Pharmacovigilance of Sodium-Glucose Cotransporter-2 Inhibitors for Genital Fungal Infections and Urinary Tract Infections: A Review of the Food and Drug Administration Adverse Event Reporting System Database

Abstract

Background: Postmarketing surveillance had previously identified the need for revisions in the labeling of the sodium-glucose cotransporter-2 (SGLT2) inhibitors drug class related to the risk of diabetic ketoacidosis. Other adverse events have been reported. Objective: To examine postmarketing surveillance data of the SGLT2 inhibitors, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, specifically to assess prevalence of urinary tract infections (UTIs) and genital fungal infections. Methods: FAERS case reports submitted between March 2013 and November 2015 were reviewed for 6 SGLT2 inhibitors (mono and combo therapies). The Medical Dictionary for Regulatory Activities (MedDRA) was used to define preferred terms (genital fungal infections: vulvovaginal mycotic infection, vulvovaginal candidiasis, urinary tract infection fungal, and genital candidiasis; UTI: urinary tract infection, genitourinary tract infection, kidney infection, cystitis, and pyelonephritis). Word frequencies were queried using the qualitative data analysis software NVivo 11 (QSR International), and results were then individually reviewed. Results: A total of 12 581 cases were received, but 466 were excluded (total n = 12 115). A total of 348 cases related to genital fungal infections were reported (2.9% of reports submitted): dapagliflozin = 53, empagliflozin/linagliptin = 6, canagliflozin = 267, canagliflozin/metformin = 3, empagliflozin = 17, and dapagliflozin/metformin HCl ER = 2. A total of 727 cases related to UTIs were reported (6% of reports submitted): dapagliflozin = 168, empagliflozin/linagliptin = 5, canagliflozin/metformin = 8, canagliflozin = 503, empagliflozin = 38, and dapagliflozin/metformin HCl ER = 5. Conclusions: A causal relationship between SGLT2 inhibitors and the adverse events reported cannot be established due to the nature of postmarketing surveillance. However, health care providers should counsel patients about these potential adverse events.

Introduction

Sodium-glucose cotransporter-2 inhibitors (SGLT2) are the newest diabetes drug class that came on the market in 2013. They are considered a second-line agent in the management of type 2 diabetes, alongside sulfonylureas, thiazolidinediones, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and insulin.¹ Potential benefits of this drug class include lowering blood glucose with minimal hypoglycemia, possible weight loss, and blood pressure lowering. SGLT2 inhibitors can target both fasting and postprandial blood glucose, and may modestly reduce A1c by 0.5% to 0.7%.² Their mechanism of action involves inhibition of the SGLT2 receptor, thereby excreting glucose through the urine and reducing the amount of glucose reabsorbed by the kidneys. The amplified glycosuria could increase the risk of developing urinary and genital infections, known adverse effects reported in the prescribing information of these medications.^3,4

The Food and Drug Administration’s Adverse Event Reporting System (FAERS) is a database that collects adverse events, and it is a useful tool to assist with postmarketing surveillance.⁵ Postmarketing surveillance had previously identified the need for revisions in the labeling of these medications in 2015, related to the risk of diabetic ketoacidosis and serious urinary tract infections (UTIs).⁶

This study aims to review reports submitted to the FAERS and assess prevalence of UTIs and genital fungal infections. Although the prescribing information for these medications warn health care providers of these potential adverse events, we sought to identify the frequency of these reports.

Methods

Study Design

A retrospective analysis was conducted to compare FAERS cases reported between March 2013 and November 2015 (Food and Drug Administration’s Freedom of Information Act Request Form sent November 6, 2015) for 6 SGLT2 inhibitors including single agents: dapagliflozin (Farxiga, approved January 2014), canagliflozin (Invokana, approved March 2013), empagliflozin (Jardiance, approved August 2014), and combination products: empagliflozin/linagliptin (Glyxambi, approved January 2015), canagliflozin/metformin (Invokamet, approved August 2014), and dapagliflozin/metformin HCl ER (Xigduo XR, approved October 2014).

Search Strategies

The Medical Dictionary for Regulatory Activities (MedDRA, Version 19.0) was used to define preferred terms within these reports.⁷ Chosen terms to review in this study consisted of the following: urinary tract infection, genitourinary tract infection, kidney infection, cystitis, and pyelonephritis to identify all UTI-related cases. For genital fungal infections, the terms vulvovaginal mycotic infection, vulvovaginal candidiasis, genital infection fungal, urinary tract infection fungal, and genital candidiasis were included in this search. The query was conducted using qualitative data analysis software NVivo 11 (QSR International). With this software, the word frequencies per term were individually assessed.

Data Collection

Results presented through NVivo 11 were validated by manually reviewing all cases. A spreadsheet database was created containing a sheet dedicated to each medication. FAERS reports contained duplications of cases from the combination products appearing in the single-agent reports. A total of 464 cases were omitted due to duplication. Two cases did not have the patient listed as taking an SGLT2 inhibitor when the event occurred. These cases were individually removed, and adjustments were made to the data accordingly. Cases in which the patient was listed as taking both the single and combination products were not excluded.

Results

A total of 12 115 cases were included in the analysis. From these cases, 1075 met criteria for the preferred terms. Figure 1 illustrates the combined reported cases per month for UTI and genital fungal infections. The highest number of reports received occurred in May 2015.

Figure 1.

Total reported results per month for combined urinary tract infection and genital fungal infection related cases.

Table 1 presents the number of incidents for each adverse event found per SGLT2 inhibitor (mono and combo therapy). From the monotherapy agents, canagliflozin had the highest number of received FAERS reports, as well the most reported UTI and genital infection reports. From the combination agents, canagliflozin/metformin had the highest number of received FAERS reports and UTIs reported. Percentagewise, canagliflozin had the largest proportion of UTIs (6.4%), as determined by taking the total number of events (503) divided by number of reports submitted (7883) regarding canagliflozin. Empagliflozin/linagliptin had the largest proportion (3.7%) of patients reporting genital tract infections (6/163).

Table 1.

Number of Urinary Tract Infections and Genital Fungal Infections Cases Reported.

Preferred Term Adverse Event	Canagliflozin (Invokana)	Dapagliflozin (Farxiga)	Empagliflozin (Jardiance)	Canagliflozin/Metformin HCl (Invokamet)	Dapagliflozin/Metformin HCl ER (Xigduo XR)	Empagliflozin/Linagliptin (Glyxambi)	Total Cases Reported
Urinary tract infection	410	113	28	5	5	4	565
Pyelonephritis	30	29	4	2	0	0	65
Kidney infection	20	6	1	1	0	0	28
Cystitis	42	19	5	0	0	1	67
Genitourinary tract infection	1	1	0	0	0	0	2
Vulvovaginal mycotic infection	77	18	15	1	2	3	116
Urinary tract infection fungal	7	0	0	1	0	2	10
Genital infection fungal	176	26	2	1	0	1	206
Vulvovaginal candidiasis	5	6	0	0	0	0	11
Genital candidiasis	2	3	0	0	0	0	5
Subtotal urinary tract infection cases reported	503	168	38	8	5	5	727
Subtotal genital fungal infection cases reported	267	53	17	3	2	6	348
Total cases reviewed from all FAERS products reports	7883	2992	734	227	116	163	12 115

Abbreviation: FAERS, Food and Drug Administration Adverse Event Reporting System.

Discussion

Within the dapagliflozin, canagliflozin, and empagliflozin prescribing information, UTIs accounted for 4.3% to 9.3% of adverse events reported during clinical trials.^8-10 Female genital mycotic infections accounted for 5.4% to 11.6%. Male genital mycotic infections ranged from 2.7% to 4.2% of adverse events. For the combination agents, the adverse events reported in the prescribing information for canagliflozin/metformin was not specific to the combination of canagliflozin and metformin, just those agents individually.¹¹ UTIs ranged from 5.5% to 12.5% for empagliflozin/linagliptin and dapagliflozin/metformin HCl ER.^12,13 Rates of genital fungal infections were not reported in the prescribing information for empagliflozin/linagliptin, but for dapagliflozin/metformin HCl ER clinical trials, these accounted for 9.3% to 9.4% of adverse events in females, and 3.6% to 4.3% in males. Although canagliflozin had the most reports of both urinary tract and genital fungal infections, there was also a larger number of cases for canagliflozin received, since this SGLT2 inhibitor has been on the market the longest (approved March 2013) and is the most widely prescribed.^9,14 It is unknown why there was such a large reporting spike in May 2015.

A causal relationship between this class of medications and the reported adverse events could not be established with the postmarketing surveillance data provided based on the voluntary subjective reporting format of the FAERS database.⁵ Information such as dose, age, or sex were frequently unreported. Therefore, finding correlations between these factors and UTIs or genital fungal infections could not be pursued. Subjective reporting to FAERS was also limiting since some cases reported symptoms consistent with a possible UTI or genital fungal infection but were never termed as such using MedDRA terminology or several cases were reported as an unspecified fungal infection, which did not meet our predetermined criteria for identification as a genital fungal infection. It cannot be assessed whether the UTIs or genital fungal infections reported were disease related, drug related, or if the patient is more prone to developing these infections.¹⁵ Last, the MedDRA term balanitis was not used within this research query. This term relates to genital mycotic infections in males.

Further research is needed to evaluate the likelihood of developing incidence of UTIs and genital fungal infections with SGLT2 inhibitors. Health care professionals should continue to counsel patients receiving these medications about symptoms of UTIs and genital fungal infections to be aware of and what to do should these events occur. The prescribing information for these medications state to evaluate patients for signs and symptoms of urinary tract and genital fungal infections, and to treat promptly if needed. Common UTI symptoms include, but are not limited to, dysuria, frequency, nocturia, and pain. Depending on the pathogen, comorbidities, and concurrent medication use, patients may be prescribed a quinolone, nitrofurantoin, or trimethoprim-sulfamethoxazole as a first-line therapy.¹⁶ Common symptoms for a female genital fungal infection include vulvar itching, irritation, and burning on urination. For uncomplicated Candida vulvovaginitis, topical antifungal agents are preferred, and a single 150-mg oral dose of fluconazole is an alternative option.¹⁷ Males may complain of swelling or tenderness in relation to a genital fungal infection, and treatment options are similar to those used in female fungal infections.¹⁸

Conclusions

Overall, this evaluation was unable to identify a causal connection between the SGLT2 inhibitors and urinary tract/genital fungal infections. This was due to the nature of the FAERS system as well as the time series analysis and reported rate comparisons within the class of medications based on the preferred terms used. However, these are known adverse events of this medication class, and health care providers must educate their patients accordingly. Regardless of adverse event, patients and health care providers should continue to report these findings to the FAERS database.