Sodium-glucose cotransporter-2 inhibitors and risk for genitourinary infections in older adults with type 2 diabetes

Abstract

Background and aims: Although landmark clinical trials have demonstrated an increased risk for genitourinary infection (GUI) after initiation of sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy that led to an FDA label warning, real world findings have been inconsistent and evidence specifically in older adults is lacking. The objective of the study was to examine the incidence of GUI in patients aged 65 years or older initiated on SGLT2i compared with glucagon-like peptide-1 receptor agonist (GLP1-RA) therapy at a large academic health system. Methods: A retrospective population-based cohort study was conducted using electronic health records of patients aged 65 years and older with a diagnosis of type 2 diabetes mellitus. Patients newly initiated on SGLT2i or GLP1-RA therapy with estimated glomerular filtration rate (eGFR) ⩾30 mL/min per 1.73 m² and active within the health system for at least 1 year prior to initiation were included. We compared the incidence of inpatient, emergency room, or outpatient diagnosis of GUI (bacterial and mycotic) within 6 months of SGLT2i or GLP1-RA initiation. A chi-square or Fisher’s exact test were used to analyze between-group differences for categorical variables, while a t-test was used for continuous variables. A Cox proportional hazards model was used to estimate the impact of confounding variables on the primary outcome. Results: One hundred and thirty-three patients were initiated on SGLT2i therapy and 341 patients newly initiated on GLP1-RA therapy. After adjusting for differences in age, A1c, body mass index, eGFR, race and sex, there was no statistically significant difference in GUI incidence within 6 months of SGLT2i versus GLP1-RA initiation (3.8% versus 6.5%, adjusted hazard ratio: 0.784, 95% confidence interval 0.260–2.367). Conclusion: We found no increased risk of composite GUI within 6 months of initiating SGLT2i compared with GLP1-RA therapy. These real-world data in older adults add to previous findings, which suggest no increased risk of urinary tract infection with SGLT2i initiation. Plain language summary A class of antidiabetic medications and risk for genitourinary infections in older adults with type 2 diabetes Older adults with type 2 diabetes often benefit from a class of antidiabetic medications known as sodium-glucose cotransporter-2 inhibitors (SGLT2is) which help to lower blood glucose, decrease risk for cardiovascular disease and prevent kidney disease progression. However, there is concern that these medications may increase risk for urinary tract infections and/or genital fungal infections in older adults based on clinical trial evidence. Our study evaluated the real-world occurrence of these safety events in patients aged 65 years or older who were newly started on these medications. We compared these patients with a group of patients newly started on an alternative class of antidiabetic agents which are not expected to increase risk for infections, known as glucagon-like peptide-1 receptor agonists (GLP1-RA). In our study, we included 133 patients who started an SGLT2i and 341 patients who started a GLP1-RA at a large teaching hospital. We evaluated the occurrence of infection up to 6 months after initiation of these mediations. We found no significant difference in infection rate between these two groups. We conclude in the study that the use of SGLT2i in older adults was not associated with increased risk for urinary tract infections or genital fungal infections when compared with GLP1-RA use.

Five comparative cohorts to assess the risk of genital tract infections associated with sodium‐glucose cotransporter‐2 inhibitors initiation in type 2 diabetes mellitus

“…[13][14][15] Specifically, large RCTs have found between a 3-to 5-fold increase in risk of GTIs. [13][14][15] Additionally, several observational studies using a variety of data sources, GTI definitions, and exposure contrasts have supported an increased risk associated with SGLT-2 inhibitors, [16][17][18][19][20][21][22][23][24] albeit only one of which used Canadian data and was limited to those 65 years and older. 18 Moreover, several of these studies did not have a comparator group [21][22][23] were limited to specific or small populations 18,20,22 and follow-up periods of 6 months or less.…”

“…[13][14][15] Additionally, several observational studies using a variety of data sources, GTI definitions, and exposure contrasts have supported an increased risk associated with SGLT-2 inhibitors, [16][17][18][19][20][21][22][23][24] albeit only one of which used Canadian data and was limited to those 65 years and older. 18 Moreover, several of these studies did not have a comparator group [21][22][23] were limited to specific or small populations 18,20,22 and follow-up periods of 6 months or less. 18,20,24 Therefore, the aim of this study is to provide additional population based real-world evidence on the risk of GTI associated with the initiation of SGLT-2 inhibitors compared with clinically relevant active comparators.…”

“…18 Moreover, several of these studies did not have a comparator group [21][22][23] were limited to specific or small populations 18,20,22 and follow-up periods of 6 months or less. 18,20,24 Therefore, the aim of this study is to provide additional population based real-world evidence on the risk of GTI associated with the initiation of SGLT-2 inhibitors compared with clinically relevant active comparators.…”

“…Additionally, several observational studies using a variety of data sources, GTI definitions, and exposure contrasts have supported an increased risk associated with SGLT‐2 inhibitors, 16‐24 albeit only one of which used Canadian data and was limited to those 65 years and older 18 21‐23 were limited to specific or small populations 18,20,22 and follow‐up periods of 6 months or less 18,20,24 …”

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

“…The appearance of genital candidiasis does not imply the withdrawal of SGLT2i treatment. Analysis of real-world data and meta-analysis of safety data from randomised trials did not suggest an increased risk of harm with SGLT2i inhibitors over placebo or active comparators with respect to UTIs [ 106 , 109 , 110 ]. Genital infections and UTIs should be treated with antifungals or antibiotics, respectively, with advice on hydration as well as hygiene given.…”