CLINICAL RESEARCH STUDY

EMPA-REG OUTCOME: The Cardiologist’s Point

of View
Son V. Pham, MD, Robert Chilton, DO
The University of Texas Health Science Center, San Antonio, Tex.

ABSTRACT

Cardiologists could view empagliflozin as a cardiovascular drug that also has a beneficial effect on reducing
hyperglycemia in patients with type 2 diabetes mellitus (T2DM). The effects of empagliflozin in lowering
the risk of cardiovascular death and hospitalization for heart failure in T2DM patients with high cardio-
vascular risk during the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes
Mellitus PatientseRemoving Excess Glucose (EMPA-REG OUTCOME) trial may be explained principally
in terms of changes to cardiovascular physiology; namely, by the potential ability of empagliflozin to
reduce cardiac workload and myocardial oxygen consumption by lowering blood pressure, improving aortic
compliance, and improving ventricular arterial coupling. These concepts and hypotheses are discussed in
this report.
Ó 2017 The Authors. 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, S57-S62

KEYWORDS: Cardiac workload; Cardiovascular outcomes; Empagliflozin; Myocardial oxygen consumption; Sodium
glucose cotransporter 2 inhibitors

The Steno-2 trial, which was launched in 1993 and ran-
domized 160 patients with type 2 diabetes mellitus (T2DM)
and microalbuminuria to receive either conventional multi-
factorial treatment or intensified multifactorial treatment for
Funding: This work was supported by Boehringer Ingelheim Phar-
maceuticals, Inc. Writing support was provided by Debra Brocksmith, MB
ChB, PhD, of Envision Scientific Solutions, which was contracted and
funded by Boehringer Ingelheim Pharmaceuticals Inc. The authors received
no direct compensation related to the development of the manuscript.
Conflict of Interest: SVP has no disclosures. RC has received
consulting fees from Boehringer Ingelheim and Lilly.
Authorship: The authors meet criteria for authorship as recommended
by the International Committee of Medical Journal Editors (ICMJE). The
authors were fully responsible for all content and editorial decisions, were
involved at all stages of manuscript development, and approved the final
version that reflects the authors’ interpretation 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 Robert Chilton, DO,
Division of Cardiology, Department of Medicine, The University of Texas
Health Science Center at San Antonio, 7703 Floyd Curl Drive, San
Antonio, TX 78229.
E-mail address: chilton@uthscsa.edu
global risk reduction regarding vascular damage (mean
treatment duration 7.8 years),1,2 recently reported long-term
follow-up data.2 After a median observation period of
approximately 21 years, patients in the intensive therapy
group (n ¼ 42) survived for a median of 7.9 years longer
than those in the conventional therapy group (n ¼ 24).2
Nevertheless, there still was a high rate of deaths and car-
diovascular (CV) events in the intensive treatment group
(>30% events at 10 years).2 Thus, these data demonstrate
that the high CV event rate observed in T2DM patients
continues unabated even with rigorous treatment. Recently,
empagliflozin, “a new CV agent with antihyperglycemic
effects” was reported to significantly reduce CV death and
hospitalization for heart failure, and slow the progression of
kidney disease in T2DM patients when compared with pla-
cebo e the median duration of treatment was 2.6 years and
the median observation period was 3.1 years.3,4 Empagli-
flozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor.
SUMMARY OF EMPA-REG OUTCOME RESULTS
During the Empagliflozin Cardiovascular Outcome Event
Trial in Type 2 Diabetes Mellitus PatientseRemoving
Excess Glucose (EMPA-REG OUTCOME) trial, patients

0002-9343/Ó 2017 The Authors. 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.2017.04.006
S58
with T2DM and a high risk of CV events were randomized
to receive either empagliflozin (10 mg or 25 mg) or placebo
in addition to standard care.3 More than 99% of patients had
established CV disease. The trial was continued until an
adjudicated primary outcome event had occurred in at least
691 patients. The primary outcome was a composite of
death from CV causes, nonfatal myocardial infarction (MI;
excluding silent MI), or nonfatal stroke (ie, 3-point major
adverse cardiovascular events [MACE]). The key secondary
outcome was a composite of the primary outcome plus
hospitalization for unstable angina (ie, 4-point MACE). A
total of 7020 patients were included in the primary analysis
(empagliflozin groups pooled, n ¼ 4687; placebo,
n ¼ 2333).3 The patient population with T2DM and high-
risk CV disease in EMPA-REG OUTCOME had a yearly
event rate of approximately 4.5%, which was similar to that
in the previously published sitagliptin CV outcome study,
Trial Evaluating Cardiovascular Outcomes with Sitagliptin
(TECOS).5 There was a significant reduction in the primary
outcome (ie, 3-point MACE) for those receiving empagli-
flozin vs placebo (hazard ratio [HR] 0.86; 95.02% confi-
dence interval [CI], 0.74-0.99; P <.001 for noninferiority,
P ¼ .04 for superiority).3 Moreover, significant reductions
in the risk of CV death (HR 0.62; 95% CI, 0.49-0.77; P
<.001) and all-cause mortality (HR 0.68; 95% CI, 0.57-
0.82; P <.001) for empagliflozin vs placebo were reported.3
Separation between the empagliflozin and placebo event
curves for these endpoints occurred early in the trial,3 within
6 to 12 weeks of treatment commencement. A significant
reduction in the risk of hospitalization for heart failure also
occurred with empagliflozin vs placebo (HR 0.65; 95% CI,
0.50-0.85; P ¼ .002),3 with event curve separation occur-
ring almost immediately (within 6 weeks). No significant
risk reductions with empagliflozin vs placebo were reported
for the rate of nonfatal MI (excluding silent MI) (HR 0.87;
95% CI, 0.70-1.09; P ¼ .22) or the rate of nonfatal stroke
(HR 1.24; 95% CI, 0.92-1.67; P ¼ .16).3
EMPA-REG OUTCOME also investigated renal outcomes
in T2DM patients with a high risk of CV events and an estimated
glomerular filtration rate (eGFR) 30 mL/min/1.73 m2.4
Compared with placebo, empagliflozin was associated with
reduced incident or worsening nephropathy (HR 0.61; 95% CI,
0.53-0.70; P <.001), reduced risk of doubling of serum creati-
nine (accompanied by eGFR 45 mL/min/1.73 m2) (HR 0.56;
95% CI, 0.39-0.79; P <.001), and reduced risk of renal
replacement therapy initiation (HR 0.45; 95% CI, 0.21-0.97;
P ¼ .04).4 Renal outcomes data and potential mechanisms of
renal protection associated with SGLT2 inhibitors are discussed
in detail by Wanner in this Supplement.6
BACKGROUND CONCEPTS IN CARDIOVASCULAR
PHYSIOLOGY
The mechanism of action of empagliflozin in reducing the
risk of adverse CV outcomes in the EMPA-REG
OUTCOME trial is currently unknown, and various
potential explanations have been suggested, including
The American Journal of Medicine, Vol 130, No 6S, June 2017
hemodynamic, metabolic, or hormonal effects (as discussed
by Staels7 in this issue). Here, we offer an explanation based
on changes in CV physiology. Some background concepts
in CV function are first described for the reader to fully
appreciate the mechanisms proposed (Figure 1).
MYOCARDIAL OXYGEN CONSUMPTION
Myocardial oxygen supply is determined primarily by
blood flow and vascular resistance in the coronary vessels.
Myocardial oxygen consumption (MVO2) is governed by
the frequency and strength of cardiac myocyte contraction,
and these are determined primarily by heart rate, left ven-
tricular contractility, and left ventricular wall tension (ie,
mechanical stress).8 Changes in stroke volume have only a
modest influence on MVO2,8 as does basal myocardial
metabolism and activation of cardiac contraction. If cardiac
afterload increases (eg, in patients with hypertension),
meaning the pressure against which the heart pumps is
increased, cardiac myocytes must produce greater tension
to generate forward blood flow, thus increasing their oxy-
gen consumption. The law of Laplace states that left ven-
tricular wall tension is proportional to the product of
intraventricular pressure and ventricular radius, and
inversely proportional to twice the ventricular wall thick-
ness.9 The close relationship between MVO2 and left
ventricular wall tension has important consequences for the
diabetic heart.
As discussed by Lehrke and Marx in this Supplement,10
heart failure is a common complication in patients with
diabetes and a major contributor to CV morbidity and
mortality.11 Furthermore, such myocardial dysfunction in
diabetes may develop in the absence of risk factors such as
hypertension or coronary artery disease or valvular disease,
and it is known as diabetic cardiomyopathy.12 In a diabetic
patient with heart failure, various mechanisms attempt to
compensate for the resulting decrease in cardiac output. Left
ventricular wall tension may increase to overcome a higher
cardiac afterload; thereafter, sustained elevation in intra-
ventricular pressure and left ventricular radius may stimulate
hypertrophy of ventricular myocytes. The resulting
increased mass of cardiac muscle fiber maintains contractile
force to counteract the increased left ventricular wall ten-
sion; however, eventual dilatation of the left ventricle may
occur and lead to a decrease in the left ventricular ejection
fraction.13 The dilated heart has a greater MVO2, as more
energy is required to maintain cardiac output than for a
normal-sized heart.13 Consequently, reducing left ventricu-
lar wall tension is a common therapeutic target in the
treatment of heart failure.
VENTRICULAR ARTERIAL COUPLING
The left ventricle pumps the stroke volume of blood into the
aorta and systemic arterial system. The interaction between
the left ventricle and systemic arterial system, called ven-
tricular arterial coupling, is a significant determinant of CV
Pham and Chilton EMPA-REG OUTCOME: Cardiology S59

Systolic ejection
(End-systole)
120

Impaired cardiac relaxation

Impaired cardiac cellular

Pressure (mm Hg)

function in diabetes
in diabetes, BP
Isovolumetric Isovolumetric
relaxation contraction

T2DM with High pressure Metabolic effects

filling of diabetes:
diastolic dysfunction Poor relaxation tolic
Dias (End-diastole) Hyperglycemia
Normal LVEDP 6 Glucotoxicity
Structural Other metabolic
50 125 components of abnormalities

Volume (mL) diabetes:

Hypertrophy
Fibrosis
Fat

Figure 1 Cardiometabolic relationships in diabetes. The loop shows pressure-volume changes during a
single cardiac cycle. Diastolic dysfunction, a common occurrence in patients with T2DM, is manifest by
elevated LVEDP, and results in the clinical manifestation of heart failure with a normal ejection fraction.
Metabolic effects of diabetes adversely affect cardiac cellular function, as do diabetes-related structural ab-
normalities, via effects on diastolic filling. BP ¼ blood pressure; LVEDP ¼ left ventricular end-diastolic
pressure; T2DM ¼ type 2 diabetes mellitus.

function,14 and contributes to the body’s capacity to increase
cardiac output, regulate systemic blood pressure (BP), and
respond to increases in heart rate and cardiac preload (ie,
ventricular filling pressure, which is affected by central
venous pressure and venous return).14,15 In a healthy heart
in which ventricular and arterial stiffness (ie, elastance) are
low, the compliance (ie, increase in volume with increased
pressure) in the heart and arteries prevents wide changes in
pressure that could lead to vascular or end-organ damage;
thus, optimal ventricular arterial coupling enables maximal
cardiac work and efficiency.16 Ventricular and arterial
stiffness increase with age, and with comorbid conditions
such as diabetes, hypertension, and kidney disease.17 This
stiffening affects various markers of cardiac performance,
including CV reserve, BP lability, ventricular systolic and
diastolic function, coronary and peripheral flow regulation,
and endothelial function.15,16 These parameters increase the
hydraulic work required to maintain cardiac output and, in
turn, increase MVO2.16 The adverse interaction between a
stiff heart and arteries has been described as a form of
“coupling disease” that limits the ability of the CV system to
respond to stress.16,17 The “gold standard” noninvasive
method of assessing arterial stiffness is via aortic pulse wave
velocity, but pulse pressure (systolic BP minus diastolic BP)
may be used as a surrogate marker.18 A recent analysis from
the Framingham Heart Study reported that a substantial
proportion of patients treated for hypertension (60% of
controlled treated patients and 90% of uncontrolled treated
patients) had increased arterial stiffness, measured as
elevated carotid-femoral pulse wave velocity, and this was
associated with increased CV disease risk.19 It is also
important to note that arterial stiffness may be driven by
matrix and mineralization events in the absence of atheroma,
particularly in dysmetabolic states such as diabetes,20,21 and
the subsequent impairment of normal vessel functioning
(called Windkessel physiology) is an important contributor
to CV risk.22,23
EMPAGLIFLOZIN: CARDIAC CONSIDERATIONS
AND HEMODYNAMIC HYPOTHESES
Although heart rate is one of the most important factors
relating to MVO2, most SGLT2 inhibitor trials, including
those investigating empagliflozin, have demonstrated no
significant changes in heart rate.18,24 However, changes in
other factors that influence MVO2 have been observed with
SGLT2 inhibitor therapy. A post hoc analysis of data pooled
from 5 Phase III trials of empagliflozin in T2DM patients
(N ¼ 3300; treatment duration 12-24 weeks) reported that
markers of arterial stiffness (pulse pressure and ambulatory
arterial stiffness index) and vascular resistance (mean arte-
rial pressure) were significantly improved with empagli-
flozin.18 In addition, empagliflozin had a beneficial effect on
MVO2, assessed indirectly via heart rate, BP, and the double
product (also known as the rate pressure product [heart rate
multiplied by systolic BP], an indirect measure of MVO2,
and thus, of cardiac workload).18 Arterial stiffness measured
via aortic pulse wave velocity was also shown to be reduced
S60 The American Journal of Medicine, Vol 130, No 6S, June 2017

in patients with type 1 diabetes mellitus after shorter-term
treatment (8 weeks) with empagliflozin.25 New data from
EMPA-REG OUTCOME about the effects of empagliflozin
and its impact on MVO2 (presented at the 2016 American
Heart Association Scientific Sessions) revealed reduced
markers of arterial stiffness, vascular resistance, and cardiac
workload for T2DM patients treated with empagliflozin vs
placebo.26 Further analyses are needed to determine the
potential contribution of these changes to risk reduction for
CV outcomes, all-cause mortality, and heart failure hospi-
talization observed with empagliflozin.26
The ability of SGLT2 inhibitors to lower BP is also an
important contributor in reducing cardiac workload. Modest
reductions in systolic (3-5 mm Hg) and diastolic (2-3 mm Hg)
BP without increases in heart rate have been reported with
canagliflozin, dapagliflozin, and empagliflozin,27 and a
decrease in systolic and diastolic BP of approximately
5/2 mm Hg was observed during the EMPA-REG
OUTCOME study.28 Clinical trials of SGLT2 inhibitors in
T2DM patients with hypertension, in which BP was assessed
via 24-hour ambulatory monitoring, recorded significant
reductions in mean systolic and diastolic BP vs placebo by
week 12.29-31 Previous analyses have reported beneficial
effects of even small reductions in BP (3 mm Hg) in
decreasing CV events, such as coronary heart disease and
heart failure.32,33 Reduced BP increases the compliance of
the aorta, lowers cardiac afterload, and decreases ventricular
filling pressure; this “unloads” the ventricle, reducing ven-
tricular wall tension and making the ventricle smaller, which
in turn reduces MVO2 and decreases the power needed to
pump the stroke volume. Unloading the ventricle also lowers
the pressure on the intracardial surface and helps to decrease
microcellular ischemia. Thus, ventricular arterial coupling is
improved and the heart functions with greater efficiency,

A. Coronary volumetric B. Coronary flow C. Myocardial contractile

flow velocity reserve
20
121.7 80 5.0
120 71.8 18
4.5
70
16 15.1
98.7a 4.0 3.8
100
60 14
55.5
3.5
80 50 3.0 12
3.0
2.6 b 2.7b
10 9.3
40 2.5
60
8
2.0
30 27.0b
40 37.6 6
32.2 1.5
20
14.9 4
1.0
20
10 2
0.5

0 0 0 0
Baseline flow Maximal Baseline flow Maximal Coronary Coronary Change in
(mL/min) hyperemic velocity hyperemia diameter flow reserve LVEF
flow (mL/min) (cm/s) (mm) (mm)

T2DM group (n=20)

Control group (n=15)

Figure 2 Mean coronary volumetric flow (A) and coronary flow velocity (B) data in patients with T2DM vs controls.38 The
diameter of the proximal left anterior descending coronary artery was significantly smaller in patients with T2DM than in control
subjects (2.6  0.1 vs 3.0  0.1 mm; P <.05). The baseline coronary flow velocity in T2DM patients showed a significant
increase as compared with that in controls (27.0  3.2 vs 14.9  1.7 cm/s; P <.005), however, baseline coronary volumetric
flow was similar. Although there was no significant difference in maximal hyperemic coronary flow velocity in the 2 groups,
coronary volumetric flow during maximal hyperemia was significantly less in T2DM patients (98.7  7.8 vs 121.7  6.7 mL/
min; P <.05). Consequently, coronary flow reserve was significantly lower in the patients with T2DM than in control subjects
(2.7  0.1 vs 3.8  0.2; P ¼ .0001). Percentage change in LVEF during dobutamine infusion (DLVEF) (C) was calculated and
served as an index of myocardial contractile reserve; DLVEF was significantly lower in T2DM patients than in control subjects
(9.3  2.0 vs 15.1  1.5; P <.01).38 aP <.05 vs controls; bP <.005 vs controls. LVEF ¼ left ventricular ejection fraction;
T2DM ¼ type 2 diabetes mellitus.
Pham and Chilton EMPA-REG OUTCOME: Cardiology
using less energy each time it pumps. The early reductions in
the risks of adverse CV events described with empagliflozin
during EMPA-REG OUTCOME suggest that this agent acts
promptly to reduce cardiac workload. The aforementioned
reports of significant BP reductions occurring within
12 weeks of commencing SGLT2 inhibitor treatment add
further support to this role for empagliflozin.
Hemodynamic factors to consider regarding the possible
CV effects of empagliflozin in EMPA-REG OUTCOME
primarily include changes in preload (ie, venous return)
and afterload. As no significant changes in heart rate were
noted during the study, it is likely that the changes in
preload and afterload were balanced. For example, nitro-
glycerin, a drug used commonly to treat angina symptoms,
is primarily a preload reducing agent and is noted to pro-
duce a mild increase in heart rate via changes in barore-
ceptor stimulation. The precise mechanism for this is not
yet determined, but it has been suggested that there is an
unmasking of underlying sympathetic modulation by a
decrease in vagal tone, resulting in a greater relative
sympathetic influence.34 A simultaneous reduction in
afterload would potentially balance this effect, and thus
there would be no change in heart rate, as observed with
“balanced” vasodilator agents such as angiotensin-
converting enzyme inhibitors or dihydropyridine calcium
channel blockers. A recent study using a rodent model of
diabetes reported a significant reduction in both cardiac
preload (defined as diastolic relaxation) and myocardial
fibrosis in animals treated with empagliflozin vs untreated
animals.35 Diastolic dysfunction, defined by delayed dia-
stolic relaxation,36 is an important component of diabetic
cardiomyopathy.37 It is associated with myocardial fibrosis
and results in diastolic heart failure.35 The effect of
empagliflozin in significantly lowering preload (ie, left
ventricular end-diastolic pressure), as demonstrated in the
aforementioned rodent study, could also lead to improved
myocardial perfusion by increasing the myocardial perfu-
sion pressure (defined as diastolic BP minus left ventricular
end-diastolic pressure). Another important consideration of
reduced preload is the associated improvement in coronary
perfusion: a smaller preload would reduce ventricular wall
tension, which, in turn, would reduce compression of
endocardial arteries and allow greater blood to flow to the
heart tissue. Also, by decreasing preload, ventricular filling
is reduced and the heart has to pump a smaller volume of
blood, which lowers cardiac work and MVO2.
In addition, reduced coronary flow reserve is another
physiologic abnormality observed in patients with diabetes.
It is associated with microvascular functional or structural
impairment, and is revealed by an impairment of myocardial
contractile reserve (Figure 2).38 An improvement in coro-
nary microvascular function would be expected to produce a
decrease in mortality;39 thus, a positive effect of empagli-
flozin on coronary flow reserve could contribute to the
decreased risk of CV death observed in EMPA-REG
OUTCOME. Preclinical studies and clinical trials are
needed to investigate this hypothesis.
S61
In addition to these benefits in CV function, metabolic
improvements in patients with T2DM that lead to reduced
MVO2 (such as the use of ketones as a cardiac fuel source,
and reduced glucose toxicity effects7) have the potential to
play a key role in the reduction of CV death and reduced
hospitalization for heart failure in the high-CV-risk patient
population in EMPA-REG OUTCOME. Other effects of
empagliflozin (also observed with other SGLT2 inhibitors),
such as modest diuretic and natriuretic activity, and asso-
ciated body weight reduction, would also be expected to
contribute to reducing cardiac workload.
CONCLUSION
From the cardiologist’s perspective, empagliflozin could be
viewed as a CV drug that also has a beneficial effect on
reducing hyperglycemia in patients with T2DM. The effects
of empagliflozin in reducing the risk of CV death and
hospitalization for heart failure during the EMPA-REG
OUTCOME study may be explained principally by its
apparent ability to alter cardiac physiology; specifically, to
reduce cardiac workload and MVO2 by lowering BP,
improving aortic compliance, and improving ventricular
arterial coupling. Clinical trials to investigate the effect of
SGLT2 inhibitors on unloading the ventricle in patients with
heart failure but without diabetes are commencing, and will
provide valuable information on the role of these agents as
CV drugs.
References
1. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial
intervention in patients with type 2 diabetes mellitus and micro-
albuminuria: the Steno type 2 randomised study. Lancet. 1999;353:
617-622.
2. 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.
3. 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.
4. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression
of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323-334.
5. 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.
6. Wanner C. EMPA-REG OUTCOME: the nephrologist’s point of view.
Am J Med. 2017;130(suppl 6):S63-S72.
7. Staels B. Cardiovascular protection by sodium glucose cotransporter 2
inhibitors: potential mechanisms of action. Am J Med. 2017;130(suppl
6):S30-S39.
8. Braunwald E. 50th anniversary historical article. Myocardial oxygen
consumption: the quest for its determinants and some clinical fallout.
J Am Coll Cardiol. 1999;34:1365-1368.
9. Valentinuzzi ME, Kohen AJ. Laplace’s law: what it is about, where it
comes from, and how it is often applied in physiology. IEEE Pulse.
2011;2:74-84.
10. Lehrke M, Marx N. Diabetes mellitus and heart failure. Am J Med.
2017;130(suppl 6):S40-S50.
11. Kasznicki J, Drzewoski J. Heart failure in the diabetic population -
pathophysiology, diagnosis and management. Arch Med Sci. 2014;10:
546-556.
S62
12. Seferovic PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-
faced disease with restrictive and dilated phenotypes. Eur Heart J.
2015;36:1718-1727, 1727a-1727c.
13. Yelle D, Chaudhry S. Heart failure (McMaster Pathophysiology Re-
view). Available at: http://www.pathophys.org/heartfailure/. Accessed
January 18, 2017.
14. Kass DA. Age-related changes in venticular-arterial coupling: patho-
physiologic implications. Heart Fail Rev. 2002;7:51-62.
15. Antonini-Canterin F, Carerj S, Di Bello V, et al. Arterial stiffness and
ventricular stiffness: a couple of diseases or a coupling disease? A review
from the cardiologist’s point of view. Eur J Echocardiogr. 2009;10:36-43.
16. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure.
Heart Fail Clin. 2008;4:23-36.
17. Kass DA. Ventricular arterial stiffening: integrating the pathophysi-
ology. Hypertension. 2005;46:185-193.
18. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on
blood pressure and markers of arterial stiffness and vascular resistance in
patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180-1193.
19. Niiranen TJ, Kalesan B, Hamburg NM, Benjamin EJ, Mitchell GF,
Vasan RS. Relative contributions of arterial stiffness and hypertension
to cardiovascular disease: the Framingham Heart Study. J Am Heart
Assoc. 2016;5(11), pii: e004271.
20. Thompson B, Towler DA. Arterial calcification and bone physiology:
role of the bone-vascular axis. Nat Rev Endocrinol. 2012;8:529-543.
21. Towler DA. Commonalities between vasculature and bone: an osseo-
centric view of arteriosclerosis. Circulation. 2017;135:320-322.
22. Lyle AN, Raaz U. Killing me unsoftly: causes and mechanisms of
arterial stiffness. Arterioscler Thromb Vasc Biol. 2017;37:e1-e11.
23. Stabley JN, Towler DA. Arterial calcification in diabetes mellitus:
preclinical models and translational implications. Arterioscler Thromb
Vasc Biol. 2017;37:205-217.
24. Storgaard H, Gluud LL, Bennett C, et al. Benefits and harms of sodium-
glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a
systematic review and meta-analysis. PLoS One. 2016;11:e0166125.
25. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagli-
flozin on arterial stiffness and heart rate variability in subjects with un-
complicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.
26. Chilton R, Gullestad L, Fitchett D, et al. Empagliflozin reduces
markers of arterial stiffness, vascular resistance and cardiac workload
in EMPA-REG OUTCOME. Circulation. 2016;134 (A13520).
27. Tikkanen I, Chilton R, Johansen OE. Potential role of sodium glucose
cotransporter 2 inhibitors in the treatment of hypertension. Curr Opin
Nephrol Hypertens. 2016;25:81-86.
The American Journal of Medicine, Vol 130, No 6S, June 2017
28. 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.
29. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood
pressure in patients with type 2 diabetes and hypertension. Diabetes
Care. 2015;38:420-428.
30. Townsend RR, Machin I, Ren J, et al. Reductions in mean 24-hour
ambulatory blood pressure after 6-week treatment with canagliflozin
in patients with type 2 diabetes mellitus and hypertension. J Clin
Hypertens (Greenwich). 2016;18:43-52.
31. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S,
Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin
versus placebo in patients with type 2 diabetes on combination
antihypertensive therapy: a randomised, double-blind, placebo-
controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4:
211-220.
32. Cook NR, Cohen J, Hebert PR, Taylor JO, Hennekens CH. Implica-
tions of small reductions in diastolic blood pressure for primary pre-
vention. Arch Intern Med. 1995;155:701-709.
33. Hardy ST, Loehr LR, Butler KR, et al. Reducing the blood pressure-
related burden of cardiovascular disease: impact of achievable im-
provements in blood pressure prevention and control. J Am Heart
Assoc. 2015;4:e002276.
34. Gori T, Floras JS, Parker JD. Effects of nitroglycerin treatment on
baroreflex sensitivity and short-term heart rate variability in humans.
J Am Coll Cardiol. 2002;40:2000-2005.
35. Habibi J, Aroor AR, Sowers JR, et al. Sodium glucose transporter 2
(SGLT2) inhibition with empagliflozin improves cardiac diastolic
function in a female rodent model of diabetes. Cardiovasc Diabetol.
2017;16(1):9.
36. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—abnormal-
ities in active relaxation and passive stiffness of the left ventricle.
N Engl J Med. 2004;350:1953-1959.
37. Ernande L, Derumeaux G. Diabetic cardiomyopathy: myth or reality?
Arch Cardiovasc Dis. 2012;105:218-225.
38. Yonaha O, Matsubara T, Naruse K, et al. Effects of reduced coronary
flow reserve on left ventricular function in type 2 diabetes. Diabetes
Res Clin Pract. 2008;82:98-103.
39. Taqueti VR, Hachamovitch R, Murthy VL, et al. Global coronary flow
reserve is associated with adverse cardiovascular events independently
of luminal angiographic severity and modifies the effect of early
revascularization. Circulation. 2015;131:19-27.