oral hypoglycaemic drugs approved for treatment of type 2 DM. SGLT2i acts mainly on proximal tubules of kidneys where they inhibit glucose re absorption, thus increasing urinary glucose excretion 9,10 .These drugs are relatively safe and well tolerated but since they induce glycosuria, it may results in growth of microbials in the genital tract thus favouring mycotic infections and urinary tract infections (UTIs) 11,12 . Previous studies have shown that patients on SGLT2i have 2 to 3-fold higher risk of genital mycotic infections (~8-10%) compared to patients receiving placebo. (3-5%) 13,14,15 . In most of these patients' infections are mild and resolve spontaneously or some patients may require local antifungal treatment. The SGLT2i available in India are empagliflozin, dapagliflozin and canagliflozin. Not many studies have been done about the prevalence of genital and urinary tract infections due to SGLT2i, more so in south India. Thus, we did a retrospective analysis to find out the prevalence of genitourinary infections in diabetes mellitus patients receiving SGLT2 inhibitors.

Methods
This was retrospective study in the department of endocrinology, tertiary care hospital in south India. We pooled the data of all patients with T2D receiving SGLT2i. All patients who were taking SGLT2i for at least 12-months, were included in the analysis. We also collected the demographic data such as age, sex, duration of diabetes, HbA1c etc. SGLT2i were usually added when patients failed to respond to metformin and glimepiride combination therapy and if their HbA1c level was more than 7. All the symptoms of genitourinary infections like itching, redness, white discharge, fever, burning micturition were recorded. Any past history of genitourinary infection was also recorded.

Statistical analysis
We analysed the data using SPSS version 17.0 software. All the data regarding continuous variables were presented as means and ± SD. The relationship between two variables were determined by Pearson's Chi square test. P < 0.05 was considered statistically significant. We obtained institutional ethical board permission for retrospective analysis of data.

Results
The patients' demographic features are shown in Table  1. Most were above 50 years of age with mean age of 54.4 ± 7.7 years. Of these 120 patients, 62 were males. Most of the patients had diabetes of more than 5 years with mean duration of 10.5±6.4 years. They had poor glycerine control with mean HbA1c 8.8±1.8%; and most HbA1c above 7. Empagliflozin was the most commonly used SGLT2i with 60% patients on it. Meanwhile 28.33% of the patients were on dapagliflozin and 11.66% patients on canagliflozin.   fection while dapagliflozin in 30%, and canagliflozin in 10 (P = ns). We did not find any correlation between age of the patient, gender, duration of disease and therapy, HbA1c, different types of SGLT2i with the prevalence of genital urinary infections [ Table 3]. Most men had infection with Candida albicans while in women Candida glabrata was main pathogen. Urinary tract infection was seen in 4 patients, (3 female and one male). Escherichia coli was the isolated organism in all four patients. All the patients responded well to topical or oral antifungal and antibacterial treatment. Four patients (20%) gave a history of previous genital infection compared to 7 patients (7%) without genital infection.  [15] . 16664 10 mg 2.46% -4.99% Johnsson et al [16] . Zinman et al [19] . 6563 10 mg or 25 mg 6.5% with 10 mg dose and 6.3% with 25mg Kim et al [20] . 2477 10 mg or 25 mg 4.2%with 10 mg dose and 3.6% with 25 mg SGLT2i Empagliflozin Dapaglifl ozin-Canagliflozin-Agarwal et al [21] 205 ( [20]. Therefore, we should be careful about the side effects of SGLT2i and monitor for them. Relatively higher proportion in males may be due to lack of circumcision. Various studies have shown that balanoposthitis is rare in circumcised men. Since most of south Indian population consume high carbohydrate containing diet, the resulting glucosuria may increase the chance of genital infection. Knowledge about the drug and its action found to be useful in reducing the incidence of genital infection. We should educate the patients about possibility of genital infection and how to prevent it. The measures to prevent infection are proper hydration, maintaining genital hygiene by washing the genital after urination, withholding SGLT2i if develop symptoms for short period and use of local anti fungals. We did not find any difference in frequency of genital mycotic infections with individual SGLT2i. Geerlings et al 12 reported that genitourinary infection is a class effect rather than individual drug effect. We don't have studies comparing the drugs in terms of genitourinary infections.

Limitations
One main limitation of our study is small sample size.
Since majority of our patients had poor glycaemic control, this may be confounding factor in increasing the incidence of genital infection thus falsely increasing the event rate. In our study there was no correlation between HbA1c and frequency of genital infection.

Conclusion
The risk of urogenital infections is more among Indian patients with T2D on SGLT2i therapy. We need to counsel the patient before starting SGLT2i regarding possible chance of getting genitourinary infection, proper genital hygiene, drinking plenty of water and consult the doctor if develops any symptoms at the earliest.