SGLT-2 inhibitors in obesity and its associated cardiometabolic disorders: where do we stand?

Abstract

As the tide of obesity and its complications is on the rise, there is an urgent need for new drugs with weight-lowering and beneficial metabolic properties. Obesity-related disorders, such as metabolic syndrome, prediabetes, type 2 diabetes mellitus (T2DM), cardiovascular disease and non-alcoholic fatty liver disease (NAFLD) make this need more than mandatory. Sodium-Glucose Co-Transporter-2 (SGLT-2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are the latest class of agents to receive approval for the treatment of T2DM. Not long after their marketing, a wide spectrum of target organ-protective and overall beneficial health effects associated with their use began to unveil. An increasing bulk of evidence points towards that these actions are to a great degree independent of glucose lowering, which has led to the broadening of the indications of SGLT-12 inhibitors outside the frame of antihyperglycemic therapy. Additionally, their unique mode of action including an increased renal glucose excretion and hence, net energy loss could render SGLT-2 inhibitors attractive candidates for the treatment of obesity. Very few reviews in the literature have appraised holistically the therapeutic potential of SGLT-2 inhibitors in obesity and its associated complications. Herein, we synopsize the currently available evidence regarding the effects of drugs of this class on body adiposity, together with considerations which accompany their potential use with the aim of weight loss. Furthermore, we attempt an overview of their actions and future perspectives of their use with respect to a range of obesity-related disorders, which include cardiovascular, renal, as well as NAFLD, malignancy, and ovarian dysfunction.

Full text

REVIEW ARTICLE SGLT ‑2 inhibitors in obesity and its comorbidities 1
those of obesity, and anestimated 422 million
individuals were affected as of2014. estrong
causal relationship between these2 conditions
is mediated through theinteraction of avariety
of genetic and environmental factors that culmi‑
nate in thedevelopment of systemic insulin resis
‑
tance and eventually β ‑cell failure; hence there‑
cently coined term “diabesity.”7-9
As thetide of obesity and its complications
is on therise, there is anurgent need for new
drugs with weight ‑lowering and beneficial met‑
abolic properties.
10
Obesity and obesity ‑related
Introduction
For thelast few decades obesity has
constituted agrowing worldwide public health is‑
sue that affects therisk and prognosis of sever‑
al conditions, including cardiovascular disease
(CVD), metabolic syndrome (MetS), type 2 di‑
abetes (T2D), non alcoholic fatty liver disease
(NAFLD), COVID ‑19, and cancer.
1-5
According to
theWorld Health Organization data, in 2016 more
than 1.9 billion adults were overweight (body
mass index [BMI] between 25 and 30kg/m
2
),
among whom more than 650 million were obese
(BMI>30kg/m2).6 Global trends in T2D parallel
REVIEW ARTICLE
Sodium ‑glucose co transporter ‑2 inhibitors
in obesity and associated cardiometabolic
disorders: where do we stand?
NataliaG.Vallianou
1*
, DimitriosTsilingiris
2*
, DimitrisKounatidis
1
,
IoannisG.Lempesis
3,4
, IreneKarampela
5
, MariaDalamaga
6
1 Department of Internal Medicine and Endocrinology, Evangelismos General Hospital, Athens, Greece
2 First Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
3 Institute of Metabolism and Systems Research (IMSR), College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
4 Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
5 Second Department of Critical Care, Medical School, University of Athens, Attikon General University Hospital, Chaidari, Athens, Greece
6 Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Correspondence to:
Maria Dalamaga, MD, MSc, MPH,
PhD, National and Kapodistrian
University of Athens, Medical
School, Mikras Asias 27,
Goudi, 11527 Athens, Greece,
phone: +302 107 462 624,
email: madalamaga@med.uoa.gr
Received: August 23, 2022.
Accepted: September 12, 2022.
Published online:
September 12, 2022.
Pol Arch Intern Med. 2022;
132 (10): 16342
doi:10.20452/pamw.16342
Copyright by the Author(s), 2022
* NGV and DT equally contributed to
this work.
KEY WORDS
cardiometabolic
disorders,
cardiovascular
disease, diabetes,
obesity, SGLT ‑2
inhibitors
ABSTRACT
As the tide of obesity and its complications are on the rise, there is an urgent need for new drugs with
weight ‑lowering and beneficial metabolic properties. Obesity ‑related disorders, such as metabolic syn‑
drome, prediabetes, type 2 diabetes (T2D), cardiovascular disease, and nonalcoholic fatty liver disease
(NAFLD) make this need more than mandatory. Sodium ‑glucose cotransporter ‑2 (SGLT ‑2) inhibitors (em‑
pagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are the latest class of agents to receive approval
for the treatment of T2D. Not long after their marketing, a wide spectrum of target organ ‑protective and
overall beneficial health effects associated with their use began to unveil. An increasing bulk of evidence
indicates that these actions are to a great degree independent of glucose lowering, which has led to
the broadening of the indications for SGLT ‑2 inhibitors outside the frame of antihyperglycemic therapy.
Additionally, their unique mode of action including increased renal glucose excretion, and hence net
energy loss, could render SGLT ‑2 inhibitors attractive candidates for the treatment of obesity. Very few
reviews in the literature have holistically appraised the therapeutic potential of SGLT ‑2 inhibitors in obe‑
sity and its associated complications. Herein, we summarize the currently available evidence regarding
the effects of drugs of this class on body adiposity, together with considerations on their potential use
as weight loss agents. Furthermore, we attempt to overview their actions and future perspectives of
their use with respect to a range of obesity ‑related disorders, which include cardiovascular, renal, and
ovarian dysfunctions, as well as NAFLD and malignancy.

POLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (10)2
chronic kidney disease (n = 20), type 1 diabetes
(n = 15), COVID ‑19 (n = 10), prediabetes (n = 9),
dual inhibition of SGLT ‑1 and SGLT ‑2 (n = 8),
merely heart failure (n = 6), merely hyperten‑
sion (n = 5), asthma and obstructive sleep apnea
(n = 3), or neurological diseases (n = 3), and there‑
maining 11 studies were not written in English
(3 studies in Japanese, 2 in Spanish, 2 in French,
1 in Polish, 1 in Russian, 1 in Swedish, and 1 in He‑
brew). In addition, there were 6 books and docu‑
ments that were excluded, leaving atotal of 601
studies included in this search.
Mechanisms of action of sodium -glucose cotransporter -2
inhibitors Animportant milestone in thecourse
of SGLT ‑2‑inhibition–based therapy was thedis‑
covery of theantihyperglycemic effects of phlori
‑
zin, asubstance isolated from thebark of anap‑
ple tree by Josef von Mering in1886. Although
he additionally postulated that thekidneys are its
pharmacological target, it was not until the1970s
that inhibition of renal tubular glucose reabsorp‑
tion was specified as themechanism of action of
phlorizin,16 while Rossetti et al17 demonstrat‑
ed amelioration of insulin resistance and hyper‑
glycemia after phlorizin administration in1987.
edevelopment of thefirst orally absorbable,
phlorizin ‑derived SGLT ‑1 and SGLT ‑2 inhibitor
was followed by arapid discovery of more oral‑
ly active agents, and in 2013 canagliflozin was
thefirst SGLT‑2 inhibitor that received Food and
Drug Administration (FDA) approval for thetreat‑
ment of T2D, followed by dapagliflozin and em‑
pagliflozin in 2014.
18
SGLT cotransporters are di
‑
vided into 2 categories: SGLT ‑1 and SGLT ‑2 co‑
transporters. SGLT ‑1 cotransporters are mainly
located in thesmall intestine and are responsi
‑
ble for glucose absorption there and for there‑
absorption of approximately 10% of thefiltered
glucose in theupper part of therenal proximal tu‑
bule. eir major mechanism of action is to delay
glucose absorption in thesmall intestine, leading
to adecrease in theserum postprandial glucose
levels.19 SGLT ‑1 cotransporters are also located
in thekidneys, thebrain, theheart, thetrachea,
thetestis, and theprostate gland.19 On thecon‑
trary, SGLT ‑2 cotransporters are mainly found
in theproxy part of therenal proximal tubule,
where they act by reabsorbing approximately 90%
of thefiltered glucose. Apart from thekidneys,
SGLT ‑2 cotransporters are expressed in thebrain,
theheart, theliver, thethyroid gland, themus‑
cles, and theα pancreatic cells. eir major func‑
tion in thekidneys is to impede renal glucose re‑
absorption, causing glucosuria.2 0,21
Apart from lowering serum glucose levels,
SGLT ‑2 inhibitors have been documented to pro‑
vide significant cardiovascular benefits in patients
with T2D. Until now, there are 4 selective SGLT ‑2
inhibitors with demonstrated cardiovascular ben‑
efit: empagliflozin, canagliflozin, dapagliflozin,
and ertugliflozin.
22
eabovementioned drugs
have been documented to control blood glucose
levels, as well as to decrease body weight and
disorders, such as MetS, prediabetes, T2D,
NAFLD, and CVD complications, as well as thein‑
creased prevalence of certain types of cancer make
this need more than mandatory. Lifestyle modifi
‑
cations, such as decreased calorie intake and in‑
creased physical activity play akey role in com‑
bating obesity but are not always very easy to pur‑
sue.11 ere are several weight‑lowering drugs,
mainly lorcaserine, phentermine, topiramate, and
glucagon ‑like peptide ‑1 (GLP ‑1) receptor agonists,
but their use is restricted by their adverse effects
and limited effectiveness. Bariatric surgery offers
amore drastic and more lasting weight‑lowering
potential, and it may reverse prediabetes and T2D
in asignificant proportion of patients.10 Howev‑
er, bariatric surgery, while offering theeffective
solution regarding severe obesity, is also associ‑
ated with severe adverse effects.12,13
Sodium ‑glucose cotransporter ‑2 (SGLT ‑2) in‑
hibitors are arelatively new class of antidiabetic
drugs, which act atthe level of therenal proximal
tubule, causing glucosuria. Apart from theglu
‑
cosuric effects, they seem to exert pleiotropic bi‑
ological effects, which are not directly attributable
to thereduction of hyperglycemia, such as there‑
duction of cardiovascular mortality, heart failure
(HF) hospitalizations, and hard renal outcomes.
is has led to agradual generalization of thein
‑
dications for individual SGLT ‑2 inhibitors outside
of theframe of antihyperglycemic therapy or car‑
diovascular risk reduction among patients with
T2D. ey are now indicated for patients with HF
with preserved (empagliflozin) and reduced ejec‑
tion fraction (EF) (empagliflozin, dapagliflozin),
as well as chronic kidney disease (CKD) of etiol‑
ogy other than diabetic kidney disease, such as
ischemic or immunoglobulin Anephropathy, fo‑
cal segmental glomerulosclerosis, chronic pyelo‑
nephritis, and chronic interstitial nephritis (dapa‑
gliflozin).
14
Furthermore, their unique mode of
action, which results in aglucosuria ‑induced net
caloric loss, renders theagents of these category
attractive candidates for obesity therapy.
Very few reviews in theliterature have dis‑
cussed holistically thetherapeutic potential of
SGLT ‑2 inhibitors in obesity and its associated
complications.
15
In this narrative review, we aim
to 1) present themechanisms of action of SGLT ‑2
inhibitors, with aspecial focus on obesity and its
associated disorders; 2) appraise their therapeutic
applications; 3) discuss adverse effects and toler‑
ability issues, and 4) review potential future per‑
spectives and challenges.
Literature search In August 2022, aliterature
search of 2 bibliographical databases (MEDLINE
and Scopus) was conducted to assess theeffects
of SGLT ‑2 inhibitors on obesity. is search used
thefollowing terms: “sglt2 inhibitors” and “obe‑
sity.” esearch for theabovementioned terms
yielded atotal of 697 papers, most of which (539
results) were published between 2017 and 2022
(during thepast 5 years). Of these 697 studies,
90 were excluded, as 79 dealt with issues such as

REVIEW ARTICLE SGLT ‑2 inhibitors in obesity and its comorbidities 3
clinically relevant loss of 0.8kg under SGLT ‑2 in‑
hibitor monotherapy, or up to 5.7kg when SGLT ‑2
inhibitors were combined with GLP ‑1 receptor
agonists or medications including sulfonylureas.
ese findings are consistent in patients with
and without T2D and are attributable to anet
fat mass loss in studies that included measures
of body composition estimates, most common‑
ly magnetic resonance tomography. Additional‑
ly, thetherapy with SGLT ‑2 inhibitors is well tol‑
erated and adverse events are scarce.
Furthermore, SGLT ‑2 inhibitors reduce body
weight by interfering with excess adipose tissue,
which is known to synthesize inflammatory ad‑
ipocytokines.28-32 In obesity and obesity ‑related
disorders, such as NAFLD and T2D, adipose tissue
macrophages exhibit polarization toward theM1
phenotype, which produces proinflammatory cy‑
tokines, such as tumor necrosis factor α (TNF ‑α)
and interleukin (IL)‑6, thus inducing alow ‑grade
inflammatory state.
33,34
On thecontrary, theM2
phenotype is restricted in obesity and obesity‑
‑related disorders, thereby resulting in mitigation
of theanti ‑inflammatory cytokines, such as IL ‑4
and IL ‑10.
35-37
SGLT ‑2 inhibitors have been docu‑
mented to reverse thepolarization of adipocytes
from type 1 macrophages (M1), which release pro‑
inflammatory cytokines, to type 2 macrophages
(M2), which produce anti ‑inflammatory cyto‑
kines.24,38 is increase in the M2 phenotype ac‑
counts for thebeneficial effects of SGLT ‑2 inhibi‑
tors regarding obesity, and is suggested to reduce
thechronic inflammatory state, which character‑
izes and promotes obesity. By bolstering theM2
phenotype, SGLT ‑2 inhibitors suppress this chron‑
ic inflammation, and thus induce weight loss.
36,39
reduce systolic and diastolic blood pressure.
23
FIGURE 1 summarizes themain biological actions
of SGLT‑2 inhibitors, which are considered to
contribute to their cardiorenal protective effects.
Effects on body wei ght and adiposity indexes SGLT ‑2
inhibitors cause glucosuria, and thus they alone
induce weight loss of approximately 1.5–2 kg.
is weight loss phenomenon is dose ‑dependent
and may be maximized, when combining oth‑
er types of anti diabetic drugs, especially GLP ‑1
analogs, which suppress appetite by acting di‑
rectly atthe hypothalamus level.24 Notably,
Ferrannini et al25 demonstrated adisproportion‑
ate decrease in body weight induced by SGLT ‑2
inhibitors used alone due to their glucosuric ef‑
fects. In particular, SGLT ‑2 inhibitors produce
asmaller weight loss than can be expected based
on their glucosuric potential. is discrepancy
could be attributed to anincrease in energy in‑
take as anadaptive mechanism of thebody to
prevent any further changes in body weight. Ac‑
cording to Ferrannini et al,
25
thehuman body
might have developed anadaptive enhancement
in appetite in aneffort to induce stability in body
weight to counterbalance theweight loss effects
of SGLT ‑2 inhibitors. is notion is also increas‑
ingly being supported by other researchers.
24-26
erefore, thecombined use of SGLT ‑2 inhibitors
with drugs suppressing theappetite atthe hypo‑
thalamus level, such as GLP ‑1 analogs, is gaining
much interest nowadays.
24,27
TABLE 1 presents main
studies linking SGLT ‑2 inhibitors with weight loss
among patients with and without T2D. In short,
theresults from different studies using awide se‑
lection of agents have demonstrated amodest but
FIGURE 1 Overview of
biological actions of
sodium ‑glucose
cotransporter ‑2 inhibitors,
which may drive their
cardiovascular and renal
protective effects based
on Braunwald23 and
Tuttle et al100
• Blood pressure normalization
• Increased erythrocyte mass
• Promotion of ketogenesis
• Amelioration of insulin
resistance
• Increased glucagon levels
• Plasma volume reduction
• Increased erythropoietin activity
• Reduced plasma glucose levels
• Weight loss
• Increased circulating fatty acids
• Increased urinary sodium
and glucose excretion
• Augmentation of
glomerulotubular reflex
• Reduced tubular workload
• Reduced left ventricular
wall stress
• Promotion of ketone
body oxidation
• Increased oxygen delivery
• Reduced sodium-hydrogen
exchanger-3 activity

POLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (10)4
TABLE 1 List of studies associating overweight / obesity and the effects of sodium ‑glucose cotransporter ‑2 inhibitors on body weight among patients with and without type 2 diabetes (continued on the next pages)
Research / year Population, type of study Treatment Main findings Remarks
List of studies among patients without T2D
Hussey et al,(S1)a 2010 18 overweight / obese patients without T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 1 trial
I) Sergliflozin etabonate 500 mg/tid
II) Sergliflozin etabonate 1000 mg/tid
III) Placebo
Sergliflozin induced significant weight
loss of approximately 1.55 kg for
sergluflozin 500 mg/tid to 1.74 kg for
sergluflozin 1000 mg/tid, from baseline
after 15 days of administration
Sergluflozin was generally well tolerated;
No major adverse effects reported
Bays et al,54 2014 376 overweight / obese patients without
T2D;
A double ‑blind, placebo ‑controlled, phase 2b
trial
I) Canagliflozin 50 mg
II) Canagliflozin 100 mg
III) Canagliflozin 300 mg
IV) Placebo
↓ body weight by
I) 2.2%
II) 2.9%
III) 2.7%
IV) 1.3%
Canagliflozin ↓ body weight without any severe
adverse effects
Napolitano et al,(S2)
2014
30 overweight / obese patients without T2D;
A double ‑blind, placebo ‑controlled,
randomized, pilot trial
I) Sergliflozin etabonate 1000 mg/tid
II) Remogliflozin etabonate 250 mg/tid
III) Placebo
No changes in body weight reported in
the 3 groups;
All patients except 1 exhibited weight
loss
↓ in the leptin / adiponectin ratio in the groups receiving
sergliflozin or remogliflozin when compared with
placebo
Lundkvist et al,(S3)
2017a
50 obese patients without T2D;
A randomized, placebo‑controlled, phase 2a
trial
I) Dapagliflozin 10 mg/d + exanetide 2 mg sc
every week for 24 weeks
II) Placebo
↓ body weight by 4.13 kg (SD) (95% CI,
6.44–1.81 kg; P <0.001);
↓ in total adipose tissue by 3.8 l
36% of the patients enrolled lost ≥5% of their body
weight;
The loss in body weight was attributed to ↓ in adipose
tissue with no ↓ in lean tissue, as estimated by MRI
Lundkvist et al,(S4)
2017b
50 obese adults without T2D;
Open ‑label extension trial
I) Dapagliflozin 10 mg/d + exanetide 2 mg sc
every week for 1 year
II) Placebo
↓ body weight by 5.7 kg;
↓ in total adipose tissue by 5.3 l
↓ body weight lasting for 1 year;
↓ in adipose tissue, as estimated by MRI
Hollander et al,(S5)
2017
335 overweight / obese patients without
T2D;
A double ‑blind, placebo ‑controlled, phase 2a
trial
I) Canagliflozin 300 mg/d
II) Phentermine 15 mg/d
III) Canagliflozin 300 mg/d + phentermine
15 mg/d
IV) Placebo
↓ body weight by 6.9% [95% CI,
8.6%–5.2%], P <0.001 in
the combination group
↓ body weight ≥5%, without any severe adverse
effects
Ramirez ‑Rodriguez
et al,(S6) 2020
24 patients with prediabetes;
A double ‑blind, placebo ‑controlled,
randomized trial
I) Dapagliflozin 10 mg/d
II) Placebo
↓ body weight by 3.0 kg or 3.7% vs 1 kg
in placebo (P = 0.019)
↓ body weight;
↓ BMI;
↓ WC
Faecher et al,(S7) 2021 120 overweight / obese patients with
prediabetes;
A controlled, randomized, parallel ‑arm,
non ‑blind, open label trial
I) Metformin 1700 mg/d
II) Dapagliflozin 10 mg/d
III) Placebo
IV) Exercise group
Dapagliflozin and exercise led to small
improvements in glycemic control
among patients with prediabetes, when
compared with metformin and placebo
The study revealed uncertainty about glycemic control
in prediabetic patients;
The study did not mention any differences in body
weight between the groups
List of studies in patients with T2D
Ferrannini et al(S8),
2010
485 patients with T2D;
A double ‑blind, placebo ‑controlled
randomized, phase 3 trial
I) Dapagliflozin 2.5 mg/d
II) Dapagliflozin 5 mg/d
III) Dapagliflozin 10 mg/d
IV) Placebo
↓ in mean HbA1c of 0.58%, 0.77%, 0.89%
in group I, II, and III, respectively,
P <0.0005;
↓ in mean HbA1c of 0.23% in the placebo
group
No severe adverse effects reported;
Noninsulin‑dependent mode of action

REVIEW ARTICLE SGLT ‑2 inhibitors in obesity and its comorbidities 5
TABLE 1 List of studies associating overweight / obesity and the effects of sodium ‑glucose cotransporter ‑2 inhibitors on body weight among patients with and without type 2 diabetes (continued on the next pages)
Research / year Population, type of study Treatment Main findings Remarks
Strojek et al,(S9) 2011 597 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Dapagliflozin 2.5 mg/d + glimepiride 4 mg/d
II) Dapagliflozin 5 mg/d + glimepiride 4 mg/d
III) Dapagliflozin 10 mg/d + glimepiride 4 mg/d
IV) Placebo + glimepiride 4 mg/d
↓ in mean HbA1c of 0.58%, 0.63% and
0.82% in group I, II, and III, respectively,
P <0.0001
Dapagliflozin as an addition to therapy with glimepiride
↓↓ HbA1c and TBW;
↑ in hypoglycemia reported
Nauck et al,(S10) 2011 814 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized noninferiority, phase 3 trial,
lasting for 1 year
I) Metformin 1500–2500 mg/d + dapagliflozin
5–10 mg/d
II) Metformin 1500–2500 mg/d+ glipizide
10–20 mg/d
↓ in mean HbA1c of 0.52%, for both
dapagliflozin and glipizide;
Weight loss of 3.2 kg vs weight gain of
1.2 kg for glipizide, P <0.0001
↓ in body weight of ≥5% in 33.33% of the patients on
dapagliflozin;
↑ infections of the genitalia and UTIs on dapagliflozin
↑ of hypoglycemia on glipizide
Bailey et al,(S11) 2012 282 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Dapagliflozin 1 mg/d
II) Dapagliflozin 2.5 mg/d
III) Dapagliflozin 5 mg/d
IV) Placebo
↓ in mean HbA1c of 0.68%, 0.72%, and
0.82%, in group I, II, and III, respectively,
P <0.0001
Insulin ‑independent mode of action;
No severe adverse effects reported
Bolinder et al,(S12)
2012
182 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized trial
I) Dapagliflozin 10 mg/d + metformin
II) Placebo + metformin
↓ TBW of 2.08 kg (95% CI, 2.84–1.31 kg;
P <0.0001)
Dapagliflozin further ↓ TBW, ↓ of FM, VAT, and SAT
Bailey et al,(S13) 2013 546 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Dapagliflozin 2.5 mg/d
+ metformin ≥1500 mg/d
II) Dapagliflozin 5 mg/d + metformin ≥1500 mg/d
III) Dapagliflozin 10 mg/d
+ metformin ≥1500 mg/d
IV) Placebo + metformin ≥1500 mg/d
↓ in mean HbA1c of 0.48%, 0.58%, and
0.78% in group I, II, and III, respectively,
P <0.0008;
↑ in mean HbA1c of 0.02% in the placebo
group
Dapagliflozin as an addition to the therapy with
metformin ↓↓ HbA1c and TBW;
No severe adverse effects reported
Lambers Heerspink
et al,(S14) 2013
75 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 2 trial
I) Dapagliflozin 10 mg/d
II) Hydrochlorothiazide 25 mg/d
III) Placebo
↓ body weight 2.4 kg vs 0.1 kg in
the placebo group
Dapagliflozin and hydrochlorothiazide ↓ body weight;
Comparison of the diuretic and blood pressure
lowering effects of dapagliflozin and
hydrochlorothiazide
Kaku et al,(S15) 2014 261 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Dapagliflozin 5 mg/d
II) Dapagliflozin 10 mg/d
III) Placebo
↓ in mean HbA1c of 0.41% and 0.45% in
group I and II, respectively
Dapagliflozin ↓↓ HbA1c and TBW;
Hypoglycemia only in 2 patients on dapagliflozin
10 mg/d
Ji et al,(S16) 2014 393 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Dapagliflozin 5 mg/d
II) Dapagliflozin 10 mg/d
III) Placebo
↓ in mean HbA1c of 1.04% and 1.11% in
group I and II, respectively, P <0.0001
Dapagliflozin ↓↓ HbA1c and TBW;
Infrequent hypoglycemia
Nauck et al,(S17) 2014 814 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial, lasting for 2 years
I) Metformin 1500–2500 mg/d + dapagliflozin
5–10 mg/d
II) Metformin 1500–2500 mg/d + glipizide
10–20 mg/d
↓ in body weight of 5.1 kg (95% CI,
5.7–4.4 kg) after 2 years
↓ in body weight and ↑ glycemic durability that lasted
longer on dapagliflozin than on glipizide;
Hypoglycemia much (10 ‑fold) less frequent on
dapagliflozin than on glipizide;
Genital infections and UTIs more frequent on
dapagliflozin than on glipizide

POLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (10)6
TABLE 1 List of studies associating overweight / obesity and the effects of sodium ‑glucose cotransporter ‑2 inhibitors on body weight among patients with and without type 2 diabetes (continued on the next pages)
Research / year Population, type of study Treatment Main findings Remarks
Jabbour et al,(S18)
2014
432 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Sitagliptin 100 mg/d ± metformin ≥1500 mg/d
+ dapagliflozin 10 mg/d
II) Sitagliptin 100 mg/d ± metformin ≥1500 mg/d
+ placebo
↓ in body weight of 2.3 kg on
dapagliflozin vs 0.3 kg on placebo
↓ in body weight and HbA1c on dapagliflozin vs placebo;
Genital infections more frequent on dapagliflozin, UTI
frequency almost the same on dapagliflozin and
placebo
Kovacs et al,(S19) 2014 498 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Pioglitazone ≥30 mg/d ±
metformin ≥1500 mg/d + empagliflozin 10 mg/d
II) Pioglitazone ≥30 mg/d ±
metformin ≥1500 mg/d + empagliflozin 25 mg/d
III) Pioglitazone ≥30 mg/d ±
metformin ≥1500 mg/d + placebo
↓ in mean body weight (SD) of 1.62 kg
(0.21) and 1.47 kg (0.21) on
empagliflozin 10 mg and 25 mg,
respectively, vs weight gain of 0.34 kg
(0.21) on placebo (both P <0.001)
Empagliflozin 10 mg/d or 25 mg/d resulted in ↓ in both
body weight and HbA1c;
Empagliflozin generally well tolerated
Strojek et al,(S20) 2014 597 patients with T2D;
A double ‑blind, parallel ‑group, randomized,
phase 3 trial
I) Glimepiride 4 mg/d
II) Glimepiride 4 mg/d + dapagliflozin 2.5 mg/d
III) Glimepiride 4 mg/d + dapagliflozin 5 mg/d
IV) Glimepiride 4 mg/d + dapagliflozin 10 mg/d
No significant changes in mean HbA1c
were observed;
↓ in body weight of 1.36 kg, 1.54 kg, and
2.41 kg reported on dapagliflozin
2.5 mg/d, 5 mg/d, and 10 mg/d,
respectively, over 48 weeks
Addition of dapagliflozin led to sustained weight loss;
No severe adverse effects reported
Bolinder et al,(S21)
2014
182 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, multi ‑arm, parallel ‑group, phase
3 trial
I) Metformin ≥1500 mg/d
II) Metformin ≥1500 mg/d +
dapagliflozin 10 mg/d
↓ in mean HbA1c;
↓↓ in body weight of 4.54 kg and ↓ in WC
of 5 cm
↓↓ in body weight and ↓↓ in FM of 2.8 kg;
No severe adverse effects reported
DeFronzo et al,(S22)
2015
674 patients with T2D;
A double ‑blind, parallel ‑group, randomized,
phase 3 trial
I) Metformin ≥1500 mg/d + linagliptin 5 mg/d
II) Metformin ≥1500 mg/d + empagliflozin
10 mg/d
III) Metformin ≥1500 mg/d + empagliflozin
25 mg/d
IV) Metformin ≥1500 mg/d + linagliptin 5 mg/d
+ empagliflozin 10 mg/d
V) Metformin ≥1500 mg/d + linagliptin 5 mg/d
+ empagliflozin 25 mg/d
↓↓ in body weight and HbA1c No severe adverse effects reported attributable to
the use of empagliflozin;
Allergic reactions in 3 patients occurred when
linagliptin was used alone or in combination with
empagliflozin
Del Prato et al,(S23)
2015
814 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Metformin ≥1500 mg/d + glipizide 10–20 mg/d
II) Metformin ≥1500 mg/d + dapagliflozin up to
20 mg/d
↓ in mean HbA1c and ↓↓ in TBW of 4.38 kg
(95% CI, 5.31–3.46 kg), when comparing
dapagliflozin with glipizide at 4 years
↓↓ in mean HbA1c and TBW at 4 years on dapagliflozin
vs glipizide;
Genital infections and UTIs more frequent on
dapagliflozin but tended to disappear with time and
antibiotics
Bailey et al,(S24) 2015 274 patients with T2D;
A double ‑blind, placebo ‑controlled,
parallel ‑group, phase 3 trial
I) Placebo, ie patients who after completion of 24
weeks of the study received metformin 500 mg/d
(low dose), therefore:
II) Metformin 500 mg/d + dapagliflozin 2.5 mg/d
III) Metformin 500 mg/d + dapagliflozin 10 mg/d
IV) Metformin 500 mg/d + dapagliflozin 10 mg/d
↓ in mean HbA1c and ↓↓ in TBW of
2.016 kg, P = 0.016
↓↓ in mean HbA1c and TBW at 2 years on dapagliflozin
vs low ‑dose metformin;
Genital infections and UTIs more frequent on
dapagliflozin;
Hypoglycemia uncommon on dapagliflozin

REVIEW ARTICLE SGLT ‑2 inhibitors in obesity and its comorbidities 7
TABLE 1 List of studies associating overweight / obesity and the effects of sodium ‑glucose cotransporter ‑2 inhibitors on body weight among patients with and without type 2 diabetes (continued on the next page)
Research / year Population, type of study Treatment Main findings Remarks
Rosenstock et al,(S25)
2015
534 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Metformin ≥1500 mg/d + saxagliptin 5 mg/d
+ placebo
II) Metformin ≥1500 mg/d + dapagliflozin
10 mg/d + placebo
III) Metformin ≥1500 mg/d + saxagliptin 5 mg/d
+ dapagliflozin 10 mg/d
↓↓ in mean HbA1c and ↓↓ in body weight in
patients on saxagliptin + dapagliflozin
apart from metformin
Triple combination of metformin + dapagliflozin +
saxagliptin resulted in ↓↓ in HbA1c and ↓↓ in body weight;
No episodes of severe hypoglycemia reported with
the triple combination
Fulcher et al,(S26) 2016 411 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) DPP ‑4 inhibitor + placebo
II) DPP ‑4 inhibitor + canagliflozin 100 mg/d
III) DPP ‑4 inhibitor + canagliflozin 300 mg/d
IV) GLP ‑1 analog + placebo
V) GLP ‑2 analog + canagliflozin 100 mg/d
VI) GLP ‑1 analog + canagliflozin 300 mg/d
↓ in mean HbA1c and ↓ in body weight
with canagliflozin 100 mg/d or 300 mg/d
In the patients receiving incretin mimetics,
canagliflozin 100 mg/d or 300 mg/d ↓ body weight;
Incidence of hypoglycemia ↑ with canagliflozin addition
Frias et al,(S27) 2016 695 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Metformin ≥1500 mg/d + exanetide
2 mg/weekly
II) Metformin ≥1500 mg/d + dapagliflozin
10 mg/d
III) Metformin ≥1500 mg/d + exanetide
2 mg/weekly + dapagliflozin 10 mg/d
↓ in mean HbA1c and body weight on
the combination of exanetide +
dapagliflozin
As expected, exanetide + dapagliflozin were superior
regarding lowering mean HbA1c and weight loss, and
more patients with weight loss ≥5% of their body
weight;
No major adverse effects reported
Mathieu et al,(S28)
2016
294 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Metformin + saxagliptin + placebo
II) Metformin + saxagliptin + dapagliflozin
10 mg/d
HbA1c, –0.74% vs 0.07%; FPG, –27 mg/dl
vs 10 mg/dl; body weight, –2.1 kg vs
–0.4 kg on dapaglifozin vs placebo
Triple combination of metformin + dapagliflozin +
saxagliptin resulted in ↓↓ in mean HbA1c and ↓↓ in body
weight;
Overall, the triple combination was well tolerated and
provided sustainable effects;
Only genital infections with Candida species were
more common in the dapagliflozin group
Neal et al,58 2017 10 142 patients with T2D and high CVD risk
receiving standard care;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial (CANVAS
program)
I) Canagliflozin 100 mg/d
II) Canagliflozin 300 mg/d
III) Placebo
Body weight loss of 1.46 kg ↓ risk of CVD event;
↑ risk of lower limb amputation
Wanner et al,(S29)
2018
7020 patients with T2D and CVD receiving
standard care;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial (EMPAREG‑
‑OUTCOME trial)
I) Empagliflozin 10 mg/d
II) Empagliflozin 25 mg/d
III) Placebo
Body weight loss of 2 kg Empagliflozin addition to standard care led to ↓ in body
weight;
No severe adverse effects reported
Ludvik et al,(S30) 2018 424 patients with T2D;
A double ‑blind, placebo ‑controlled, parallel‑
‑arm, randomized, phase 3b trial
I) SGLT ‑2 inhibitor + placebo
II) SGLT ‑2 inhibitor + dulaglutide 0.75 mg/weekly
III) SGLT ‑2 inhibitor + dulaglutide 1.5 mg/weekly
Patients on dulaglutide instead of
placebo had ↓↓ in mean HbA1c and
↓↓ body weight
Although the addition of dulaglutide to SGLT ‑2 inhibitor
resulted in significant ↓↓ in body weight, adverse side
effects were more frequent in the groups that received
dulaglutide;
Nausea, diarrhea, vomiting were more frequent in
patients on dulaglutide instead of placebo

POLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (10)8
TABLE 1 List of studies associating overweight / obesity and the effects of sodium ‑glucose cotransporter ‑2 inhibitors on body weight among patients with and without type 2 diabetes (continued from the previous pages)
Research / year Population, type of study Treatment Main findings Remarks
Pratley et al,(S31) 2018 1233 patients with T2D;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial
I) Metformin ≥1500 mg/d + ertugliflozin 5 mg/d
II) Metformin ≥1500 mg/d + ertugliflozin 15 mg/d
III) Metformin ≥1500 mg/d + ertugliflozin 5 mg/d
+ sitagliptin 100 mg/d
IV) Metformin ≥1500 mg/d + ertugliflozin
15 mg/d + sitagliptin 100 mg/d
V) Metformin ≥1500 mg/d + sitagliptin 100 mg/d
↓ in mean HbA1c and ↓ in body weight
with the combination of ertugliflozin
+ sitagliptin, when compared with
sitagliptin alone
↓ in glucose levels and body weight after 52 weeks of
observation;
Only genital infections with Candida species more
common in patients on ertugliflozin
Perkovic et al,90 2019 4401 patients with T2D and albuminuric
CKD;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial (CREDENCE trial)
I) Canagliflozin 100 mg/d
II) Placebo
Canagliflozin induced weight loss of
0.8 kg
Canagliflozin ↓↓ the risk of CVD events and renal failure,
↓ body weight;
No differences in the risk of amputations
Wiviott et al,57 2019 17 160 patients with T2D receiving standard
care;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial (DECLARE ‑TIMI
58)
I) Dapagliflozin 10 mg
II) Placebo
Weight loss of 1.8 kg Dapagliflozin as an additional treatment to standard
care was associated with ↓↓ risk of CVD events and
↓↓ risk of renal events;
DKA more common on dapagliflozin when compared
with placebo (0.3% vs 0.1%, P = 0.02);
Genital infections more common on dapagliflozin
Cannon et al,(S32) 2020 8246 patients with T2D and atherosclerotic
CVD receiving standard care;
A double ‑blind, placebo ‑controlled,
randomized, phase 3 trial (VERTIS CV)
I) Ertugliflozin 5 mg/d
II) Ertugliflozin 15 mg/d
III) Placebo
Weight loss of 2.4 kg on ertugliflozin
5 mg/d and 2.8 kg on ertugliflozin
15 mg/d
Ertugliflozin was not inferior to placebo regarding CVD
risk;
Amputations performed in 2% of patients on
ertugliflozin 5 mg/d and in 2.1% of patients on
ertugliflozin 15 mg/d, vs 1.6% in the placebo group
a References S1–S32 are listed in Supplementary material
Abbreviations: ↓, decrease; ↓↓, strong decrease; ↑, increase; BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; FM, fat mass; HbA1c, glycated hemoglobin; MRI,
magnetic resonance imaging; RCT, randomized controlled trials; SAT, subcutaneous adipose tissue; T2D, type 2 diabetes mellitus; TBW, total body weight; tid, thrice daily; UTIs, urinary tract infections; VAT, visceral adipose
tissue; WC, waist circumference

REVIEW ARTICLE SGLT ‑2 inhibitors in obesity and its comorbidities 9
effects on lipid metabolism and biomarkers will
most probably appear in thenear future.
Cardiovascular effects Despite the fact that
SGLT ‑2 inhibitors have been mainly introduced
for thetreatment of patients with T2D, they pos‑
sess pleiotropic properties over and beyond their
antidiabetic potential.
49
Among these pleiotropic
effects, their cardioprotective ability is of theut‑
most importance. In particular, theEMPA ‑REG
OUTCOME study55 was thefirst to show asig‑
nificant decrease in therate of death from CVD
causes, nonfatal infarction, or nonfatal stroke
among 7020 patients with T2D athigh risk of
anadverse CVD effect. eCANVAS study56 fol‑
lowed, which enrolled 10 142 patients with T2D
and high CVD risk, and confirmed alower risk
of thesame adverse CVD effects. eDECLARE‑
‑TIMI 58 study,
57
also published, like prior trials,
in New England Journal of Medicine, has document‑
ed asignificant reduction in therate of hospital‑
ization due to HF among 10 186 patients with
T2D and lowered risk of atherosclerotic CVD in
thepatients followed for amedian of 4.2 years.
Furthermore, theEMPEROR ‑Reduced study,
58
which enrolled 3730 patients with HF and thelat‑
est EMPEROR ‑Preserved study,59 which investi‑
gated 5988 patients with HF, have shown ben‑
eficial cardiovascular effects associated with
theuse of empagliflozin. In particular, asignif‑
icant decrease in death or hospitalization rate
due to HF was noted in both studies, regardless
of thepresence of T2D. eDAPA ‑HF study
60
in‑
cluding 4744 patients with HF and reduced EF
has also confirmed theabovementioned findings
for dapagliflozin.
ese remarkable cardioprotective effects of
SGLT ‑2 inhibitors have led to their use in patients
even without T2D but with established HF. Re‑
garding their beneficial effects in patients with
HF, these may be attributed to theincreased pro‑
duction of ketones by SGLT ‑2 inhibitors, which,
in turn, ameliorate mitochondrial dysfunction
observed in HF and increase adenosine triphos‑
phate production, resulting in animproved ven‑
tricular contractility.23 In particular, SGLT ‑2 in‑
hibitors may lead to changes in intracellular sodi‑
um and calcium concentrations, resulting in im‑
proved ventricular contractility and fewer cardiac
arrhythmias.
23
In addition, cardiac inflamma‑
tion and thesubsequent cardiac fibrosis are at‑
tenuated by theuse of SGLT ‑2 inhibitors. is
effect is mainly attributed to decreased produc‑
tion of free radicals in thecardiomyocytes, as
these antidiabetic drugs induce anantioxidative
and anti ‑inflammatory milieu that supports cor‑
onary endothelial function. It is also important
to highlight that theepicardial fat surrounding
theheart, characterized by increased production
of proinflammatory cytokines, is decreased fol‑
lowing theuse of SGLT ‑2 inhibitors, thus result‑
ing in areduction of proinflammatory cytokines
and amelioration of thesurrounding environ‑
ment.
61
Besides, due to theweight loss induced by
In addition, it is widely known that brown
adipose tissue (BAT) plays akey role in obesity
and obesity ‑related disorders. More specifically,
browning of thewhite adipose tissue (WAT) has
been suggested to be acrucial factor in combating
obesity.
40-43
is is mainly achieved by increasing
energy expenditure by means of increased expres‑
sion of uncoupling protein 1 (UCP ‑1) in BAT, as
well as anenhancement of cells expressing UCP ‑1
in WAT. ese brown ‑like adipocytes, often called
beige cells, are characterized by anincreased ex‑
pression of UCP ‑1, and thus by their transforma‑
tion into brown adipocytes.39 SGLT ‑2 inhibitors
have been documented to increase body energy
expenditure by increasing theexpression of UCP ‑1
in WAT and BAT, leading to browning of thead‑
ipose tissue. In this process, adiponectin and fi‑
broblast growth factor 21 have been found to be
elevated as aresult of chronic administration of
SGLT ‑2 inhibitors.44-48
Overall, SGLT ‑2 inhibitors seem to be associ‑
ated with weight loss via their glucosuric effects,
polarization toward theM2 phenotype of macro‑
phages, and browning of theWAT.
Effects on glycemic control
SGLT ‑2 inhibitors in‑
duce glucosuria, thereby ameliorating theserum
glucose levels, while their ability to promote fat
utilization and browning of theWAT improves
insulin sensitivity.24 SGLT ‑2 inhibitors used as
monotherapy have been shown to lower fasting
plasma glucose (FPG) by 20–46mg/dl and gly‑
cated hemoglobin (HbA1c) by 0.54% to 1.45% in
patients with baseline HbA1c of 7% to 9.1%, as
compared with placebo. Notably, theaddition of
SGLT ‑2 inhibitors as anadd ‑on therapy to met‑
formin may lower FPG by 15–40mg/dl and HbA
1c
by 0.54%–0.77% as compared with placebo in
patients with baseline HbA1c between 7.9% and
8.2%.49
Although SGLT ‑2 inhibitors are widely used
for thetreatment of patients with T2D, individ‑
uals with T1D may also benefit from their pleio‑
tropic properties, apart from theglucose low‑
ering effects.
49-51
In fact, sotagliflozin, adual
SGLT ‑1 and SGLT ‑2 inhibitor, is authorized in
theEuropean Union only for thetreatment of
patients with both T1D and obesity.
52
Howev‑
er, theuse of SGLT ‑2 inhibitors or even sota‑
gliflozin among patients with T1D has been as‑
sociated with higher rates of euglycemic diabetic
ketoacidosis (EDKA), as these patients are more
prone to ketoacidosis than patients with T2D.
Besides, there is always ahigher risk of hypogly‑
cemia among patients with T1D due to thecon‑
current use of insulin.53
Regarding theeffects of SGLT ‑2 inhibitors on
lipid parameters, it has been suggested that this
class of antidiabetic drugs may lead to asmall
increase in serum high‑density lipoprotein cho‑
lesterol levels, whereas other reports have also
shown aslight increase in low‑density lipopro‑
tein cholesterol levels.
10,54
As these drugs are now
extensively used, more research in terms of their

POLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (10)10
theuse of canagliflozin with kidney function as
aprimary end point. is trial showed that the
relative risk of death from renal causes among
theenrolled 4401 patients was reduced by 34%,
while therelative risk of ESRD was reduced by
32% during themedian follow ‑up of 2.62 years.
68
eDAPA ‑CKD study,
69
which dealt with thead‑
ministration of another SGLT ‑2 inhibitor, dapa‑
gliflozin, in 4304 patients with kidney dysfunc‑
tion and with or without T2D, has also demon‑
strated aslower decline in eGFR in thelong term,
especially among patients with higher HbA
1c
and
higher urinary to creatinine ratio atthe begin‑
ning of thestudy. econsistent results demon‑
strating areduction of adverse renal outcomes
across abroad selection of different SGLT ‑2 in‑
hibitors point toward aclass renoprotective ef‑
fect of SGLT ‑2 inhibitors. erefore, theusage
of SGLT ‑2 inhibitors has been expanded even in
lower eGFR, where their antidiabetic potential is
compromised but their nephroprotective as well
as cardioprotective properties are still sustained.
In particular, atGFRbelow 45ml/min/1.73m2,
SGLT ‑2 inhibitors have lower glycemic efficacy
and usually another agent should be added to
achieve glycemic goals. However, depending on
thelabeling of representative drugs, they should
be initiated even when eGFR is between 30 and
45ml/min/1.73m2 due to their dual beneficial car‑
diorenal effects. eresults of DAPA ‑CKD study
7
generalized these findings outside of theframe
of diabetic nephropathy, and led to approvals by
theFDA and theEuropean Medicines Agency, re‑
garding theuse of dapagliflozin among patients
with CKD of nondiabetic etiology.
Regarding CKD and theobesity paradox, it
should be noted that thephenomenon of “re‑
verse epidemiology” is observed in CKD patients,
whereas increased BMI has been associated with
better survival outcomes.
70
However, this phe‑
nomenon, which apart from CKD has been ob‑
served in heart disease, liver cirrhosis, and chron‑
ic obstructive lung disease, may be attributed to
protein wasting and cachexia, which characterize
theadvanced stages of theabovementioned dis‑
orders.70 SGLT ‑2 inhibitors act mainly by caus‑
ing glucosuria and natriuresis, thereby inducing
weight loss without leading to sarcopenia and
cachexia.71 In addition, it should be pointed out
that SGLT ‑2 inhibitors, by interfering with thein‑
flammasome pathway, may result in reduced re‑
lease of IL ‑1β, which is widely known for its key
role in thepathogenesis of CKD.72
Effects on hepatic function and nonalcoholic fatty
liver disease Nowadays, NAFLD has been as‑
sessed to affect almost 70% to 80% of patients
with T2D,
73,74
while in obesity its prevalence rang‑
es from 50% to 90%, depending on thedegree of
excess adiposity.
76
NAFLD, which is character‑
ized by excess fat accumulation in thehepato‑
cytes, may be associated with nonalcoholic ste‑
atohepatitis (NASH), cirrhosis, and even hepato‑
cellular carcinoma.
76,77
Apart from these severe
SGLT ‑2 inhibitors, there is also ageneral decrease
in theproduction of proinflammatory cytokines
by theadipose tissue, which accounts for abetter
and more functional cardiac microenvironment.
62
Effects on arterial blood pressure Due to their na‑
triuretic effects, SGLT ‑2 inhibitors slightly reduce
arterial blood pressure (3–7mmHg for systolic
and 2mmHg for diastolic blood pressure).
63
is
anti hypertensive potential is reported to be pres‑
ent regardless of theuse of other antihypertensive
drugs, such as loop diuretics. However, it has been
demonstrated that SGLT ‑2 inhibitors and loop di‑
uretics may share asynergistic natriuretic effect.
64
Notably, theantihypertensive potential of SGLT ‑2
inhibitors does not induce further release of re‑
nin by themacula densa. edecreased intravas‑
cular volume resulting from thenatriuretic prop‑
erties of SGLT ‑2 inhibitors does not seem to ac‑
tivate therenin ‑angiotensin ‑aldosterone system
or thesympathetic activity tone. is unique fea‑
ture of SGLT ‑2 inhibitors may be thecornerstone
of thebeneficial effects of SGLT ‑2 inhibitors re‑
garding blood pressure.
64
Apart from their natri‑
uretic effect, SGLT ‑2 inhibitors decrease thearte‑
rial stiffness, thus reducing thearterial tone and
decreasing thearterial blood pressure. is de‑
crease in arterial stiffness may be attributed to
reduction in theperivascular fat caused by SGLT ‑2
inhibitors, as reported by Batzias et al65 in their
meta ‑analysis. Furthermore, theweight loss ef‑
fect may also account for thereduction in arterial
blood pressure.65 Overall, thenatriuretic effects
together with theweight loss and thereduction
in arterial stiffness all result in decreased arteri‑
al blood pressure.
Effects on renal function Among patients with
T2D, theincreased reabsorption of sodium and
glucose by theSGLT ‑2 cotransporters accounts
for thestate of hyperfiltration noted in thevery
early stages of diabetic kidney disease.
10
is phe‑
nomenon is mainly attributed to anenhanced re‑
absorption of sodium leading to vasoconstriction
of theafferent arteriole. euse of SGLT ‑2 inhib‑
itors may result in reduced hyperfiltration as well
as lowered intraglomerular pressure, and there‑
fore ameliorated renal function. Interestingly, in
theEMPA ‑REG Outcome study,
55
theadministra‑
tion of empagliflozin was associated with areduc‑
tion in therate of doubling of serum creatinine
levels, areduction in albuminuria, progression to
end‑stage renal disease (ESRD), and death related
to kidney dysfunction. eEMPA ‑REG Outcome
study
55
was thefirst to report these favorable re‑
nal effects associated with theuse of aSGLT ‑2 in‑
hibitor. eCANVAS trial ensued,66 which con‑
firmed that theuse of another SGLT ‑2 inhibitor,
canagliflozin, resulted in reduction in theprogres‑
sion of albuminuria and a40% decline in dete‑
rioration of estimated glomerular filtration rate
(eGFR), theneed for renal replacement treat‑
ment, and death of renal origin causes. eCRE‑
DENCE study
67
was thefirst one investigating

REVIEW ARTICLE SGLT ‑2 inhibitors in obesity and its comorbidities 11
are among themost beneficial features regard‑
ing their use in women with PCOS.81 Notably,
1 current RCT studying theadministration of
25mg of empagliflozin or 1500mg of metfor‑
min in 39 women with PCOS, has showed are‑
duction in body weight, BMI, waist circumfer‑
ence, and total fat, but no significant differences
in insulin resistance and androgen levels.
82
An‑
other RCT is ongoing regarding theadministra‑
tion of canagliflozin vs metformin among wom‑
en with PCOS [NCT04700839]. Overall, due to
theweight loss and blood pressure lowering ef‑
fects of SGLT ‑2 inhibitors, there is anongoing
interest in theadministration of SGLT ‑2 inhibi‑
tors in women with PCOS to also improve vari‑
ous CVD risk parameters.
Adverse events and tolerability emost com‑
mon adverse effect of SGLT ‑2 inhibitors is geni‑
tal candidiasis. ephenomenon of glucosuria,
which is themain mechanism of action in this
category of drugs, confers afavorable environ‑
ment for thegrowth of Candida species. Apart
from mycotic genitalia infections, which are re‑
ported to be 4 to 6 times increased, bacterial
infections of theurinary system may also de‑
velop, although less frequently. ese urinary
tract infections are rarely severe enough to cause
pyelonephritis.
83,84
Another adverse effect of this
class of drugs is that they may provoke EDKA,
which, however, is highly preventable and may
be managed by discontinuation of thedrug and
intravenous administration of fluids together
with insulin and potassium supplementation, if
needed. Nevertheless, if apatient is adequate‑
ly hydrated, this adverse effect occurs very rare‑
ly.
23,85
Atransient increase in serum creatinine
levels, albeit of questionable clinical relevance,
is observed frequently following theinitiation
of SGLT‑2 inhibitor therapy.86 is is in contrast
with documented long ‑term nephroprotective ef‑
fects of SGLT ‑2 inhibitors (see section Effects on
renal function), while therapy with dapagliflozin
appears to be safe even in patients with stage
4 CKD.
87
Regarding canagliflozin, theCANVAS
study
56
reported that canagliflozin therapy was
associated with anincreased risk of limb ampu‑
tation and bone fractures. However, these results
were not confirmed in theCREDENCE study,
88
while they have not been reported with theuse
of other SGLT ‑2 inhibitors. Furthermore, ather‑
apy with SGLT ‑2 inhibitors does not seem to in‑
crease fracture risk in patients with CKD, regard‑
less of baseline eGFR.89
Perspectives and challenges According to
theAmerican Diabetes Association and theAmeri‑
can Heart Association recommendations for 2022,
in patients with T2D and established CVD or re‑
nal disease, SGLT ‑2 inhibitors or GLP ‑1 analogs
or both are recommended.
23,90,91
Regarding obesi‑
ty treatment, despite thefact that SGLT ‑2 inhibi‑
tors induce weight loss, their weight ‑lowering ef‑
fects are counterbalanced by anincreased appetite
liver consequences, NAFLD, especially in patients
with obesity and T2D, calls for action in terms of
CVD, as it is related to increased cardiovascular
adverse effects.78,79 In their recent meta ‑analysis,
Mantovani et al
80
have concluded that SGLT ‑2 in‑
hibitors have beneficial effects regarding NAFLD.
In particular, they have documented asignificant
decrease in liver fat content as estimated by mag‑
netic resonance techniques as well as reductions
in liver enzymes, such as alanine aminotrans‑
ferase (ALT) and gamma ‑glutamyl ‑transferase
(γ ‑GT). eir meta ‑analysis included random
‑
ized controlled trials (RCTs) involving theuse of
empagliflozin, dapagliflozin, canagliflozin, and
ipragliflozin in patients with NAFLD defined by
magnetic resonance techniques and not by liver
biopsy, as there were no eligible RCTs regarding
SGLT ‑2 inhibitors and NAFLD assessed by liv‑
er biopsy. e participants in theincluded stud‑
ies were overweight or obese and 90% had T2D.
When compared with theplacebo group, theuse
of SGLT ‑2 inhibitors for 24 weeks resulted in ame‑
lioration of serum ALT and γ‑GT levels as well as
improvement in liver fat content (pooled weight‑
ed mean differences, −2.05%; 95% CI, −2.61% to
−1.48%), and reduction in body weight of approx‑
imately 3.5kg.
80
Overall, evidence points toward
abeneficial class effect of SGLT ‑2 inhibitors in liv‑
er steatosis among patients with T2D. More stud‑
ies in thefield are needed to generalize thecur‑
rent findings in patients without overt dysgly‑
cemia. Additionally, in order to assess potential
synergistic effects of SGLT ‑2 inhibition and oth‑
er treatment approaches, atleast 1 ongoing study
aims to compare theeffects of combined SGLT ‑2
inhibitor (empagliflozin 10mg) and GLP‑1 ago‑
nist (1mg semaglutide weekly) vs empagliflozin
monotherapy or placebo in NASH among T2D
patients, with invasive (liver biopsy) and non‑
invasive (elastography) measures to asses liver
steatosis, fibrosis, and inflammation (clinical‑
trials.gov registration number: NCT04639414)
Effects on ovarian function Polycystic ovary syn‑
drome (PCOS) affects approximately 20% of wom‑
en of reproductive age.
28
It is characterized by ab‑
normalities in ovulation, hyperandrogenemia,
and / or pathologic ovarian ultrasound morpholo‑
gy, and may be associated with insulin resistance
and subsequent hyperinsulinemia. elatter fea‑
ture is responsible for themetabolic derangement
related to PCOS and theincreased CVD risk. In
this case, insulin sensitizers, such as metformin
or thiazolidinediones may be alternatives to oral
contraceptives.81 Approximately 60% to 70% of
women with PCOS finally develop insulin resis‑
tance and hyperinsulinemia. euse of other an‑
tidiabetic agents, especially with weight‑lower‑
ing effects is also under investigation regarding
thetreatment options for women with PCOS. De‑
spite thelack of SGLT ‑2 cotransporters in theova‑
ries, theeffects of SGLT ‑2 inhibitors, which in‑
duce glucosuria leading to weight loss and natri‑
uresis resulting in reduction of blood pressure,

POLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (10)12
associated with theuse of these agents continue
to be elucidated, broadening of their clinical in‑
dications outside of thestrict frame of diabetes
will not come as asurprise.
SUPPLEMENTARY MATERIAL
Supplementary material is available at www.mp.pl/paim.
ARTICLE INFORMATION
ACKNOWLEDGMENTS None.
FUNDING This work did not receive any funding.
CONFLICT OF INTEREST None declared.
OPEN ACCESS This is an Open Access article distributed under the terms
of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 Inter‑
national License (CC BY ‑NC ‑SA 4.0), allowing third parties to copy and re‑
distribute the material in any medium or format and to remix, transform, and
build upon the material, provided the original work is properly cited, distrib‑
uted under the same license, and used for noncommercial purposes only. For
commercial use, please contact the journal office at pamw@mp.pl.
HOW TO CITE Vallianou NG, Tsilingiris D, Kounatidis D, et al. Sodium‑glu‑
cose cotransporter‑2 inhibitors in obesity and its associated cardiometa‑
bolic disorders: where do we stand? Pol Arch Intern Med. 2022; 132:
16342. doi:10.20452/pamw.16342
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and calorie intake. erefore, they are not prob‑
able to be used alone in obesity treatment. How‑
ever, their combination with drugs suppressing
appetite and / or inducing satiety would be much
more feasible and welcome. Indeed, acombina‑
tion of aSGLT ‑2 inhibitor with aGLP ‑1 analog,
especially aonce ‑weekly administered GLP ‑1 an‑
alog, would be more convenient and more potent
in this regard. In addition, it would be interest‑
ing to combine aSGLT ‑2 inhibitor with adual
GLP ‑1 analog and glucose ‑dependent insulino‑
tropic polypeptide, which may be even more ef‑
ficient in suppressing appetite and in promoting
reduced gastric emptying. Regarding thealready
used weight ‑lowering drugs, such as lorcaserine,
GLP ‑1 analogs, phentermine and topiramate, and
bupropione and naltrexone combinations, they
are known to act centrally atthe central nervous
system level to suppress appetite.
10,23
erefore,
a combination with a SGLT‑2 inhibitor that may
increase appetite would be really intriguing in
terms of the weight‑lowering efficacy.
Combinations of SGLT ‑2 inhibitors with
other drugs for thetreatment of T2D, such as
dipeptidyl ‑peptidase inhibitors and insulin se‑
cretagogues, have been studied much better than
theweight ‑lowering combinations.92 In particu‑
lar, there is growing evidence in favor of thecom‑
bination of SGLT ‑2 inhibitors with GLP ‑1 analogs
in T2D, if thecost is not abarrier.93 In addition,
thecombination of SGLT ‑2 inhibitors with insulin
has been suggested to lower HbA
1c
levels and body
weight gain caused by insulin treatment. How‑
ever, anadjustment of theinsulin dose to avoid
hypoglycemia and theadvent of EDKA should
be borne in mind by theattending physicians.94
Conclusions SGLT ‑2 inhibitors, theclass of anti‑
diabetic agents named “the new kids on theblock”
in 2015 by Cefalu and Riddle,20 seem to possess
pleiotropic properties ranging from glycosuria
to weight loss, cardioprotection and renoprotec‑
tion.10,20,23,95 Apart from their glucose ‑lowering
effects, SGLT ‑2 inhibitors exhibit renoprotective
properties, as they significantly improve theintra‑
glomerular pressure, thereby ameliorating eGFR,
while also reducing albuminuria.10,2 3 In addition,
they confer cardioprotection, especially in terms
of improving HF, as documented by thedecrease
in thenumber of hospitalizations due to HF.
23
Furthermore, they seem to ameliorate NAFLD
indices and promote weight loss, particularly in
conjunction with theuse of GLP ‑1 analogs.
96,97
eir utilization in obesity and obesity ‑related
disorders seems beneficial, as they are also safe
with rare severe adverse effects.98 While therole
of SGLT ‑2 inhibitors in thetreatment of T2D and
lately cardiac failure and chronic renal disease of
non diabetic etiology is already firmly established,
their utility in thetherapy of obesity, NAFLD,
and other indications, alone or in combination
with other agents will continue to be researched
in theforthcoming years. Since themultifac‑
eted mode of action and thepotential benefits

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