(PDF) SGLT2 Inhibitors, What the Emergency Physici...

Journal of

Clinical Medicine

Review

SGLT2 Inhibitors, What the Emergency Physician Needs to

Know: A Narrative Review

Henri Lu 1, * , Hortense Lu 2, Christophe Kosinski 3, Anne Wojtusciszyn 3, Anne Zanchi 3,

Pierre-Nicolas Carron 4, Martin Müller 5, Philippe Meyer 6, Jehan Martin 7, Olivier Muller 1and Roger Hullin 1





Citation: Lu, H.; Lu, H.; Kosinski, C.;

Wojtusciszyn, A.; Zanchi, A.; Carron,

P.-N.; Müller, M.; Meyer, P.; Martin, J.;

Muller, O.; et al. SGLT2 Inhibitors,

What the Emergency Physician Needs

to Know: A Narrative Review. J. Clin.

Med. 2021,10, 2036. https://doi.org/

10.3390/jcm10092036

Academic Editor: Giorgio Costantino

Received: 1 April 2021

Accepted: 7 May 2021

Published: 10 May 2021

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in

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iations.

Copyright: © 2021 by the authors.

Licensee MDPI, Basel, Switzerland.

This article is an open access article

distributed under the terms and

conditions of the Creative Commons

Attribution (CC BY) license (https://

creativecommons.org/licenses/by/

4.0/).

1Service of Cardiology, Cardiovascular Department, Lausanne University Hospital,

1011 Lausanne, Switzerland; [e-mail] (O.M.); [e-mail] (R.H.)

2Emergency Department, Saint-Joseph Hospital, 75014 Paris, France; [e-mail]

3Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital,

1011 Lausanne, Switzerland; [e-mail] (C.K.); [e-mail] (A.W.);

[e-mail] (A.Z.)

4Emergency Department, Lausanne University Hospital, 1011 Lausanne, Switzerland;

[e-mail]

5Emergency Department, Bern University Hospital, 3010 Bern, Switzerland; [e-mail]

6Cardiology Service, Geneva University Hospitals, 1205 Geneva, Switzerland; [e-mail]

7Emergency Department, Geneva University Hospital, 1205 Geneva, Switzerland; [e-mail]

*Correspondence: [e-mail]; Tel.: [phone]

Abstract:

Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin belong to a class of antidi-

abetic treatments referred to as sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors, or

SGLT2is). SGLT2is are currently indicated in North America and in Europe in type 2 diabetes mel-

litus, especially in patients with cardiovascular (CV) disease, high CV risk, heart failure, or renal

disease. In Europe, dapagliflozin is also approved as an adjunct to insulin in patients with type 1 dia-

betes mellitus. New data provide evidence for benefits in heart failure with reduced ejection fraction

and chronic kidney disease, including in patients without diabetes. The use of SGLT2is is expected to

increase, suggesting that a growing number of patients will present to the emergency departments

with these drugs. Most common adverse events are easily treatable, including mild genitourinary

infections and conditions related to volume depletion. However, attention must be paid to some

potentially serious adverse events, such as hypoglycemia (when combined with insulin or insulin

secretagogues), lower limb ischemia, and diabetic ketoacidosis. We provide an up-to-date practical

guide highlighting important elements on the adverse effects of SGLT2is and their handling in some

frequently encountered clinical situations such as acute heart failure and decompensated diabetes.

Keywords: diabetes; heart failure; renal; guidelines

1. Introduction

Sodium glucose-cotransporter 2 inhibitors (SGLT2is) are a class of oral antihyper-

glycemic agents that block glucose and sodium reabsorption in the proximal tubule of

the kidney, causing glucosuria and osmotic diuresis. They improve glycemic control in

patients with type 2 diabetes mellitus (T2DM) and provide cardiovascular (CV) and renal

benefits independently of diabetes status [1–3].

Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are indicated as first- or

second-line treatments in T2DM individuals with CV disease, high CV risk, heart failure,

and chronic kidney disease (CKD) both in Europe and North America, provided that

in some European countries, their use may be prohibited if kidney clearance is below

45 mL/min [

4

,

5

]. Dapagliflozin is also indicated in patients with heart failure with reduced

ejection fraction (HFrEF) independently of diabetes status and, in Europe, as an adjunct

to insulin in T1DM [

6

,

7

]. Despite an overall favorable safety profile, a few side effects of

these medications are important to be aware of, especially in the emergency setting, such as

J. Clin. Med. 2021,10, 2036. https://doi.org/10.3390/jcm10092036 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2021,10, 2036 2 of 10

conditions related to volume depletion (hypotension, acute kidney injury), genitourinary

infections, and euglycemic diabetic ketoacidosis (eDKA) [

8

]. As SGLT2is will be adminis-

tered in a substantial number of patients in the coming years, emergency physicians should

be aware of the action of these drugs and their side effects. In this review, we present

practical considerations and recommendations for emergency department (ED) physicians,

focusing on side effects and the management of SGLT2is in particular clinical situations.

2. Adverse Events Related to SGLT2is

Adverse events are categorized as very frequent (incidence of

≥

10%), frequent (

≥

1%

and <10%), uncommon (

≥

0.1% and <1%), rare (

≥

0.01% and <0.1%) and very rare (<0.01%),

using the Council for Organizations of Medical Sciences working group definitions, and

available evidence in literature [9].

2.1. Genitourinary Infections (Frequent to Very Frequent)

An increased risk of genital mycotic infection is associated with SGLT2is, particularly

in women (vulvovaginitis) and uncircumcised men (balanitis). Although it is the most

common adverse event, most infections are mild or moderate [

10

]. In a meta-analysis

including 36689 patients, canagliflozin, dapagliflozin, and empagliflozin were associated

with higher risks of genital mycotic infections compared with placebo, with respective odd

ratios (ORs) ranging from 3.64 (95% confidence interval (CI), 2.87–4.63) for empagliflozin

to 4.99 (95% CI, 3.74–6.67) for canagliflozin [11].

Concerning the risk of urinary tract infections (UTIs), data are less consistent. Reports

of pyelonephritis and complicated UTIs (urosepsis) have prompted the EMA and FDA

to add warnings about an increased risk of UTIs [

12

]. However, in a large meta-analysis

which included 110 trials, SGLT2is did not demonstrate an increased risk of UTIs [

13

].

These data were recently completed by a large population based cohort study which com-

pared SGLT2is with dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide

1 receptor agonists (GLP-1 RAs) and did not show an increased risk of UTIs associated

with SGLT2is [

14

]. In practice, patients taking SGLT2is should be regularly informed about

the importance of maintaining good local hygiene and should be educated about the signs

and symptoms of genital mycotic infection and UTIs. The management of the latter is

not different from usual care, with the administration of local/oral antifungal therapy or

oral/intravenous anti-biotherapy as needed.

2.2. Hypoglycemia (Frequent)

SGLT2is inherently present a low risk of hypoglycemia because of their insulin-

independent pathway of action [

8

]. In clinical trials, hypoglycemic events were rare

and not more frequent in nondiabetic patients [

1

,

2

]. However, a concomitant use of insulin

or insulin secretagogues (glinides, sulfonylureas) may increase the risk of hypoglycemia.

Some authors have therefore suggested reducing the dose of sulfonylurea or glinide by

50% or the basal insulin dose by 20% when starting a SGLT2i, especially when glycated

hemoglobin (HbA1C) at baseline is normal or when the patient has a known history of

hypoglycemic events [

15

]. Episodes of hypoglycemia in the ED should be managed ac-

cording to standard protocol, with administration of oral or intravenous glucose, and

temporary withholding of the SGLT2i. The dose of other antihyperglycemic agents should

subsequently be adapted.

2.3. Volume Depletion and Acute Kidney Injury (Frequent)

Because of its effect on osmotic diuresis, SGLT2is may cause symptomatic hypotension

or dehydration (incidence of 1.2% to 1.5%), especially in elderly patients or those already

taking diuretics [

16

]. In patients presenting to the ED with hypotension or symptoms or

signs of dehydration, temporary withholding of SGLT2is may be considered.

Regarding the risk of acute kidney injury (AKI), reports have provided conflicting

conclusions. In 2016, the FDA issued warnings regarding the use of canagliflozin and

J. Clin. Med. 2021,10, 2036 3 of 10

dapagliflozin after 101 cases of AKI, some requiring dialysis [

17

]. Most occurred within

1 month of SGLT2i initiation. This observation has been challenged by a meta-analysis

of the main clinical trials, which suggested the risk of AKI may slightly decrease via the

reno-protective effects of SGLT2is [

18

]. In practice, a modest decrease in estimated glomeru-

lar filtration rate (eGFR) of around 3–4 mL/min/1.73 m

2

is expected when starting a

SGLT2i [

16

]. Kidney function should be assessed before treatment initiation and monitored

thereafter, especially in patients with comorbidities or medications predisposing to AKI.

In patients presenting to the ED with severe AKI, SGLT2i therapy and other potentially

nephrotoxic drugs should be withheld, with the correction of any electrolyte imbalance

and the initiation of a standard protocol for fluid resuscitation in severe AKI resulting from

circulatory hypovolemia and hemodialysis as a last resort, if needed.

2.4. Euglycemic Diabetic Ketoacidosis (Rare)

First reported in 2015 [

19

], euglycemic diabetic ketoacidosis (eDKA) associated with

SGLT2is is a rare and life-threatening condition. On a physio-pathological level, it is thought

that the lowered plasma glucose levels induced by glucosuria reduce the amount of insulin

while increasing glucagon release [

20

]. The increased glucagon/insulin ratio is responsible

for increased lipolysis and upregulated ketone body production (β-hydroxybutyrate, ace-

toacetate), which may lead to ketoacidosis [

20

]. Because of the lowered plasma glucose

levels related to glucosuria, ketoacidosis under SGLT2i is generally characterized by the

absence of major hyperglycemia (<250 mg/dL), hence the name eDKA. Delays in diagnosis

can be important because emergency physicians may not be used to ketoacidosis without

severe hyperglycemia.

In clinical trials investigating patients with T2DM and those with HFrEF, SGLT2i-

associated DKA was rare, with incidence rates ranging from 0.1% (empagliflozin) to

0.6/1000 patient-years (canagliflozin) [

21

–

23

]. In fact, a real-world propensity-matched

study found that SGLT2is were twice more likely to cause eDKA compared with DPP-

4 inhibitors [

24

]. Using the FDA Adverse Event Reporting System (FAERS), Blau and

colleagues estimated that SGLT2is increase the risk of eDKA seven-fold [

25

]. The reason

why these observations are different from the clinical trials is unclear. However, participants

in randomized trials receive closer medical attention, and this may have contributed to

lowering the risk of eDKA.

EDKA should systematically be considered in patients taking SGLT2is, regardless

of blood sugar levels presenting with nausea, vomiting, malaise, or abdominal pain or,

in more severe cases, altered consciousness, Kussmaul breathing, or clinical signs of

shock [

19

]. This is especially true when an additional trigger is present such as fasting,

dehydration, discontinuation of insulin therapy, surgery, infections, or excessive alcohol

intake [

26

]. EDKA may also be found in patients with T1DM, for example, when the

insulin pump is defective, or in pregnant women with T1DM, as pregnancy may cause

significant physiological glucosuria. Initial evaluation is similar to classic DKA and should

rapidly include screening with serum pH. If the latter is below 7.3, rapid

β

-hydroxybutyrate

capillary checking should be considered [19].

In the ED setting, physicians may be confronted with other forms of acidosis, partic-

ularly metformin-associated lactic acidosis (MALA), which should not be confused with

eDKA in patients treated by a SGLT2i and metformin at the same time. The difference

between eDKA and MALA is the absence of

β

-hydroxybutyrate elevation in MALA, but

the two disorders can coexist in theory, especially in patients with CKD [

27

]. Diagnostic

criteria of eDKA, as defined by the American College of Endocrinology, and MALA, are

presented in Table 1.

Once the diagnosis of eDKA is confirmed, SGLT2is should immediately be discontin-

ued, and treatment should be started including fluid resuscitation, insulin with concomitant

glucose infusion, careful electrolyte and glycemia monitoring, and treatment of the un-

derlying trigger if feasible [

28

]. Patients taking SGLT2is should be instructed to maintain

J. Clin. Med. 2021,10, 2036 4 of 10

sufficient oral hydration and carbohydrate intake and to stop the drug in the case of

emergency surgery or unexpected external severe stress events [19].

Table 1.

Diagnostic criteria of euglycemic diabetic ketoacidosis and metformin-associated lactic

acidosis [19,27].

Parameters Laboratory Values

eDKA MALA

Arterial pH <7.3 <7.35

β-hydroxybutyrate ≥

31 mg/dL (3.0 mmol/L) in children

≥40 mg/dL (3.8 mmol/L) in adults Normal

Serum ketone Positive Negative

Serum lactate Normal or slightly elevated >5 mmol/L

Anion gap >10 mmol/L >10 mmol/L

eDKA: Euglycemic diabetic ketoacidosis, MALA: Metformin-associated lactic acidosis.

2.5. Necrotizing Fasciitis of the Perineum (Very Rare)

Necrotizing fasciitis of the perineum, also known as Fournier’s gangrene (FG), is a

potentially fatal acute necrotic infection of the subcutaneous tissues around the genital

or perianal regions. Classic risk factors for FG include hypertension, obesity, tobacco use,

immunosuppression, heart failure, and T2DM [

29

]. Using the FAERS, Bersoff-Matcha and

colleagues identified 55 cases of FG in patients receiving SGLT2is from March 2013 to

January 2019 versus 19 cases in patients receiving other classes of antidiabetic therapy

during a 35-year period in the U.S. population [

30

]. The physio-pathological explanation

behind this observation is unknown.

FG should be suspected in any patient taking a SGLT2i who presents with fever along

with pain, erythema, or swelling of the genital or perianal area. If diagnosed, immediate

discontinuation of the SGLT2i, hospitalization, close monitoring, prompt introduction of

broad-spectrum anti-biotherapy, and surgical debridement, if necessary, are required [10].

2.6. Fractures (Unknown Incidence)

Canagliflozin was the only SGLT2i associated with a slightly higher risk of fractures,

most of them nonvertebral, in the CANVAS-Program trial, but this has not been confirmed

in subsequent studies [

21

]. Possible explanations include a greater risk of falls due to

volume depletion and a reduction in bone density [31].

2.7. Lower Limb Amputations (Unknown Incidence)

An increased risk of lower limb amputations (LLA) with canagliflozin, mostly toe and

metatarsal ones, was reported in the CANVAS-Program trial with a HR of 1.97 (95% CI

1.41–2.75

) [

21

]. Although dapagliflozin and empagliflozin were not associated with the

same risk in their respective clinical trials [

22

,

23

], a meta-analysis confirmed the slight

increase in the risk of LLA for SGLT2is compared to controls or placebo. The mechanism

by which SGLT2is might increase the risk of amputations is unknown, and whether it

concerns all drugs remains controversial.

SGLT2is should be used with caution in patients with previous amputations, active

cutaneous ulcers, or lower extremity artery disease [

16

]. In the case that peripheral arterial

disease is suspected, screening should be rapidly performed.

2.8. Stroke

Of note, some data have reported an increased rate of stroke associated with SGLT2is,

the mechanism of which is not fully understood [

32

]. This was, however, not confirmed in

a large meta-analysis, which did not find any significant differences between dapagliflozin,

canagliflozin, and empagliflozin compared with control groups [33].

J. Clin. Med. 2021,10, 2036 5 of 10

Table 2summarizes adverse events, their respective incidence rates, and proposed

management.

Table 2. Adverse events associated with SGLT2is and proposed courses of action.

Adverse Events Incidence Practical Considerations

Mycotic genital infections

Very frequent

Male

C: 34.9 p/1000 p-y

E: 5%

Female

C: 68.8 p/1000 p-y

E: 10%

- Local or oral antifungal therapy

-

Reinforce patient education: Adequate hydration, good local hygiene,

and self-monitoring

Urinary tract infections

C: 40 p/1000 p-y

D: 1.5%

E: 1.8%

- Oral or intravenous anti-biotherapy

-

Reinforce patient education: Adequate hydration, good local hygiene,

and self-monitoring

Hypoglycemia

Frequent

C: 50 p/1000 p-y

D: 0.7%

E: 1.3%

- Administration of oral or intravenous glucose

- Withholding of SGLT2i

- Hospitalization if required

- When restarting antidiabetic therapy, the dose of other

antihyperglycemic agents should be adapted: Sulfonylurea or glinide

by at least 50% and basal insulin by at least 20%

Hypotension

Frequent

C: 26 p/1000 p-y

E: 5.1%

- Oral or intravenous fluid administration

- Hospitalization if required

- Adapt the dose of antihypertensive treatments

- Inform patients to maintain adequate oral hydration

- Treat concomitant conditions (diarrhea . . . )

- If severe condition related to volume depletion, consider temporary

withholding of SGLT2i

Acute kidney injury

Frequent

C: 3 p/1000 p-y

D: 1.5%

E: 1.0%

- Oral or intravenous fluid administration

- Hospitalization if required

- Adapt the dose of other medications that may cause AKI

(nonsteroidal anti-inflammatory drugs, diuretics,

renin-angiotensin-aldosterone inhibitors)

- Inform patients to maintain adequate oral hydration

- Treat concomitant conditions such as diarrhea, if indicated

- If severe AKI, consider temporary withholding of SGLT2i

Diabetic ketoacidosis

Rare

C: 0.6 p/1000 p-y

D: 0.3%

E: 0.1%

- Hospitalization in intensive care unit

- SGLT2i discontinuation

- Fluid resuscitation, intravenous insulin and glucose continuous

infusion, careful electrolyte and glycemia monitoring

(target: 8–11 mmol/L)

- Treatment of the underlying trigger

- Inform patients to avoid precipitating factors: Fasting, dehydration,

discontinuation of insulin therapy, surgery, infections, or excessive

alcohol intake

Fournier’s gangrene Very rare

C, D and E: <0.1%

- Hospitalization and close monitoring

- Broad-spectrum anti-biotherapy and surgical debridement,

if necessary

J. Clin. Med. 2021,10, 2036 6 of 10

Table 2. Cont.

Adverse Events Incidence Practical Considerations

Fractures C:15.4 p/1000 p-y

- Conservative or surgical management

- Instruct patients to maintain adequate calcium uptake

- Consider osteoporosis screening

Lower limb amputations C: 6.4 p/1000 p-y

D: 1.4%

- Use SGLT2is with caution in patients with previous amputations or

peripheral artery disease

- Low threshold to screen for peripheral arterial disease

- Remind patients to perform regular foot exams

AKI: Acute kidney injury. Incidence rates of side effects are based on the CANVAS-Program [

21

], DECLARE-TIMI 58 [

22

], and EMPAREG-

OUTCOME [

23

] trials. They are expressed as number of patients for 1000 patient-years (p/P-y=patients/1000 patient-years) for canagliflozin

(C), as percentages for dapagliflozin (D) and empagliflozin (E). SLGT2i: Sodium-glucose cotransporter 2 inhibitor.

3. Use of SGLT2is in Particular Clinical Situations

In general, it is advised to discontinue SGLT2is in patients undergoing urgent surgery

or hospitalized with any acute serious medical condition (e.g., infections, stroke, acute kid-

ney or liver dysfunction) because of the risk of eDKA. In case of scheduled surgery, the FDA

recommends discontinuing SGLT2is 72 h prior to intervention (96 h for ertugliflozin) [34].

However, in certain acute clinical situations, discontinuing the SGLT2i may be debat-

able. In the following section, we discuss the management of patients taking SGLT2is at

baseline, presenting to the ED in four different clinical situations.

3.1. Acute Heart Failure

It is estimated that more than 26 million people suffer from heart failure worldwide,

with up to 77% presenting at least once to the ED with decompensated acute heart failure

(AHF) [

35

]. As such, the ED serves as the portal of entry for the majority of AHF admissions,

and managing SGLT2is in patients presenting with AHF is already and will become

an increasingly frequent challenge in the coming years. The role and use of SGLT2is

in AHF has not yet been investigated in large-scale trials. However, in a randomized

pilot study comparing empagliflozin against placebo in 80 patients with AHF (with and

without T2DM), Damman et al. showed that empagliflozin was associated with a greater

urinary output and a reduction in a combined outcome of worsening HF, death, and/or

rehospitalization for AHF at 60 days [

36

]. In a position statement from the Heart Failure

Association of the European Society of Cardiology, SGLT2is are considered as third-line

diuretic treatment with added loop diuretics, after thiazides or acetazolamide/amiloride,

based on their natriuretic and osmotic diuretic effect [

37

]. In view of these data, in an

AHF patient with a SGLT2i at baseline, it seems reasonable to continue the treatment

provided the patient does not have any sign of hemodynamic instability and does not

present contraindications or side effects as described above (e.g., eDKA, AKI, hypotension).

In patients with “wet” (congestive) AHF, temporarily increasing the dose of the SGLT2i

(if possible) may be an option if additional diuretic effect is necessary after the initiation of

standard diuretic therapy. In patients with “dry” AHF, keeping the same dose of SGLT2i is

an option.

3.2. Atrial Fibrillation with Rapid Ventricular Response

Literature regarding the management of SGLT2is in the setting of patients presenting

with atrial fibrillation (AF) with rapid ventricular response is very scarce. However, in

authors’ opinion, the decision to discontinue or not the SGLT2i primarily depends on the

hemodynamic tolerance of the AF and the volume status. In patients with hemodynamic

instability (symptomatic hypotension, cardiogenic shock) and in those presenting with

hypovolemia based on clinical and biological evaluation, it seems reasonable to withhold

J. Clin. Med. 2021,10, 2036 7 of 10

the SGLT2i in addition to general AF management (initiation of rhythm or rate control,

fluid resuscitation, and initiation of anticoagulation, if needed).

3.3. Acute Diabetes Decompensation

Acute diabetes decompensation is another commonly encountered condition in the ED

and includes hyperosmolar hyperglycemic state (HHS), eDKA, and marked hyperglycemia

without hyperosmolar or ketosis conditions. Although historically considered as two dis-

tinct clinical entities, HHS and eDKA share the same basic pathophysiologic mechanisms:

Significant insulin deficiency and increased concentration of counterregulatory hormones

such as glucagon, catecholamines, cortisol, and growth hormone. Furthermore, similar to

patients with eDKA, those with HHS frequently may present with signs of dehydration,

dry mucous membranes and poor skin turgor, or hypotension [

38

]. Although no clear

recommendation regarding HHS and the use of SGLT2is exists, in patients with a SGLT2i

at baseline presenting to the ED with HHS, it seems reasonable to initiate standard HHS

treatment: fluid resuscitation, insulin infusion, careful electrolyte and glycemia monitoring,

and treatment of the underlying cause.

3.4. Gout Attack

SGLT2is have been shown to consistently reduce uric acid concentrations via increased

urinary uric acid excretion by approximately 35 45

µ

mol/L to 45

µ

mol/L (0.60–0.75 mg/dL).

The lowering of uric acid by SGLT2is may partly explain the beneficial CV and renal effects

associated with this class of treatments [

8

]. When compared with traditional hypouricemic

treatments (xanthine oxidase inhibitors), their mode of action is different and potentially

complementary [

39

]. Whether SGLT2is may be useful in the management of hyperuricemia

is still unknown, but it seems reasonable, in patients with a SGLT2i at baseline and present-

ing with a gout attack, to continue the SGLT2i, providing they do not have any condition

which might put them at risk of developing eDKA (AKI, significant inflammatory syn-

drome . . . ).

Table 3summarizes the management of SGLT2is associated with the four precited

clinical situations.

Table 3.

Proposed management of patients taking SGLT2is at baseline in the case of acute heart failure, atrial fibrillation

with rapid ventricular response, acute diabetes decompensation, and gout attack.

Conditions Proposed Course of Actions

Any planned or unplanned surgery

Any acute serious medical condition with need of

hospitalization, apart from the ones discussed below

Discontinue SGLT2i

Acute heart failure

Hemodynamically stable patients

-

“Wet” AHF: Continue SGLT2i at the same or at an increased dosage,

along with standard diuretic therapy

- “Dry” AHF: Continue SGLT2i at the same dosage

Hemodynamically unstable patients

- Discontinue SGLT2i

Atrial fibrillation with rapid ventricular response

Hemodynamically unstable patients

- Discontinue SGLT2i

Hemodynamically stable patients

- Hypovolemic patients: Discontinue SGLT2i

- Euvolemic or hypervolemic patients: Continue SGLT2i at the

same dosage

J. Clin. Med. 2021,10, 2036 8 of 10

Table 3. Cont.

Conditions Proposed Course of Actions

Acute diabetes decompensation

Thoroughly evaluate the patient for eDKA or HHS

In case of eDKA or HHS

- Immediately discontinue SGLT2i

- Associated measures: fluid resuscitation, insulin infusion, careful

electrolyte and glycemia monitoring, treatment of the

underlying trigger

In case of isolated hyperglycemia

- Switching to insulin therapy may be preferable

Gout attack SGLT2i may be continued

AHF: Acute heart failure, eDKA: Euglycemic diabetic ketoacidosis, HHS: Hyperosmolar hyperglycemic state, SLGT2i: Sodium-glucose

cotransporter 2 inhibitor.

3.5. Pregnancy

No well-controlled studies of SGLT2is have been performed in the context of preg-

nancy. According to animal studies, these drugs may affect renal development. There-

fore, SGLT2is should be used in pregnant women only if the benefits justify the risk to

the fetus [40].

4. Conclusions

SGLT2is are antidiabetic drugs for which indications are currently rapidly expanding,

as new data show beneficial effects not only in patients with T2DM, but also in those

with HFrEF and CKD, regardless of the diabetes status. Overall, they are well-tolerated

treatments, with mild genital mycotic infections and volume depletion being the most

common adverse events. However, as the number of patients taking SGLT2is increases,

emergency physicians may be faced with rarer adverse events, some of which, if left

unrecognized, could be life-threatening. The risk of adverse events may be reduced by

careful patient information and education about self-monitoring. Although it is advised to

discontinue SGLT2is in patients undergoing urgent surgery or hospitalized with any acute

serious medical condition, in certain acute clinical situations, such as acute heart failure,

this may be debatable, as SGLT2 inhibition may actually yield beneficial effects.

Author Contributions:

H.L. (Henri Lu), H.L. (Hortense Lu). and R.H. were responsible for the article

concept. H.L. (Henri Lu) and H.L. (Hortense Lu) drafted the first version of the article. All authors

were responsible for content analysis, assisted in drafting the article, and made critical revisions for

important intellectual content. R.H. takes responsibility for the paper as a whole. All authors have

read and agreed to the published version of the manuscript.

Funding: This article received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Conflicts of Interest:

H.L. (Henri Lu), H.L. (Hortense Lu), C.K., P.-N.C., M.M., J.M., O.M. and R.H. do

not have any conflict of interest in relation with this article. A.W. reports consulting honoraria from

Boehringer Ingelheim, Astra Zeneca and Janssen. A.Z. reports consulting honoraria from Boehringer

Ingelheim, Astra Zeneca and Mundipharma. A.Z. also participated in clinical trials for Boehringer

Ingelheim. P.M. has participated to meetings organized by Boehringer Ingelheim, whose honoraria

have been entirely paid to a private research foundation of the Cardiology Service of the University

Hospitals of Geneva (GeCor foundation). The funders had no role in the writing or in the decision to

publish the manuscript.

J. Clin. Med. 2021,10, 2036 9 of 10

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