Journal of

Clinical Medicine

Review
Clinical Recommendations for Managing Genitourinary Adverse
Effects in Patients Treated with SGLT-2 Inhibitors:
A Multidisciplinary Expert Consensus
Juan J. Gorgojo-Martínez 1, * , José L. Górriz 2 , Ana Cebrián-Cuenca 3 , Almudena Castro Conde 4
and María Velasco Arribas 5

1 Department of Endocrinology and Nutrition, Hospital Universitario Fundación Alcorcón, Alcorcón,

28922 Madrid, Spain
2 Department of Nephrology, Valencia Clinic University Hospital, Instituto de Investigación
Sanitaria (INCLIVA), Universitat de València, 46010 Valencia, Spain; jlgorriz@gmail.com
3 Health Centre Casco Antiguo Cartagena, Primary Care Research Group, Biomedical Research Institute of
Murcia (IMIB), 30201 Cartagena, Murcia, Spain; anicebrian@gmail.com
4 Department of Cardiology, University Hospital La Paz, IdiPAZ, Biomedical Research Center-Cardiovascular
Diseases (CIBERCV-ISCIII), 28046 Madrid, Spain; almudenacastroc@gmail.com
5 Department of Infectious Diseases, Research Department, Hospital Universitario Fundación Alcorcón,
28922 Madrid, Spain; mvelascoa@salud.madrid.org
* Correspondence: juanjose.gorgojo@salud.madrid.org; Tel.: +34-916219666

Abstract: Background: SGLT-2 inhibitors (SGLT-2is) are considered to be a first-line treatment for
common conditions like type 2 diabetes, chronic kidney disease, and heart failure due to their
proven ability to reduce cardiovascular and renal morbidity and mortality. Despite these benefits,
SGLT-2is are associated with certain adverse effects (AEs), particularly genitourinary (GU) events,
which can lead to treatment discontinuation in some patients. Preventing these AEs is essential for
maintaining the cardiorenal benefits of SGLT-2is. Methods: A multidisciplinary panel of experts from
various medical specialties reviewed the best available evidence on GU AEs associated with SGLT-2i
Citation: Gorgojo-Martínez, J.J.; therapy. The panel focused on the prevention and management of genital mycotic infections, urinary
Górriz, J.L.; Cebrián-Cuenca, A.; tract infections, and lower urinary tract symptoms in both the general population and high-risk
Castro Conde, A.; Velasco Arribas, M. groups, such as renal and cardiac transplant recipients. Results: The panel found that permanent
Clinical Recommendations for
discontinuation of SGLT-2is results in a rapid loss of cardiorenal benefits. Preventive strategies,
Managing Genitourinary Adverse
including identifying high-risk patients before initiating therapy, are critical for minimizing GU AEs.
Effects in Patients Treated with
Clinical trials show that most GU infections linked to SGLT-2i therapy are mild to moderate in severity
SGLT-2 Inhibitors: A
Multidisciplinary Expert Consensus. J.
and typically respond to standard antimicrobial treatment, without the need for discontinuation.
Clin. Med. 2024, 13, 6509. https:// Conclusions: Routine discontinuation of SGLT-2is due to GU AEs is not recommended. Therapy
doi.org/10.3390/jcm13216509 should be resumed as soon as possible, unless severe or persistent conditions contraindicate their use,
in order to preserve the significant benefits of SGLT-2is in reducing cardiovascular and renal events
Academic Editor: Javier C. Angulo

Received: 29 September 2024 Keywords: SGLT-2 inhibitors; genitourinary infection; genital mycotic infection; urinary tract infection
Revised: 23 October 2024
Accepted: 29 October 2024
Published: 30 October 2024
1. Introduction
Sodium-glucose cotransporter type 2 inhibitors (SGLT-2is) have revolutionized dia-
Copyright: © 2024 by the authors.
betes care, providing not only glycemic control, but also significant cardiovascular (CV)
Licensee MDPI, Basel, Switzerland. and renal benefits that surpass those of traditional glucose-lowering therapies [1]. These
This article is an open access article medications lower blood glucose, enhance insulin sensitivity, and promote weight loss by
distributed under the terms and increasing urinary glucose excretion, making them particularly beneficial for individuals
conditions of the Creative Commons with insulin resistance or metabolic syndrome [1]. SGLT-2is also exhibit CV pleiotropic
Attribution (CC BY) license (https:// effects, including direct metabolic changes in the myocardium, blood pressure (BP) reduc-
creativecommons.org/licenses/by/ tion, and diuretic and natriuretic properties, which alleviate fluid overload and reduce
4.0/). cardiac strain. Additionally, SGLT-2i slower intraglomerular pressure, reduce glomerular

J. Clin. Med. 2024, 13, 6509. https://doi.org/10.3390/jcm13216509 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 6509 2 of 28

hyperfiltration, and decrease albuminuria—a marker of kidney damage—thus helping to

preserve kidney function over time, independent of their glucose-lowering effects [1–4].
Numerous randomized clinical trials (RCTs) have highlighted the significant CV bene-
fits of SGLT-2is in patients with type 2 diabetes mellitus (T2DM), chronic kidney disease
(CKD), and heart failure (HF). The EMPA-REG OUTCOME study [2], published in 2015, was
groundbreaking, as it was the first to demonstrate a reduction in major adverse CV events
(MACEs), such as myocardial infarction, stroke, and CV death, in patients with T2DM and
established CV disease (CVD). Similar results were later observed with canagliflozin in the
CANVAS program [3] and dapagliflozin in the DECLARE-TIMI 58 study [4] in patients with
T2DM, both with and without CVD. Moreover, SGLT-2is have been shown to reduce the risk
of hospitalization for HF, regardless of diabetes status, prior HF diagnosis, or ejection frac-
tion, as demonstrated in several RCTs, including the SCORED (sotagliflozin) [5], DAPA-HF
(dapagliflozin) [6], DELIVER (dapagliflozin) [7], EMPEROR-Reduced (empagliflozin) [8],
and EMPEROR-Preserved (empagliflozin) studies [9]. Additionally, SGLT-2is have shown
promise in acute HF settings. The EMPULSE trial [10] demonstrated empagliflozin’s clinical
benefits in reducing CV mortality, HF hospitalizations, and improving quality of life in
patients hospitalized for acute HF, irrespective of their ejection fraction or T2DM status.
Although the EMPACT-MI study [11], which initiated empagliflozin shortly after acute
myocardial infarction, did not show a significant reduction in the combined incidence
of all-cause death and first HF hospitalization, secondary analyses suggested potential
reductions in both first and total HF hospitalizations with empagliflozin.
SGLT-2is have also been demonstrated to slow CKD progression in patients with
and without T2DM. Specifically, the CREDENCE study [12] highlighted the significant
renal benefits of canagliflozin in patients with advanced CKD and T2DM, while the DAPA-
CKD [13] and EMPA-KIDNEY trials [14] showed similar benefits with dapagliflozin and
empagliflozin, respectively, in patients with CKD, regardless of their T2DM status.
Overall, these findings underscore the paradigm shift in the treatment of T2DM,
CKD, and HF with the advent of SGLT-2is, which offer substantial CV and renal benefits
beyond glucose control. However, SGLT-2is are sometimes temporarily or permanently
discontinued due to adverse effects (AEs), depriving patients of their metabolic CV and
renal benefits.
Few evidence-based consensus documents specifically address the prevention and
management of the most common AEs associated with SGLT-2is, and those that do exist
are typically not multidisciplinary [15,16]. This review, developed by a panel of experts
from various medical specialties with wide experience in SGLT-2i management, aims to
evaluate the available evidence and provide practical recommendations for clinicians. The
ultimate objective is to reduce the number of patients in real-world settings who miss out
on the cardiorenal benefits of these medications due to AEs.

2. Materials and Methods

A multidisciplinary panel of experts, including a primary care physician, an internist
specializing in infectious diseases, a cardiologist, a nephrologist, and an endocrinologist—
each with clinical experience in SGLT-2i therapy across various clinical settings—held
virtual meetings to reach a consensus. The panel conducted an extensive literature search
using PubMed, prioritizing RCTs, systematic reviews, and meta-analyses. In cases where
no RCTs were available, high-quality observational studies or international expert recom-
mendations were used, supplemented by the authors’ real-world clinical experience.
The experts agreed that preventing and managing genitourinary (GU) AEs should be
the primary focus when optimizing care for patients receiving SGLT-2is, in order to avoid
unnecessary treatment discontinuations that could have significant medium- to long-term
clinical consequences. The panel also extended these recommendations to patients without
T2DM, given the emerging evidence supporting the use of SGLT-2is in patients with HF
or CKD.
J. Clin. Med. 2024, 13, 6509 3 of 28

Finally, the experts emphasized the need for a dedicated section addressing high-risk
patients who are more susceptible to GU infections when using SGLT-2is, ensuring that the
best available evidence is applied to this patient population, who may also benefit from
this therapeutic class.

3. Risks Associated with SGLT-2i Withdrawal

The permanent discontinuation of SGLT-2i therapy may not only lead to worsening
glycemic control, but also result in the loss of the cardiometabolic and renal benefits
provided by these medications. In the DELIGHT study, after 24 weeks of dapagliflozin
treatment in patients with T2DM and CKD, a 3-week follow-up period without medication
revealed an almost complete reversal of the drug’s effects on fasting plasma glucose, weight,
systolic BP, albuminuria, and eGFR [17]. Similarly, an increase in eGFR one month after
the discontinuation of empagliflozin was observed in patients with T2DM and established
CVD enrolled in the EMPA-REG OUTCOME study, reflecting the loss of its effects on
tubular–glomerular feedback and glomerular hyperfiltration [18].
In a joint sub-analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials in
patients with HF, 6799 participants randomized to placebo or empagliflozin 10 mg/day
for 1 to 3 years were prospectively evaluated 30 days after treatment withdrawal [19].
Compared to those in the placebo group, patients previously treated with empagliflozin
showed a higher risk of CV death or hospitalization for HF, along with greater clinical
deterioration, as measured by the KCCQ-CSS score. Additionally, the discontinuation of
empagliflozin was associated with significant increases in fasting glucose, body weight,
systolic BP, eGFR, NT-proBNP, and uric acid, as well as a significant decrease in hematocrit.
These changes were opposite to those observed during the active treatment phase with the
drug in the same cohort.
These findings suggest that the abrupt cessation of SGLT-2i therapy, even for short
periods, can have serious consequences due to the rapid loss of their beneficial pharma-
cological effects. Therefore, clinicians should carefully weigh the decision to discontinue
SGLT-2is due to AEs, and discontinuation should only occur when the risks posed by AEs
outweigh the overall cardiometabolic and renal benefits provided by SGLT-2is, as well as
the reductions in morbidity and mortality achieved by continuing treatment.

4. Main Causes of SGLT-2i Withdrawal

Withdrawal from SGLT-2i treatment can be temporary or permanent (Table 1) [16,20–23].
Temporary discontinuation is sometimes necessary prior to scheduled surgery or during
prolonged, intense physical activity (e.g., long-distance running) to reduce the risk of diabetic
ketoacidosis (DKA). Likewise, temporarily pausing treatment is often recommended when
a patient experiences acute illness leading to reduced oral intake or is hospitalized for a
medical or surgical condition until the acute phase resolves. Other indications for temporary
interruption include an initial eGFR decline of more than 30%, which requires the correction
of hypovolemia, or the occurrence of genital mycosis with significant clinical manifestations,
in which case, treatment is resumed after the infection is resolved with antifungal therapy.
However, the permanent discontinuation of SGLT-2i therapy may deprive patients of the
drug’s metabolic and cardiorenal benefits, potentially increasing morbidity and mortality.

Table 1. Causes of SGLT-2i treatment interruption in clinical trials and in real-world studies [16,20–23].

1. Temporary Interruption

a. Scheduled surgery (72 hours before)

b. Intense and prolonged physical activity
c. Acute illness with reduced oral intake
J. Clin. Med. 2024, 13, 6509 4 of 28

Table 1. Cont.

d Hospitalization for severe medical illness or major surgery

e Volume depletion
f Initial drop in eGFR > 30%
g Severe genital mycosis
h Pyelonephritis or urinary sepsis
i Fournier’s gangrene
j Pregnancy and lactation

2. Permanent Interruption

a. Recurrent GU infections
b. DKA
c. Increased urinary frequency not tolerated by the patient
d. Initiation of dialysis or renal transplant
e. Diagnostic reclassification from type 2 diabetes to type 1
f. Hypersensitivity reaction to the drug or the excipients

The AEs most frequently leading to SGLT-2i discontinuation in RCTs are summarized
in Table 2 [2–4,12,24–32]. In the four major CV safety studies of SGLT-2is, the frequency
of AEs leading to treatment discontinuation was similar between the active treatment
and placebo groups, as follows: CANVAS (canagliflozin): 35.5 vs. 32.8 participants with
an event per 1000 patient years; DECLARE (dapagliflozin): 8.1% vs. 6.9%; EMPA-REG
OUTCOME (empagliflozin): 17.3% vs. 19.4%; and VERTIS CV (ertugliflozin): 7.3% vs.
6.8% [2–4,32]. Genital mycotic infections (GMIs) are definitely the leading cause of SGLT-2i
withdrawal due to AEs, as seen in both RCTs and real-world observational studies [33–35].
Nonetheless, the absolute increase in the risk of AEs associated with SGLT-2i use remains
lower than the absolute risk reductions in CV and renal morbidity and mortality offered by
these drugs [36].

Table 2. Frequency of AEs in RCTs with SGLT-2is. Comparison of maximum dose of SGLT-2is vs.
placebo. References [3,4,12,24–32]. GMIs: genital mycotic infections. UTIs: urinary tract infections.
DKA: diabetic ketoacidosis. NR: not reported.

Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin

GMIs
Females 11.6% vs. 2.8% 6.9% vs. 1.5% 6.4% vs. 1.5% 12.2% vs. 3.3%
Males 3.8% vs. 0.7% 2.7% vs. 0.3% 1.6% vs. 0.4% 4.2% vs. 0.4%
UTIs 4.3% vs. 4.0% 4.7% vs. 3.5% 7.0% vs. 7.2% 4.1% vs. 3.9%
Volume depletion 1.3% vs. 1.1% 1.1% vs. 0.7% 0.4% vs. 0.3% <2% vs. <2%
Increased urination 4.6% vs. 0.7% 3.8% vs. 1.7% 3.3% vs. 1.4% 2.4% vs. 1.0%
DECLARE: EMPA-REG: VERTIS-CV:
DKA - CANVAS: 0.6/1000 pat-y vs. 0.3/1000 pat-y
0.31% vs. 0.14% <0.1% vs. <0.1% 0.4% vs. 0.1%

- CANVAS: 2.4% vs. 1.1% DECLARE: EMPA-REG: VERTIS-CV:

Amputations
- CREDENCE: 3.2% vs. 3.1% 1.4% vs. 1.3% 1.9% vs. 1.8% 2.1% vs. 1.6%

- CANVAS: 1.8/100 pat-y vs. 1.1/100 pat-y

DECLARE: EMPA-REG: VERTIS-CV:
Bone fractures - CANVAS-R: 1.1/100 pat-y vs. 1.3/100 pat-y
5.3% vs. 5.1% 3.7% vs. 3.9% 3.7% vs. 3.6%
- CREDENCE 1.2/100 pat-y vs. 1.2/100 pat-y

Fournier’s DECLARE: VERTIS-CV:

NR NR
Gangrene 0.01% vs. 0.06% 0% vs. 0%
J. Clin. Med. 2024, 13, 6509 5 of 28

5. AES Most Frequently Associated with SGLT-2is

A systematic review and network meta-analysis of 816 RCTs, involving 471,038 pa-
tients and evaluating 13 different drug classes for T2DM, confirmed that SGLT-2is signifi-
cantly increase the risk of GMIs (OR 3.30) and DKA (OR 2.07) compared to other therapeutic
classes [37]. These AEs occur less frequently in individuals without diabetes [38,39].
In a recent meta-analysis of nine SGLT-2is across 113 RCTs versus placebo, including
105,293 adult patients, statistically significant increases in GMIs (4.5% vs. 1.0% with placebo)
and polyuria (2.7% vs. 0.8% with placebo) were observed [40]. The incidence of other AEs
did not differ significantly between SGLT-2is and placebo, as follows: hypovolemia (2.4%
vs. 2.0%), renal insufficiency (1.7% vs. 1.2%), acute renal failure (2.0% vs. 2.2%), urinary
tract infections (UTIs) (6.8% vs. 5.1%), fractures (3.4% vs. 3.3%), DKA (0.3% vs. 0.1%),
amputations (1.6% vs. 1.4%), and severe hypoglycemia (1.9% vs. 1.9%).
When restricted to large CV and renal safety trials, the risk of certain AEs, including
GMIs (RR 3.75), volume depletion (RR 1.14), and DKA (RR 2.57), significantly increased
compared to placebo [36,41]. However, the association between SGLT-2i use and other
AEs, such as amputations, fractures, and UTIs, remains inconsistent across published meta-
analyses [36,41,42]. The controversial increase in amputations observed with canagliflozin
in the CANVAS trial has not been corroborated by other RCTs or meta-analyses specifically
evaluating this AE [43]. The safety outcomes identified in RCT meta-analyses have also
been confirmed in real-world cohort studies [44,45]. A cohort study of patients with HF
found no significant difference in the risk of UTIs or GMIs among those who initiated
treatment with canagliflozin, dapagliflozin, or empagliflozin [46].
Other notable AEs, while not life-threatening, can be bothersome. Lower urinary
tract symptoms (LUTSs), including polyuria, nocturia, urinary frequency, and urgency, are
common due to the diuretic and natriuretic effects of SGLT-2is [16]. The degree of polyuria
tends to be greater in individuals with more pronounced hyperglycemia, although this
effect is typically transient. In some patients, particularly those on high-dose diuretics,
these effects can lead to volume depletion and hypotension, which may be more severe
in patients with diabetes and autonomic neuropathy [47]. These AEs are less common in
individuals without diabetes [13].

5.1. Genital Mycotic Infections

The risk of developing GMIs can increase up to fivefold in patients treated with
SGLT-2is, with the greatest risk occurring within the first month of treatment and persist-
ing throughout its duration [16,48]. GMI is the most common AE listed in the prescrib-
ing information for the four EMA-approved SGLT-2is, with an incidence rate of 5% or
higher [2–4,12,24–31]. In RCTs, most GMIs were mild and did not lead to drug discon-
tinuation. However, their proper identification and management are essential to patient
care [23]. Glycosuria resulting from diabetes likely creates a favorable substrate for the
growth of organisms, particularly Candida species, and this effect is further amplified
by the pharmacologic glycosuria induced by SGLT-2is. Additionally, Candida albicans
has unique mechanisms that promote growth in glucose-rich environments, including a
glucose-inducible protein that enhances adhesion and impairs phagocytosis by the host
immune system [49]. Other species, such as Candida glabrata, may also be implicated in
GMIs, posing a challenge due to their poor response to azole antifungal agents. Identifying
these species is important for tailoring treatment strategies and assessing the potential need
to discontinue SGLT-2is [50].
GMIs associated with SGLT-2is are more common in women than in men and in
patients with a history of chronic or recurrent GMIs. Poor genital hygiene can exacerbate
these infections by further promoting fungal growth, especially in uncircumcised men with
diabetes [23]. However, other variables, such as the duration of diabetes, HbA1c levels,
BMI, eGFR, and previous urinary issues, have not been found to be associated with an
increased risk of infection in observational studies [51].
J. Clin. Med. 2024, 13, 6509 6 of 28

5.2. Urinary Tract Infections

Individuals diagnosed with T2DM are more susceptible to UTIs and recurrent UTIs
compared to those without T2DM. A large retrospective cohort study, which included
179,580 individuals with T2DM, found that UTIs were more prevalent among patients with
diabetes (9.4% vs. 5.7%), with a higher incidence in women (14% vs. 5%) [52]. Although the
exact mechanisms underlying the increased risk of UTIs in diabetes remain only partially
understood, several pathogenetic factors likely contribute to this association. These include
the following: (1) higher glucose concentrations in the urine, which alter the urinary
microenvironment and promote the growth of various uropathogens; (2) impaired immune
responses in patients with diabetes, including defects in polymorphonuclear leukocyte
function, adhesion, chemotaxis, and phagocytosis, which may reduce the body’s ability
to defend against bacterial proliferation; (3) increased bacterial adherence to uroepithelial
cells, which correlates with elevated HbA1c levels; (4) diabetic autonomic neuropathy,
which can cause GU dysfunction, leading to bladder dysfunction and increasing the risk of
UTIs; and (5) patient-related factors such as age, poor metabolic control, and the duration
of diabetes, which further elevate the risk of infection [52,53].
While Escherichia coli (E. coli) is the most common pathogen in uncomplicated UTIs,
patients with diabetes are more susceptible to a broader range of uropathogens, including
Klebsiella spp., Staphylococcus aureus, Enterobacter spp., Proteus spp., Pseudomonas spp., Group
B Streptococci, and Enterococcus faecalis, among others [53]. The glucose-rich environment
in the urine of patients with diabetes may contribute to an increased virulence of certain
pathogens, such as Proteus spp., which utilize glucose as a primary nutrient source. Con-
versely, studies indicate that E. coli primarily relies on peptides and amino acids for growth
in the urinary tract, with glucose playing a less central role in its metabolism [54]. Under
the nutrient-limited conditions of the urinary system, E. coli has adapted to utilize these
smaller molecules through various metabolic pathways, such as peptide import and amino
acid catabolism, in order to meet its carbon and nitrogen needs. In contrast, the Proteus
species, another common uropathogen, is known to utilize glucose more efficiently as a
nutrient source under these conditions [55]. This distinction is important, as it reflects how
different bacterial species adapt to the nutrient restrictions of the urinary environment and
how glucose may contribute to the virulence of certain pathogens like Proteus spp., but not
necessarily E. coli. These findings highlight the complexity of bacterial metabolism and its
role in UTIs among patients with diabetes, where the presence of glucose in the urine may
favor the growth of specific pathogens, while other bacteria like E. coli thrive on different
nutrient sources.
Since SGLT-2is increase glucose availability in the urinary tract, they provide a poten-
tial substrate for bacterial growth, raising concerns about their association with GU tract
infections [56]. While SGLT-2is have been consistently associated with an increased risk
of GMIs, the link between these drugs and bacterial UTIs remains unclear, with previous
publications reporting conflicting findings. The incidence of UTIs in patients receiving
SGLT-2is is significantly lower than that of GMIs, ranging from 3% to 9%. The incidences
of both complications, as reported in prescribing information, are presented in Table 2.
However, real-world studies have communicated a lower-than-expected prevalence of
UTIs [57]. In these studies, UTIs were typically mild to moderate and rarely resulted in treat-
ment discontinuation. In an analysis of 1663 patients, where the reasons for dapagliflozin
discontinuation were evaluated, UTIs accounted for only 0.45% of cases [33].
A recent analysis of the FDA Adverse Event Reporting System, which included
1714 UTI cases in patients taking SGLT-2is, suggested an increased risk of UTIs [58]. However,
most meta-analyses and RCTs have not demonstrated a significant association between SGLT-2i
use and UTI risk [3,4,12,13,18,36,40,41,59–65] For instance, a meta-analysis of multiple RCTs
involving over 50,000 individuals did not show an increased risk of UTIs with SGLT-2i use
compared to placebo [60] (Table 3). Similarly, meta-analyses and retrospective cohort studies
comparing the UTI risk between SGLT-2is and active comparators did not detect a significant
increased risk of UTIs in patients receiving SGLT-2is [3,4,12,13,18,36,40,41,59–65].
J. Clin. Med. 2024, 13, 6509 7 of 28

Table 3. Studies comparing UTI risk between SGLT-2is and placebo or active comparators. Adapted
from [59].

Studies Comparing UTI Risk Between SGLT2is and Placebo

Comparison Study [ref.] Patients (n) Outcome
Meta-analysis
SGLT2is vs. placebo Puckrin et al [60] 72 trials: 37,116 Risk ratio 1.03; (95% CI: 0.96 to 1.11)
Risk ratio: 1.08; (95% CI: 1.00 to 1.18).
SGLT2is vs. placebo Johansen et al [36] 8 trials; 49,587
p = 0.77
Risk ratio: 1.09; (95% CI: 0.99 to 1.15).
SGLT2is vs. placebo Qiu et al [41] 8 trials 63,237
p = 0.77
Risk ratio: 1.29; (95% CI: 1.06 to 1.57)
SGLT2is vs. placebo Liu et al [61] 17 trials: 4,997,145
p = 0.65
Randomized controlled trials
CREDENCE: Canagliflozin
Perkovic et al [12] 4397 HR 1.08; (95% CI: 0.90 to 1.29)
(100 mg) vs. placebo
CANVAS: Canagliflozin 40 vs. 37 participants with an event per
Neal et al [3] 4330
(all doses) vs. placebo 1000 patient years; p = 0.38
DAPA-CKD: Dapagliflozin No difference reported; details
Heerspink et al [13] 4298
(10 mg) vs. placebo unpublished
DECLARE: Dapagliflozin
Wiviott et al [4] 17,143 HR 0.93; (95% CI: 0.73 to 1.18); p = 0.54
(10 mg) vs. placebo
eGFR < 60 mL/min per 1.73 m2 : Rate
EMPA REG OUTCOME:
ratio: 1.06; (95% CI: 0.86 to 1.3)
Empagliflozin (all doses) vs. Wanner et al [18] 7018
eGFR ≥ 60 mL/min per 1.73 m2 : Rate
placebo
ratio 0.92; (95% CI: 0.8 to 1.07)
SGLT2is vs. placebo Bai et al [62] 3 trials 17,802 HR 1.00; (95% CI: 0.90 to 1.11), p = 0.958
Studies comparing UTI risk between SGLT2is and active comparators
Comparison Study [ref.] Patients (n) Outcome
Meta-analysis
Random-effects model risk ratio 1.08;(95%
SGLT2is vs. Active comparator Puckrin et al [60] 22 trials: 15,966 patients
CI: 0.93 to 1.25)
Retrospective cohort
Composite genitourinary infection
SGLT2is vs. GLP1-RA Varshney et al [64] 474 patients
HR 0.78; (95% CI: 0.26 to 2.37)
SGLT2is vs. DPP4i Fisher et al [65] 416,488 patients Urosepsis HR 0.58; (95% CI: 0.42 to 0.80)
Severe UTI:
- SGLT2is vs. DPP4i: HR 0.98; (95%
CI: 0.68 to 1.41)
- SGLT2is vs. GLP1-RA: HR 0.72;
SGLT2is vs. DPP4i: (95% CI: 0.53 to 0.99)
n 123,752;
SGLT2is vs. DPP4i or GLP1-RA Dave et al [63] Treated outpatient UTI:
SGLT2is vs. GLP1-RA:
n 111,978 - SGLT2is vs. DPP4i: HR 0.96; (95%
CI: 0.89 to 1.04)
- SGLT2is vs. GLP1-RA: HR 0.91;(95%
CI: 0.84 to 0.99)

SGLT2is vs. active comparator Li CX et al [40] 40 trials, 9,911,454 patients HR 0.99; (95% CI: 0.89 to 1.10), p = 0.83

A possible explanation for the lack of real-world evidence for increased clinically
significant UTIs, despite glycosuria and the favorable environment for bacterial growth,
may be related to the increased urinary flow rate resulting from the osmotic diuresis and
natriuresis effects of SGLT-2is. This diuretic effect may reduce bacterial loads and/or
prevent the ascension of bacteria within the urinary tract [49]. Nevertheless, anecdotal
reports of serious complications such as urosepsis have been noted for patients receiving
SGLT-2is, particularly in cases of urinary tract obstruction or an abnormal urinary flow [66].
J. Clin. Med. 2024, 13, 6509 8 of 28

It is important to consider these risks in patients with bladder outlet obstruction prior to
prescribing SGLT-2is.
In summary, current data from multiple real-world studies and meta-analyses suggest
no increased risk of clinically significant UTIs with SGLT-2i use. The discontinuation of
SGLT-2is due to mild UTI-related complications may deprive patients of the significant CV
and renal benefits that these drugs provide. Although a clear association between SGLT-2i
use and UTIs has not been established, clinicians should remain cautious when prescribing
these drugs to patients with serious or recurrent urogenital infections, an abnormal urinary
flow (e.g., incomplete bladder emptying with urinary stasis), or indwelling Foley catheters.

5.3. Pollakiuria and Nocturia

SGLT-2is exert their antihyperglycemic and diuretic effects by inhibiting the reabsorp-
tion of sodium and glucose in the proximal tubule, leading to natriuresis and osmotic
diuresis. These effects can potentially cause LUTSs, which include urinary frequency,
urgency, polyuria, and nocturia. This condition, known as overactive bladder, is more
common in older adults and individuals with diabetes, especially those with poor metabolic
control and/or autonomic neuropathy [67]. Although these new-onset LUTSs are typically
mild, they can significantly impact quality of life by increasing urinary frequency and
causing sleep disturbances [68].
Any intervention that increases urine output, including SGLT-2is, can exacerbate
LUTSs. While no definitive mechanism has been established for these findings, it is specu-
lated that natriuresis and glycosuria-induced osmotic diuresis may contribute to symptoms
like pollakiuria and nocturia. The increase in urine output after starting SGLT-2i treatment
is transient, typically returning to baseline between the second and fifth day of treatment,
with an average increase of about 267 mL/day in people with diabetes [69]. This transient
effect may occur due to compensatory sodium reabsorption by other nephrons following
the initial natriuresis triggered by SGLT-2is. Additionally, SGLT-2i-induced reductions in
plasma volume and BP activate the sympathetic nervous system and the renin–angiotensin–
aldosterone system, further increasing sodium reabsorption [70]. Natriuresis following
SGLT-2i treatment is dose-dependent, with increases observed 24 h after administration
and returning to baseline within 2–15 days, depending on the study [69–71].
In individuals without diabetes, SGLT-2 accounts for only about 5% of their total
renal sodium chloride reabsorption, but this percentage is much higher in patients with
diabetes. This occurs because changes in glucose or sodium filtration modulate SGLT-2
gene expression in the renal proximal tubule’s epithelial cells [72]. This difference may
explain why these AEs are less common in individuals without diabetes.
When combined with loop diuretics, SGLT-2is exert synergistic effects. In patients
with HF, the coadministration of SGLT-2is and loop diuretics resulted in a fourfold increase
in fractional sodium excretion compared to monotherapy [73]. Despite this, SGLT-2is
are generally well-tolerated, with few reports of renal function decline, hypokalemia, or
hyponatremia [6].
While few studies have examined the effects of SGLT-2is on LUTSs outside of RCTs,
one case series involving 50 men with T2DM reported an increase in urinary frequency
and nocturia after initiating SGLT-2is, affecting nearly all participants [68]. Therefore, these
symptoms may be more significant in real-world settings, where patients are often older
than those enrolled in RCTs.
In general, it is not necessary to recommend an increased fluid intake after initiating
SGLT-2i therapy, as the diuresis is typically transient. However, it is crucial to inform
patients about this potential effect. In some cases, loop diuretic doses may need to be re-
duced upon the initiation of SGLT-2is to avoid excessive diuresis. Conversely, encouraging
additional fluid intake could be harmful, as it may exacerbate LUTSs and lead to drug
discontinuation or noncompliance. Identifying the patients most likely to develop LUTSs
after starting SGLT-2is—such as older adults, individuals with diabetes and poor metabolic
control, and those with preexisting LUTSs—is important for providing appropriate coun-
 upon the initiation of SGLT-2is to avoid excessive diuresis. Conversely, encouraging ad-
ditional fluid intake could be harmful, as it may exacerbate LUTSs and lead to drug dis-
continuation or noncompliance. Identifying the patients most likely to develop LUTSs af-
ter starting SGLT-2is—such as older adults, individuals with diabetes and poor metabolic
J. Clin. Med. 2024, 13, 6509 9 of 28
control, and those with preexisting LUTSs—is important for providing appropriate coun-
seling and making necessary adjustments to their treatment. The CV and renal benefits of
SGLT-2is definitely outweigh the mild AEs some patients may experience.
seling and making necessary adjustments to their treatment. The CV and renal benefits of
6. SGLT-2is
Preventiondefinitely
of GU AEsoutweigh the mild
Associated withAEs some patients may experience.
SGLT-2is
As previously
6. Prevention mentioned,
of GU the mostwith
AEs Associated common AEs associated with SGLT-2is are GMIs.
SGLT-2is
While UTIs are not definitively linked to SGLT-2is, they may still occur during therapy,
As previously mentioned, the most common AEs associated with SGLT-2is are GMIs.
and are often cited as a reason for discontinuation. Healthcare professionals should coun-
While UTIs are not definitively linked to SGLT-2is, they may still occur during therapy, and
sel patients receiving these medications on preventive measures, inform them about the
are often cited as a reason for discontinuation. Healthcare professionals should counsel
clinical manifestations of GU infections, and provide guidance on appropriate actions if
patients receiving these medications on preventive measures, inform them about the clinical
they occur. The prescribing
manifestations information
of GU infections, for SGLT-2is
and provide guidancerecommends
on appropriatemonitoring
actions if for
theysigns
occur.
and symptoms of UTIs and GMIs, with prompt treatment if necessary [74,75].
The prescribing information for SGLT-2is recommends monitoring for signs and symptoms
In a real-world
of UTIs and GMIs, study, 125 patients
with prompt withifT2DM
treatment who[74,75].
necessary initiated SGLT-2i therapy were
given hygiene advice [76]. The incidence of GMIs in these
In a real-world study, 125 patients with T2DM who initiated patients SGLT-2i
was compared
therapywithwere
that of 125
given individuals
hygiene advicewho
[76].did
Thenot receive of
incidence hygiene advice.
GMIs in these The studywas
patients showed a significant
compared with that
reduction in the risk who
of 125 individuals of GMIs among
did not patients
receive whoadvice.
hygiene receivedThehygiene guidancea (4.8%
study showed vs.
significant
40.8% over 6 months, p = 0.015), and compliance was significantly higher in
reduction in the risk of GMIs among patients who received hygiene guidance (4.8% vs.this group.
40.8% over 6 months, p = 0.015), and compliance was significantly higher in this group.
6.1. Urinary Tract Infections
6.1.The
Urinary Tract Infections
following practices can help to maintain genital health and reduce the risk of
infections
Theand discomfort
following (Figure
practices can1):help
[74–78].
to maintain genital health and reduce the risk of
infections and discomfort (Figure 1): [74–78].

Figure
Figure 1. 1. Clinical
Clinical recommendations
recommendations forfor
thethe prevention
prevention of of urinary
urinary tract
tract infections
infections in in patients
patients treated
treated
with
with SGLT-2
SGLT-2 inhibitors.
inhibitors.

Stay
Stay hydrated—drinking
hydrated—drinking plenty
plenty of of fluids
fluids helps
helps toto maintain
maintain urinary
urinary tract
tract health
health byby
increasing urine output, which dilutes the urine and assists in flushing out
increasing urine output, which dilutes the urine and assists in flushing out bacteria. bacteria.
Avoid
Avoid holding
holding urine—delaying
urine—delaying urination
urination can
can lead
lead to to bacterial
bacterial growth
growth in in
thethe bladder,
bladder,
increasing
increasing thethe risk
risk ofof recurrent
recurrent UTIs.It It
UTIs. is is important
important toto empty
empty thebladder
the bladderregularly.
regularly.
Urinate before and after sexual activity—this simple habit can reduce the likelihood of
UTIs by up to 80%.
Evaluate contraceptive methods—some contraceptives, such as spermicides or certain
types of condoms, may increase the risk of UTIs. If a woman is prone to UTIs, she should
consult her gynecologist about alternative methods that may be better suited for her.
Ensure proper lubrication during sexual activity—insufficient lubrication can lead to
vaginal irritation, which may increase the risk of infection. Using a high-quality lubricant
can help to prevent this.
 Urinate before and after sexual activity—this simple habit can reduce the likelihood
of UTIs by up to 80%.
Evaluate contraceptive methods—some contraceptives, such as spermicides or cer-
tain types of condoms, may increase the risk of UTIs. If a woman is prone to UTIs, she
should consult her gynecologist about alternative methods that may be better suited for
J. Clin. Med. 2024, 13, 6509 10 of 28
her.
Ensure proper lubrication during sexual activity—insufficient lubrication can lead to
vaginal irritation, which may increase the risk of infection. Using a high-quality lubricant
can help to prevent
Avoid this.intimate products—overly perfumed or irritating hygiene products
irritating
Avoid irritating
can disrupt intimate
the natural pH products—overly
balance, increasing perfumed or irritating
vulnerability hygiene products
to infections. Instead, gentle,
can
pH-balanced products should be opted for, and their use should beInstead,
disrupt the natural pH balance, increasing vulnerability to infections. limitedgentle,
to once daily.
pH-balanced productsover
Favor showers should be opted for,an
baths—while and their use bath
occasional should be limited
is fine, showersto once
are daily.
recommended
Favor showers over baths—while an occasional bath is fine, showers are recom-
for daily hygiene to reduce the risk of introducing bacteria into the genital area.
mended for daily hygiene to reduce the risk of introducing bacteria into the genital area.
Address constipation—chronic constipation can contribute to UTIs by allowing bacte-
Address constipation—chronic constipation can contribute to UTIs by allowing bac-
ria to colonize areas near the urinary tract. Managing constipation and not delaying bowel
teria to colonize areas near the urinary tract. Managing constipation and not delaying
movements
bowel can help
movements to reduce
can help thisthis
to reduce risk.
risk.
Choose appropriate clothing—cotton
Choose appropriate clothing—cotton underwear underwear
shouldshould
be opted befor
opted for and
and overly overly tight
tight
clothingshould
clothing should bebe avoided,
avoided, which
which can create
can create a moist
a moist environment
environment conducive conducive to bacterial
to bacterial
growth.
growth.
Avoidtampons
Avoid tampons if prone
if prone to UTIs—tampon
to UTIs—tampon use, particularly
use, particularly during during the premenstrual
the premenstrual
period,
period,hashasbeen associated
been with an
associated increased
with incidenceincidence
an increased of UTIs. IfofthisUTIs.
is a concern,
If thisalter-
is a concern,
natives such as pads or menstrual cups, or changing tampons more frequently,
alternatives such as pads or menstrual cups, or changing tampons more frequently, should be should
considered.
be considered.
6.2.
6.2.Genital
GenitalInfections
Infections
To help prevent these infections in patients using SGLT-2is, healthcare professionals
To help prevent these infections in patients using SGLT-2is, healthcare professionals
may recommend the following recommendations (Figures 2 and 3): [76,78–83].
may recommend the following recommendations (Figures 2 and 3): [76,78–83].

J. Clin. Med. 2024, 13, x FOR PEER REVIEW 11 of 29

Figure 2. Clinical recommendations for the prevention of genital mycotic infections in women treated
Figure 2. Clinical recommendations for the prevention of genital mycotic infections in women
with SGLT-2
treated inhibitors.
with SGLT-2 inhibitors.

Figure 3. Clinical recommendations for the prevention of genital mycotic infections in men treated
Figure 3. Clinical recommendations for the prevention of genital mycotic infections in men treated
withSGLT-2
with SGLT-2 inhibitors.
inhibitors.

6.2.1. Daily Intimate Hygiene for Females

Cleanse with water and mild soap—the intimate area should be washed twice daily—
once in the morning and once before bed. The vulva should be cleaned thoroughly, in-
cluding the folds of the labia majora and minora and around the clitoris.
J. Clin. Med. 2024, 13, 6509 11 of 28

6.2.1. Daily Intimate Hygiene for Females

Cleanse with water and mild soap—the intimate area should be washed twice
daily—once in the morning and once before bed. The vulva should be cleaned thoroughly,
including the folds of the labia majora and minora and around the clitoris.
Keep the area dry—maintaining dryness is critical in preventing infections. The area
is prone to moisture accumulation due to contact with urine, sweat, vaginal discharge,
menstruation, and limited ventilation, making it susceptible to microbial growth.
Wear breathable underwear—cotton underwear should be chosen and tight-fitting or
synthetic fabrics should be avoided.
Change immediately after physical activities—after exercising or swimming, people
should dry themselves thoroughly and change into clean, dry underwear.
Avoid perfumes and antiseptic—perfumes or antiseptics should not be applied to the
intimate area unless prescribed by a healthcare professional.
Change menstrual products regularly—during menstruation, pads or tampons must
be changed frequently to maintain hygiene.

6.2.2. Daily Intimate Hygiene for Males

Wash daily with soap and water—the genital area should be cleansed daily, while
avoiding using sponges or gloves, which can harbor contaminants like fungi.
Wipe after urination—clean paper should be used to wipe the genital area after
urinating.
Thoroughly clean the area—cleansing should be performed from the anus to the penis,
groin, testicles, and scrotum, then rinsed thoroughly to avoid irritation.
Uncircumcised men should clean under the foreskin—the foreskin should be gently
pulled back and the glans should be washed to ensure proper hygiene.
Avoid creams, deodorants, or powders—these should only be used if prescribed for
irritation, injury, or dryness. Products recommended by a healthcare professional should
always be used.
Dry thoroughly—the area must be completely dry after washing to prevent moisture
buildup, which fosters fungal and bacterial growth. A towel dedicated exclusively for this
purpose can be used.
If patients experience any signs of infection—such as irritation, itching of the external
genital area, burning during urination, painful intercourse, swelling of the vulva, or
unusual discharge with an unpleasant odor—they should consult their healthcare provider
immediately.

7. Treatment of GU AEs Associated with SGLT-2is

7.1. Genital Infections
Patients with certain risk factors are more susceptible to fungal GU infections, and
screening for infections should be part of every appointment. Risk factors, other than SGLT-
2is, include a history of genital infections, obesity (especially in postmenopausal women),
uncircumcised men, and concurrent use of sulfonylurea or insulin. Patients experiencing
infection or undergoing antibiotic treatment should not start SGLT-2i therapy until the
infection has resolved.
Asymptomatic candiduria should not be treated unless specific conditions are present.
Antifungal treatment is recommended for neutropenic patients and those undergoing
urinary tract procedures. There is no evidence to support treating asymptomatic candiduria
in patients on SGLT-2i therapy. Addressing predisposing factors may help to prevent further
infections [23,58,84–86].
Most genital infections associated with SGLT-2i therapy are mild to moderate and
respond to standard antimicrobial treatment, without the need to discontinue therapy
(Figure 4) [58,84,86]. Prompt treatment is associated with better outcomes, and reinforcing
perineal hygiene significantly reduces the incidence of genital infections in patients on SGLT-
2is [15,23,87]. Patients can generally expect improvement in 24 to 48 h. Complete resolution
 vent further infections [23,58,84–86].
Most genital infections associated with SGLT-2i therapy are mild to moderate and
respond to standard antimicrobial treatment, without the need to discontinue therapy
(Figure 4) [58,84,86]. Prompt treatment is associated with better outcomes, and reinforcing
J. Clin. Med. 2024, 13, 6509 perineal hygiene significantly reduces the incidence of genital infections in patients on
12 of 28
SGLT-2is [15,23,87]. Patients can generally expect improvement in 24 to 48 h. Complete
resolution may take one to two weeks. Routine discontinuation of SGLT2is in the setting
of
mayGUtake
infections
one to istwo
notweeks.
recommended.
RoutinePatients with fungal
discontinuation pyelonephritis
of SGLT2is in the require
setting hospi-
of GU
talization, and surgical treatment is indicated cases involving fungal balls. This severe
infections is not recommended. Patients with fungal pyelonephritis require hospitalization,
condition
and surgicalnecessitates
treatmentthe discontinuation
is indicated of SGLT-2is,
cases involving which
fungal should
balls. Thisalso be avoided
severe in
condition
the future [88].
necessitates the discontinuation of SGLT-2is, which should also be avoided in the future [88].

Figure
Figure 4.
4. Clinical
Clinical recommendations
recommendations for for the
the management
management of
of genital
genital mycotic
mycotic infections
infections in patients
in patients
treated with SGLT-2 inhibitors. * Plus hydrocortisone 1% cream in balanitis. ** In vulvovaginal
treated with SGLT-2 inhibitors. * Plus hydrocortisone 1% cream in balanitis. ** In vulvovaginal can-
didiasis. *** In balanitis.
candidiasis. *** In balanitis.

Genital candidiasis
candidiasis should
should be
be treated with standard antifungal therapy. Since most
safety studies
studies report
reportinfection
infectiononset
onset within
within thethe
firstfirst
3–6 3–6 months
months of SGLT-2i
of SGLT-2i therapy,
therapy, main-
taining a high clinical suspicion and ensuring rapid management during this period are
recommended [89]. Clinical trial data with canagliflozin suggest that the frequency of
genital infections decreases over time, with the lowest incidence observed after 21 months
of therapy [90,91]. Additionally, there is no clear dose–response relationship between
SGLT-2is and genital infections [89].
Genital infections associated with SGLT-2is are classified as sporadic if they occur
fewer than three times per year [87,91,92]. When treating these sporadic episodes, several
key factors must be considered, as follows: patient preferences, allergies and tolerance,
preferred treatment duration, prior response history, drug interactions, the patient’s preg-
nancy status, the presence of mild to moderate symptoms, the likelihood of Candida albicans
infection (responsible for approximately 90% of cases), the patient’s immunocompetence,
availability, and cost [79,92–95].

7.1.1. Acute Episodes in Women

Treatment is recommended for women with symptomatic fungal vaginal infections.
Asymptomatic women identified through screening, such as Pap smears, do not require
treatment. Culture sampling is generally unnecessary for a first episode unless there is
suspicion of other infections, such as trichomoniasis or bacterial vaginosis [88,92]. Most
vulvovaginal candidiasis (VVC) cases are caused by Candida albicans, with Candida glabrata
and Candida krusei being less common.
Treatment should be individualized, as previously noted. Uncomplicated VVC can
be managed with oral azoles, topical azoles, or triterpenoid drugs (Table 4, Figure 4), with
no single regimen demonstrating superiority [84,87,88,92,94]. A single 150 mg dose of oral
J. Clin. Med. 2024, 13, 6509 13 of 28

fluconazole may be considered as the first-line option for patients with poor adherence to
therapy, a preference for oral treatment, a history of poor response to topical therapies, or
moderate-to-severe infection. In cases of severe vaginitis, oral fluconazole at 150 mg every
72 h for two or three doses, depending on severity, is recommended. A low-potency topical
corticosteroid can be applied to the vulva for up to 48 h to alleviate symptoms until the
antifungal medication takes effect [88].

Table 4. Antifungal therapy for genital candidiasis. VVC: vulvovaginal candidiasis.

Genital Infection Treatment Recommendations

Topical antifungal agents, with no one agent being superior to another OR a single
150 mg oral dose of fluconazole
Topical agents:
- Clotrimazole 1% (1 application per day for 7 days) or 2% (1 application per
day for 5 days), OR
Uncomplicated acute VVC - Clotrimazole tablets 100 mg/d for 7 days, 200 mg/d for 3 days or 500 mg
single dose, OR
- Miconazole 2% daily for 7 days or 1200 mg vaginal suppository; OR
- Terconazole 0.8% vaginal cream daily for 3 days, OR
- Nystatin cream (100,000 units/g for 7 days) is an alternative for patients
allergic to imidazole

Topical antifungal agents, with no one agent superior to another OR a single

150 mg oral dose of fluconazole
Topical agents:
Uncomplicated acute Candida balanitis - Clotrimazole 1% once daily for 7 days or 2% once daily for 5 days
- Miconazole 2% twice daily for 7 days.
- Nystatin cream 100,000 units/g for 7 days if allergy to imidazole

Severe acute VVC or balanitis Oral fluconazole at 150 mg, given every 72 h for a total of 2 or 3 doses

- Topical intravaginal boric acid, administered in a gelatin capsule, 600 mg

daily, for 14 days OR
Candida glabrata or non albicans Candida VVC - Nystatin intravaginal suppositories, 100,000 units daily for 14 days OR
that is unresponsive to oral azoles - Topical 17% flucytosine cream alone or in combination with 3%
Amphotericin cream administered daily for 14 days
- Amphotericin B suppository 50 mg daily for 14 days

- Oral fluconazole at 150 mg with repeated doses on days 1, 3, and 7

- Topical agent 10–14 days of therapy, followed by oral fluconazole at 150 mg
weekly for 6 months OR
- Monthly oral fluconazole at 150 mg
- Weekly oral fluconazole at 150 mg for 6 months, with re-evaluation at
4–6 weeks. Repeat for another 6 months if no side effects or interactions
occur. Discontinue after one year.
Recurrent VVC or balanitis - Itraconazole 100 mg once daily orally for 6–12 months
- Oteseconazole—this oral azole is FDA-approved for non-pregnant adult
women. It is not approved in Europe for use in sporadic or acute VVC
infections
- Ibrexafungerp 300 mg orally twice a day for one day. Limit use to
non-pregnant patients who prefer oral dosing but cannot use oral
fluconazole (e.g., due to intolerance, allergy, or Candida infection resistant to
fluconazole). Dose reduction required if taken with strong CYP3A inhibitors

7.1.2. Acute Episodes in Men

Candida balanitis, the most common identifiable cause of balanitis, occurs more fre-
quently in men with diabetes, obesity, a history of sexually transmitted infections, and
those who are uncircumcised [95,96].
J. Clin. Med. 2024, 13, 6509 14 of 28

No studies on patients receiving SGLT-2is have demonstrated a superior efficacy of

any specific topical or oral regimen. Therefore, treatment choice should be reached in
consultation with the patient. First-line treatment includes topical antifungal agents or a
single 150 mg dose of oral fluconazole, following the same criteria used for women (Table 4,
Figure 4). Most RCTs involving SGLT-2is have shown that discontinuing therapy during an
episode of genital infection does not improve prognosis [81].
Clotrimazole 1% (applied once daily for 7 days) or 2% (applied once daily for 5 days)
or miconazole 2% (applied twice daily) can be used. Nystatin cream (100,000 units/g
for 7 days) is an alternative for patients allergic to imidazoles. For severe symptoms,
oral fluconazole every 72 h for two or three doses or a combination of topical imidazole
and hydrocortisone 1% cream applied twice daily may be considered. In uncircumcised
patients with nonspecific balanitis, saline solution baths may be effective. Alternative
therapies, such as dietary supplementation with lactobacillus-containing yogurt, are not
J. Clin. Med. 2024, 13, x FOR PEER REVIEW
recommended [92–94]. Female sexual partners of patients with balanitis should be 16 offered
of 29
testing for Candida or empiric treatment to reduce the likelihood of reinfection.

- 7.2. Acute UTIs

Amoxicillin–clavulanate 875 - Inpatient stay at a healthcare fa-
mg 7.2.1.
orally General
twice dailyRecommendations
for 7 cility
to 10 days Patients
or receiving SGLT-2is, particularly those- withUse ofdiabetes, should be TMP-
a fluoroquinolone, informed
- TMP-SMX
about theone double-
potential risk of UTIs and advised to seek SMX, or broad-spectrum
medical beta-
attention if symptoms
strength
arise tablet orally twice
[58,84,94,97]. lactam
daily for Routine
7 to 10 days
urine Avoid antibiotics
or cultures and prophylactic or preemptive with regional
antimicrobial therapyprev-
are not
- Cefpodoxime
recommended 200 mg fororally alence ofinitiating
preventing UTIs in asymptomatic patients resistanceSGLT-2is
known to[79,97].
twice daily for
Treating 7 to 10 days bacteriuria does not reduce thebe
asymptomatic >10%
risk of complicated infections and
or may contribute to increased antibiotic resistance [85,94,98].
Tailor antimicrobial therapy with re-
- Cefadroxil 1 g orally twice
Conversely, urine cultures should be obtainedsults of urine culture
in symptomatic susceptibility pre-
patients—those
daily for 7 to 10 days testing results
senting with dysuria, urinary frequency, urgency, suprapubic pain, abdominal or lumbar
- If low riskor
pain, offever—who
fluoroquino-are undergoing SGLT-2i treatment [85,94,99]. Empiric antimicrobial
lonetherapy
resistance/toxicity:
should be initiated in symptomatic patients and adjusted based on urine culture
• Ciprofloxacin 500 mg orally
and susceptibility test results, which are generally available within 48 h [94,99,100]. The
twice daily for 5 to 7 days
choice of empiric or should be based on the severity of illness, risk factors for resistant
therapy
• Levofloxacin 750 mg orally
pathogens, and patient factors such as allergies and prior antimicrobial use (Table 5 and
once daily for 5 to 7 days
Figure 5) [99].

Figure 5. Clinical recommendations for the management of urinary tract infections in patients treated
Figure 5. Clinical recommendations for the management of urinary tract infections in patients
with SGLT-2 inhibitors.
treated with SGLT-2 inhibitors.

Patients in RCTs taking SGLT-2is who developed a UTI did not stop taking the
blinded assigned study drug and there was no increased risk of UTI severity or recurrent
UTI compared to placebo [15]. Temporary discontinuation of the drug should, therefore,
be individualized and discussed with the patient.
J. Clin. Med. 2024, 13, 6509 15 of 28

Table 5. Antibacterial treatment for UTIs. IM: intramuscular; IV: intravenous; MDR: multidrug
resistance; TMP-SMX: trimethoprim-sulfamethoxazole; UTI: urinary tract infection.

Treatment
Agent Dosage Duration Comment
Acute cystitis
Trimethoprim–sulfamethoxazole One double-strength tablet (160 mg/800 Avoid if regional prevalence of resistance
3–7 days
(TMP-SMX) mg) orally twice daily known to be >20%
3 g of powder mixed in water and
Fosfomycin- trometahine Single dose Avoid if concern for early pyelonephritis
administered orally
Avoid if concern for early pyelonephritis
Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily 5–7 days OR
CrCl < 30 mL/min
400 mg pivmecillinam orally three times
Pivmecillinam 5–7 days Check for beta-lactam allergy
daily
Amoxicillin–clavulanate 500 mg orally twice daily 5–7 days Check for beta-lactam allergy
Cefadroxil 500 mg orally twice daily 5–7 days Check for beta-lactam allergy
Cephalexin 500 mg orally twice daily 5–7 days Check for beta-lactam allergy
250 mg orally twice daily
Ciprofloxacin or 3–5 days
500 mg extended release orally once daily
Levofloxacin 250 mg orally once daily 3–5 days
Recurrent cystitis
6 months with
re-evaluation at 4–6 weeks.
Fosfomycin- trometahine 3 g every 7 to 10 days Repeat for another
6 months if no side effects
or interactions occur
40 mg/200 mg once daily
Trimethoprim–sulfamethoxazole OR
40 mg/200 mg three times weekly
Trimethoprim 100 mg once daily
125 mg once daily
Cephalexin OR Check for beta-lactam allergy
250 mg once daily
Pyelonefritis

- Ceftriaxone 1 g IV or IM once daily

OR Use ertapenem in the case of risk factors
- Ertapenem 1 g IV or IM once daily for MDR Gram-negative UTIs
OR Any one of the following in the prior
Use urine culture to tailor therapy three months:
Some therapies could be the following: - Urinary isolate isolation of
- Amoxicillin–clavulanate 875 mg previous MDR, Gram-negative
orally twice daily for 7 to 10 days or (Pseudomonas deserves a different
- TMP-SMX one double-strength treatment)
tablet orally twice daily for 7 to - Inpatient stay at a healthcare
10 days or facility
- Cefpodoxime 200 mg orally twice - Use of a fluoroquinolone,
daily for 7 to 10 days or TMP-SMX, or broad-spectrum
- Cefadroxil 1 g orally twice daily for beta-lactam
7 to 10 days Avoid antibiotics with regional
- If low risk of fluoroquinolone prevalence of resistance known to be
resistance/toxicity: >10%
Tailor antimicrobial therapy with results
• Ciprofloxacin 500 mg orally twice of urine culture susceptibility testing
daily for 5 to 7 days or results
• Levofloxacin 750 mg orally once
daily for 5 to 7 days

Patients in RCTs taking SGLT-2is who developed a UTI did not stop taking the blinded
assigned study drug and there was no increased risk of UTI severity or recurrent UTI
compared to placebo [15]. Temporary discontinuation of the drug should, therefore, be
individualized and discussed with the patient.

7.2.2. Treatment of Outpatients

Patients with acute complicated UTIs of mild to moderate severity who can reliably
take oral medications may be treated on an outpatient basis.
J. Clin. Med. 2024, 13, 6509 16 of 28

Empiric antibiotic treatment—for patients without multidrug-resistant (MDR) infec-

tion risk, the antibiotic should be selected based on local resistance patterns. Beta-lactam
antibiotics, trimethoprim–sulfamethoxazole, and fluoroquinolone-based regimens are ef-
fective, but should be avoided in patients with allergies or intolerance. Fluoroquinolones
should not be used in patients with a prolonged QT interval or other risk factors for tor-
sades de pointes, and trimethoprim–sulfamethoxazole should be avoided in cases of renal
failure. Fosfomycin-tromethamine is an effective oral option for a first episode. Treatment
options are listed in Table 5 [94,99].
Guided antibiotic treatment—urine culture and susceptibility results should be moni-
tored to confirm the appropriateness of the empiric antimicrobial regimen and guide any
necessary adjustments. The treatment duration is typically 3–7 days, depending on the
clinical syndrome and the antibiotic chosen (see Table 5). Extended durations or further
evaluation may be required for patients with delayed improvement [94,99].

7.2.3. Hospitalization Indications

Patients with severe symptoms, high fever, low BP, marked debility, or suspected
urinary tract obstruction should be hospitalized. Outpatients with mild to moderate
symptoms can be treated with oral medications, considering the risk factors for MDR
infections [94,99]. These risk factors include prior MDR colonization, recent antibiotic use
(within the past month), anatomical abnormalities, urological manipulation, or healthcare-
associated infections [99].

7.3. The Challenge of Resistance to Antibiotic and Antifungal Therapy

Antibiotic and antifungal resistance poses a significant challenge in clinical man-
agement. Preventing the emergence of resistance through the proper treatment of acute
infections, reducing recurrences, and addressing modifiable risk factors is essential. The
use of antifungal and antibiotic therapies guided by susceptibility testing, along with
consultation from infectious disease specialists for multidrug-resistant species, can improve
outcomes in managing resistant infections [100].
Resistance patterns should be monitored regularly, with adjustments made to treat-
ment regimens based on susceptibility testing results. In some cases, combining antifungal
agents or rotating therapies may help to manage resistant infections. Reducing unneces-
sary antibiotic use and adhering to evidence-based guidelines are critical strategies for
mitigating resistance development [101–104].
Non-albicans Candida species, particularly C. glabrata and C. krusei, present significant
therapeutic challenges due to their inherent resistance to common antifungal agents and
the diversity of species involved. Guided antifungal therapy is recommended to enhance
effectiveness, minimize treatment burden, and reduce toxicity risks [50,105,106].

7.3.1. Assessment and Diagnosis

- Suspicion—C. glabrata or C. krusei infection should be suspected in cases of recurrence,
slow response to treatment, or poor progression of the episode.
- Identification of the causal agent—diagnosis should be confirmed through cultures
and susceptibility testing to identify the specific Candida species and its resistance
profile.
- Exclusion of other causes—before initiating treatment for VVC, it is important to
rule out other causes of vaginal symptoms, such as bacterial infections or sexually
transmitted diseases.

7.3.2. Treatment for Resistant Candida Species (Table 4)

- Vaginal Boric Acid—administration of 600 mg boric acid capsules vaginally each
night for 2 to 3 weeks. This treatment is effective in approximately 70% of patients
with confirmed C. glabrata infections. However, its use is contraindicated in pregnant
women due to limited safety data and the risk of toxicity if ingested [50].
J. Clin. Med. 2024, 13, 6509 17 of 28

- Topical azole—for individuals with C. krusei infection, treatment with a topical azole
(cream or suppository) is recommended.
- Amphotericin B Suppository—a 50 mg vaginal suppository of Amphotericin B, ad-
ministered for 14 nights, is effective in persistent cases of C. glabrata infection [105].
- Itraconazole—if topical treatments are ineffective, oral itraconazole can be considered
(200 mg twice daily). However, due to its potential toxicity, topical therapies should
remain as first-line treatments.
- Voriconazole—due to limited efficacy data and its potential hepatic toxicity, voricona-
zole should only be considered when all other topical and systemic therapies
have failed.
- Ibrexafungerp—this oral triterpenoid antifungal may be an option for resistant Can-
dida species, though data on its use are limited. Its mechanism of action helps to avoid
cross-resistance. Ibrexafungerp is FDA-approved for treating VVC in postmenarchal
women and girls, but is not yet approved by the EMA and may not be available in
certain countries [107].

7.3.3. Prevention
Preventive treatments, such as oral nystatin or probiotics, have shown limited suc-
cess [23,92]. Treating sexual partners is not recommended unless recurrent VVC is con-
firmed. It is also important to avoid potential triggers for recurrence, such as unnecessary
antibiotic use, and to discuss the continuation of SGLT-2is with patients in severe cases.

8. Treatment of GU AEs Associated with SGLT-2is in High-Risk Patients

8.1. Recurrent Infections
8.1.1. Genital Recurrent Infections
Recurrent genital infections are defined as more than three episodes per year. These
infections should be thoroughly evaluated using differential diagnosis to distinguish them
from conditions such as bacterial vaginosis, trichomoniasis, sexually transmitted infections,
or other forms of balanitis [88,92,101,108]. A genital exudate culture is essential to confirm
the diagnosis and assess for concurrent infections that may involve multiple organisms
requiring different treatments. While initial infections may not require microbiological
evaluation, recurrent episodes must be evaluated both clinically and microbiologically. A
culture-proven diagnosis with in vitro susceptibility testing is mandatory for recurrent
cases [88,101,108].
Recurrent infections can present with severe symptoms, including extensive erythema,
edema, and fissures. In males, chronic balanitis may result in ulcerative lesions of the glans
and foreskin, and potentially lead to meatal or urethral stricture. Chronic balanitis can
also predispose patients to premalignant and malignant lesions. In males with chronic
balanitis, careful inspection for phimosis and paraphimosis is essential. Circumcision
may be considered when balanitis recurs despite proper hygiene measures and directed
treatment [94,95].
Recurrent infections may be associated with persistent risk factors, drug resistance,
or inadequate prior treatments. Chronic management involves patient-specific treatment
plans considering drug interactions, prior response history, preferred treatment duration,
potential side effects, and cost. To date, high-quality evidence for treating recurrent VVC is
limited [101]. Given the lack of robust evidence for managing recurrent genital infections
in patients taking SGLT-2is, it is essential to discuss the risk–benefit balance of continuing
SGLT-2i therapy with the patient. Avoiding SGLT-2is may be considered for female patients
with a history of severe, recurrent fungal infections. Patients with balanoposthitis who are
already on SGLT-2is need not discontinue treatment. However, if the condition becomes
refractory or recurs frequently, switching from SGLT-2is might be considered.
The optimal treatment for recurrent VVC has yet to be defined, and must be indi-
vidualized [101,108]. Continuous or intermittent antifungal therapy may be necessary.
Some treatment regimens are provided in Table 4, assuming that sensitivity is confirmed.
J. Clin. Med. 2024, 13, 6509 18 of 28

Maintenance therapy with fluconazole at 150 mg weekly or itraconazole at 200 mg weekly

may help to control recurrences [101]. An extended fluconazole regimen comprises oral
induction with 150 mg every 72 h for three doses, followed by an oral maintenance dose of
150 mg once per week for six months. Oral fluconazole can cause gastrointestinal intoler-
ance, headaches, rash, and transient liver function abnormalities, and should not be used
in pregnant women. Potential interactions between azole treatments and some drugs, for
example, statins, should be revised, although such interactions are not very common at the
dose used to treat GMIs.

8.1.2. Recurrent Bacterial UTIs

Recurrent UTIs are defined as more than two episodes in six months or three episodes
in twelve months [94,99]. Diagnostic urine testing with urine culture is recommended
for each acute episode to guide antibiotic therapy, especially when considering antibiotic
prophylaxis, and to differentiate between recurrent and relapsing UTIs (the recurrence
of the same uropathogen strain within two to four weeks after treatment) [85,94,99]. Dis-
tinguishing between recurrent and relapsing UTIs is crucial, as inadequate treatment of
anatomical abnormalities may contribute to relapse [99].
Imaging and urologic evaluations are recommended for men and women with sus-
pected structural or functional abnormalities of the GU tract [99]. Indicators for evaluation
include the following: (1) relapsing infection; (2) repeated isolation of Proteus species;
(3) history of nephrolithiasis; (4) persistent hematuria; and (5) voiding abnormalities.
Patients with diabetes mellitus and recurrent cystitis should also undergo imaging and
urologic evaluation [94,99].
A comprehensive risk factor assessment should be conducted. In addition to the clas-
sic risk factors for recurrent cystitis—such as urinary anatomical abnormalities, atrophic
vaginitis, spermicide use, genetic predisposition, diabetes, and hygiene factors—the role of
SGLT-2is should be evaluated. Furthermore, the risks and benefits of continuing these med-
ications must be discussed with the patient, particularly considering their discontinuation
in severe cases [84,85,97].
Initial preventive strategies—non-antimicrobial preventive strategies include the
following:
- Increase fluid intake—if possible, fluid intake should be increased to 2 to 3 L daily to
reduce the risk of recurrence [109].
- Behavioral changes—while not extensively studied, behavioral changes such as avoid-
ing spermicides and postcoital voiding are reasonable to attempt.
- Vaginal estrogen—for postmenopausal women with recurrent cystitis, vaginal estro-
gen is suggested [110].
Antibiotic prophylaxis—antibiotic prophylaxis is one of the most effective
measures [104,111]. Postcoital prophylaxis is used for women with cystitis associated
with sexual activity, while continuous prophylaxis is used for other cases. Long-term
low-dose antibiotic prophylaxis (at least six months) is the gold standard for preventing
recurrent UTIs (Figure 5). The choice of antibiotic should be based on previous uropathogen
susceptibility patterns, drug allergies, and potential drug interactions [104,111]. Specific
doses and options are outlined in Table 5.
Additional Preventive Interventions—antibiotic-sparing strategies, such as cranberry
products (e.g., an 8 ounce glass of cranberry juice once or twice daily or cranberry concen-
trate tablets at 500–1000 mg daily), may be used, though their efficacy is lower than that of
antibiotic prophylaxis [112]. In a small RCT, the daily administration of 120 mg of highly
standardized cranberry in postmenopausal women with T2DM taking SGLT-2 inhibitors
led to a statistically significant reduction in UTI episodes in the supplemented group in
comparison to those with placebo administration [113]. Methenamine hippurate (1 g orally
twice daily) was shown to be not inferior to daily low-dose antibiotics in a large pragmatic
clinical trial [114,115]. D-mannose did not demonstrate efficacy in a recent clinical trial [116].
There is conflicting evidence regarding the efficacy of probiotics [117,118]. Some vaccines
J. Clin. Med. 2024, 13, 6509 19 of 28

for preventing recurrent UTIs, such as MV140 [119], have shown promising clinical efficacy
in small trials.
Reevaluation—preventive strategies should be reevaluated after three to six months
to ensure effectiveness and patient adherence. Discontinuing SGLT-2is can be considered if
episodes cannot be controlled or are highly symptomatic, after discussing the risk–benefit
balance with the patient [58,85,97].

8.2. Catheter Use

Patients using catheters are at an increased risk for GU infections. However, a pre–post
study involving catheterized patients treated with empagliflozin did not demonstrate an
increased risk of UTIs [120]. Management strategies should include rigorous hygiene
protocols, tailored antifungal or antibiotic treatments based on the specific infection, and
proper catheter care [121].
Asymptomatic bacteriuria is common among catheterized patients. Treating asymp-
tomatic bacteriuria does not improve outcomes and may promote the emergence of resis-
tant bacteria [97,98]. Therefore, screening and treatment for asymptomatic bacteriuria in
catheterized patients are generally not recommended. Similarly, asymptomatic candiduria
rarely requires antifungal therapy [121]
The selection of empiric antimicrobial therapy for symptomatic episodes should
consider the likelihood of resistant infections and the extent of the infection, such as cystitis
or more severe conditions like pyelonephritis or prostatitis. Fever is often present in
infections beyond the bladder [94,121]. Once culture and susceptibility results become
available, the antimicrobial regimen should be tailored to target the specific organism
identified [121].
Recent catheter removal may increase the risk of catheter-associated infection. In
the absence of fever, patients may be managed as having acute simple cystitis. There is
no evidence supporting the use of prophylactic antibiotics before catheter changes [99].
Whenever feasible, bladder catheters or urologic stents should be removed. If complete
removal is not possible, replacing the devices or intermittent bladder catheterization may
help to reduce colonization [94,121].

8.3. Kidney Transplant

Diabetes is a common complication following kidney transplantation. Post-transplant
diabetes mellitus (PTDM) is associated with an increased mortality and morbidity, primarily
due to higher rates of CVD and infections, which are the leading causes of death in kidney
transplant recipients (KTRs) [122]. Over the past decade, significant advances have been
made in understanding PTDM, alongside the rapid evolution of treatment algorithms for
managing diabetes in the general population.
Since the mechanisms driving renal disease progression are likely similar in patients
with T2DM with CKD and in KTRs with diabetes, it seems plausible that SGLT2is could
offer unique benefits to kidney transplant recipients with diabetes, proteinuria, or HF,
potentially improving both allograft longevity and CV risk. However, these renal benefits
are not fully understood in the context of a solitary, denervated kidney [123].
While there is substantial evidence supporting the use of SGLT2is in patients with
diabetic kidney disease, particularly for nephroprotection and a reduction in CV and mor-
tality risk, clinical trials focused specifically on kidney transplant patients are lacking [124].
A systematic review of eight studies concluded that, among KTRs with T2DM and ex-
cellent kidney function, SGLT2is effectively lowered HbA1c, reduced body weight, and
preserved kidney function, with no reported serious AEs such as euglycemic ketoacido-
sis or acute rejection [125]. In recent years, several new studies on SGLT2i use in KTRs
have been published; however, only one was an RCT, and it involved a small number of
patients [126–130].
SGLT2is remain underutilized in the management of PTDM, largely due to limited
transplant-specific evidence and concerns about increased risks of GMIs and UTIs, both of
J. Clin. Med. 2024, 13, 6509 20 of 28

which are already more common in KTRs. UTIs are the most frequent infectious complica-
tion in KTRs, affecting up to 25% of recipients in the first year and accounting for up to
30% of hospitalizations due to sepsis [131]. Their use in KTRs also raises concerns related
to the presence of a solitary functioning kidney with abnormal genitourinary anatomy
post-surgery, the placement of urinary catheters, concurrent use of maintenance immuno-
suppression, a high prevalence of immunomodulatory viral infections, and the overall
compromised immune status of these patients. Consequently, the recent KDIGO guide-
lines on CKD and diabetes recommend a cautious approach to adopting SGLT2is in this
population [124].
Although no specific studies have assessed the safety of SGLT2is in KTRs, some
observational data are available. A Spanish multicenter observational study involving
338 patients from 16 centers evaluated the incidence of UTIs and GMIs in KTRs with T2DM
or PTDM following SGLT2i treatment [130]. Over six months, 26% of patients experienced
an adverse event, with UTIs being the most common, affecting 14% of individuals. In
10% of cases, SGLT2i treatment was discontinued, primarily due to UTIs. However, a
post hoc subgroup analysis found that the incidence of UTIs was similar between KTRs
with diabetes treated with SGLT2is over 12 months and KTRs without diabetes (17.9%
versus 16.7%).
In the absence of specific guidelines for SGLT2i use in transplant patients, an inter-
national PTDM consensus was recently published, which includes recommendations for
SGLT2i use in KTRs [122]. Since KTRs are exposed to numerous risk factors for hemody-
namic ischemic injury during the immediate and early post-transplant period, including
infections, the consensus recommends that SGLT2is can be used to treat PTDM once stable
graft function is achieved. Initiation should be guided by comorbidities such as heart
failure (favoring use) and significant urosepsis or a high risk of severe GMI (discouraging
use), although current studies have not shown an increased risk of UTIs with SGLT2is [122].
While there are no specific recommendations regarding the timing of SGLT2i ini-
tiation in KTRs, most patients in published studies began treatment at least one year
post-transplant. This suggests a preference for later initiation, likely due to nephrologists’
comfort levels and the potentially lower infection risk in patients further from transplant,
as they tend to be on lower doses of immunosuppressants [123]. Earlier use could be
considered, but extra caution is warranted, taking into account patient-specific factors such
as recent UTI history, surgical requirements, kidney function, and current immunosup-
pression levels [132]. Large RCTs with longer follow-up periods are needed to assess the
long-term cardiovascular and renal outcomes, as well as the safety of SGLT2i therapy in
the transplant setting.

8.4. Heart Transplant

SGLT-2is may be considered for heart transplant (HT) patients in several scenarios,
including pre-existing T2DM, CKD, and the onset of post-transplant diabetes. In these
cases, the safety profile and usage recommendations for SGLT-2is remain consistent.
Emerging data on the use of SGLT-2is in HT patients are promising. Both T2DM and
post-transplant diabetes are associated with an increased morbidity and mortality. The
efficacy and safety of SGLT-2is in transplant recipients are still being investigated. In a
retrospective analysis [133], 22 HT recipients treated with empagliflozin were compared
to 79 patients receiving other glucose-lowering therapies. In this study, empagliflozin
appears to be a safe and effective option for managing select HT patients with diabetes.
Minimal AEs were reported with empagliflozin, with only one case requiring treatment
discontinuation and no observed GU infections. Over 12 months, empagliflozin resulted in
reductions in weight, BMI, HbA1c, and furosemide dose compared to the control group.
No significant differences in BP or renal function were observed between the empagliflozin
and control groups. In another retrospective analysis [134], the safety and effectiveness of
GLP-1RAs and SGLT-2is were evaluated in patients who had undergone orthotopic HT
at a high-volume center. Among the 21 patients studied, significant reductions in weight,
J. Clin. Med. 2024, 13, 6509 21 of 28

insulin usage, HbA1c, and LDL-cholesterol were observed. Both SGLT-2is and GLP-1RAs
were well tolerated, with no AEs leading to treatment discontinuation. Although larger
studies are warranted, this exploratory study suggests that both SGLT-2i and GLP-1RAs
are safe and effective therapeutic options for managing T2DM post-HT.
In HT recipients, who are often on immunosuppressive therapy, the risk of GU AEs
associated with SGLT-2is, particularly GMIs, may be heightened. A recent review of
20 studies in solid organ transplant recipients receiving SGLT-2is, including four studies in
patients with HT, showed that the use of these drugs in this scenario seems to have a similar
A1c-lowering effect and rate of AEs compared with the general patient population [132].
The authors conclude that, according to the available data, an SGLT2i could be prescribed
in solid organ transplant recipients for diabetes at 1 year after transplant. Patients are on the
highest amount of immunosuppression in the months right after transplant; after this initial
period, they tend to be on less immunosuppression, hence, they also have a lower risk of
infection. Earlier use of SGLT-2is could be considered in special cases, but extra caution
surrounding patient-specific factors, including recent UTI history and immunosuppression,
would need to be assessed prior to initiation.
The management of GU AEs in these individuals typically follows the same protocols
as for other patients, including topical and antifungal medications for GMIs and antibiotics
for UTIs, based on the bacteria identified and its antibiotic sensitivity profile and hygiene
practices. Close monitoring for GU AEs is essential in HT recipients on SGLT-2is. Regular
follow-up visits can facilitate the early detection and prompt management of complications.
It is crucial for HT recipients to report any GU symptoms or concerns to their healthcare
provider. In some cases, adjusting medication dosages or treatment regimens may be
necessary to minimize AEs while still allowing patients to benefit from the CV benefits
of SGLT-2is. Although larger safety trials are needed, preliminary findings suggest that
SGLT-2is are appropriate for post-HT patients. Given the beneficial non-glycemic effects of
SGLT-2is, these agents may become a key component in managing post-transplant diabetes
mellitus and other conditions in the future [135].

9. Strengths and Limitations

The main strengths of this review are, first, its multidisciplinary and highly practical
approach from the perspective of various specialties involved in managing patients who
benefit from treatment with SGLT-2is. Additionally, an exhaustive literature search was
conducted, prioritizing publications with the highest level of evidence. The primary
limitation of this publication is that it was not carried out following a formal clinical
practice guideline methodology, so it should be considered merely a consensus, which does
not hold the same weight as a guideline. Moreover, the number of high-quality studies
evaluating the management of GU infections in patients treated with SGLT-2is is currently
very limited.

10. Conclusions
SGLT-2is are now considered to be a first-line treatment for prevalent conditions
such as T2DM, CKD, and HF due to their well-established benefits in reducing CV and
renal morbidity and mortality, as demonstrated in numerous RCTs. Most GU infections
associated with SGLT-2i therapy have been shown in clinical trials to be mild to moderate
in severity and typically respond to standard antimicrobial treatment, without the need
to discontinue therapy. However, some patients permanently stop SGLT-2i treatment due
to GU AEs. GMIs are the leading cause of SGLT-2i withdrawal in both RCTs and real-
world observational studies. While most meta-analyses and RCTs have not demonstrated a
significant association between SGLT-2i use and increased UTI risk, UTIs remain a common
reason for SGLT-2i discontinuation.
Notably, there is a lack of high-quality evidence to guide the prevention and man-
agement of GU AEs in patients on SGLT-2i therapy. Consequently, our recommendations
(Figures 1–5) are primarily based on previous clinical trials involving patients with GMIs
J. Clin. Med. 2024, 13, 6509 22 of 28

or UTIs unrelated to SGLT-2i therapy. The most important interventions for minimizing
treatment discontinuation involve identifying patients at a high risk for GU infections and
implementing preventive strategies prior to initiating therapy.
Based on the favorable outcomes observed in RCTs for patients experiencing UTIs or
GMIs who continued treatment, routine discontinuation of SGLT-2is is not recommended
when a GU AE occurs, except in severe cases. SGLT-2i therapy should be resumed as
soon as possible, unless a severe or persistent condition contraindicates its use, given
the risk-benefit profile of this drug class. Discontinuing SGLT-2i therapy may increase
cardiorenal risk, as the benefits of these agents can be lost within just a few weeks.
Further epidemiological, mechanistic, and interventional studies on GU infections in
patients treated with SGLT-2is are urgently needed to strengthen the current evidence and
improve the management of these AEs.

Author Contributions: All authors participated in the design, literature search, data interpretation,
and critical review of the article. J.J.G.-M. wrote the final version of the manuscript, which was
approved by all authors. All authors have read and agreed to the published version of the manuscript.
Funding: This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
Conflicts of Interest: Juan J Gorgojo-Martínez has the following financial relationships: advisor on
scientific boards for Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim Pharmaceuticals Inc and
Novo-Nordisk; lectures for Amarin, Astra-Zeneca, Boehringer Ingelheim Pharmaceuticals Inc, Menar-
ini and Novo-Nordisk, and research activities for Astra-Zeneca, Mundipharma Pharmaceuticals and
NovoNordisk. José L Górriz Teruel declares funding to conduct clinical trials from AstraZeneca,
Bayer, Boehringer Ingelheim, and Novo Nordisk (all to the INCLIVA Research Institute); consulting
fees from AstraZeneca, Bayer, Boehringer-Ingelheim and Novo Nordisk; payment of honoraria for
lectures from AstraZeneca, Novo Nordisk, Bayer, Menarini, Boehringer-Ingelheim and Eli Lilly. Ana
Cebrián Cuenca declares funding to conduct clinical trials MSD and Sanofi (all to the IMIB institute);
consulting fees from AstraZeneca, Bayer, Eli Lilly, MSD, Novo Nordisk and Sanofi; payment of hono-
raria for lectures from AstraZeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Menarini, MSD, Sanofi and
Novo Nordisk. Almudena Castro Conde has the following financial relationships: consulting fees and
payment of honoraria for lectures from Novo Nordisk, Bayer, Lilly, Novartis, MSD and Servier. María
Velasco Arribas has received research funding from the Carlos III Health Institute, Gilead Sciences,
and Angellini; funding for teaching activities from Gilead Sciences, Merck Sharp & Dohme, ViiV
Healthcare, Janssen Cilag, Cinfa, and Takeda; financial compensation for educational presentations
from Gilead Sciences; compensation for scientific advisory services from Gilead Sciences, ViiV, and
Angellini, and funding for conference attendance from ViiV Healthcare, Gilead Sciences, Janssen
Cilag, and Angellini.

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