JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 75, NO.

4, 2020

ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Mechanisms of Cardiorenal Effects

of Sodium-Glucose
Cotransporter 2 Inhibitors
JACC State-of-the-Art Review

Thomas A. Zelniker, MD, MSC, Eugene Braunwald, MD

ABSTRACT

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been
shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for
heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered
to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being
studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore
critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class.
This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the
cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.
(J Am Coll Cardiol 2020;75:422–34) © 2020 by the American College of Cardiology Foundation.

T ype 2 diabetes mellitus (T2DM) and its most

serious consequences—heart
kidney disease—represent 1 of the greatest
pandemics of chronic disease in the world today
disease and
cular risk of new glucose-lowering agents in pa-
tients with T2DM (8,9). A number of these trials
confirmed the safety of approved
drugs. However, quite unexpectedly, they also
antidiabetic

(1–4). Modern treatment of T2DM began with paren-
teral insulin, discovered by Banting and Best,
almost a century ago (5). Since then, several classes
of orally active drugs that improve glycemic control
have become available and have been widely used.
Concerns emerged early in this century about the
cardiovascular safety of some of these antidiabetic
compounds (6,7). As a consequence, regulatory
bodies now require pharmaceutical manufacturers
to conduct trials to exclude an excess of cardiovas-
identified 2 drug classes, sodium-glucose cotrans-
porter 2 inhibitors (SGLT2i) and glucagon like pep-
tide 1 receptor agonists, that reduce major adverse
cardiovascular events, including cardiovascular
death (10,11). These findings are revolutionizing
the care of patients with T2DM, and in the case of
the SGLT2i, have been found to be beneficial in
nondiabetic patients with heart failure (HF) as
well (12). Important new information on SGLT2i is
growing rapidly, and although we reviewed this

Listen to this manuscript’s

audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
From the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and Department of Medicine, Harvard
Medical School, Boston, Massachusetts. Dr. Zelniker is currently affiliated with the Division of Cardiology, Vienna General Hos-
pital, Medical University of Vienna, Vienna, Austria. Dr. Zelniker is supported by the German Research Foundation (Deutsche
Forschungsgemeinschaft ZE 1109/1-1); and has received lecture fees from AstraZeneca. Dr. Braunwald has received research grants
through his institution from AstraZeneca, Daiichi-Sankyo, GlaxoSmithKline, Merck, and Novartis; has consultancies with Amgen,
Cardurion, MyoKardia, NovoNordisk, and Verve; has received personal fees for lectures from Medscape; and has performed
uncompensated consultancies and lectures for Novartis and The Medicines Company.

Manuscript received October 2, 2019; revised manuscript received November 15, 2019, accepted November 17, 2019.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.11.031

JACC VOL. 75, NO. 4, 2020
FEBRUARY 4, 2020:422–34
HIGHLIGHTS
 T2DM, HF, and CKD are closely
intertwined.
 SGLT2i exert pleiotropic metabolic and
direct cardioprotective and neph-
roprotective effects.
 SGLT2i reduce inflammation, oxidative
stress, fibrosis, intraglomerular hyper-
tension, and sympathetic nervous system
activation, and may improve mitochon-
drial function and myocardial efficiency.
 Cardiologists, diabetologists, nephrolo-
gists, and primary care physicians should
be familiar with this drug class.
subject in the Journal in 2018 (13), we now bring it
up to date in this 2-part series. Here we focus on
the mechanisms of the cardiac and renal effects of
these agents.
GLUCOSE-LOWERING AND METABOLIC
EFFECTS MEDIATED BY SGLT2i
Under physiological conditions in normal adults,
approximately 180 g of glucose are filtered by the
renal glomeruli and reabsorbed completely by the
renal tubules each day. In patients with T2DM,
glucose can be detected in the urine when blood
glucose concentration exceeds a threshold of
approximately 200 mg/dl (11.1 mmol/l); marked glu-
cosuria is a hallmark of untreated T2DM.
Cell membranes are impermeable to glucose and
require facilitated diffusion carriers or specific mem-
brane transport proteins for its uptake. In the kid-
neys, tubular glucose reabsorption is coupled with
sodium (Naþ) that follows the electrochemical
gradient of a higher Naþ concentration in the
glomerular filtrate to a lower intracellular concen-
tration in epithelial tubular cells. This gradient is
maintained through the basolateral Na þ/K þ ATPase of
the epithelial tubular cell. Glucose enters the cell
coupled with Na þ through sodium-glucose cotrans-
porters 1 and 2 (SGLT1/2) and then exits the cell
passively via the basolateral glucose transporter 2.
SGLT2 are expressed nearly exclusively in the kidney;
SGLT1 is present in the kidney as well, but has also
been detected in the intestines and heart (14). SGLT2
is located in the S 1 (first) segment of the proximal
convoluted tubule and accounts for approximately
90% of the reabsorbed glucose. Residual glucose is
Zelniker and Braunwald 423
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
then reabsorbed by SGLT1 located further ABBREVIATIONS
AND ACRONYMS
distal in the S2 /S3 segments of the proximal
convoluted tubules.
AMPK = 50 adenosine
SGLT2 are high-capacity/low-affinity monophosphate-activated
transporters and are expressed in higher protein kinase
concentrations as compared with SGLT1, CaMKII = CaDD/calmodulin
which are low-capacity/high-affinity trans- dependent kinase
porters (13). Moreover, the 2 transporters are CKD = chronic kidney disease
characterized by different stoichiometries: eGFR = estimated glomerular
SGLT1 transports 2 Na þ per molecule of filtration rate
glucose and SGLT2 transports 1 (15). SGLT2, NAFLD = nonalcoholic fatty
þ liver disease
but not SGLT1, colocalize with the renal Na /
RAAS = renin-angiotensin-
hydrogen exchanger NHE3, which is largely
aldosterone system
responsible for Naþ reabsorption in the
SGLT2i = sodium-glucose
proximal tubule, and SGLT2i appear to cross- cotransporter 2 inhibitor
react with NHE3 and thereby inhibit reab-
T2DM = type 2 diabetes
sorption and augment natriuresis (16,17). mellitus
Both homozygous as well as heterozygous
mutations in the SGLT2 coding gene SLC5A2 can
result in familial renal glucosuria (18,19). Patients
with these rare conditions are normoglycemic, have
normal kidney function, and may exhibit incomplete
penetrance.
The glucose-lowering ability of the inhibition of
SGLT2 through urinary glucose excretion has been
reported to reduce glycated hemoglobin A1c in pa-
tients with T2DM, generally by between 0.5% and
1.0%. The glucosuria depends on the circulating
glucose concentration and kidney function (20).
SGLT2i requires glomerular filtration rate for
glucose-lowering, which declines in patients
with estimated glomerular filtration rate (eGFR)
<45 ml/min/1.73 m 2. Similarly, glucosuria with
SGLT2i is attenuated in patients without hypergly-
cemia. Therefore, the risk of hypoglycemia with this
drug class is low.
SGLT2i also promote weight loss, resulting from
loss of adipose tissue. Although the caloric loss
through urinary glucose excretion equals approxi-
mately 200 kcal/day, data from randomized clinical
trials indicate that weight loss of approximately 2 to
3 kg develops in about 6 months and then plateaus. It
has been suggested that compensatory hyperphagia
with hunger for sugar-rich foods may explain the
diminishing effect of continued caloric loss (21).
Experimental data suggest that SGLT2i triggers a
fasting-like state with increased fatty acid oxidation
and ketogenesis, and reduces adipose tissue and liver
steatosis (22). Molecular mechanisms mediating these
metabolic effects include: 1) activation of the 5 0
adenosine monophosphate-activated protein kinase
(AMPK); 2) inhibition of mechanistic target of rapa-
mycin; and 3) increased hepatic and plasma levels of
424 Zelniker and Braunwald
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
fibroblast growth factor 21, independent of insulin or
glucagon activity, as has been shown in obese,
nondiabetic mice (22). Moreover, SGLT2i have been
linked to a reduction in epicardial fat (23), a biologi-
cally highly-active tissue involved in leptin and the
renin-angiotensin-aldosterone system (RAAS)
signaling, and may thereby be cardioprotective. In a
mouse model, ipragliflozin, an SGLT2i approved for
clinical use in Japan, has also been shown to reduce
inflammation of adipose tissue by a reduction in the
ratio of pro-inflammatory M-1-like adipose tissue
macrophages to anti-inflammatory M-2 tissue mac-
rophages (24).
CARDIORENAL INTERACTIONS IN
PATIENTS WITH TYPE 2 DIABETES
T2DM, particularly long-standing and/or requiring
insulin, is frequently complicated by HF and chronic
kidney disease (CKD). These 3 entities (T2DM, HF,
and CKD) have interconnected pathways and share
several metabolic and signaling cascades; the pres-
ence of any of the 3 conditions worsens the other 2
(25). Dyslipidemia, hypertension (Figure 1), and a
prothrombotic state, which occur commonly in pa-
tients with T2DM, contribute to the development of
accelerated atherosclerosis. The latter increases the
risk of myocardial infarction, which may be respon-
sible for, or contribute to, the development of HF
with reduced ejection fraction (26–28).
A variety of pathophysiological mechanisms that
contribute to the development of HF in T2DM are
shown in Table 1. A specific diabetic cardiomyopathy,
considered to be a separate entity independent of
coronary artery disease and arterial hypertension, has
been described (27,29,30). The hyperglycemia of
T2DM, especially when it is prolonged, results in
advanced glycation end-products, oxidative stress,
inflammation, and apoptosis, which together with
microvascular coronary artery disease appear to be
responsible for the development of diabetic cardio-
myopathy. This condition, like myocardial infarction,
may also be responsible for and/or contribute
importantly to the development of HF. In long-
standing T2DM, the combination of multiple
myocardial infarcts and diabetic cardiomyopathy can
cause HF, which, until the development of SGLT2i,
had been difficult to treat and associated with poor
prognosis. The low cardiac output of HF causes a
reduction of renal blood flow and elevated renal
venous pressure, which are accompanied by
JACC VOL. 75, NO. 4, 2020
FEBRUARY 4, 2020:422–34
activation of the RAAS, leading to a vicious circle (25).
SGLT2i have the potential to mitigate these patho-
physiological changes.
Patients with T2DM are also at high risk of
developing CKD, which serves as an additional
driver for multiple cardiovascular complications
including HF. Diabetic CKD is the leading cause of
end-stage kidney disease and, therefore, the need
for renal replacement therapy. SGLT2i have emerged
as a promising drug class that may interrupt this
other vicious circle in patients with T2DM.
EFFECTS OF SGLT2i ON THE
CARDIOVASCULAR SYSTEM
SGLT2i-mediated natriuresis and glucosuria lower
cardiac pre-load and reduce pulmonary congestion
and systemic edema. These effects appear to play a
role in the reduction of hospitalizations for HF
observed in the cardiovascular and kidney outcomes
trials in patients with T2DM discussed in Part 2 of this
review (31). Urinary output returns to normal within
12 weeks after treatment is begun (32,33). As is the
case with other diuretic agents, the natriuresis
induced by SGLT2i is attenuated over time through
compensatory mechanisms and achievement of a
stable state. It is possible that SGLT2i-mediated glu-
coresis (compared with other diuretic agents whose
actions are primarily natriuretic) results in greater
proportional reductions of interstitial compared with
intravascular volume. This may occur as a conse-
quence of greater electrolyte-free water clearance by
peripheral sequestration of osmotically inactive so-
dium (34).
SGLT2i have been shown to significantly reduce
the Na þ content of the skin, as measured by 23
Na-
magnetic resonance imaging (35). An increased
(cutaneous) tissue Naþ content has been correlated
with left ventricular hypertrophy (36). The SGLT2i-
induced Naþ depletion may improve left ventricular
remodeling and ejection fraction. SGLT2i also reduce
cardiac afterload by lowering arterial pressure by 3 to
5 mm Hg without increasing heart rate, and have been
shown to reduce arterial stiffness (37,38). The
reduction of blood pressure is preserved, even in
patients with reduced glomerular filtration rate,
suggesting that SGLT2i may reduce the sympathetic
nervous system overdrive of HF (Figure 1) (39).
Studies carried out both in vitro and in vivo have
shown that norepinephrine up-regulates expression
of SGLT2, thereby enhancing Na þ and glucose reab-
sorption by the proximal tubule, while, conversely,
JACC VOL. 75, NO. 4, 2020
FEBRUARY 4, 2020:422–34
F I G U R E 1 Inter-Relationships Between SGLT2i and the Sympathetic Nervous System and Illustration of the Positive Role of SGLT2i in
Hypertension and Heart Failure
Adapted from Scheen (39). SGLT2i ¼ sodium-glucose cotransporter 2 inhibitors; SNS ¼ sympathetic nervous system.
SGLT2i reduces tyrosine hydroxylase and noradren-
aline in the kidney and heart thereby contributing to
the natriuresis and glucoresis (40).
EFFECTS OF SGLT2i ON
CARDIAC METABOLISM
The heart requires energy continuously and is capable
of consuming a variety of substrates, including both
glucose and free fatty acids. Under conditions of
stress, such as HF and/or T2DM, glucose utilization is
impaired, and the heart relies more heavily on the
metabolism of free fatty acids and ketones (41,42).
Beta-hydroxybutyrate has been suggested to act as a
“superfuel” by increasing the metabolic efficiency of
the heart (43). The shift toward more consumption of
ketone bodies has been hypothesized to improve the
ATP supply to the failing heart (44). Chronic infusion
of beta-hydroxybutyrate has been shown to improve
cardiac function, efficiency, and remodeling in a
canine tachypacing-induced HF model (44). Further-
more, ketone bodies also exert anti-inflammatory ef-
fects by suppressing activation of the nucleotide-
binding oligomerization domain-like receptor P3
(NLRP3) inflammasome activity (45) (Table 2).
It has been suggested that SGLT2i alter fuel con-
sumption with an increase in oxidation of fatty acids
and ketogenesis and with a concomitant reduction in
utilization of carbohydrates. These
Zelniker and Braunwald 425
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
improve the state of an “energy starved” heart, a
condition observed in T2DM and HF. In support of the
suggestion that SGLT2i improves cardiac metabolism
in these patients is the observation that treatment of
nondiabetic pigs with ischemic HF with empagliflozin
reduces adverse cardiac remodeling by switching
myocardial substrate utilization from glucose toward
oxidation of free fatty acids, ketone bodies, and
branched-chain amino acids (46,47). Treatment of
diabetic mice with empagliflozin resulted in an
increased cardiac production of ATP by about 30%
T A B L E 1 Pathophysiological Mechanisms That Contribute to
the Development of Heart Failure in Patients With Type 2
Diabetes Mellitus
Altered myocardial substrate metabolism
Mitochondrial bioenergetics
Oxidative stress
Lipotoxicity
Inflammation
Endoplasmic reticulum stress
Insulin signaling
Beta-2 adrenergic receptor signaling
G protein-coupled receptor kinase 2 signaling
Renin angiotensin aldosterone signaling
Autophagy
Advanced glycation end products
Modified with permission from Kenny and Abel (26).
alterations
426 Zelniker and Braunwald JACC VOL. 75, NO. 4, 2020

Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors FEBRUARY 4, 2020:422–34

Studies in patients with T2DM have linked mito-

T A B L E 2 Lessons Learned on Presumed Mechanisms of SGLT2i Activity
chondrial dysfunction with ventricular hypertrophy
SGLT2i and heart failure
1. Osmotic diuresis and natriuresis reduce cardiac overload.
and fibrosis (54). It has been suggested that SGLT2i
a. Greater reductions of interstitial fluid compared with other diuretic agents (34) may improve mitochondrial function and reduce
2. Direct cardiac effects:
a. SGLT2i inhibit NHE-1 (60–62)
oxygen-reactive stress (55).
b. SGLT2i reduce CaMKII (reduces sarcoplasmic Caþþ leak / improves contractility) (59) Hyperglycemia contributes to activation of the
c. Increased phosphorylation levels of myofilament regulatory proteins? (66)
d. Epigenetic modification? (65)
RAAS, which leads to overproduction of angiotensin
3. Reduction of sympathetic nervous system overdrive (39,40) II and aldosterone, both of which induce cardiac hy-
4. Possible improvement in myocardial efficiency (43,44,46–48,69)
5. Improved oxygen delivery through stimulation of renal EPO secretion (52,90)
pertrophy and fibrosis and impair cardiac relaxation.
6. Reduction in inflammation (/ activation of adenosine monophosphate-activated Hyperglycemia also results in the formation of
protein kinase) (57,64)
7. Reduction of oxidative stress (improving mitochondrial function) (58,96,101)
advanced glycation end products, which cause cross-
8. Metabolic: lowering of HbA1c, blood pressure, body weight, vascular stiffness (71) linking of collagen (56), leading to increased fibrosis
SGLT2i and atherosclerosis with increased myocardial stiffness and impaired
1. Reduction in inflammation (72)
2. Reduction in epicardial fat and noxious signals including leptin and RAAS (23) cardiac relaxation. Studies in mice suggest that
3. Reduction in oxidative stress (58,95,96,100,101) dapagliflozin reduces inflammation in myofibro-
4. Improved endothelial function (58,73)
5. Cardioprotective effects by shifting circulating vascular progenitor cell toward M2 blasts, an effect mediated through increased activa-
polarization (74) tion of AMPK independently of SGLT2i (57).
6. Reduction in uric acid (91,92)
7. Improvement in NAFLD? (78,79) Moreover, empagliflozin has been shown to prevent
8. Metabolic: lowering of HbA1c (/AGE, fibrosis), blood pressure, body weight (link to HF) hyperglycemic impairment of proteinase-activated
a. Reduction in vascular stiffness (71)
9. BUT! Small increases LDL-C (clinical implications unknown) (80) receptor 2–mediated vasodilation by inhibition of
SGLT2i and progression of kidney disease aortic endothelial SGLT2 and minimizing oxidative
1. Metabolic: lowering of HbA1c (/AGE, fibrosis), and body weight (link to HF) (20)
stress (58).
2. Reduction in blood pressure and vascular stiffness (71)
3. Restoration of the tubuloglomerular feedback (84,85,87) Empagliflozin has been shown to reduce Ca þþ/
4. Reduction in workload regarding ATP production (90)
calmodulin dependent kinase (CaMKII) activity in
5. Anti-inflammatory and antifibrotic effects, reduction in oxidative stress (95–102)
6. Reduction in uric acid (91,92) murine ventricular myocytes, which is increased in
Interaction between heart and kidney HF (Table 2). Empagliflozin also reduces the CaMKII
1. Prevention of progress of disease in one organ may prevent deterioration of the
phosphorylation of the cardiac ryanodine receptor in
other (25)
both murine and human ventricular myocytes,
CaMKII ¼ Caþþ/calmodulin dependent kinase; EPO ¼ erythropoietin; HbA1c ¼ glycated hemoglobin A1c; resulting in significantly reduced sarcoplasmic Ca þþ
HF ¼ heart failure; LDL-C ¼ low-density lipoprotein cholesterol; NAFLD ¼ nonalcoholic fatty liver disease;
RAAS ¼ renin-angiotensin-aldosterone system; SGLT2i ¼ sodium glucose cotransporter inhibitor. leak and thereby improved contractility (59). Another
important biological explanation for the benefit of
SGLT2i has been proposed by Uthman et al. (60,61),
who found that SGLT2i directly inhibits the Naþ/
through an increase in the rate of glucose and fatty Hydrogen exchanger 1 (NHE1) in the myocardium.
acid oxidation (48–50). Inhibition of cardiac NHE1 by SGLT2i reduces cyto-
Furthermore, treatment with the SGLT2i cana- plasmic Na þ and Caþþ levels and increases mito-
gliflozin for 4 weeks has been shown to attenuate chondrial Ca þþ levels (Figure 2) (60,62). Empagliflozin
myocardial ischemia and reperfusion injury ex vivo also exerts direct cardioprotective effects during
in both diabetic and nondiabetic rats (51). More- ischemia by inhibiting NHE1 (61).
over, SGLT2i-mediated stimulation of renal eryth- Experimental data also suggest that treatment with
ropoietin secretion leading to new red blood cell empagliflozin protects cardiac function in a nondia-
formation and increased hematocrit has been hy- betic mouse model of HF with preserved ejection
pothesized to contribute to improved oxygen de- fraction induced by transverse aortic constriction
livery to the heart with resultant improvement in (63). In a nondiabetic porcine model of HF with pre-
cardiac function (52). The improved cardiac meta- served ejection fraction, treatment with dapagliflozin
bolism and the increased reabsorption of magne- reversed left ventricular concentric remodeling by
sium and potassium from the tubular fluid might reducing sympathetic tone, mitigating inflammatory
also exert antiarrhythmic effects that could result response in the aorta and reactivation of the nitric
in lower rates of sudden cardiac death (53). Dysre- oxide–cyclic guanosine 30 ,5 0 -monophosphate (cGMP)–
gulation of metabolic substrate, inflammation, cGMP-dependent protein kinase (NO-cGMP-PKG)
increased apoptosis, and impaired calcium handling pathway (64).
have all been suggested to explain the cardiac In addition, a transcriptomics study suggested
impairment in diabetic cardiomyopathy (29). that SGLT2i may exhibit favorable effects on HF by
JACC VOL. 75, NO. 4, 2020 Zelniker and Braunwald 427
FEBRUARY 4, 2020:422–34 Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors

F I G U R E 2 Direct Effects of SGLT2i on the Cardiomyocyte

HF and/or T2DM Na+/Ca++ Na+/K+

NHE1 Anporter ATPase
Na+ Ca++ 2K+

H+ 3Na+ 3Na+
ATP
Nac+ Cac++
H+

3Na++
Na++ CaM++
Ca++
ATP
Mitochondrion
A Cardiomyocyte
SGLT2i Na+/Ca++ Na+/K+
SGLT2i NHE1 Anporter ATPase
Na+ Ca++ 2K+

H+ 3Na+ 3Na+
ATP

Nac + ++
Cac
Na+
CaM++
Ca++ ATP
Mitochondrion
B Cardiomyocyte

(A) Conditions, such as heart failure and/or type 2 diabetes mellitus (T2DM), increase the expression of Naþ/Hydrogen exchanger 1 (NHE-1)
and result in increased cytosolic Naþ and Caþþ concentrations, but reduced mitochondrial Caþ and mitochondrial ATP generation.
(B) Inhibition of cardiac NHE-1 reduces cytoplasmic Naþ and Caþþ levels and increases mitochondrial Caþþ levels, resulting in improved
mitochondrial respiration (and increase in ATP production) and viability of cardiomyocytes. Modified from Uthman et al. (55).
SGLT2i ¼ sodium-glucose cotransporter 2 inhibitors.

epigenetic modification (65). Furthermore, empagli- absence of T2DM, and this is now being studied in
flozin has also been shown to reduce passive dia- patients, as summarized in Part 2 of this review (31).
stolic tension in isolated ventricular trabeculae In summary, SGLT2i improve ventricular loading
obtained from patients with end-stage HF with conditions, cardiac metabolism, bioenergetics, ven-
preserved ejection fraction (66) (Figure 3). This tricular remodeling, and exert direct cardioprotective
improvement was observed immediately after and possibly antiarrhythmic effects (Tables 2 and 3,
intravenous administration of empagliflozin, sug- Central Illustration) (70).
gesting that SGLT2i increased phosphorylation
levels of myofilament regulatory proteins (66). VASCULAR EFFECTS
SGLT2i have also been shown to significantly reduce
E/eʹ from 13.7 to 12.1 cm/s and from 9.3 to 8.5 cm/s SGLT2i lowers systolic and diastolic pressures
in patients with heart failure with preserved ejec- without increasing heart rate (71) (Tables 2 and 3).
tion fraction (67,68). Empagliflozin has also SGLT2i exert anti-inflammatory effects through
been reported to improve left ventricular pump multiple mechanisms, including weight loss,
function in mice with doxorubicin-induced cardio- reduction in inflammation of adipose tissue, in-
myopathy (69). Taken together, these findings crease in ketone bodies, and reduction in uric acid
suggest that SGLT2i may be effective in HF with (72). Canagliflozin may improve endothelial function
preserved ejection fraction (Figure 3), even in the by inhibiting inflammatory pathways through
428 Zelniker and Braunwald JACC VOL. 75, NO. 4, 2020

Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors FEBRUARY 4, 2020:422–34

F I G U R E 3 Skinned Cardiomyocytes Isolated From Patients With HFpEF and From Healthy Donors

4.0

3.5

3.0
Fpassive norm.
2.5
P < 0.0001
2.0

1.5
P < 0.0001
1.0

0.5

0
1.8 1.9 2 2.1 2.2 2.3 2.4
Sarcomere Length (µm)
HFpEF HFpEF After Empagliflozin
NF NF After Empagliflozin

Normalized passive stiffness (F) measured at various sarcomere lengths from 1.8 to 2.4 mm of cardiomyocytes from HFpEF and nonfailing (NF)
myocardium from patients incubated 60 min with empagliflozin. Reproduced with permission from Pabel et al. (66)

blocking interleukin-1 b–stimulated cytokine and NONALCOHOLIC FATTY LIVER DISEASE

chemokine secretion in vascular endothelial cells
(73). Empagliflozin may exert cardioprotective anti- Nonalcoholic fatty liver disease (NAFLD) is
inflammatory and vessel-regenerative effects by frequently observed in patients with T2DM as well as
shifting circulating vascular progenitor cell toward in patients with metabolic syndrome, and is associ-
M2 polarization (74). Furthermore, empagliflozin ated with an increased risk of adverse cardiovascular
has been shown to improve coronary microvascular events (76). Multiple mechanisms, including sys-
function and increase cardiac output in mice, as temic inflammation, oxidative stress, endothelial
evidenced by increases in coronary blood flow and dysfunction, and changes in lipid profiles, by which
fractional ventricular area change as shown by ul- NAFLD increases cardiovascular risk have been
trasound imaging (75). identified (76). To date, only limited treatment stra-
tegies exist to address this condition with an esti-
mated worldwide prevalence of 25% (77). SGLT2i
T A B L E 3 Overview of Mechanisms of Favorable Cardio-Metabolic-Renal Effects
have been shown to reduce adipose tissue,
Heart Atherosclerotic Diabetic Kidney and therefore, may favorably influence NAFLD. In
Failure Effect Disease
diabetic mice, dapagliflozin compared with insulin
Glucose lowering U
prevented NAFLD (78). In a double blind, controlled,
Reduction in body weight U U U
randomized trial of patients with T2DM, dapagli-
Lowering of blood pressure U U U
Natriuresis U U
flozin lowered serum aminotransferases, as corre-
Anti-inflammation U U U lates of liver fat, and reduced liver fat content as
Antifibrotic U U quantified using CT/MR imaging (79). No data for
Reduction in extracellular matrix turnover U U the effect of SGLT2i on NAFLD in the absence of
Amelioration of intrarenal hypoxia U T2DM have been reported to date. However, SGLT2i
Restoration of the tubuloglomerular feedback U
have been shown to increase levels of low-density
Reduction in natriuretic peptides U U
lipoprotein cholesterol by 3 to 5 mg/dl (80), an
Reduction in energy demand U U
effect that could oppose slightly the aforementioned
Reduction in liver fat U
benefits of this drug class.
JACC VOL. 75, NO. 4, 2020
FEBRUARY 4, 2020:422–34
C ENTR AL I LL U STRA T I O N Sodium-Glucose Cotransporter 2 Inhibitor Cardiorenal Protection
Mechanistic Overview
Zelniker, T.A. et al. J Am Coll Cardiol. 2020;75(4):422–34.
Adapted from Vergara et al. (106).
EFFECTS OF SGLT2i ON KIDNEY FUNCTION
T2DM results in multiple metabolic and hemody-
namic changes that promote structural changes in the
kidneys, affecting primarily the microcirculation
(Table 2). In the early stage of diabetic kidney disease,
glomerular hyperfiltration is observed, which is
associated with an increase of single-glomerular
filtration rate to adapt to a reduced number of
nephrons, systemic arterial hypertension,
increased metabolic demand (81). Hemodynamic
changes through vasodilation of afferent and/or
contraction of efferent glomerular arterioles exert
mechanical (shear and tensile) stress on the glomer-
ular capillaries, basement membrane, podocytes, and
the proximal tubular epithelium, ultimately causing
renal hypertrophy and expansion of the mesangial
matrix (82). These changes activate further harmful
Zelniker and Braunwald 429
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
pathways promoting inflammation, and glomerular
fibrosis causing progressive reduction of glomerular
filtration rate, progressive albuminuria, and ulti-
mately, end-stage kidney disease.
The protective effects of SGLT2i on the kidney are
believed to be mediated by a number of both hemo-
dynamic and nonhemodynamic mechanisms (Central
Illustration). The improvements of cardiac function
by SGLT2i may contribute to their favorable effects on
or the kidneys halting the “vicious cardiorenal circle”
(Tables 2 and 3, Figure 4) (25). Activation of the
tubuloglomerular feedback has been hypothesized to
be mainly responsible. The action of SGLT2i in the
proximal convoluted tubule results in increased
concentrations of Na þ at the macula densa. Primarily
driven through adenosine-mediated signal cascades,
this causes vasoconstriction of the afferent arterioles
and thereby lowers the intraglomerular pressure and
430 Zelniker and Braunwald
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
F I G U R E 4 Suggested Mechanisms for Cardiorenal Protection With SGLT2i
Adapted from Evans et al. (105).
consequently reduces hyperfiltration and related
damage (83). An elegant study recently confirmed
the SGLT2i-mediated restoration of the tubuloglo-
merular feedback, demonstrating afferent arteriolar
vasoconstriction after administration of empagli-
flozin in a diabetes mouse model (84,85). A recent
secondary analysis from the EMPA-REG (Empagli-
flozin, Cardiovascular Outcomes, and Mortality in
Type 2 Diabetes) Outcome trial reported that empa-
gliflozin reduced the incidence of a composite renal
outcome irrespective of baseline medication but the
magnitude of the observed reductions tended to be
larger in patients treated with angiotensin-converting
enzyme inhibitors/angiotensin receptor blocker (86).
After causing reduction of eGFR in the range of 3 to
5 ml/min/1.73 m 2 over the first few weeks of SGLT2i,
eGFR then stabilizes and SGTL2i preserves and delays
the progression of CKD (Figure 5) (87,88).
A mediation analysis from the EMPA-REG Outcome
trial suggested that changes in hematocrit and he-
moglobin were important mediators of the risk
reduction of cardiovascular death by empagliflozin
(89). Given that the urinary output returns to baseline
values shortly after start of treatment, Sano and
Goto (90) have suggested that the hypoxic microen-
vironment of renal tubular cells was improved by the
persistent increase in hematocrit resulting from an
elevation in erythropoietin levels by lowering the
energy requirement of renal tubular cells. The
JACC VOL. 75, NO. 4, 2020
FEBRUARY 4, 2020:422–34
SGLT2i-induced reduction in glucose reabsorption
reduces the ATP demand of the basolateral Naþ/Kþ
ATPase of the tubular cells, which maintain the
electrochemical Na þ-gradient between the tubular
fluid and the tubular cells. Consequently, myofibro-
blasts, transformed through cell injury, revert into
erythropoietin-producing fibroblasts. It has been
proposed that by this mechanism, SGLT2i attenuates
metabolic stress in kidney cells and subsequently also
reduces the sympathetic nervous system overdrive
(90).
SGLT2i-mediated glucosuria and consequent
increased glucose concentrations in the distal seg-
ments of the renal tubular cells trigger the secretion
of uric acid through urate transporter 1 and glucose
transporter 9 into the tubular fluid (91,92). SGLT2i
might thereby prevent harmful downstream effects of
uric acid including inflammation, oxidative stress,
and activation of RAAS (93).
Hyperglycemia generates reactive oxygen species
and activates inflammatory responses, which
contribute to the pathogenesis of diabetic kidney
disease (94). In a diet-induced mouse model of T2DM,
canagliflozin reduced intrarenal angiotensinogen
production, monocyte/macrophage infiltration and
oxidative stress and thereby reduced renal inflam-
mation and renal tubular fibrosis (95,96). In a diabetic
mouse model with nephropathy, SGLT2i have been
found to reduce the activity of NLRP3 inflammasome
JACC VOL. 75, NO. 4, 2020
FEBRUARY 4, 2020:422–34
F I G U R E 5 eGFR Over Time Was Different Between Empagliflozin and Placebo in the EMPA-REG OUTCOME Trial in Type 2 Diabetes Mellitus Patients
78
76
Adjusted Mean (SE) eGFR
(mL/min/1.73m2)
74
72
70
68
66
Baseline
Patients analyzed
Placebo 2,323
Empagliflozin 4,644
Estimated glomerular filtration rate (eGFR) is according to Modification of Diet in Renal Disease formula. Reproduced with permission from Wanner et al. (87).
(97), a multimeric protein complex that is involved in
inflammatory processes including the production of
interleukin-1 b and interleukin-18 (98). Further evi-
dence of anti-inflammatory and antifibrotic effects of
SGLT2i stems from an intriguing study that selected
biomarkers through a systems biology approach and
linked data from diabetic kidney disease models with
information on SGLT2i molecular effects (99). When
compared with the widely used sulfonylurea agent
glimepiride, canagliflozin reduced plasma levels of
tumor necrosis factor receptor 1, IL-6, matrix metal-
loproteinase 7, and fibronectin (99). These findings
lend further support to
inflammatory properties of SGLT2i.
Empagliflozin has also been shown to improve
mitochondrial function and autophagy, improving
renal morphology in diabetic mice by reducing frag-
mentation of renal tubular mitochondria through
activation of AMPK (100). In a study of patients with
T2DM and urinary albumin to creatinine ratio
>100 mg/g dapagliflozin significantly reduced urinary
metabolites linked to mitochondrial metabolism
(101). These findings suggest that improvements in
mitochondrial function may mediate, or at least
contribute to, the nephroprotective properties of this
drug class. Another putative mechanism is that
SGLT2i regulate endoplasmic
mediated apoptosis in proximal tubular cells (102).
Zelniker and Braunwald 431
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
4 12 28 52 66 80 94 108 122 136 150 164 178 192
Week
2,295 2,267 2,205 2,121 2,064 1,927 1,981 1,763 1,479 1,262 1,123 977 731 448
4,578 4,533 4,451 4,318 4,225 4,018 4,131 3,710 3,103 2,654 2,387 2,087 1,623 1,037
Although the reductions in arterial pressure and
circulating glucose concentrations may contribute to
the salutary effects of SGLT2i on the kidney (Table 2)
(71), it is unlikely that the rather modest reductions
in these functions would translate into an effect size
of the observed magnitude of approximately 45% of
the composite kidney outcome (worsening in eGFR,
end-stage kidney disease, or death from renal cause)
as observed in a pooled analysis of the 3 SGLT2i
cardiovascular outcomes trials (10). Exploratory an-
alyses from the EMPA-REG Outcome trial and
CANTATA-SU (Canagliflozin Versus Glimepiride in
antifibrotic and anti- Patients With Type 2 Diabetes Inadequately
Controlled With Metformin), a phase 3 trial that
compared canagliflozin with glimepiride, indicate
that the nephroprotective effects of SGLT2i are in-
dependent of their hypoglycemic actions (103,104).
CONCLUSIONS
The cardio-metabolic-renal effects of SGLT2i are most
likely multifactorial, and although initially conceived
only as glucose-lowering agents, they have expanded
far beyond this action (Table 2). The unexpected and
impressive reductions in important clinical endpoints
reticulum stress- observed in large-scale clinical trials, described in
Part 2 of this review (31), have led investigators from
432 Zelniker and Braunwald
Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
the bedside back to the bench to improve the under-
standing of the drugs in this class and elucidate their
mechanisms of action.
For several important papers on this subject that
were published after submission of this paper on
October 3, 2019, please see the Online Appendix.
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KEY WORDS diabetes, heart failure, renal
function, SGLT2 inhibitor
A PPE NDI X For an addendum, please see the
online version of this paper.