Opinion
VIEWPOINT
The Metabolodiuretic Promise of Sodium-
Dependent Glucose Cotransporter 2 Inhibition
The Search for the Sweet Spot in Heart Failure
Subodh Verma, MD, Clinical trials often yield surprising results, and in the
PhD contemporary era, undoubtedly, the Empagliflozin
Division of Cardiac Removal of Excess of Glucose Outcome (EMPA-REG
Surgery, Department of
OUTCOME) trial stands out as one such example.1,2 No
Surgery, St Michael’s
Hospital, University of one could have predicted that a sodium-dependent glu-
Toronto, Toronto, cose cotransporter 2 (SGLT2) inhibitor, which works to
Ontario, Canada. promote urinary glucose excretion as a treatment ap-
proach to hyperglycemia, would cut all-cause mortality
John J. V. McMurray,
by about one-third in patients with type 2 diabetes. Just
BSc (Hons), MB ChB
(Hons), MD as surprising were the observations that the reductions
British Heart in mortality were possibly driven by a reduction in heart
Foundation failure as opposed to atherothrombotic events. De-
Cardiovascular
Research Centre, spite these salutary clinical effects, the physiological
University of Glasgow, mechanisms responsible for these benefits are not yet
Glasgow, United known. The time frame of the effect precludes a glucose-
Kingdom.
mediated effect, and furthermore, many other equally
or more effective antihyperglycemic therapies are not
David Z. I. Cherney,
MD, PhD associated with reduced heart failure. The remarkable
Division of Nephrology, renal benefits noted in the trial were also surprising.2 Be-
Department of cause the glycosuric effects of SGLT2 inhibition are de-
Medicine, Toronto
pendent on the amount of filtered glucose and there-
General Hospital,
University of Toronto, fore diminished in participants with low glomerular
Toronto, Ontario, filtration rate, it was surprising to note that treatment
Canada. with empagliflozin resulted in a marked approximately
40% reduction in proteinuria and doubling of serum cre-
atinine in the absence of marked differences in glyce-
mia. While the scientific community struggles to under-
stand the biologic basis and clinical implications of these
observations, several questions related to EMPA-REG
OUTCOME have come into focus: can SGLT2 inhibitors
be used to treat heart failure as opposed to prevent heart
failure in diabetes? Can SGLT2 inhibitors be a treat-
ment for heart failure in patients without type 2 diabe-
tes? It is also tempting to ask whether SGLT2 inhibitors
will emerge as primary renoprotective strategies irre-
spective of glycemic or baseline renal status.
Regarding mechanism(s) that might underlie the
marked reductions in heart failure hospitalizations, the
prevailing thought is that these may be mediated at least
in part through effects on volume status.3 It is hypoth-
esized that osmotic diuresis accompanied by sustained
Corresponding
natriuresis may result in a reduction in preload and over-
Author: Subodh
Verma, MD, PhD, all myocardial strain. The effect of this might be particu-
FRCSC, FAHA, Division larly relevant in the setting of patients with diastolic dys-
of Cardiac Surgery, function who may function on a steeper Frank-Starling
Department of Surgery,
St Michael's Hospital,
curve, making them particularly sensitive to changes in
University of Toronto, intravascular volume. Diabetes is associated with an im-
30 Bond St, Bond paired natriuretic response, diminished atrial natri-
Wing, Ste 8-003,
uretic peptide, and blunted cyclic guanine mono-
Toronto, ON M5B 1W8,
Canada (vermasu phosphate response to volume expansion, and patients
@smh.ca). with diabetes are very susceptible to sodium-volume
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changes. In addition, it has been speculated that SGLT2
inhibition may serve as a metabolic modulator pro-
moting improved cardiac substrate use and overall
energetics.4,5 Accordingly, SGLT2 inhibition mediated in-
creases in ketone bodies and may provide a more energy-
efficient source of adenosine triphosphate than other
conventional substrates. Although no specific data on
measures of left ventricular structure and function are
available from the EMPA-REG OUTCOME study, such
studies are currently under way (clinicaltrials.gov
NCT02998970). A small case series also demonstrates
that short-term treatment caused a marked reduction
in left ventricular mass index while also improving mea-
sures of diastolic dysfunction.6
The putative renal protective effects and their
biological basis must also be addressed. In EMPA-REG
OUTCOME, patients treated with empagliflozin had a
39% reduction in the composite renal end point of pro-
gression to macroalbuminuria, doubling of creatinine
level, renal replacement therapy, or renal death.2 Many
of the physiological changes associated with SGLT2 in-
hibition may be renal-protective including lowering of
blood pressure, hemoglobin A1c level, and plasma uric
acid level. In addition to these changes outside of the kid-
ney, SGLT2 inhibition is associated with decreases in in-
traglomerular pressure and hyperfiltration, likely inde-
pendent of systemic circulatory effects, glycemia, or
weight. These direct intrarenal hemodynamic effects
have been most widely attributed to vasoconstriction of
the afferent renal arteriole in response to increased so-
dium chloride delivery to the macula densa, an effect
called tubuloglomerular feedback. The decline in glo-
merular hypertension is also likely to be responsible for
the antiproteinuric effect of SGLT2 inhibitors because the
30% to 40% decline in urinary albumin-to-creatinine ra-
tio is mostly independent of changes in blood pressure
and hemoglobin A1c level.7
The final issue that requires reflection is whether the
cardio-renal benefits of these agents can be observed in
euglycemic individuals without diabetes. The effect of
SGLT2 inhibition on renal hemodynamic parameters and
hence proteinuria is most closely associated with natri-
uresis leading to tubuloglomerular feedback, rather than
glycosuria, and the antiproteinuric effects of these agents
are seen across the spectrum of estimated glomerular fil-
tration rate, down to chronic kidney disease stage 4, al-
though hemoglobin A1c level–lowering and glycosuria ef-
fects are attenuated. In addition, other proximal tubular
diuretic agents, such as acetazolamide, reduce renal hy-
perfiltration in patients without diabetes. This observa-
tion suggests that tubuloglomerular feedback is an
(Reprinted) JAMA Cardiology Published online June 21, 2017 E1
 Opinion Viewpoint

Figure. Proposed Mechanism of Cardiorenal Protection With Sodium-Dependent Glucose

Cotransporter 2 (SGLT2) Inhibitors

Afferent
arteriole Normal

ATP Efferent
arteriole

Myocardial Afferent arteriolar dilatation

energetics
β-hydroxybutyrate Intraglomerular pressure
(ketone body) Na+/glucose cotransport At the level of the kidney, SGLT2
inhibition promotes glycosuria and
natriuresis. It also promotes afferent
arterioral constriction resulting in a
decrease in intraglomerular pressure.
Afterload A reduction in preload and resultant
left ventricular (LV) wall stress
SGLT2 inhibitors cause improves overall LV filling conditions.
afferent arteriolar
Additionally, metabolic effects of
constriction
SGLT2 inhibition to improve
LV wall myocardial energetics and reduce
stress afterload have also been proposed as
cardioprotective mechanisms.
ATP indicates adenosine
Diuresis triphosphate.
Natriuresis
Preload Glycosuria This figure was specifically
Proteinuria commissioned for this article and has
not been reproduced in any form in
any media format. Figure created by
M. Gail Rudakevich, BSc, MScBMC.

important regulator of glomerular filtration rate and renal risk, regard-
less of ambient glucose levels. For cardiovascular benefits, natriuresis
leading to contraction of plasma volume, rather than glycosuria, is a
strong candidate that may mediate the reduction of hospitalizations
for heart failure. Because sodium, rather than glucose, is likely to be an
important physiological factor that is common to both renal and car-
diovascularbenefitswithSGLT2inhibition,itishasbeensuggestedthat
cardiorenal benefits with SGLT2 inhibitors may extend to patients who
do not have diabetes.7
Whether SGLT2 inhibitors will be used in the treatment of heart
failure and renal disease remains to be seen, but large, ongoing out-
come trials in these populations will inform us whether we have hit
the “sweet spot” or not. Indeed, empagliflozin is being studied in pa-
tients who have heart failure with reduced and preserved ejection
fraction. Similarly, dapagliflozin is being studied in dedicated stud-
ies to evaluate efficacy in heart failure (clinicaltrials.gov:
NCT01730534) and renal preservation (clinicaltrials.gov:
NCT03036150). It is important to emphasize that whereas the
hypothesis emerged in the potential prevention of heart failure in pa-
tients with diabetes, whether an osmotic diuretic will work in the
treatment of established heart failure, who will be treated with
loop diuretics remains to be seen. As we await the results of these
trials, we need to develop appropriate terminology to describe
this class of agents. Accordingly, based on physiological data, we
suggest that SGLT2 inhibitors be considered as metabolodiuretic
agents (Figure).

ARTICLE INFORMATION
Published Online: June 21, 2017.
doi:10.1001/jamacardio.2017.1891
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Verma has received speaker’s honoraria from
AstraZeneca, Boehringer Ingelheim, Eli Lilly, and
Janssen and research support from AstraZeneca
and Boehringer Ingelheim. Dr McMurray reports
that his employer, Glasgow University, paid for his
participation in clinical trial committees by Abbvie,
AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb,
Dalcor, GlaxoSmithKline, Merck, Novartis,
Resverlogix, Stealth, and Theracos. In addition, his
travel and accommodation have been paid to
attend meetings related to some of the clinical trials
funded by these sponsors. Dr McMurray’s employer
has also been paid for his attendance at advisory
boards organized by Novartis and Sanofi-Aventis.
Dr Cherney has received consulting and/or
speaker's honoraria from AstraZeneca, Boehringer
Ingelheim, Eli Lilly, Janssen, Sanofi, Merck, and
Mitsubishi-Tanabe and research support from
Merck, AstraZeneca, and Boehringer Ingelheim.
Additional Contributions: We thank Hwee Teoh,
PhD, St Michael’s Hospital, for assisting with
editing. No compensation was received for such
contributions.
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