CLINICAL RESEARCH STUDY

EMPA-REG OUTCOME: The Endocrinologist’s 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 benefits of lowering
plasma glucose were largely limited to improvements in microvascular complications. The Empagliflozin
Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose
(EMPA-REG OUTCOME) study demonstrated for the first time that a glucose-lowering agent, the sodium
glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, 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 benefits. 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.
Ó 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; Empagliflozin; EMPA-REG OUTCOME; Major adverse cardiovascular

events; Type 2 diabetes mellitus

Macrovascular disease remains the leading cause of death in

Funding: This work was supported by Boehringer Ingelheim Phar-
maceuticals, Inc. Writing support was provided by Linda Merkel, PhD, of
Envision Scientific 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.
Conflict of Interest: LP receives personal fees from Novo Nordisk,
Merck, Pfizer, Sanofi, 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 final
version that reflects the author’s interpretations and conclusions. Boehringer
Ingelheim was given the opportunity to review the manuscript for medical
and scientific accuracy as well as intellectual property considerations.
This article is co-published in The American Journal of Medicine
(Vol. 130, Issue 6S, June 2017) and The American Journal of Cardiology
(Vol. 120, Issue 1S, July 1, 2017).
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
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
failed to demonstrate any macrovascular benefits 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

0002-9343/Ó 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
Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI
53) study (hazard ratio [HR], 1.27; 95% confidence interval
[CI], 1.07-1.51; P ¼ .007),10 although no statistically sig-
nificant 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%
CI, 0.79-1.46; P ¼ .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 ¼ .98).7
The Empagliflozin 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 empagliflozin, was the first 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 first point out that EMPA-REG
OUTCOME was not designed to assess the glucose-
lowering effects of empagliflozin or how glucose-lowering
affects cardiovascular outcomes. Instead, EMPA-REG
OUTCOME was designed to assess the cardiovascular
safety of empagliflozin. Nevertheless, the study design did
prespecify that it would test the superiority of empagliflozin
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 empagliflozin 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 empagliflozin 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
The American Journal of Medicine, Vol 130, No 6S, June 2017
3-point MACE outcome of cardiovascular death, nonfatal
myocardial infarction, and nonfatal stroke in patients
receiving empagliflozin compared with those receiving
placebo (HR, 0.86; 95.02% CI, 0.74-0.99; P <.001 for
noninferiority). With no significant decrease in the relative
risk of stroke or myocardial infarction, the MACE risk
reduction was primarily driven by a 38% relative risk
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 ¼ .002). An analysis of secondary micro-
vascular outcomes demonstrated that patients on empagli-
flozin 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 beneficial effects of empagliflozin 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-
flozin,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 signifi-
cant time exposure to the drugs (ie, 1-2 years), with
generally more pronounced effects on cardiovascular events
than on cardiovascular mortality.21,22 Specifically, 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 Intensified
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
Perreault EMPA-REG OUTCOME S53

resembles 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) significantly 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
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 empagliflozin on
cardiac hemodynamics is an area of intense scientific
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 empagliflozin
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 benefits of empagliflozin
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

Liver
Pancreas – α 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 empagliflozin 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 ¼ angiotensin 1-7; AT2 ¼ angiotensin 2 receptor; ECFV ¼ extracellular fluid volume;
FFA ¼ free fatty acids.
S54
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
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 efficient.
One small study was able to demonstrate a 2- to 3-fold in-
crease in plasma ketone concentration in people with T2DM
treated with empagliflozin 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
efficiency and function, a scenario that can occur quickly
and may partially explain the cardiovascular benefits
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 benefits
observed in EMPA-REG OUTCOME.
As a relevant aside, it is important to note that ketosis cannot
occur unless a patient is insulin deficient. In the EMPA-REG
OUTCOME postrandomization, more patients on placebo
received add-on treatment with insulin (11.5% vs 5.8% with
empagliflozin, respectively) and sulfonylurea (7.0% vs 3.8%
with empagliflozin, 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 empagliflozin. This com-
panion hypothesis for the observed benefit is not mutually
exclusive of the shift in myocardial substrate use, but rather
underscores that the cardiovascular benefit 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, identification of patients with T2DM at high risk
for cardiovascular disease is an essential first 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.
The American Journal of Medicine, Vol 130, No 6S, June 2017
However, only 4% of these patients are currently treated with
SGLT2 inhibitors.38 It will be interesting to see whether this
number will increase now that empagliflozin also is indicated
for the reduction of the risk of cardiovascular death in adult
patients with T2DM and established cardiovascular disease,39
and the American Diabetes Association recommends empa-
gliflozin (or liraglutide) in patients with long-standing sub-
optimally controlled T2DM and established cardiovascular
disease.37 Whether empagliflozin can improve cardiovascular
outcomes in patients with T2DM without pre-existing car-
diovascular disease or in patients with preexisting cardio-
vascular disease without T2DM is not known. Second, it is not
currently known whether the benefits observed in EMPA-
REG OUTCOME are specific to empagliflozin or are a
class effect of SGLT2 inhibitors. Long-term cardiovascular
outcomes trials with other SGLT2 inhibitors are currently
ongoing, namely, the CANagliflozin CardioVascular
Assessment Study (CANVAS; NCT01032629),40 the Dapa-
gliflozin Effect on CardiovascuLAR Event 58 study
(DECLARE-TIMI 58; NCT01730534), and the Cardiovas-
cular Outcomes Following Ertugliflozin 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 recommendations
on how to minimize the risk.6,39 Other adverse events remain
unique to individual drugs.41 For example, for canagliflozin,
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 canagliflozin 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 result-
ing in a label update for canagliflozin.43 In addition, dapa-
gliflozin use is not recommended in patients with an estimated
glomerular filtration rate (eGFR) <60 mL/min/1.73 m2,44
whereas canagliflozin and empagliflozin should not be initi-
ated or should be discontinued if the eGFR persistently de-
creases to < 45 mL/min/1.73 m2.39,43 Therefore, although one
can speculate about the potential benefits 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
benefit of empagliflozin was observed in addition to (not in
place of) standard care. As the mechanism behind the benefit
undergoes investigation, attention to current standard care—
with or without empagliflozin—remains 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, scientific investigations have
begun to unmask the mechanisms behind the observed
benefits. However, other questions remain to be answered,
including the following: (1) Can empagliflozin reduce car-
diovascular events in people with T2DM without pre-
existing cardiovascular disease? (2) Can empagliflozin
reduce cardiovascular events in people without T2DM with
preexisting cardiovascular disease? (3) Can empagliflozin
reduce cardiovascular events or deterioration of renal
function in people without T2DM and an eGFR <45 mL/
min/1.73 m2? (4) Can empagliflozin 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. Empagliflozin, 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 nephrologist’s 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. Empagliflozin 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. Efficacy 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-
sified 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
empagliflozin in patients with type 2 diabetes at high cardiovascular
risk: results of the EMPA-REG OUTCOMEÒ 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 cardiologist’s
point of view. Am J Med. 2017;130:S57-S62.
30. DeFronzo RA. The EMPA-REG study: what has it told us? A
diabetologist’s 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 beneficial 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. Defining 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) JARDIANCEÒ (empagliflozin) 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 Canagliflozin 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 find increased risk of leg and foot amputa-
tions, mostly affecting the toes, with the diabetes medicine canagliflozin
(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 canagliflozin. J Clin Endocrinol Metab. 2016;101:44-51.
43. Janssen Pharmaceuticals. Prescribing Information (02/2017)
INVOKANAÒ (canagliflozin) tablets, for oral use. Available at: https://
www.invokanahcp.com/sites/www.invokanahcp.com/files/prescribing-
information-invokana.pdf. Accessed April 11, 2017.
44. AstraZeneca Pharmaceuticals LP. Prescribing information (03/2017)
FARXIGAÒ (dapagliflozin) tablets, for oral use. Available at: https://
www.accessdata.fda.gov/drugsatfda_docs/label/2017/202293s011lbl.
pdf. Accessed April 11, 2017.