CLINICAL RESEARCH STUDY

EMPA-REG OUTCOME: The Endocrinologists Point

of View
Leigh Perreault, MD
University of Colorado Anschutz Medical Campus, Aurora.

ABSTRACT

For many years, it was widely accepted that control of plasma lipids and blood pressure could lower
macrovascular risk in patients with type 2 diabetes mellitus (T2DM), whereas the benets of lowering
plasma glucose were largely limited to improvements in microvascular complications. The Empagliozin
Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose
(EMPA-REG OUTCOME) study demonstrated for the rst time that a glucose-lowering agent, the sodium
glucose cotransporter 2 (SGLT2) inhibitor empagliozin, could reduce major adverse cardiovascular
events, cardiovascular mortality, hospitalization for heart failure, and overall mortality when given in
addition to standard care in patients with T2DM at high cardiovascular risk. These results were entirely
unexpected and have led to much speculation regarding the potential mechanisms underlying cardiovas-
cular benets. In this review, the results of EMPA-REG OUTCOME are summarized and put into
perspective for the endocrinologist who is treating patients with T2DM and cardiovascular disease.
2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
The American Journal of Medicine (2017)
130, S51-S56

KEYWORDS: Cardiovascular outcomes; Empagliozin; EMPA-REG OUTCOME; Major adverse cardiovascular

events; Type 2 diabetes mellitus

Macrovascular disease remains the leading cause of death in
people with type 2 diabetes mellitus (T2DM). Thus, it is
somewhat surprising that major landmark trials using
glucose-lowering interventions in people with T2DM have
Funding: This work was supported by Boehringer Ingelheim Phar-
maceuticals, Inc. Writing support was provided by Linda Merkel, PhD, of
Envision Scientic Solutions, which was contracted and funded by Boeh-
ringer Ingelheim Pharmaceuticals, Inc. The authors received no direct
compensation related to the development of the manuscript.
Conict of Interest: LP receives personal fees from Novo Nordisk,
Merck, Pzer, Sano, AstraZeneca, Janssen, Orexigen, and Boehringer
Ingelheim outside of the submitted work.
Authorship: The author meets criteria for authorship as recommended
by the International Committee of Medical Journal Editors (ICMJE). The
author was fully responsible for all content and editorial decisions, was
involved at all stages of manuscript development, and approved the nal
version that reects the authors interpretations and conclusions. Boehringer
Ingelheim was given the opportunity to review the manuscript for medical
and scientic accuracy as well as intellectual property considerations.
Requests for reprints should be addressed to Leigh Perreault, MD,
University of Colorado Anschutz Medical Campus, PO Box 6511, MS
F8106, Aurora, CO 80045.
E-mail address: leigh.perreault@ucdenver.edu
failed to demonstrate any macrovascular benets at the end
of the intervention period, even when stringent glycemic
control was achieved.1-4 In addition, the contention that
some glucose-lowering interventions (eg, rosiglitazone)
might actually increase the risk of cardiovascular events and
death was worrisome.5 Pursuant to the latter, in 2008, the
US Food and Drug Administration (FDA) mandated car-
diovascular safety studies for all new glucose-lowering
therapies.6 Subsequently, results from many cardiovascular
outcome trials have been published.7-11 For dipeptidyl
peptidase-4 inhibitor cardiovascular outcome trials, there
was an unexpected increase in the risk of hospitalization
for heart failure in patients receiving saxagliptin versus
those on placebo in the Saxagliptin Assessment of Vascular
Outcomes Recorded in Patients with Diabetes Mellituse
Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI
53) study (hazard ratio [HR], 1.27; 95% condence interval
[CI], 1.07-1.51; P .007),10 although no statistically sig-
nicant differences in this end point were noted for
alogliptin versus placebo in a post hoc analysis of the Ex-
amination of Cardiovascular Outcomes with Alogliptin
versus Standard of Care (EXAMINE) study (HR, 1.07; 95%

0002-9343/ 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.amjmed.2017.04.005
S52
CI, 0.79-1.46; P .657)12 or for sitagliptin in the Trial
Evaluating Cardiovascular Outcomes with Sitagliptin
(TECOS) primary analysis (HR, 1.00; 95% CI, 0.83-1.20;
P .98).7
The Empagliozin Cardiovascular Outcome Event Trial in
Type 2 Diabetes Mellitus PatientseRemoving Excess
Glucose (EMPA-REG OUTCOME), the cardiovascular
outcome trial investigating the sodium glucose cotransporter
2 (SGLT2) inhibitor empagliozin, was the rst clinical study
of a glucose-lowering agent to demonstrate superiority for the
primary end point and boasted a particularly robust reduction
in the risk of cardiovascular death in patients with T2DM and
established cardiovascular disease.13 Although the major
action of SGLT2 inhibitors is to target the kidney to reduce
the reabsorption of glucose and promote urinary glucose
excretion (reviewed in the articles by Thrasher14 and
Wanner15), the surprising results of EMPA-REG
OUTCOME have generated numerous postulated mecha-
nisms of action for the observed reduction in cardiovascular
disease risk in patients with T2DM (reviewed in the article by
Staels16 in this Supplement).
SUMMARY OF EMPA-REG OUTCOME RESULTS
It is important to rst point out that EMPA-REG
OUTCOME was not designed to assess the glucose-
lowering effects of empagliozin or how glucose-lowering
affects cardiovascular outcomes. Instead, EMPA-REG
OUTCOME was designed to assess the cardiovascular
safety of empagliozin. Nevertheless, the study design did
prespecify that it would test the superiority of empagliozin
over placebo for cardiovascular protection if noninferiority
was achieved. The results demonstrated a reduction in major
adverse cardiovascular events (MACE), cardiovascular
mortality, and hospitalization for heart failure in patients
with T2DM and preexisting cardiovascular disease who
received empagliozin in addition to standard care13 when
tested for both noninferiority and superiority. The trial
continued until a primary outcome event had occurred in at
least 691 patients; the median duration of treatment was 2.6
years, and the median observation time was 3.1 years. The
EMPA-REG OUTCOME population had a mean age of 63
years and long-standing diabetes (>10 years in 57% of
patients), and more than 99% of patients had established
cardiovascular disease (76% had coronary artery disease;
47% had a history of myocardial infarction). The primary
end point occurred in 490 of 4687 patients (10.5%) in the
pooled empagliozin group (10 mg and 25 mg doses) and in
282 of 2333 patients (12.1%) in the placebo group, resulting
in a 14% relative risk reduction for the primary composite
3-point MACE outcome of cardiovascular death, nonfatal
myocardial infarction, and nonfatal stroke in patients
receiving empagliozin compared with those receiving
placebo (HR, 0.86; 95.02% CI, 0.74-0.99; P <.001 for
noninferiority). With no signicant decrease in the relative
risk of stroke or myocardial infarction, the MACE risk
reduction was primarily driven by a 38% relative risk
The American Journal of Medicine, Vol 130, No 6S, June 2017
reduction in cardiovascular death (HR, 0.62; 95% CI,
0.49-0.77; P <.001). In addition, there was a 32% relative
risk reduction in all-cause mortality (HR, 0.68; 95% CI,
0.57-0.82; P <.001) and a 35% relative risk reduction in the
incidence of hospitalization for heart failure (HR, 0.65; 95%
CI, 0.50-0.85; P .002). An analysis of secondary micro-
vascular outcomes demonstrated that patients on empagli-
ozin experienced slower progression of kidney disease and
a lower risk of progressing to macroalbuminuria than those
on placebo17 (this is discussed in the article by Wanner15).
MULTIPLE RISK FACTOR REDUCTION WITH
EMPAGLIFLOZIN
Given the benecial effects of empagliozin on glycated
hemoglobin (HbA1c), blood pressure, and body weight, it is
intuitive to liken EMPA-REG OUTCOME to a traditional
multiple risk factor intervention trial.18 For example, HbA1c
was reduced by 0.45%, blood pressure was reduced by
approximately 5/2 mm Hg, and body weight was reduced by
approximately 2% in the active treatment group.19 Never-
theless, the difference in the primary outcome became
evident approximately 3 months after starting empagli-
ozin,20 making it highly unlikely that the mechanism is
related to glucose-lowering or antiatherosclerotic effects.
For example, statin trials have demonstrated reduction in
cardiovascular events in patients with T2DM after signi-
cant time exposure to the drugs (ie, 1-2 years), with
generally more pronounced effects on cardiovascular events
than on cardiovascular mortality.21,22 Specically, statins
have been shown to reduce myocardial infarction and stroke
by approximately 20%, whereas the effect on cardiovascular
death and all-cause mortality is more limited (e13% and
e9%, respectively, per mmol/L low-density lipoprotein
cholesterol reduction).22 Even when a formal multifactorial
intervention is undertaken, such as in the Intensied
Multifactorial Intervention in Patients With Type 2 Diabetes
and Microalbuminuria (STENO-2) trial (ie, renin-
angiotensin system blockers, aspirin, and lipid-lowering
agents), cardiovascular protection is not observed for
several years.23 Last, although the glucagon-like peptide-1
agonist, liraglutide, has been shown to lower 3-point MACE
(in addition to lowering HbA1c and body weight),8 its
impact on cardiovascular outcomes did not become apparent
until 12 to 18 months of treatment. Collectively, the short
time course for risk reduction in cardiovascular outcomes
seen in EMPA-REG OUTCOME has generated as much
discussion as the major results themselves.
The early separation of the Kaplan-Meier survival curves
for cardiovascular death in EMPA-REG OUTCOME re-
sembles results observed in heart failure studies, which
showed separation of survival curves within 3 to 6 months
of starting treatment with a b-blocker.24,25 In addition,
eplerenone (a diuretic selectively targeting aldosterone re-
ceptors) signicantly reduced the risk of the composite end
point of cardiovascular mortality and cardiovascular hospi-
talization by 17% in a subgroup of patients with T2DM and
Perreault EMPA-REG OUTCOME S53

congestive heart failure; this effect was reported within
months of beginning study treatment.26 Given that only 10%
of participants (706/7020) in EMPA-REG OUTCOME had
known heart failure on enrollment, the 35% reduction in
hospitalization for heart failure may represent prevention of
new-onset heart failure or prevention of an exacerbation of
existing, potentially undiagnosed heart failure in this
population.27,28 Indeed, the effect of empagliozin on
cardiac hemodynamics is an area of intense scientic
investigation.29
Finally, the results of EMPA-REG OUTCOME become
even more impressive when we consider that they occurred
in addition to a background of near-optimal treatment of
blood pressure, plasma lipids, and coagulation status. For
example, 95% of patients received antihypertensive therapy
(angiotensin-converting enzyme inhibitors/angiotensin re-
ceptor blockers, 81%; b-blockers, 65%; and diuretics, 43%),
77% of patients received statins, and 83% of patients
received aspirin. This speaks to the ability of empagliozin
to tackle some of the residual cardiovascular risk not ach-
ieved by traditional means.
POTENTIAL MECHANISMS INVOLVED IN
CARDIORENAL BENEFITS OF EMPAGLIFLOZIN
Multiple potential mechanisms of action have been pro-
posed to explain the cardiovascular benets of empagliozin
since the completion of EMPA-REG OUTCOME30 and are
discussed in detail in the articles by Wanner,15 Staels,16 and
Pham and Chilton29 in this Supplement. These include
metabolic factors, such as reductions in HbA1c, body
weight, uric acid, and visceral adiposity; hemodynamic ef-
fects, such as reductions of blood pressure and intravascular
volume, osmotic diuresis, and sympatholysis; hormonal ef-
fects, such as increased glucagon, and effects on the renin-
angiotensin-aldosterone system; and fuel energetics, such as
a shift from glucose or fatty acids to ketone use (Figure).
The fuel shift hypothesis is particularly interesting for the
endocrinologist because people with T2DM display altered
fatty acid oxidation and impaired glucose uptake/oxidation
in the heart, predisposing them to myocardial dysfunction
and heart failure.31,32 Unlike those individuals without
T2DM, in individuals with T2DM, the heart is less adapt-
able in using usual energy sources, such as glucose and free

Liver
Pancreas cells
Improved
Glycemic Control

Glucagon
Ketones FFA

FFA

Preload
Aortic stiffness
Wall stress Adipose tissue

Weight
ECFV loss

Blood
AT2 pressure
Ang 1-7

Uric acid excretion Systemic vascular

resistance
NaCI/H2O excretion

Figure Schematic representation of the potential metabolic and hemodynamic pathways responsible for the
reduction in mortality and hospitalization for heart failure observed with empagliozin in EMPA-REG
OUTCOME.19 American Diabetes Association SGLT2 Inhibitors and Cardiovascular Risk: Lessons
Learned From the EMPA-REG OUTCOME Study. American Diabetes Association, 2016 Copyright and all
rights reserved. Material from this publication has been used with the permission of American Diabetes
Association. Ang 1-7 angiotensin 1-7; AT2 angiotensin 2 receptor; ECFV extracellular uid volume;
FFA free fatty acids.
S54
fatty acids, and will preferentially mobilize ketones for fuel
when they are available.32 The glucosuria caused by SGLT2
inhibitor therapy creates a plasma milieu that favors hepatic
ketone production (ie, lowering glucose and insulin and
increasing glucagon and free fatty acids).33 This mild and
persistent hyperketonemia is thought to induce a shift in fuel
metabolism in the heart, making it more energy efcient.
One small study was able to demonstrate a 2- to 3-fold in-
crease in plasma ketone concentration in people with T2DM
treated with empagliozin for as little as 4 weeks.34
Experimental evidence in animals and humans demon-
strates that ketones are preferentially oxidized over fatty
acids by myocardial cells.32,34 This shift to ketone use is
associated with increased energy release in the form of
adenosine triphosphate and translates into increased cardiac
efciency and function, a scenario that can occur quickly
and may partially explain the cardiovascular benets
observed in EMPA-REG OUTCOME.35,36 The shift in
metabolic fuel also occurs in other organs, including the
kidney, possibly explaining some of the renal benets
observed in EMPA-REG OUTCOME.
As a relevant aside, it is important to note that ketosis
cannot occur unless a patient is insulin decient. In the
EMPA-REG OUTCOME postrandomization, more patients
on placebo received add-on treatment with insulin (11.5%
vs 5.8% with empagliozin, respectively) and sulfonylurea
(7.0% vs 3.8% with empagliozin, respectively). Although
no difference in the number of hypoglycemic events was
found between the 2 groups, it is possible that placebo-
treated patients experienced more episodes of low blood
glucose and arrhythmic events compared with those treated
with empagliozin. This companion hypothesis for the
observed benet is not mutually exclusive of the shift in
myocardial substrate use, but rather underscores that the
cardiovascular benet observed in EMPA-REG OUTCOME
was likely multifactorial.
IMPLICATIONS FOR CLINICAL PRACTICE
Cardiovascular survival has dramatically improved with the
advent of cardiovascular outcomes trials in T2DM using
antihypertensives, statins, and aspirin,18,37 and the adoption
of these results into evidence-based medical practice.
Nonetheless, although trials are conducted in populations,
healthcare providers have to decide how these results can be
applied to individual patients.
Several take-away messages from EMPA-REG
OUTCOME are relevant to practitioners caring for
individuals with T2DM and preexisting cardiovascular dis-
ease. First, identication of patients with T2DM at high risk
for cardiovascular disease is an essential rst step in
improving their outcomes. Observations from the Diabetes
Collaborative Registry, a US outpatient registry of patients
with T2DM, found that approximately 1 in 6 patients (16%)
meets the main EMPA-REG OUTCOME eligibility criteria.
However, only 4% of these patients are currently treated
with SGLT2 inhibitors.38 It will be interesting to see
The American Journal of Medicine, Vol 130, No 6S, June 2017
whether this number will increase now that empagliozin
also is indicated for the reduction of the risk of cardiovas-
cular death in adult patients with T2DM and established
cardiovascular disease,39 and the American Diabetes Asso-
ciation recommends empagliozin (or liraglutide) in patients
with long-standing suboptimally controlled T2DM and
established cardiovascular disease.37 Whether empagliozin
can improve cardiovascular outcomes in patients with
T2DM without pre-existing cardiovascular disease or in
patients with preexisting cardiovascular disease without
T2DM is not known. Second, it is not currently known
whether the benets observed in EMPA-REG OUTCOME
are specic to empagliozin or are a class effect of SGLT2
inhibitors. Long-term cardiovascular outcomes trials with
other SGLT2 inhibitors are currently ongoing, namely, the
CANagliozin CardioVascular Assessment Study
(CANVAS; NCT01032629),40 the Dapagliozin Effect on
CardiovascuLAR Event 58 study (DECLARE-TIMI 58;
NCT01730534), and the Cardiovascular Outcomes
Following Ertugliozin Treatment in Type 2 Diabetes
Mellitus Participants With Vascular Disease Study
(VERTIS CV; NCT01986881). This drug class has a shared
mechanism of action, and most adverse events observed in
clinical trials and in postmarketing reports have been similar
within a class, such as the postmarketing reports of acute
kidney injury with SGLT2 inhibitors, which have prompted
the FDA to revise and strengthen the existing warning about
this condition in the drug labels and to add recommenda-
tions on how to minimize the risk.6,39 Other adverse events
remain unique to individual drugs.41 For example, for can-
agliozin, an increased risk of leg and foot amputations
(mostly affecting the toes) was observed in the ongoing
CANVAS trial, resulting in a safety alert from the FDA.41 In
addition, clinical data demonstrated that canagliozin was
associated with an increased risk of bone fractures as early
as 12 weeks after starting the drug and caused a greater loss
of bone density in the hip in older individuals compared
with placebo,42 resulting in a label update for canagli-
ozin.43 In addition, dapagliozin use is not recommended
in patients with an estimated glomerular ltration rate
(eGFR) <60 mL/min/1.73 m2,44 whereas canagliozin and
empagliozin should not be initiated or should be dis-
continued if the eGFR persistently decreases to < 45 mL/
min/1.73 m2.39,43 Therefore, although one can speculate
about the potential benets of the SGLT2 class, issues
related to small differences in the drugs and the clinical trial
designs used to assess their safety remain. Last, the benet
of empagliozin was observed in addition to (not in place
of) standard care. As the mechanism behind the benet
undergoes investigation, attention to current standard care
with or without empagliozinremains imperative.
CONCLUSIONS
As recently as 18 months ago, we had almost abandoned the
notion that a glucose-lowering agent could prevent cardio-
vascular disease in people with T2DM. The results from
Perreault EMPA-REG OUTCOME
EMPA-REG OUTCOME, showing a reduction in adverse
cardiovascular outcomes with the study drug versus pla-
cebo, were wholly unexpected and have rekindled enthu-
siasm for tackling residual cardiovascular risk in patients
with T2DM. Furthermore, scientic investigations have
begun to unmask the mechanisms behind the observed
benets. However, other questions remain to be answered,
including the following: (1) Can empagliozin reduce car-
diovascular events in people with T2DM without pre-
existing cardiovascular disease? (2) Can empagliozin
reduce cardiovascular events in people without T2DM with
preexisting cardiovascular disease? (3) Can empagliozin
reduce cardiovascular events or deterioration of renal
function in people without T2DM and an eGFR <45 mL/
min/1.73 m2? (4) Can empagliozin reduce cardiovascular
events in people without T2DM who have hypertension,
obstructive sleep apnea, or heart failure? Results from the
EMPA-REG OUTCOME trial remind us there is much to be
learned about diabetes and SGLT2 inhibition.
References
1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with con-
ventional treatment and risk of complications in patients with type 2
diabetes (UKPDS 33). Lancet. 1998;352:837-853.
2. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular
complications in veterans with type 2 diabetes. N Engl J Med.
2009;360:129-139.
3. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:
2545-2559.
4. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose
control and vascular outcomes in patients with type 2 diabetes. N Engl
J Med. 2008;358:2560-2572.
5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial
infarction and death from cardiovascular causes. N Engl J Med.
2007;356:2457-2471.
6. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for industry: diabetes mellitus evaluating car-
diovascular risk in new antidiabetic therapies to treat type 2 diabetes.
Available at: http://www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/ucm071627.pdf. Accessed November
28, 2016.
7. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on
cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:
232-242.
8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and
cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:
311-322.
9. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type
2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:
2247-2257.
10. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardio-
vascular outcomes in patients with type 2 diabetes mellitus. N Engl J
Med. 2013;369:1317-1326.
11. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coro-
nary syndrome in patients with type 2 diabetes. N Engl J Med.
2013;369:1327-1335.
12. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality
outcomes in patients with type 2 diabetes taking alogliptin versus
placebo in EXAMINE: a multicentre, randomised, double-blind trial.
Lancet. 2015;385:2067-2076.
S55
13. Zinman B, Wanner C, Lachin JM, et al. Empagliozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:
2117-2128.
14. Thrasher J. Management of type 2 diabetes mellitus: available thera-
pies. Am J Med. 2017;130:S4-S17.
15. Wanner C. EMPA-REG OUTCOME: the nephrologists point of view.
Am J Med. 2017;130:S63-S72.
16. Staels B. Cardiovascular protection by sodium glucose cotransporter
2 inhibitors: potential mechanisms of action. Am J Med. 2017;130:
S30-S39.
17. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliozin and pro-
gression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:
323-334.
18. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by
multifactorial intervention in patients with type 2 diabetes mellitus and
microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.
Diabetologia. 2016;59:2298-2307.
19. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2
inhibitors and cardiovascular risk: lessons learned from the EMPA-
REG OUTCOME study. Diabetes Care. 2016;39:717-725.
20. Trujillo JM, Wettergreen SA, Nuffer WA, Ellis SL, McDermott MT.
Cardiovascular outcomes of new medications for type 2 diabetes.
Diabetes Technol Ther. 2016;18:749-758.
21. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary pre-
vention of cardiovascular disease with atorvastatin in type 2 diabetes
in the Collaborative Atorvastatin Diabetes Study (CARDS): multi-
centre randomised placebo-controlled trial. Lancet. 2004;364:
685-696.
22. Kearney PM, Blackwell L, Collins R, et al. Efcacy of cholesterol-
lowering therapy in 18,686 people with diabetes in 14 randomised
trials of statins: a meta-analysis. Lancet. 2008;371:117-125.
23. Gaede P, Valentine WJ, Palmer AJ, et al. Cost-effectiveness of inten-
sied versus conventional multifactorial intervention in type 2 diabetes:
results and projections from the Steno-2 study. Diabetes Care.
2008;31:1510-1515.
24. Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled
release/extended release in patients with severe heart failure: analysis
of the experience in the MERIT-HF study. J Am Coll Cardiol. 2001;38:
932-938.
25. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the
morbidity of patients with severe chronic heart failure: results of the
carvedilol prospective randomized cumulative survival (COPERNI-
CUS) study. Circulation. 2002;106:2194-2199.
26. Zannad F, Gattis Stough W, Rossignol P, et al. Mineralocorticoid
receptor antagonists for heart failure with reduced ejection fraction:
integrating evidence into clinical practice. Eur Heart J. 2012;33:
2782-2795.
27. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with
empagliozin in patients with type 2 diabetes at high cardiovascular
risk: results of the EMPA-REG OUTCOME trial. Eur Heart J.
2016;37:1526-1534.
28. Raz I, Cahn A. Heart failure: SGLT2 inhibitors and heart failure e
clinical implications. Nat Rev Cardiol. 2016;13:185-186.
29. Pham SV, Chilton R. EMPA-REG OUTCOME: the cardiologists
point of view. Am J Med. 2017;130:S57-S62.
30. DeFronzo RA. The EMPA-REG study: what has it told us? A
diabetologists perspective. J Diabetes Complications. 2016;30:1-2.
31. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG
OUTCOME trial: a thrifty substrate hypothesis. Diabetes Care.
2016;39:1108-1114.
32. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics
explain the benecial cardiorenal outcomes in the EMPA-REG
OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39:
1115-1122.
33. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to
sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.
J Clin Invest. 2014;124:499-508.
S56
34. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utili-
zation in response to sodium-glucose cotransporter 2 inhibition in
subjects without diabetes and patients with type 2 diabetes. Diabetes.
2016;65:1190-1195.
35. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and
cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304:
H1060-H1076.
36. Dedkova EN, Blatter LA. Role of beta-hydroxybutyrate, its polymer
poly-beta-hydroxybutyrate and inorganic polyphosphate in mammalian
health and disease. Front Physiol. 2014;5:260.
37. American Diabetes Association. Standards of Medical Care in
Diabetes-2017. Diabetes Care. 2017;40:S4-S5.
38. Arnold SV, Inzucchi SE, Maddox TM, et al. Dening the potential real-
world impact of the EMPA-REG OUTCOME trial on improving car-
diovascular outcomes: observations from the Diabetes Collaborative
Registry (DCR). Diabetologia. 2016;59(Suppl 1), Abstract #729.
39. Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information
(12/2016) JARDIANCE (empagliozin) tablets, for oral use. Avail-
able at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/
204629s008lbl.pdf. Accessed December 19, 2016.
The American Journal of Medicine, Vol 130, No 6S, June 2017
40. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline
characteristics of the Canagliozin Cardiovascular Assessment Study
(CANVAS)ea randomized placebo-controlled trial. Am Heart J.
2013;166:217-223e11.
41. Food and Drug Administration. FDA drug safety communication:
interim clinical trial results nd increased risk of leg and foot amputa-
tions, mostly affecting the toes, with the diabetes medicine canagliozin
(Invokana, Invokamet); FDA to investigate. Available at: http://www.
fda.gov/Drugs/DrugSafety/ucm500965.htm. Accessed June 1, 2016.
42. Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral
density and bone biomarkers in patients with type 2 diabetes treated
with canagliozin. J Clin Endocrinol Metab. 2016;101:44-51.
43. Janssen Pharmaceuticals. Prescribing Information (02/2017)
INVOKANA (canagliozin) tablets, for oral use. Available at: https://
www.invokanahcp.com/sites/www.invokanahcp.com/les/prescribing-
information-invokana.pdf. Accessed April 11, 2017.
44. AstraZeneca Pharmaceuticals LP. Prescribing information (03/2017)
FARXIGA (dapagliozin) tablets, for oral use. Available at: https://
www.accessdata.fda.gov/drugsatfda_docs/label/2017/202293s011lbl.
pdf. Accessed April 11, 2017.