Download Sodium-glucose cotransporter-2 inhibition for the reduction of

REVIEW
European Heart Journal (2016) 37, 3192–3200
doi:10.1093/eurheartj/ehw110
Clinical update
Sodium-glucose cotransporter-2 inhibition for
the reduction of cardiovascular events in high-risk
patients with diabetes mellitus
Nikolaus Marx 1* and Darren K. McGuire2
1
Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany; and 2Division of Cardiology, Department of Internal Medicine,
University of Texas Southwestern Medical Center, Dallas, TX, USA
Received 17 December 2015; revised 19 February 2016; accepted 29 February 2016; online publish-ahead-of-print 5 May 2016
See page 3201 for the editorial comment on this article (doi:10.1093/eurheartj/ehw158)
Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk for cardiovascular (CV) events. Hyperglycaemia itself contributes to
the pathogenesis of atherosclerosis and heart failure (HF) in these patients, but glucose-lowering strategies studied to date have had little
to no impact on reducing CV risk, especially in patients with a long duration of T2D and prevalent CV disease (CVD). Sodium glucose
cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic medications that increase urinary glucose excretion, thus
improving glycaemic control independent of insulin. The recently published CV outcome trial, EMPA-REG OUTCOME, demonstrated
in 7020 patients with T2D and prevalent CVD that the SGLT2-inhibitor empagliflozin significantly reduced the combined CV endpoint
of CV death, non-fatal myocardial infarction, and non-fatal stroke vs. placebo in a population of patients with T2D and prevalent atherosclerotic CVD. In addition and quite unexpectedly, empagliflozin significantly and robustly reduced the individual endpoints of CV death,
overall mortality, and hospitalization for HF in this high-risk population. Various factors beyond glucose control such as weight loss, blood
pressure lowering and sodium depletion, renal haemodynamic effects, effects on myocardial energetics, and/or neurohormonal effects,
among others may contribute to these beneficial effects of SGLT2-inhibition. The present review summarizes known and postulated
effects of SGLT2-inhibition on the CV system and discusses the role of SGLT2-inhibition for the treatment of high-risk patients with
T2D and CVD.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Diabetes † Cardiovascular risk † Sodium glucose cotransporter-2 inhibitors † Heart failure † Empagliflizon
Cardiovascular risk in patients with
type 2 diabetes
Patients with type 2 diabetes mellitus (T2D) have an increased risk
to develop cardiovascular disease (CVD) with its key sequelae myocardial infarction (MI), stroke, and heart failure (HF).1,2 Most recent
data from the emerging risk factor collaboration showed that the
presence of diabetes is still associated with a doubling of the risk
for CV death, and that the presence of T2D together with a history
of MI is associated with a four-fold increased risk compared with
subjects without T2D or prior MI.3 These data underscore the
unmet clinical need for additional strategies to reduce CV risk in
patients with T2D.
Glucose-lowering and cardiovascular risk
reduction in diabetes
To date,4 there is little proof that glycaemic control per se affects the
risk for cardiovascular (CV) events.5,6 Over the last decade, various
CV outcome trials tested the effect of intensive glucose-lowering vs.
standard therapy on CV outcomes. The three largest trials—
ADVANCE,7 ACCORD,8 and VADT9—enrolling patients with
longstanding T2D and a high proportion of patients with prevalent
CVD and the remainder with clustered CV risk factors—failed to
show a significant effect of more intensive glucose-lowering strategies vs. standard care on macrovascular events. Thus, lowering
glucose more intensively than presently endorsed standard care is
not incrementally effective in preventing CV events within the rela-
* Corresponding author. Tel: +49 241 80 89300, Fax: +49 241 80 82545, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
3193
3 years
2015
Follow-up (estimated)
Reporting (estimated)
EMPA-REG OUTCOME, (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; CANVAS, CANagliflozin cardioVascular Assessment Study; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR
Events-TIMI 58. VERTIS: Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess Cardiovascular Outcomes Following Treatment With Ertugliflozin in Subjects With Type 2 Diabetes Mellitus and Established Vascular
Disease.
T2D, type 2 diabetes mellitus; CV, cardiovascular.
5– 7 years (estimated)
2020 (estimated)
T2D; established CV disease
T2D; high CV risk
4 –5 years (estimated)
2019 (estimated)
T2D; established CV disease
Patients
T2D; high CV risk
CV death, non-fatal MI, non-fatal stroke
7020
6– 7 years (estimated)
2017 (estimated)
Ertugliflozin vs. Placebo (2:1)
CV death, non-fatal MI, non-fatal stroke
3900
CV death, non-fatal MI, non-fatal ischaemic stroke
17 276
NCT01986881
Primary outcome measure
Patient number
CV death, non-fatal MI, non-fatal stroke
4417
Dapagliflozin vs. Placebo (1:1)
NCT01730534
NCT01032629
Intervention
Canagliflozin vs. Placebo (2:1)
NCT01131676
Empagliflozin vs. Placebo (2:1)
Clinicaltrials.gov
VERTIS
DECLARE-TIMI 58
CANVAS
EMPA-REG OUTCOME
Trial
For the currently available SGLT2-inhibitors, four large CV outcome
trials have been designed [canagliflozin-CANVAS (NCT01032629);
dapagliflozin-DECLARE-TIMI 58 (NCT01730534); ertugliflozinVERTIS (NCT01986881) and empagliflozin-EMPA-REG OUTCOME
(NCT01131676)] (Table 1). Recently, one of them—EMPA-REG
OUTCOME—has been completed and results published.16
EMPA-REG OUTCOME was a multi-centre, randomized, placebo
controlled trial enrolling 7020 patients with T2D at high CV risk. Patients were randomized to placebo or one of two doses of empagliflozin (10 mg or 25 mg/day) on the background of state-of-the-art
glucose-lowering therapy. The primary endpoint was the composite
of CV death, non-fatal MI, and non-fatal stroke. Since this study sought
to test the effect of an anti-hyperglycaemic medication compared with
placebo independent of its glucose-lowering properties, the protocol
was designed to achieve glycaemic equipoise between groups, allowing
the addition and titration of other anti-hyperglycaemic medications in
both arms to achieve the best haemoglobin A1c (HbA1c) level possible
in accordance with local and regional standards of care.17 The study enrolled a population of patients at high CV risk with a long duration of
T2D and the presence of atherosclerotic CVD at study entry: almost
50% of the patients had a history of MI, 75% had multi-vessel coronary
Cardiovascular outcome trials with sodium glucose cotransporter-2-inhibitors
Effects of the sodium glucose
cotransporter-2-inhibitor empagliflozin
on cardiovascular outcomes
Table 1
tively few years of trial observation in populations of patients with a
longer duration of T2D and a history of, or at increased risk for,
atherosclerotic CVD.
In 2008, the US Food and Drug Administration and the European
Medicines Agency released guidance for the pharmaceutical industry calling for at a minimum, the demonstration of CV safety of novel
anti-hyperglycaemic medications in high-risk populations of patients
with T2D. As a consequence, the number of CV outcome trials
completed, underway and planned in patients with T2D has tremendously increased over the last few years. Three trials assessing the
CV effects of the novel class of dipeptidyl peptidase (DPP)-4 inhibitors (saxagliptin (SAVOR-TIMI 53),10 alogliptin (EXAMINE),11 and
sitagliptin (TECOS)12) as well as one trial with a glucagon-like protein (GLP)-1 receptor agonists (GLP1-RA) lixisenatide (ELIXA)13
have been completed and published: these studies were all designed
to demonstrate non-inferiority of the respective drug vs. placebo,
added to background anti-hyperglycaemic treatment, on CV outcomes. All four trials were positive with respect to demonstrating
statistical non-inferiority of each medication, showing no differences
for the primary CV outcomes examined; however, none of the
DPP 4-inhibitors or the GLP1-RA was associated with significant
CV benefits in the trial populations comprising patients with a
long history of T2D and prevalent CVD or clustered CVD risk
factors.10 – 15
Most recently, results have been reported from a CV outcome trial
evaluating the sodium glucose co-transporter (SGLT) 2 inhibitor empagliflozin vs. placebo in a population of patients with T2D and prevalent atherosclerotic CVD at baseline, largely similar to the trials
summarized above. The principle mechanism of anti-hyperglycaemic
action of SGLT2-inhibition is increased glucosuria affected by inhibiting renal glucose reuptake via an insulin-independent mechanism.
.............................................................................................................................................................................................................................................
Sodium glucose cotransporter-2 inhibition in patients with diabetes
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artery disease, and 10% had a history of HF. This patient cohort was very
well treated at baseline with anti-hypertensive medications used in 95%
of the patients, low-density lipoprotein-cholesterol (LDL-C)-lowering
agents in 80%, and almost 90% of the patients were treated with anticoagulant/antiplatelet therapy. Moreover, 50% of all patients were on
insulin therapy at baseline. This translated into excellent control of associated CV risk factors at trial entry, with a mean blood pressure (BP) of
135/77 mmHg and an LDL-C of 2.2 mmol/L; baseline glycated HbA1c
was 8.1%. In addition, one-quarter of the patients had chronic kidney disease Stage 3 with an eGFR between 30 and 60 mL/min/1.73 m2. Thus,
EMPA-REG OUTCOME examined the effect of empagliflozin vs. placebo in a high-risk population of patients with T2D on top of standard
CV therapy and very well-controlled CV risk factors. At the end of the
study, there was a slightly lower HbA1c of 0.3–0.4% in the empagliflozin
group compared with placebo with more frequent addition of other
anti-hyperglycaemic medications throughout the trial, including insulin
initiation, in the placebo group compared with the two empagliflozin
groups. Moreover, empagliflozin compared with placebo led to a significant reduction in BP and body weight, similar to what has been reported
in earlier studies. As per the prospective statistical analysis plan, hierarchical testing for all primary and secondary CV outcomes was performed combining the two empagliflozin doses for analysis. In the
primary analysis, empagliflozin was proved statistically significantly noninferior to placebo for the primary composite outcome of major
adverse CV outcomes-CV death, non-fatal MI, and non-fatal stroke.
Subsequently, step-down testing revealed that empagliflozin significantly
reduced risk for the primary outcome of CV death, non-fatal MI, and
non-fatal stroke compared with placebo with a hazard ratio of 0.86
(95%CI 0.74–0.99; P ¼ 0.038). This reduction of the primary outcome
was mainly driven by a highly significant 38% reduction in CV death
(HR 0.62; 95%CI 0.49–0.77; P , 0.0001), with separation of the event
curves evident as early as 2 months into the trial. There was a nonsignificant 13% reduction of non-fatal MI (P ¼ 0.30) and a non-significant
24% increased risk for non-fatal stroke (HR 1.24; 95%CI 0.92–1.67; P ¼
0.16). In addition, in a secondary/exploratory analysis, empagliflozin led
to a significant 35% reduction of hospitalization for HF (HR 0.65; 95% CI
0.50–0.85; P , 0.002), with separation of the curves evident almost immediately during trial observation, suggesting a very early effect of the
SGLT2-inhibitor on HF risk (Figure 1). Finally, empagliflozin reduced
overall mortality by 32% (HR 0.68; 95% CI 0.57–0.82; P , 0.0001), a
highly significant effect translating into a number-needed-to-treat
(NNT) of 39 over 3 years to prevent one death. The results were
consistent in all subgroups reported. Major side effects of the
SGLT2-inhibitor, consistent with prior studies and consistent across
the class of SGLT2-inhibitors, were increased mycotic genital infection:
1.8% of the patients in the placebo group vs. 6.4% in the empagliflozin
group; however, no difference was found in the occurrence of urinary
tract infections.
The results of EMPA-REG OUTCOME with a significant beneficial effect on the primary composite CV outcome, CV mortality,
overall mortality, and hospitalization for HF makes this trial a landmark trial in CV risk reduction for patients with T2D. As such,
EMPA-REG OUTCOME stands in line with trials such as the Scandinavian Simvastatin Survival Study (4S) and the heart outcomes
prevention evaluation (HOPE) trial with regard to the magnitude
of CV risk reduction. In the 4S trial, simvastatin vs. placebo led to
an NNT of 30 over 5.4 years to reduce 1 death. 18 HOPE, in a
N. Marx and D.K. McGuire
population with 25% of statin-treated patients, showed that ramipril vs. placebo prevents one death if 56 patients are treated over 5
years.19 Finally, EMPA-REG OUTCOME in a population receiving
statins in .75% of the patients, and ACE-inhibitors or ARBs in
.80%, showed that 39 patients must be treated over 3 years to prevent one death.16 The observations of superiority in EMPA-REG
OUTCOME have raised important questions as to the mechanism
underpinning the observed favourable CV effects.
Role of the kidney in glucose
metabolism
Through its contribution to gluconeogenesis and its capacity to reabsorb glucose from the urine, the kidney plays an important role in
glucose homeostasis. In humans without diabetes, 160–180 g of
glucose are filtered by the kidneys per day20 and in healthy individuals without diabetes, virtually all filtered glucose is reabsorbed
in the proximal tubule. As long as the filtered glucose does not exceed the maximum renal glucose reabsorption capacity, filtered glucose is reabsorbed thus allowing energy conservation.21 About 90%
of glucose filtered in the glomeruli is reabsorbed in the first segment
of the proximal tubule by SGLT2, which is a low-affinity, highcapacity transporter.22 The remaining 10% is reabsorbed in the
more distal part of the tubule by SGLT1, a high-affinity, low-capacity
transporter (Figure 2A).23,24 Sodium glucose co-transporter proteins
are proteins localized in the apical membrane capable of actively
transporting glucose along with sodium against a concentration gradient into the cell. This process is driven by the active transport of
sodium out of the cell by the adenosine triphosphate-dependent
sodium-potassium pump. Once in the intracellular space, glucose
then passively diffuses from the basolateral membrane of the tubule
cell into the blood via GLUT2, a member of the GLUT family of proteins25,26 (Figure 2B). However, if the blood glucose load exceeds
the renal tubular glucose excretion threshold of 180 mg/dL,
glucosuria occurs. In patients with diabetes and chronic hyperglycaemia, the threshold paradoxically increases to 220 mg/dL due
to an enhanced maximum renal glucose reabsorption capacity
mediated by up-regulation of SGLT2 in the proximal tubule. This
maladaptive mechanism seems to be explained by increased
SGLT2 transcription and translation resulting in increased SGLT2
density on the apical membrane in the proximal tubule
(Figure 2C).23,25
Sodium glucose
cotransporter-2-inhibitors
Mode of action and glucose-lowering
properties
Sodium glucose cotransporter-2-inhibitors are a novel class of
glucose-lowering drugs that act in the kidney by inhibiting
SGLT2-mediated glucose reabsorption in the proximal tubule.
The resulting increase in urinary glucose excretion leads to a reduction in plasma glucose levels (Figure 2D).27,28 The concept of
SGLT2-inhibition is different from other glucose-lowering strategies
since glucose is removed from the ‘system’, thus reducing total-body
Sodium glucose cotransporter-2 inhibition in patients with diabetes
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Figure 1 Primary and key secondary outcomes in the EMPA-REG OUTCOME trial demonstrating effects of empagliflozin compared with placebo on (A) the primary composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (B) cardiovascular mortality, and (C)
hospitalization for heart failure (adapted from ref. 16).
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and cellular glucose toxicity, a mechanism that is completely independent of insulin. Overall, 24-h urinary glucose excretion in patients
treated with SGLT2-inhibitors lies between 60 and 100 g/day, corresponding to a loss of 240 – 400 kcal/day upon chronic administration.29 In addition to their glucosuric effects, SGLT2-inhibitors
N. Marx and D.K. McGuire
lead—at least temporarily—to an increase in sodium excretion,30
as well as a reduction in plasma volume due to glucose osmotic diuretic effects and natriuresis.31
Currently, three SGLT2-inhibitors are approved in Europe and the
USA: dapagliflozin, canagliflozin, and empagliflozin.32 Meta-analyses
Figure 2 Glucose filtration and reabsorption in the kidney. (A) In healthy, normoglycaemic individuals, all glomerular filtered glucose is reabsorbed in the proximal tubule through sodium glucose co-transporter proteins. (B) Sodium glucose co-transporter proteins are localized in the
apical membrane capable of actively transporting glucose along with sodium against a concentration gradient into the cell. This process is driven by
the active transport of sodium out of the cell by the adenosine triphosphate-dependent sodium-potassium pump. Once in the intracellular space,
glucose then passively diffuses from the basolateral membrane of the tubule cell into the blood via glucose transporters. (C) In patients with diabetes and hyperglycaemia, increased glucose filtration may exceed the maximum glucose transport capacity of the sodium glucose co-transporter
proteins, thus leading to urinary glucose excretion. In a maladaptive compensatory mechanism in the setting of type 2 diabetes mellitus and hyperglycaemia, sodium glucose cotransporter-2 expression in the proximal tubule is upregulated with resultant increased glucose reabsorption.
(D) Sodium glucose cotransporter-2-inhibitors block glucose and sodium absorption in the proximal tubule, resulting in an increase in urinary
glucose excretion of up to 100 g (400 kcal) per day.
Sodium glucose cotransporter-2 inhibition in patients with diabetes
Figure 2 Continued.
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for these SGLT2-inhibitors suggest that they lower HbA1c levels
between 0.7 and 0.8% relative to placebo.33 Sodium glucose
cotransporter-2-inhibitor effects are glucose-dependent, thus leading
to a very low risk of hypoglycaemia. In addition, SGLT2-inhibitors can
be combined with any other anti-hyperglycaemic medication since
the mechanism of action is different from all other agents presently
available and is completely independent of insulin.34 Interestingly, various studies suggest that SGLT2-inhibitors may improve insulinsensitivity potentially through an increase in insulin-mediated glucose
tissue disposal,35,36 and over time, due to the net caloric loss and enhanced insulin-sensitivity mediated by weight loss. Moreover, recent
data have shown that SGLT2-inhibitors increase glucagon secretion
from a-cells in the pancreatic islet, a mechanism that may contribute
to enhanced endogenous glucose production in treated patients.37 In
addition to these effects on glucose homeostasis, SGLT2-inhibitors
exhibit potential beneficial effects on CV risk factors, as has been previously published with selected observations summarized below.38,39
Effects of sodium glucose
cotransporter-2-inhibitors beyond glucose
control
Anthropometrics
The glucosuric effect of SGLT2-inhibitors causing a negative energy
balance results in an average weight-reduction of 2– 3 kg that occurs
gradually over the first few months on treatment, a consistent observation across the class of medications in studies over 1 – 2
years.40 Interestingly, the weight loss appears to reach a nadir and
thereafter stabilizes after 3 –6 months, most likely through a compensatory increased energy intake.41 These medications seem to
have no effect on energy expenditure.42 – 44
Blood pressure and diuresis
A reduction in BP in patients treated with SGLT2-inhibitors is
another effect beyond glucose control consistently observed
across the class of medications. Several trials have shown that
SGLT2-inhibitors lead to a reduction in systolic BP in a range of
3 – 5 mmHg and 2 – 3 mmHg in diastolic BP.40 In addition,
SGLT2-inhibitors reduce pulse pressure, mean arterial pressure,
and the product of heart rate-X-systolic BP (a.k.a. ‘double product’,
or rate-pressure product) vs. placebo suggesting an effect on different markers and mediators of arterial stiffness.45 Interestingly, these
BP effects occurred without a compensatory increase in heart rate,
suggesting a lack of compensatory sympathetic activation. In addition, clamp studies in patients with uncomplicated type 1 diabetes
suggest that empagliflozin reduces carotid-radial pulse wave velocity
also without inducing a reflex sympathomimetic activity.46
Renal haemodynamic effects
Sodium glucose cotransporter-2-inhibition has been suggested to
directly affect the tubulo-glomerular feedback mechanism in the kidney. The increased delivery of solute (sodium and chloride) to the
macula densa in the setting of SGLT2-inhibition may reduce
hyperglycaemia-induced glomerular hyperfiltration via tubuloglomerular feedback invoking adenosine-dependent pathways,
with direct effects on afferent glomerular arteriolar tone that may
diminish hyperfiltration acutely and consistently during treatment.47
N. Marx and D.K. McGuire
Effects on mediators and markers of cardiovascular risk
With respect to lipids, SGLT2-inhibitors mildly increase both LDL-C
as well as HDL-C through an as of yet unexplained mechanism.39,48,49
These observations may reflect direct effects on lipoprotein particle
metabolism, but could also simply reflect haemoconcentration resulting from the diuretic effects of SGLT2-inhibition, thereby having no
net effect on circulating lipid particle numbers.
Cardiac effects
Experimental data in obese and diabetic mice demonstrated that the
SGLT2-inhibitor empagliflozin significantly ameliorates cardiac fibrosis, coronary arterial thickening, as well as cardiac macrophage
infiltration suggesting a direct cardiac effect along with an attenuation of oxidative stress on the myocardium.50
Other potential direct or indirect cardiac effects might include alterations of myocardial energetics and potential anti-arrhythmic effects, postulated mechanisms that have arisen in attempts to
understand the EMPA-REG OUTCOME trial results, but with little
data to date to evaluate. From a myocardial energetics perspective,
SGLT1 but not SGLT2 is expressed in cardiac myocytes.51 In the kidney, SGLT2-inhibition results in increased SGLT1-mediated glucose
reabsorption,52 and if this is a humoral-mediated response, the possibility remains for upregulation of cardiac SGLT1. This could directly affect myocardial substrate metabolism and energetics with
enhanced glucose and decreased fatty acid (FA) metabolism that
could favourably affect myocardial function. In addition, shifting
from b-oxidation of free FA to glycolysis in the myocardium
might reduce the potential pro-arrhythmia effects of free FA
metabolites.53
Potential mechanisms explaining the
results in EMPA-REG OUTCOME
The surprising and unexpected results of EMPA-REG OUTCOME
on mortality and HF cannot be explained by glucose control per
se nor by a reduction of atherosclerotic events since the effect of
empagliflozin on non-fatal MI and hospitalization for unstable angina
was not statistically significant. More likely, the favourable outcomes
are related to effects of empagliflozin on HF and CV mortality, direct
or indirect, that are independent of effects on hyperglycaemia or on
atherosclerotic CVD (Figure 3).
In the trial, 10% of the patients enrolled had a history of HF, but
no data on left-ventricular function or surrogate parameters like
NT-proBNP were collected. Empagliflozin led to a highly significant
reduction in hospitalization for HF with an effect that became evident very early in the trial in the overall study population. Subgroup
analyses stratified by presence or absence of HF at baseline suggest a
consistent benefit observed in patients with and without baseline
HF with no evident heterogeneity of efficacy by HF status.54 It is important to note that the outcomes analysed in the study only evaluated first events, and no conclusion on the effects of empagliflozin
therapy on total HF events (i.e. first + recurrent) can yet be made.
Various factors may contribute to the observed reduction in CV
death and HF hospitalization. As with the atherosclerotic event endpoints discussed above, blood glucose reduction itself is very unlikely to account for the results observed given the minor difference in
HbA1c levels between groups as well as the fact that previous studies showed that intensified glucose control does not influence the
Sodium glucose cotransporter-2 inhibition in patients with diabetes
3199
Figure 3 Potential mechanisms involved in the reduction of cardiovascular events (cardiovascular death, total mortality, and heart failure hospitalization) observed in the EMPA-REG OUTCOME trial for empagliflozin-treated patients with type 2 diabetes mellitus and prevalent atherosclerotic cardiovascular disease.
incidence of these events in similar populations. The significant reductions in BP and body weight seen in EMPA-REG OUTCOME
have been proposed as potential contributors to the beneficial results. However, BP lowering only translates into CV risk reduction
after 6 – 12 months or even longer, making the early beneficial effects seen unlikely to be attributable to BP reduction per se.19 Still,
the decrease in markers of arterial stiffness found in
SGLT2-inhibitor-treated patients,45 all closely linked to BP reduction, may have a direct, potentially beneficial effect on myocardial
oxygen consumption via afterload reduction. Weight loss seems
to play a minor role in this context given the data from the LookAction for Health in Diabetes study, showing that intensive lifestyle
intervention, focused on weight loss, did not improve CV risk in patients with T2D.55
The diuretic effect of empagliflozin has been discussed as a potential contributor to the observed reduction of hospitalization for HF
through an at least temporary reduction in plasma volume as shown
for SGLT2-inhibitors.31 However, similar or greater decreases in
intravascular volume and net sodium balance is affected by most
commonly used diuretic medications but—in contrast to empagliflozin—treatment with loop-diuretics or thiazides has not been demonstrated to reduce CV death in previous studies, and their effects
on hospitalization for HF risk, when demonstrated, have been much
more modest in magnitude compared with the large reduction
observed with empagliflozin. Yet, SGLT2-inhibitors are different
from the loop and thiazide diuretics in several important ways. First,
they do not lead to a reflex activation of the sympathetic nervous
system. In addition, thiazides work in the distal tubule while
SGLT2-inhibitors act proximal of the macula densa, thus leading to an increased urinary sodium and chloride delivery to the
juxta-glomerular apparatus. This has been suggested to restore
the tubulo-glomerular feedback mechanism in diabetes with afferent
arteriolar vasoconstriction and subsequent reduction of hyperfiltration and normalization of transglomerular perfusion pressures.47
Similarly, the increased sodium and chloride delivery to the macular
densa upon SGLT2-inhibitor treatment may affect other neurohormonal factors such as local RAAS inhibition,27,56 – 58 which may have
contributed to pre-glomerular vasoconstriction in diabetes. It is
tempting to speculate that these effects possibly result in aldosterone withdrawal and reduced sympathetic nerve activity—either or
both of which could directly benefit CV death and HF risk. Moreover, other yet unknown mechanisms influencing the renal–cardiac
interaction may be of important in this context.
Still, the depletion of sodium and potential reduction in body sodium content by SGLT2-inhibition may play a crucial in HF in diabetes. It has been hypothesized that patients with diabetes exhibit
an excess of total-body sodium, mainly because of increased sodium
retention in the kidney as a consequence of hyperglycaemia and hyperinsulinaemia.59 – 61 Sodium-loading studies in animals and humans
suggest that excess sodium is not only distributed in the extracellular space but possibly also intracellularly as well as in osmotically inactive compartments, e.g. matrix components of skin and muscle.
Increased intracellular sodium in the myocardium may increase
the risk of arrhythmias and impair myocardial function,62,63 most
likely through an impairment of mitochondrial function.64 Interestingly, experimental data in an animal model of HF showed an increase in myocardial intracellular sodium and in this model,
blockade of the mitochondrial Na+/Ca2+ exchange prolonged survival of these animals and significantly decreased arrhythmias.64 Sodium glucose cotransporter-2-inhibition leads to an early and
3200
transient increase in urinary sodium excretion that normalizes after
2 weeks.65 This increase in sodium depletion is not reflected by
changes in plasma sodium concentration, but since plasma sodium
does not directly mirror whole body sodium content, the increase
in urinary sodium excretion is likely to rapidly reduce total-body sodium. This mechanism may thus contribute to the early beneficial
effect of empagliflozin on CV death and HF hospitalization not
only through a reduction of volume load but also through direct effects in the myocardium. Still, to date, little is known about these potential effects of empagliflozin and future research is warranted to
further explore this issue.
Other mechanisms that may explain the profound effects of empagliflozin on CV events include anti-oxidative, anti-inflammatory,
or anti-apoptotic properties of SGLT2-inhibitors as shown in
experimental models, as well as counterbalancing effects of these
drugs on cellular senescence.66,67 Still, hitherto, it remains speculative whether such effects seen in preclinical studies translate into
humans.
Finally, the increase in glucagon secretion induced by SGLT2 inhibiton37 may be interesting in light of the EMPA-REG OUTCOME results. Work in the 1970s suggested that glucagon exhibits inotropic
effects with an increased myocardial contractility and cardiac output
in glucagon-treated patients with MI.68,69 In the myocardium, glucagon generates cAMP, thus exhibiting positive inotropic and chronotropic action without the need for beta-1 adrenoreceptor
stimulation.70 In addition, glucagon has been shown to exhibit antiarrhythmic effects.71 Clinically, glucagon has previously been employed as an adjunctive therapy in shock situations and HF, but given
that catecholamines are much more effective in these conditions,
glucagon is no longer used for this indication. Still, a continous increase in glucagon levels in SGLT2-inhibitor-treated patients could
contribute to a cardioprotective effect.
Most likely, the early and profound reduction on CV death and
hospitalization for HF by empagliflozin is not caused by a single
mechanism, but can rather be explained by the interplay of some
of the effects outlined above, as well as by as of yet unknown mechanisms. Future studies are warranted to further explore the
underlying mechanisms to explain the findings in EMPA-REG OUTCOME, and importantly to assess whether such effects are evident
across the SGLT2-inhibitor class of medications or unique to empagliflozin. In addition, the point estimate of increase in the risk for
non-fatal stroke—although not significant—needs to be examined
in more detail to identify potentially harmful mechanisms and to figure out whether this trend may become significant in larger patient
populations or is just a play of chance. In addition, like with all new
drugs, post-marketing analyses are required to evaluate the longterm beneficial action of SGLT2-inhibitors or to detect undefined
side effects. However, for clinicians, the data from this trial are
straightforward with a clear reduction in the primary CV composite
outcome, CV death, HF hospitalization, and most importantly, overall mortality in empagliflozin-treated patients. These convincing data
provide diabetologists, cardiologists, and primary care providers
with a potent, evidence-based medication to reduce CV events in
the high-risk population of patients with T2D who have prevalent
atherosclerotic CV disease. Finally, so far, only data for the effects
of empagliflozin on CV risk are available. Since many of the mechanistic effects outlined above have also been described for other
N. Marx and D.K. McGuire
SGLT2-inhibitors, it will be interesting to see the results of the ongoing CV outcome trials with dapagliflozin, canagliflozin, and ertugliflozin to find out whether the beneficial CV outcome effects
reported from the EMPA-REG OUTCOME trial are a class effect
or unique to empagliflozin.
Authors’ contributions
N.M. and D.M. conceived and designed the research. N.M. drafted
the manuscript. D.M. made critical revision of the manuscript for
key intellectual content.
Funding
This work was supported by grants from the Hans-Lamers-Stiftung as
well as the European Foundation for the Study of Diabetes to N.M.
Conflict of interest: N.M. has given lectures for Amgen, Boehringer
Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk,
has received unrestricted research grants from Boehringer Ingelheim,
and has served as an advisor for Amgen, Boehringer Ingelheim,
Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk. In addition,
N.M. reports honoraria for trial leadership from Boehringer Ingelheim.
D.K.M. reports honoraria for trial leadership from Boehringer Ingelheim,
Janssen Research and Development LLC, Merck Sharp and Dohme
Corp, Lilly USA, Novo Nordisk, GlaxoSmithKline, Takeda Pharmaceuticals North America, AstraZeneca, Lexicon, and honoraria for consultancy from Janssen Research and Development LLC, Sanofi Aventis
Groupe, Merck Sharp and Dohme Corp., Novo Nordisk and
Regeneron.
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