Risk of genitourinary infections with SGLT2 inhibitors

Genitourinary infections and diabetes

Patients with diabetes are at an increased risk of genitourinary infections. Genitourinary infections include bacteriuria associated with glycosuria, urinary tract infections (UTI) and non-sexually transmitted genital infections, which are usually fungal in nature and presents as mycotic vulvovaginitis in women or mycotic balanitis in men.

Based on a UK observational study of T2DM patients in primary care, the one-year incidence of UTI among patients (n = 135,920) is about 50 to 60% higher compared to non-diabetic patients (46.9 vs 29.9 per 1000 person-years).¹ The study also showed that patients with T2DM have an increased risk of developing genital infections with the relative risk of  1.81 [1.64-2.00] (RR [95% Cl]) for the vaginitis female group and 2.85 [2.39-3.38] for the balanitis male cohort.¹

Other than the underlying diabetes condition, the study identified other possible risk factors for UTI such as the female gender, pregnancy, older age, history of UTIs in the last six months and poor glycaemic control (HbA1c > 8.0%).¹ While the risk of developing UTI increases with age, the finding is contrary for genital infection. Studies have shown that the incidence of genital infection is higher among younger adults compared to older adults.²

Risk of genitourinary infections with use of SGLT2 inhibitors

While the underlying diabetic condition predisposes T2DM patients to genitourinary infections, the use of SGLT2 inhibitors adds on to this risk. The incidence of UTI reported in clinical trials vary between 4 – 9% for T2DM patients who used SGLT2 inhibitors, with a difference of 1.0 – 1.5% above that reported with placebo. These infections have also been found to be more common in women than in men. Genital infections have been reported to be significantly more common with the use of SGLT2 inhibitors compared to placebo^3-5 and are five times more likely than other anti-diabetic agents.² It is estimated that genital infections affect 5 - 10% of patients using SGLT2 inhibitors and this risk increases in premenopausal women, patients with history of genitourinary infections, and patients who are obese.⁶ Most first events of genital infections occurred early in the course of treatment (within six months) and recurrent infections were uncommon.¹ Majority of the infections were treated with standard antifungal therapy (oral and/or topical) while the patients continued their SGLT2 inhibitors. Symptoms usually resolved within a week upon treatment initiation.²

The mechanism of action of SGLT2 inhibitors to pharmacologically induce renal glycosuria plays a large role in increasing the risk of genitourinary infections in T2DM patients. The increased urinary glucose concentration creates a favourable environment in the urogenital area for the growth of microorganisms e.g., bacteria and yeast.

In our AE case in focus, while the patient was on empagliflozin, she developed genitourinary infection and was treated with antifungal medication. Despite antifungal treatment, her infection persisted for two months. She discontinued empagliflozin on her own. Her non-compliance with empagliflozin resulted in her mean glycosylated haemoglobin (HbA1c) level to increase from 7.6% to 8.3%.  When she was switched to another anti-diabetic agent, her HbA1c decreased to 7.7%.

Local reports

As of October 2017, HSA has received 12 reports of genitourinary infection associated with the use of SGLT2 inhibitors. Out of these, six were females and five were males. One report did not list the gender of the patient. Their ages ranged from 49 to 77 years old. Seven reports which had listed UTI (without genital co-infection) affected the older group of patients (63 to 77 years old). This is consistent with the findings from studies that UTI generally affects older adults as compared those at risk of genital infections. The five patients who had experienced genital infection were aged between 49 to 68 years old. One of the report did not indicate the patient’s age and the other reported both genital and urinary infection (cystitis). One patient was noted to be clinically overweight (83kg, 27.7kg/m²) and another was clinically obese class III (107kg, 43.4kg/m²) [weight, Body Mass Index (BMI)].  Of the 12 cases, six patients had developed the infection within two months after initiating SGLT2 inhibitor treatment. Latency was not reported in four of the cases while only two patients developed the infection after seven months.

Please refer to Table 1 for the number of AE reports of genitourinary infections submitted to HSA by public healthcare institutions and the drug utilisation rates of the different SGLT2 inhibitors.

Potential for non-compliance and/or discontinuation

Although genitourinary infections are generally deemed as non-serious, the severity of the symptoms experienced (pruritus, soreness, redness in the genital area) may be discomforting and unbearable, resulting in patients being non-compliant with their SGLT2 inhibitors therapy.

In three of the local cases, it was reported that patients’ adherence to SGLT2 inhibitors therapy were compromised due to the intolerable symptoms of genitourinary infections, resulting in deterioration in their glycaemic control. One of the patient’s HbA1c levels increased to 8.7% during the infection period.

International individual case safety reports (ICSRs) from the World Health Organisation’s (WHO) global safety database (VigiBase) revealed similar occurrences where patients stopped taking these medications because of the genital infection AE.⁶

Most genital infections reported in clinical trials were mild to moderate and only rarely led to discontinuation of treatment.^3-5 However, such ‘non-serious’ AEs may manifest in the post marketing period as severe events which may have large enough impact on the patient’s quality of life that discontinuation of the medication is deemed necessary.⁶

HSA’s advisory

HSA encourages healthcare professionals to closely monitor patients on SGLT2 inhibitors and be vigilant to seemingly non-serious AEs such as genitourinary infections which in severe cases could potentially adversely affect patients’ quality of life and compliance of their SGLT2 inhibitor therapy. This may result in poor glycaemic control and potentially lead to serious life-threatening consequences e.g., hyperglycaemia with ketoacidosis. Healthcare professionals are advised to report any suspected adverse events associated with the use of SGLT2 inhibitors to the Vigilance and Compliance Branch of HSA. Your support of the national safety monitoring programme is invaluable in safeguarding public health.

Table 1. No. of AE reports from the public healthcare institutions (excluding company reports) and drug utilisation rates with the different SGLT2 inhibitors

*DDD: Defined daily dose for public healthcare institutions & Raffles Hospital; 2014-Sept 2017 Data source: IMS Health.

The figures in Table 1 are current up to October 2017. The information above is to provide a crude baseline comparison between the number of reports received with the utilisation of SGLT2 inhibitors. The data provided should not be used to draw comparisons on the safety of different brands of SGLT2 inhibitors as this is confounded by factors such as extent of use, the patient populations exposed and under-reporting. It does not include private hospital reports. It does not represent a risk assessment of this class of drugs.

References

1. Diabetes Res Clin Pract. 2014:103(3):373-81
2. Prescriber 2016:27(12):26-30
3. European Medicines Agency. Jardiance (empagliflozin) public assessment report, March 2014
4. European Medicines Agency. Forxiga (dapagliflozin) public assessment report, September 2012
5. European Medicines Agency. Canagliflozin public assessment report, September 2013
6. WHO Pharmaceuticals Newsletter No. 3, 2017:Pg 23-25