JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
16, 2024
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VOL. 83, NO.
ª 2024 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
JACC REVIEW TOPIC OF THE WEEK
Genitourinary Tract Infections in Patients
Taking SGLT2 Inhibitors
JACC Review Topic of the Week
Veraprapas Kittipibul, MD,a,b Zachary L. Cox, PHARMD,c,d Supavit Chesdachai, MD,e Mona Fiuzat, PHARMD,a
JoAnn Lindenfeld, MD,d Robert J. Mentz, MDa,b
ABSTRACT
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce adverse cardiovascular events in pa-
tients with type 2 diabetes mellitus, all-cause mortality, and heart failure hospitalization in patients with heart failure, as
well as adverse renal outcomes. However, concerns regarding the heightened risk of genitourinary (GU) infections,
particularly urinary tract infections, remain a significant barrier to their wider adoption. Addressing these misconceptions
using existing evidence is needed to ensure proper risk-benefit assessment and optimal utilization of this efficacious
therapy. This review aims to provide a balanced perspective on the evidence-based cardiovascular and renal benefits of
SGLT2is and the associated risk of GU infections. We also summarize and propose clinical practice considerations for
SGLT2i-associated GU infections focusing on patients with cardiovascular disease.
(J Am Coll Cardiol 2024;83:1568–1578) © 2024 by the American College of Cardiology Foundation.
S
failure
odium-glucose
(HF). A
cotransporter-2
(SGLT2is) are increasingly used in patients
with type 2 diabetes mellitus (T2DM) and heart
significant milestone
inhibitors
has been
recommendations.3,4 This review aimed to describe
the benefits of SGLT2i and the risk of GU infections
associated
evidence-based
with SGLT2i. Furthermore,
recommendations for
we offer
managing
reached, as SGLT2is are the first class of medications SGLT2i in the context of SGLT2i-associated GU
to significantly reduce the risk of cardiovascular infections.
(CV) death and heart failure hospitalization (HFH) in
patients with heart failure with preserved ejection SGLT2is: MECHANISMS OF ACTION AND
fraction (HFpEF).1,2 Among potential side effects of ADVERSE EVENTS
SGLT2is, genitourinary tract (GU) infection remains
a barrier to SGLT2i initiation and long-term use. Under normal physiologic conditions, sodium-
Persistent misconceptions within the medical and glucose cotransporters, predominantly SGLT2 iso-
public communities regarding the risks of urinary form, reabsorb most filtered glucose in the proximal
tract infection (UTI) prevent the wider adoption of convoluted tubules preventing glycosuria.5 SGLT2is
this beneficial therapy, despite new guideline induce a sustained urinary glucose excretion of 40 to
From the aDivision of Cardiology, Duke University Medical Center, Durham, North Carolina, USA; bDuke Clinical Research
Institute, Durham, North Carolina, USA; cDepartment of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville,
Tennessee, USA; dDivision of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville,
Tennessee, USA; and the eDivision of Public Health, Infectious Diseases and Occupational Medicine, Department of Medicine,
Mayo Clinic, Rochester, Minnesota, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received December 27, 2023; revised manuscript received January 18, 2024, accepted January 22, 2024.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2024.01.040
JACC VOL. 83, NO. 16, 2024
APRIL 23, 2024:1568–1578
HIGHLIGHTS

Treatment with SGLT2is is associated
with an increased risk of GMI but not UTI
or necrotizing fasciitis of the perineum
(Fournier’s gangrene).

The benefits of SGLT2is usually outweigh
the risk of treatment-associated GU
infections.

In most cases, patients developing mild-
moderate or stable severe GU infections
can continue SGLT2is.
80 g/d in patients without T2DM at normal plasma
glucose concentrations (Figure 1). In patients with
T2DM receiving SGLT2is, urinary glucose excretion
further increases with increasing plasma glucose
concentrations.6
SGLT2i also results in natriuresis that is transient
due to a compensatory increase in sodium reabsorp-
tion in distal nephrons. 7 The increase in sodium de-
livery to the macula densa in the distal nephron,
before the sites of increased reabsorption, provides
negative feedback to the glomerular afferent arteri-
oles. Constriction of the afferent arterioles reduces
blood flow to glomeruli, which subsequently results in
the reduction of intraglomerular pressure and
glomerular filtration.7 As glomerular hyperfiltration
leads to glomerular inflammation and fibrosis, reduc-
tion in glomerular filtration and tubular work from
SGLT2i reduce further renal damage. 8 SGLT2is also
have cardiorenal protective effects through different
complex mechanisms such as direct actions on car-
diomyocytes via sodium/hydrogen exchanger inhibi-
tion, increased energy production from a metabolic
shift toward ketogenesis and improved mitochondrial
function, improvement in endothelial function, sym-
pathetic nervous system inhibition, and anti-
inflammatory properties. 9,10
GU infections are thought to be a result of
pharmacologically induced glycosuria providing a
favorable growth environment for GU microorgan-
isms. In vitro studies showed no difference in bac-
terial growth in the urine obtained from patients
with diabetes without glycosuria and controls.
However, the addition of glucose to urine samples
significantly enhanced the bacterial growth.11
Glycosuria has been shown in the in vitro study to
induce the virulence of the uropathogenic Escher-
ichia coli, a common pathogen of UTI. The addition
of glucose to urine samples resulted in significant
increase in biofilm formation and virulence factor
Kittipibul et al 1569
Urinary Infections With SGLT2 Inhibitors
gene expression. 12 The most common ABBREVIATIONS AND
ACRONYMS
cause of genital mycotic infection (GMI)
is Candida albicans and glucose is one of
CKD = chronic kidney disease
the growth-limiting factors of many
CV = cardiovascular
Candida species.13 In mice treated with
eGFR = estimated glomerular
dapagliflozin, urine glucose concentra-
filtration rate
tion and the number of viable C. albicans
GMI = genital mycotic infection
cells in the kidney increased with the
GU = genitourinary tract
treatment dose and duration. 14
HF = heart failure
C. albicans also has unique mechanisms
HFH = heart failure hospitalization
that promote growth in a glucose-rich
environment such as a glucose-inducible HFmrEF = heart failure with mildly
reduced ejection fraction
protein that promotes adhesion and im-
HFpEF = heart failure with
pairs phagocytosis by the host. 15
preserved ejection fraction
CLINICAL EVIDENCE OF SGLT2is HFrEF = heart failure with reduced
ejection fraction
LVEF = left ventricular ejection
TYPE 2 DIABETES. SGLT2is have inter-
fraction
mediate to high glycemic-lowering effi-
RCT = randomized controlled trial
cacy. In addition to its initial use for
SGLT2i = sodium-glucose
glycemic control in T2DM, SGLT2is also
cotransporter-2 inhibitor
have roles in reducing cardiovascular and
T2DM = type 2 diabetes mellitus
renal risk in the current diabetes guide-
UTI = urinary tract infection
lines with benefits that are independent of
16
glycemic control. Multiple large randomized
controlled trials (RCTs) across different SGLT2is
(except for ertugliflozin), originally performed for
safety purposes, unexpectedly showed benefits of
SGLT2i in reducing major adverse cardiac events in
patients with T2DM. 17-21
HEART FAILURE. The benefits of SGLT2i in reducing
HFH in patients with T2DM were also unexpectedly
discovered as safety endpoints of RCTs in T2DM,
which led to confirmatory RCTs in the HF population.
The efficacy of SGLT2i in improving outcomes in HF
was first demonstrated in heart failure with reduced
ejection fraction (HFrEF) in dapagliflozin and empa-
gliflozin. 22,23 The efficacy of SGLT2is has also been
tested in patients with HFpEF, demonstrating sig-
nificant benefits in reducing cardiovascular death and
HFH for both empagliflozin and dapagliflozin.1,2 The
benefits of SGLT2i in HFrEF and HFpEF are inde-
pendent of T2DM status. Both American Heart Asso-
ciation/American College of Cardiology/Heart Failure
Society of America and European Society of Cardiol-
ogy (ESC) guidelines give SGLT2i Class I recommen-
dation for patients with HFrEF (left ventricular
ejection fraction [LVEF] #40%).3,4 For heart failure
with mildly reduced ejection fraction (HFmrEF: LVEF
41%-49%) and HFpEF (LVEF $50%), the recommen-
dations differ slightly. The ESC guideline recently
upgraded SGLT2i to a Class I recommendation for
both HFmrEF and HFpEF, whereas the U.S. guideline
1570 Kittipibul et al JACC VOL. 83, NO. 16, 2024

Urinary Infections With SGLT2 Inhibitors APRIL 23, 2024:1568–1578

F I G U R E 1 Mechanisms of Action and Benefits of SGLT2 Inhibitors

Glucose reabsorption
DCT
Sodium reabsorption

Sodium sensing

Afferent arteriole
PCT
constriction
Glomerular pressure
Glomerular filtration
SGLT2i Compensatory
 Glucose reabsorption
Reduction in plasma glucose level
SGLT1
Transient natriuresis SGLT2
Cardiorenal protective effects Macula Densa

Induced glucose deprivation state

Improved mitochondrial function Induced urinary glucose excretion

Improved endothelial function Non-T2DM: 40-80 g/d
T2DM: higher with plasma glucose
Sympathetic system inhibition
Risk of GU infection?
Reduced inflammatory cytokines

Sodium-glucose cotransporter 2 (SGLT2) inhibition results in reduction in glucose and sodium reabsorption. Compensatory increase in glucose reabsorption
by SGLT1 is thought to prevent hypoglycemia during SGLT2 inhibitor therapy. Increase in sodium concentration in distal convoluted tubules (DCT) at the
macula densa stimulate glomerular afferent arteriole constriction leading to reduction in glomerular pressure and filtration. The SGLT2i-induced glycosuria
serves as the theoretical basis for increased risk of genitourinary tract (GU) infections. PCT ¼ proximal convoluted tubule; T2DM ¼ type 2 diabetes
mellitus.

has not yet revised the Class IIa recommendation for
3,4
both HFmrEF and HFpEF, as it was published
before the DELIVER (Dapagliflozin Evaluation to
Improve the Lives of Patients With Preserved Ejection
Fraction Heart Failure) trial. 2 Nevertheless, SGLT2is
receive the highest level of recommendation in
HFmrEF and HFpEF populations, compared with
other guideline-directed medical therapies.
KIDNEY DISEASE. The initiation of SGLT2i induces an
acute transient dip in estimated glomerular filtration
rate (eGFR) that is not associated with progressive
long-term kidney function loss and generally followed
by a slowing in the decline of eGFR over time. 24 The
renoprotective effects of SGLT2i have been demon-
strated in patients with and without T2DM. 18-20,25-27
Guidelines recommend initiation of SGLT2i in pa-
tients with T2DM and chronic kidney disease (CKD)
who have an eGFR $20 mL/min/1.73 m 2, regardless of
glycemic control. 28 Based on current evidence,
SGLT2is are also beneficial in patients with proteinuric
CKD, CKD with eGFR $20 mL/min/1.73 m 2, and
proteinuria (urine albumin-to-creatinine ratio
>200 mg/g) without T2DM. Although the U.S. Food
and Drug Administration (FDA) has approved SGLT2i
as a treatment for CKD and/or proteinuria, these in-
dications have not yet been incorporated into the
nephrology guidelines.
SGLT2is AND GU INFECTIONS
In 2015, the FDA issued a drug safety communication
about the increased risk of serious UTI associated
with SGLT2i. This warning was based on 19 cases of
life-threatening urosepsis and pyelonephritis in the
post-marketing adverse event reporting review since
the approval of first SGLT2i, canagliflozin, in 2013.
The FDA issued another warning in 2018 about the
risk of necrotizing fasciitis of the perineum, also
known as Fournier’s gangrene. This was based on 12
cases of Fournier’s gangrene in patients taking
JACC VOL. 83, NO. 16, 2024 Kittipibul et al 1571
APRIL 23, 2024:1568–1578 Urinary Infections With SGLT2 Inhibitors

C ENTR AL I LL U STRA T I O N Balancing Risks of Genitourinary Infections and Benefits of Sodium-Glucose

Cotransporter 2 Inhibitors

Cardiovascular benefits in DM
Urinary tract infection ↓ Death from CV causes, nonfatal
No increased risk of UTI with MI, and nonfatal stroke
SGLT2i
Cardiovascular benefits in HF
Genital mycotic infection Genitourinary Tract Irrespective of DM status
3X higher with SGLT2i Infections in Patients HFrEF: ↓ All-cause death/HFH
Female >Male
Taking SGLT2is HFpEF: ↓ All-cause death/HFH
Fournier's gangrene After SGLT2i discontinuation:
Very Rare • ↑ All-cause death/HFH
No increased risk with SGLT2i • ↓ Quality of life

Renal Benefits
Irrespective of DM status
Risks of Genitourinary ↓ Adverse renal outcomes
Tract Infections

Other side effects of SGLT2i

Ketoacidosis Cardiorenal Benefits
Volume depletion/orthostatic hypotension

“Minimizing Risks and Maximizing Benefits”

Risk factor assessment: glycemic control, urinary tract obstruction, history of recurrent infection
Universal counseling: recognition of signs and symptoms, perineal hygiene maintenance
Minimize interruption: continue SGLT2i in mild-moderate and stable severe infections
Timely reinitiation: as soon as infection is controlled and no other contraindications

Kittipibul V, et al. J Am Coll Cardiol. 2024;83(16):1568–1578.

The cardiorenal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2is) generally outweigh the risks of genitourinary tract (GU) infections associated with
SGLT2is. The strategy to minimize risks of SGLT2i-associated GU infections should be applied to all patients to maximize the benefits of SGLT2is. CV ¼ cardiovascular;
DM ¼ diabetes mellitus; HF ¼ heart failure; HFH ¼ heart failure hospitalization; UTI ¼ urinary tract infection.

SGLT2i during 5-year post-marketing surveillance. In
this section, we present the incidence of UTI and GMI
associated with SGLT2i based on clinical trials and
epidemiological studies (Central Illustration).
UTI IN CLINICAL TRIAL POPULATIONS. The inci-
dence of UTI in the landmark cardiovascular outcome
RCTs of SGLT2i is shown in Table 1. The incidence of
UTI varies significantly between trials—likely related
to the approach for adverse event assessment and the
evolving data in this space over time. There was no
significant difference in the incidence of UTI between
SGLT2i and placebo groups in most studies except for
the higher incidence in the ertugliflozin group in
VERTIS CV (Cardiovascular Outcomes Following
Ertugliflozin Treatment in Type 2 Diabetes Mellitus
Participants With Vascular Disease) (12.1% vs 10.2%) 21
and in the empagliflozin group in the EMPEROR-
Preserved (Empagliflozin Outcome Trial in Patients
With Chronic Heart Failure With Preserved Ejection
Fraction) trial (9.9% vs 8.1%).1
A meta-analysis of 72 smaller RCTs showed no dif-
ference in the incidence of UTI (SGLT2i 8.7% vs control
8.7%; relative risk [RR]: 1.03; 95% CI: 0.96-1.11).29 The
results of this meta-analysis mostly represent studies
in patients with T2DM. A more recent meta-analysis of
9 RCTs in patients without T2DM showed an increased
odds of UTIs with SGLT2i (OR: 1.33; 95% CI: 1.13-
1.57).30 The validity of this study’s findings, however,
may be compromised by the data obtained from RCTs
not exclusively enrolling patients without T2DM and
the lack of clear description on how subgroup data
were obtained and verified.
The incidence of severe or complicated UTI varies
among clinical trials partly because of differences in
the definitions. Generally, severe UTI in clinical
1572 Kittipibul et al JACC VOL. 83, NO. 16, 2024

Urinary Infections With SGLT2 Inhibitors APRIL 23, 2024:1568–1578

T A B L E 1 Incidence of GU Infection in Cardiovascular Outcome Trials of SGLT2is

UTI Complicated UTI Genital Mycotic Infection

Study No. of Follow-Up
Trials Drug Patients Duration, y Patient Characteristics Treatment Control Treatment Control Treatment Control

DM trials
EMPA-REG Empagliflozin 7,020 3.1 63 years, 72% male, 72% 18.0% 18.1% 1.7% 1.8% 6.4%a 1.8%a
OUTCOME17 White, BMI 31 kg/m2,
M: 10.5%
M: 9.4%
M: 5.0%a
M: 1.5%a
A1c 8.1%, 49% insulin,
F: 36.4%a
F: 40.6%a
F: 10.0% a
F: 2.6%a
GFR 74 mL/min/1.73 m2
CANVAS Canagliflozin 10,142 2.4 63 years, 64% male, 78% 40.0 per 37.0 per - - M: 34.9 per M: 10.8 per
Program18 White, BMI 32 kg/m2, 1,000 pt-year 1,000 pt-year 1,000 pt- 1,000
A1c 8.2%, insulin 50%, yeara pt-yeara
GFR 77 mL/min/1.73 m2 F: 68.8 per F: 17.5 per
1,000 pt- 1,000 pt-
yeara yeara
CREDENCE19 Canagliflozin 4,401 2.6 63 years, 66% male, 67% 48.3 per 1,000 45.1 per - - M: 8.4 per M: 0.9 per
White, BMI 31 kg/m2, pt-year 1,000 pt-year 1,000 pt- 1,000
A1c 8.3%, yeara pt-yeara
GFR 56 mL/min/1.73 m2 F: 12.6 per F: 6.1 per
1,000 pt- 1,000
year pt-year
DECLARE-TIMI Dapagliflozin 17,160 4.2 64 years, 63% male, 80% 1.5% 1.6% 0.2% 0.3% 0.9%a 0.1%a
5820 White, BMI 32 kg/m2,
A1c 8.3%, insulin 41%,
GFR 85 mL/min/1.73 m2
VERTIS CV21 Ertugliflozin 8,246 3.5 64 years, 70% male, 80% 12.1%a 10.2%a 0.7% 0.8% M: 4.8%a M: 1.2%a
White, BMI 32 kg/m2, F: 6.9%a F: 2.4%a
A1c 8.2%,
GFR 76 mL/min/1.73 m2
SCORED54 Sotagliflozin 10,584 1.3 69 years, 55% male, 83% 11.5% 11.1% - - 2.4%a 0.9%a
White, BMI 32 kg/m2,
A1c 8.3%, insulin 64%,
GFR 45 mL/min/1.73 m2
HF trials
DAPA-HF22 Dapagliflozin 4,744 1.5 66 years, 77% male, 70% 0.5% 0.7% 0.3% 0.3% - -
White, BMI 28 kg/m2,
FC III-IV 32%, DM 42%,
GFR 66 mL/min/1.73 m2
EMPEROR- Empagliflozin 3,730 1.3 67 years, 76% male, 70% 4.9% 4.5% 1.0% 0.8% 1.7%a 0.6%a
Reduced23 White, BMI 28 kg/m2,
FC III-IV 25%, DM 50%,
GFR 62 mL/min/1.73 m2
EMPEROR- Empagliflozin 5,988 2.2 72 years, 55% male, 76% 9.9%a 8.1%a 1.9% 1.5% 2.2%a 0.7%a
Preserved1 White, BMI 30 kg/m2,
FC III-IV 18%, DM 49%,
GFR 61 mL/min/1.73 m2
SOLOIST-WHF55 Sotagliflozin 1,222 0.8 69 years, 66% male, 93% 8.6% 7.2% - - 0.8% 0.2%
White, GFR 50 mL/min/
1.73 m2
DELIVER2 Dapagliflozin 6,263 2.3 72 years, 56% male, 71% 1% 1% - - - -
White, FC III-IV 24%,
DM 45%,
GFR 61 mL/min/1.73 m2
CKD trials
DAPA-CKD26 Dapagliflozin 4,304 2.4 62 years, 67% male, 53% 0.9% 0.7% 0.2% 0.1% - -
White, BMI 30 kg/m2,
DM 67%, HF 11%,
GFR 43 mL/min/1.73 m2
EMPA-KIDNEY27 Empagliflozin 6,609 2 64 years, 67% male, 58% - - 1.6% 1.6% - -
White, BMI 30 kg/m2,
M: 1.4%
M:1.4%
DM 54%,
F: 2.0%
F: 2.0%
GFR 37 mL/min/1.73 m2

a
Significant difference between the treatment and control groups.
BMI ¼ body mass index; CKD ¼ chronic kidney disease; CREDENCE ¼ Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD ¼ Dapagliflozin and Prevention of
Adverse Outcomes in Chronic Kidney Disease; DAPA-HF ¼ Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58 ¼ Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in
Myocardial Infarction 58; DELIVER ¼ Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; DM ¼ diabetes mellitus; EMPA-KIDNEY ¼ The Study of Heart and Kidney
Protection With Empagliflozin; EMPA-REG OUTCOME ¼ Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; EMPEROR-Preserved ¼ Empagliflozin Outcome Trial in Patients With Chronic
Heart Failure With Preserved Ejection Fraction; EMPEROR-Reduced ¼ Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; F ¼ female; GFR ¼ glomerular filtration rate;
GU ¼ genitourinary; HF ¼ heart failure; M ¼ male; pt-year ¼ patient-year; SCORED ¼ Effect of Sotagliflozin on Cardiovascular and Renal Events in Participants With Type 2 Diabetes and Moderate Renal Impairment
Who Are at Cardiovascular Risk; SGLT2i ¼ sodium-glucose cotransporter 2 inhibitor; SOLOIST-WHF ¼ Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF; VERTIS
CV ¼ Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.
JACC VOL. 83, NO. 16, 2024
APRIL 23, 2024:1568–1578
studies refers to UTI or pyelonephritis as a primary
cause of hospitalization and UTI leading to sepsis (ie,
urosepsis). In the cardiovascular outcome RCTs of
SGLT2i, the incidence of severe UTI was consistently
low (<2% in all trials). The meta-analysis of smaller
RCTs showed the pooled incidence of pyelonephritis
of 0.3% and urosepsis of 0.3%.29 There was no dif-
ference between SGLT2i and control in pyelonephritis
(RR: 0.78; 95% CI: 0.52-1.18) or urosepsis (RR: 1.03;
95% CI: 0.96-1.11).
UTI IN EPIDEMIOLOGICAL STUDIES. Because RCTs
are not powered to capture the differences in specific
adverse events including GU infections,
observational studies would help clarify the associa-
tions, particularly for underrepresented
groups often excluded from RCTs. In a large com-
bined U.S.-based database of commercial claims be-
tween 2013 and 2015 in patients with T2DM receiving
SGLT2is, the incidence of severe UTI over a median
follow-up of 6.5 months, derived from >190,000 pa-
31
tients, was approximately 1.9%. In the propensity
score matching analysis, SGLT2i was not associated
with higher risk of UTI or severe UTI compared with
patients receiving dipeptidyl peptidase-4 (DPP-4) in-
hibitors or glucagon-like peptide-1 receptor (GLP-1)
agonists. Similar observations were demonstrated in
a large population-based study from the United
Kingdom and Canada, although the risk of UTI with
SGLT2i was shown to be lower compared with insulin
32
(HR: 0.74; 95% CI: 0.63-0.87). The comparison be-
tween observational studies, however, is limited by
uncertainties in the granular diagnosis of UTI (eg,
disease severity, pathogen) and other unknown con-
founders in the available datasets.
GMI. GMI is more prevalent in patients receiving
SGLT2is, particularly in women. The incidence of GMI
in the cardiovascular outcome RCTs of SGLT2i ranged
between 0.8% and 6.4% in the treatment group
(compared with 0.1%-1.8% in the placebo group). A
meta-analysis of 72 RCTs showed a higher incidence
of GMI in patients receiving SGLT2i compared with
placebo (5.9% vs 1.5%; RR: 3.37; 95% CI: 2.89-3.93).29
A similar result was replicated in a meta-analysis in
patients without T2DM that showed an increased
odds of GMIs in those taking SGLT2is (OR: 3.01;
95% CI: 1.93-4.68).30 A study using Canadian admin-
istrative databases in 21,444 patients with T2DM
receiving SGLT2is showed an overall incidence of GMI
of 6.9% (female: 10.7%, male: 4.3%) and increased
risk of GMI with SGLT2i (HR: 2.47; 95% CI: 2.08-2.92)
compared with DDP-4 inhibitors.33
FOURNIER’S GANGRENE. Fournier’s gangrene is a
rare but lethal form of necrotizing fasciitis affecting
Kittipibul et al 1573
Urinary Infections With SGLT2 Inhibitors
the superficial and deep tissues of perineal and gen-
ital regions. 34 A meta-analysis of RCTs studying
SGLT2is enrolling 69,573 patients showed only 3 cases
of Fournier’s gangrene in the SGLT2i arm and 6 cases
in the control arm.35 In a large U.S. Veterans Health
cohort, the incidence of Fournier’s gangrene in pa-
tients taking SGLT2is was 1.14 per 1,000 patient-years
and there was no significant difference in the inci-
dence between SGLT2i and GLP-1 agonists.36
Although there have been more case reports on
Fournier’s gangrene following the FDA warning, the
causality and the risk of Fournier’s gangrene associ-
larger ated with SGLT2i has not been confirmed.
RISK FACTORS FOR SGLT2i-ASSOCIATED UTIs
patient
Diabetes is considered one of the risk factors for UTI
in patients receiving SGLT2is. The incidence of UTI in
the cardiovascular outcome RCTs evaluating SGLT2is
in patients with T2DM appeared to be higher (1.5%-
18.1%, pooled incidence 8.7%) compared with other
trials in HF or CKD populations (0.5%-9.9%), albeit up
to 67% of patients in the HF or CKD trials also had
T2DM. A meta-analysis of 4 RCTs found that, in pa-
tients taking SGLT2is, the odds of UTI was not
different between patients with T2DM and those
without (OR: 1.15; 95% CI: 0.83-1.59). 30 However, in
patients receiving placebo, the odds of UTI was higher
in those with T2DM (OR: 1.30; 95% CI: 1.07-1.58). The
data from observational studies on the incidence of
SGLT2i-associated UTI in patients without T2DM are
lacking. The risk of SGLT2i-associated UTI was higher
in patients with poor glycemic control as evidenced
by higher glycosylated hemoglobin level and diabetic
microvascular complications. 37,38
SGLT2is may be prescribed alongside other
glucose-lower therapies for T2DM, some of which
could potentially increase the risk of UTI. Drug-drug
interaction testing showed that SGLT2is in combi-
nation with other drugs including DPP-4 inhibitors,
statins, angiotensin II receptor blockers, and cal-
cium channel blockers was associated with
increased risk of UTI in patients with T2DM.39 The
mechanisms underlying these interactions are un-
known and the observed increased risk may, in fact,
reflect the severity of diabetes rather than the spe-
cific effects of these therapies. Although SGLT2is as
a class are not associated with higher risk of UTI,
studies showed increased risk of UTI in patients
receiving a higher dose of dapagliflozin (10 mg)
compared with placebo (RR: 1.23; 95% CI: 1.03-
1.46). 29,40 There is no other evidence to date to
suggest differences in the risk of UTI across
different SGLT2is.
1574 Kittipibul et al
Urinary Infections With SGLT2 Inhibitors
F I G U R E 2 Risk Factors for SGLT2 Inhibitor-Associated GU Infections
• Age ≥65 years
• eGFR ≤60 mL/min/1.73 m2
• Proteinuria
• Diabetic microvascular
complications
• Urinary tract obstruction
Urinary Tract Infection
Recognition of risk factors for sodium-glucose cotransporter 2 (SGLT2) inhibitor-associated genitourinary tract (GU) infections is essential in
the prevention of GU infections before and during SGLT2 inhibitor therapy. Modifiable risk factors such as glycemic control should be
corrected or optimized. eGFR ¼ estimated glomerular filtration rate.
The additional risk factors for
associated UTI include age $65 years,
#60 mL/min/1.73 m 2, and proteinuria (Figure 2). 37,38,41
The association between low eGFR and incident UTI is
not intuitive. As SGLT2i-induced glycosuria decreases
with worsening renal function, lower eGFR could
instead be protective of UTI. In general, lower eGFR
increases the incidence of pyuria but not necessarily
UTI. 42 In addition, asymptomatic pyuria or bacteriuria
at the time of SGLT2i initiation was not associated with
increased risk of UTI. 43 The complex association be-
tween lower eGFR and SGLT2i-associated UTI may
reflect increased infection risk related to impaired host
defense mechanisms with renal dysfunction. These
considerations may also apply to other risk factors,
including advanced age and proteinuria. As the risk of
UTI associated with glycosuria is postulated to be
attenuated by increased urinary flow due to osmotic
diuresis and natriuresis from SGLT2is,13 urinary tract
obstruction leading to abnormal urinary flow may in-
crease the risk of UTI.
RISK FACTORS FOR SGLT2i-ASSOCIATED GMIs
Diabetes is also a risk factor for GMI in patients
receiving SGLT2is. 44 In contrast to UTI, the odds of
GMI in patients taking SGLT2is was higher in patients
with T2DM (OR: 1.36; 95% CI: 1.07-1.72) but the odds
JACC VOL. 83, NO. 16, 2024
APRIL 23, 2024:1568–1578
• History of genital infection
Female sex • Obesity
Diabetes • Uncircumcised men
HbA1c • Concurrent use of
sulfonylurea or insulin
Genital Mycotic Infection
SGLT2i- of GMI in patients receiving placebo was not different
eGFR between those with or without T2DM (OR: 1.14;
95% CI: 0.36-3.66). 30 The risk of GMI was higher with
longer duration of T2DM and poor glycemic control. 37
Moreover, the concomitant use of sulfonylurea or
insulin with SGLT2is was associated with 3-fold
higher risk of GMI in male patients. 37 However,
there is no difference in the risk of GMI across
different SGLT2is. 44
Other risk factors for SGLT2i-associated GMI
include a history of GMI and obesity, especially in
women. 37,45 The risk of GMI might be higher in
postmenopausal women due to diminished immunity
in the reproductive tract but supporting evidence is
scarce.46 In men, circumcision was associated with
lower risk of GMI, likely attributed to improved
maintenance of genital hygiene.46
In addition to the mentioned risk factors, there are
numerous factors that influence the risk of GU in-
fections in the general population, but these have not
been specifically investigated in the context of
SGLT2i. Behavioral factors including perineal hygiene
and sexual practice, as well as environmental factors
such as indwelling urinary catheters also contribute
to the risk of developing GU infections.47 Considering
these risk factors is essential for effectively managing
the risk of GU infections in patients receiving
SGLT2is.
JACC VOL. 83, NO. 16, 2024 Kittipibul et al 1575
APRIL 23, 2024:1568–1578 Urinary Infections With SGLT2 Inhibitors

F I G U R E 3 Clinical Considerations in the Management of SGLT2i-Associated GU Infections

Development of GU SGLT2i reinitiation

New SGLT2i initiation
infections while taking SGLT2i After GU infections

SGLT2i is not contraindicated in Early recognition and prompt

• Asymptomatic bacteriuria management per usual care
• History of GU infections
Routine discontinuation of
Recurrent GU infections SGLT2i in the setting of GU
Reinitiate SGLT2i as soon as
should be evaluated for infections is not recommended
possible
underlying causes
• Infection is effectively treated
SGLT2i can be safely initiated if • Continue SGLT2i in mild-
• No other contraindications
an underlying cause is resolved moderate and clinically stable
severe GU infections
Monitor for signs of symptoms
Counseling on signs and • SGLT2i discontinuation
of GU infections
symptoms of GU infections might be warranted in the
Recurrence incidence is highest
setting of life-threatening
within first 2 weeks of SGLT2i
Counseling on the maintenance infections and the risks
initiation
of good perineal hygiene significantly outweigh the
benefits
Reiterate the greater benefits of
Identify patients at high risk for
SGLT2i over the risks of GU
GU infections for close Reassess and treat the risk
infections
monitoring factors for GU infections to
Optimize glycemic control in prevent further episodes
patients with diabetes • Poor perineal hygiene
• GU anatomical abnormalities
• Uncontrolled diabetes

Following clinical considerations should be implemented in all patients before sodium-glucose cotransporter-2 inhibitor (SGLT2i) initiation. In patients who develop
SGLT2i-associated genitourinary tract (GU) infections, SGLT2is should generally be continued throughout the treatment of GU infections. Following SGLT2i discon-
tinuation in the setting of severe GU infections, SGLT2is should be reinitiated as soon as possible.

CLINICAL IMPLICATIONS OF of UTI and GMI as well as the maintenance of good

SGLT2i-ASSOCIATED GU INFECTIONS
SHOULD RISK FACTORS FOR GU INFECTIONS PREVENT
THE PRESCRIPTION OF SGLT2 INHIBITORS? The bene-
fits of SGLT2is generally outweigh the risk of GU in-
fections even among those with risk factors. A history
of uncomplicated GU infections is not a contraindi-
cation to SGLT2is. Patients with recurrent or compli-
cated GU infections should be evaluated
underlying risk factors and it may be possible to
safely use SGLT2is if the underlying etiology has been
resolved.48 Otherwise, the presence of risk factors
should lead to a greater emphasis on preven-
tive measures.
WHAT ARE PREVENTIVE MEASURES FOR GU INFECTIONS
WHEN PRESCRIBING SGLT2is? The potential side ef-
fects of SGLT2is including GU infections should be
informed at the time of SGLT2i initiation. In addition,
patients should be counseled on signs and symptoms
perineal hygiene.49 In patients with diabetes,
adequate glycemic control would further decrease the
risk of infection, particularly GMI.44 There is no role
of antimicrobial prophylaxis or preemptive antimi-
crobial therapy. Obtaining a urine culture before
SGLT2i initiation is not recommended, as asymp-
tomatic bacteriuria is not a contraindication
to SGLT2is.48
for
SHOULD SGLT2is BE DISCONTINUED IN THE SETTING OF
GU INFECTIONS? In contrast to euglycemic ketoaci-
dosis for which temporary discontinuation of SGLT2is
is recommended, neither the FDA labels nor general
prescribing information advise discontinuation of
SGLT2is in the setting of GU infections of any
severity. In addition, patients in the prior RCTs who
developed UTI did not stop blinded assigned study
drug and there was no increased risk of UTI severity
or recurrent UTI relative to placebo.
1576 Kittipibul et al
Urinary Infections With SGLT2 Inhibitors
The substantial benefits of SGLT2is dissipate after
medication discontinuation. In the EMPEROR-
Reduced (Empagliflozin Outcome Trial in Patients
With Chronic Heart Failure With Reduced Ejection
Fraction) and EMPEROR-Preserved trials, 6,799 pa-
tients underwent prospective treatment withdrawal
in a blinded manner. At the end of the withdrawal
period (30 days), the risk of CV death or HFH
increased in patients withdrawn from empagliflozin
(HR: 1.75) but not in those withdrawn from placebo. 50
The Kansas City Cardiomyopathy Questionnaire
Clinical Summary Score declined by 1.6 in patients
withdrawn from empagliflozin vs placebo. These
findings emphasize the importance of minimizing
SGLT2i interruption as the increase in adverse out-
comes could occur as early as 30 days following
discontinuation.
Temporary discontinuation of SGLT2i might be
deemed necessary by treating clinicians in the setting
51
of life-threatening infections. On the contrary, most
GU infections are mild and can be effectively treated
while remaining on SGLT2is, following recommen-
48
dations for GU infections in the general population.
However, in real-world practice, SGLT2is may be un-
necessarily discontinued even in the high-risk pa-
tients in whom benefits overwhelmingly outweigh
the risks. In a large observational study, GMI was
associated with subsequent SGLT2i discontinuation
of 32% over 1 year.45 The rate of SGLT2i discontinu-
ation following UTI in routine practice is unknown.
SHOULD SGLT2is BE REINITIATED FOLLOWING GU
INFECTIONS? SGLT2is should be reinitiated in most
cases, although there is no recommendation on how
long after GU infections SGLT2is can be safely
resumed. 48,52 This gap in knowledge might result in
clinician reluctance to restart SGLT2is by adhering to
the principle of “first, do no harm.” Nevertheless,
delaying SGLT2i reinitiation may inadvertently lead
to clinical deterioration in previously stable patients
by withholding a disease-modifying treatment.
Therefore, SGLT2is should generally be continued
throughout the treatment of GU infections. In rare
cases, such as life-threatening GU infections in which
the risks associated with ongoing SGLT2i are excep-
tionally high or uncontrollable symptomatic GMI, the
decision to restart SGLT2is should be made promptly
once the infection is effectively managed. Following
SGLT2i reinitiation, recurrent UTI occurred in 28% of
patients with risk factors including coronary artery
disease and eGFR <45 mL/min/1.73 m2.38 In patients
at higher risk for GU infections, monitoring for signs
and symptoms of UTI and GMI after initiation of
SGLT2is is recommended, especially for UTI in which
JACC VOL. 83, NO. 16, 2024
APRIL 23, 2024:1568–1578
the risk is highest in the first 2 weeks. 53 The summary
of clinical considerations is shown in Figure 3.
LIMITATIONS. Although existing evidence strongly
suggests that SGLT2is do not increase the risk of UTI,
the overall data on SGLT2i-associated GU infections
are still more limited especially in patients without
T2DM. Whether GU infections in the setting of
SGLT2is are different from the general population
with regard to their clinical course, microbiology, or
appropriate treatment is unknown. Gaining the
knowledge on these potential differences might lead
to specific recommendations on the management of
SGLT2i-associated GU infections such as choice and
duration of antimicrobial treatment.
CONCLUSIONS
Although SGLT2is can increase the risk of GMI
especially in women, the risk of UTI associated with
SGLT2i use has been consistently low both in RCTs
and observational studies. Withdrawal of SGLT2i has
been shown to increase the risks of adverse out-
comes in patients with HF. Therefore, SGLT2is
should be continued along with the appropriate
treatment for mild-moderate GU infections and the
duration of SGLT2i interruption even in the setting
of severe infection should be minimized. Recom-
mendations and endorsements from multidisci-
plinary societies and further data are needed to
eliminate clinician hesitation and establish the best
practice across all conditions for which SGLT2is are
prescribed.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Cox has received grants from AstraZeneca; and has received per-
sonal fees from Abiomed, ROCHE, and Translational Catalyst. Dr
Lindenfeld is a consultant for Abbott, ADI, Alleviant, Amgen, Astra-
Zeneca, Axon, Boston Scientific, Cordio, CVRx, Cytokinetics, Edwards
Lifesciences, Medtronic, Merck, VWave, Vascular Dynamics, Vecto-
rious, and Whiteswell; and has received grants from Analog Devices
Inc, AstraZeneca, and Volumetrix. Dr Mentz has received research
support and honoraria from Abbott, American Regent, Amgen,
AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cyto-
kinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic,
Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos,
Relypsa, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily,
Vifor, Windtree Therapeutics, and Zoll. All other authors have re-
ported that they have no relationships relevant to the contents of this
paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr Robert J.
Mentz, Division of Cardiology, Department of Medi-
cine, Duke Clinical Research Institute, Duke Univer-
sity Medical Center, 2301 Erwin Road, Durham, North
Carolina 27710, USA. E-mail: robert.mentz@duke.
edu. @vkittipibul, @robmentz.
JACC VOL. 83, NO. 16, 2024
APRIL 23, 2024:1568–1578
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KEY WORDS diabetes, heart failure, SGLT2
inhibitors, urinary tract infection, urogenital
infection