Diabetologia (2018) 61:2108–2117

https://doi.org/10.1007/s00125-018-4670-7

REVIEW

SGLT2 inhibitors and mechanisms of cardiovascular benefit:

a state-of-the-art review
Subodh Verma 1 & John J. V. McMurray 2

Received: 27 March 2018 / Accepted: 23 April 2018 / Published online: 22 August 2018
# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Sodium–glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly
heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit.
Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect
on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further
insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we
discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney
and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and
ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without
diabetes.

Keywords Cardiovascular effects . Heart failure . Mechanisms . Review . SGLT2 inhibitors

Abbreviations βOHB β-Hydroxybutyrate

BCAA Branched-chain amino acid SGLT Sodium–glucose cotransporter
CANVAS Canagliflozin Cardiovascular Assessment
Study
EMPA-REG Empagliflozin Cardiovascular Outcome Event
OUTCOME Trial in Type 2 Diabetes Mellitus Patients– SGLT2 inhibitors and cardiovascular
Removing Excess Glucose protection: setting the stage
HFpEF Heart failure with a preserved ejection fraction
HFrEF Heart failure with a reduced ejection fraction Sodium–glucose cotransporter (SGLT)2 inhibitors have dem-
HHF Hospitalisation for heart failure onstrated unprecedented cardiorenal benefits in large-scale
NHE Na+/H+ exchanger clinical trials of people who have type 2 diabetes and either
established cardiovascular disease or multiple cardiovascular
risk factors [1–3]. In the Empagliflozin Cardiovascular
Electronic supplementary material The online version of this article Outcome Event Trial in Type 2 Diabetes Mellitus Patients–
(https://doi.org/10.1007/s00125-018-4670-7) contains a slideset of the Removing Excess Glucose (EMPA-REG OUTCOME) study,
figures for download, which is available to authorised users.
7020 individuals with type 2 diabetes who had coronary, pe-
ripheral or cerebrovascular disease were randomised to re-
* Subodh Verma
[email protected] ceive the SGLT2 inhibitor empagliflozin or placebo [2].
While the primary three-point major adverse cardiac events
1
outcome (cardiovascular death, non-fatal myocardial infarc-
Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St
Michael’s Hospital, University of Toronto, 30 Bond Street,
tion and non-fatal stroke) was significantly attenuated by
Toronto, ON M5B 1W8, Canada empagliflozin, what was particularly noteworthy were
2
British Heart Foundation, Glasgow Cardiovascular Research Centre,
the profound and early effects of empagliflozin on
Institute of Cardiovascular and Medical Sciences, University of cardiovascular death and hospitalisation for heart failure
Glasgow, Glasgow, UK (HHF), which were reduced by 38% and 35%, respectively
Diabetologia (2018) 61:2108–2117 2109

[2–4]. In addition, all-cause mortality was reduced by 32%. primary and secondary prevention cohorts (HR 0.64 and HR
Importantly, the reductions in cardiovascular death were not 0.68, respectively) [17].
clearly accounted for by the reductions in atherothrombotic Another important and unanswered question arising from
outcomes; rates of myocardial infarction and stroke remained previous trials relates to whether the observed cardiovascular
unchanged with therapy. The thesis that heart failure was the benefit of SGLT2 inhibitors occurred primarily in individuals
outcome most sensitive to SGLT2 inhibition was confirmed in with a history of heart failure and whether a specific phenotype
the Canagliflozin Cardiovascular Assessment Study (heart failure with a preserved ejection fraction [HFpEF] or
(CANVAS) Program wherein 10,142 individuals with type 2 heart failure with a reduced ejection fraction [HFrEF]) was
diabetes and either established cardiovascular disease or more sensitive to the observed benefits. Only a minority of
multiple cardiovascular risk factors received canagliflozin or participants enrolled in the EMPA-REG OUTCOME study
placebo [1]. Despite broader entry criteria, which resulted in and CANVAS Program (~10%) had a history of investigator-
the inclusion of both patients for whom canagliflozin was used reported heart failure and, as illustrated in Fig. 1, consistent
for primary and secondary prevention of cardiovascular dis- relative risk reductions were observed in people with and with-
ease, SGLT2 inhibition produced an almost identical reduc- out a history of heart failure [5, 6]. Since echocardiographic or
tion in the rates of HHF (HR 0.67 in the CANVAS Program biomarker substudies were not performed to evaluate specific
and HR 0.65 in the EMPA-REG OUTCOME study) [5, 6]. cardiac phenotypes that were most responsive to therapy, this
The concept that SGLT2 inhibitors reduced cardiovascular question remains unanswered. However, the absolute risk re-
events primarily through prevention of heart failure (vs duction appeared to be greater in those with a history of heart
atherothrombotic events) has gained broad acceptance, but failure [4, 6], suggesting that SGLT2 inhibition may be valu-
several questions remained unanswered, the most important able in both the prevention and treatment of heart failure. It is
being: ‘how’? entirely plausible that a large proportion of the individuals
In addition to the interest around mechanistic inves- enrolled in these studies had occult HFpEF or HFrEF, a notion
tigations and analyses [7], the results served as a wake- that has been substantiated in a previous study focused on
up call to remind the diabetes community of the individuals with type 2 diabetes [19].
burgeoning burden of heart failure in diabetes; this car-
diovascular outcome had seemed to have been forgotten
[8–10]. Although the atherothrombotic/macrovascular
complications of diabetes are well appreciated, these da- Mechanisms of cardiovascular protection
ta helped remind clinicians and scientists that HHF is by SGLT2 inhibitors
one of the most common and serious complications of
diabetes and is, in fact, as common (if not more evi- Several theories have been put forward to explain the pro-
dent) than rates of ischaemic events in diabetes [11]. To found salutary effects of SGLT2 inhibitors on cardiovascu-
date, much has been written about how diabetes directly lar (Text box and Fig. 2) and renal outcomes [7, 20].
(in an atherosclerosis-independent manner) affects the
myocardium, although the concept of a distinct diabetic EMPA-REG OUTCOME HR (95% CI)
cardiomyopathy predisposing individuals to the develop-
ment of heart failure remains debated [12, 13]. The No history of heart failure 0.63 (0.51, 0.78)
concept of primary vs secondary prevention is often
History of heart failure 0.72 (0.50, 1.04)
used to distinguish atherosclerotic risk (and associated
atherosclerosis-reducing therapies, such as statins, anti- CANVAS Program
platelet agents etc.); however, this approach may not be
appropriate for distinguishing risk of heart failure in No history of heart failure 0.87 (0.72, 1.06)

those with diabetes [14]. Individuals who have long- History of heart failure 0.61 (0.46, 0.80)
standing diabetes and healthy coronary arteries do not
necessarily have normal ventricular mechanics and, 0.4 0.6 0.8 1.0 1.4
hence, are predisposed to developing heart failure [15]. HR (95% CI)
These individuals appear to be equally responsive to Fig. 1 The cardiovascular benefits (relative risk reduction of cardiovas-
SGLT2 inhibitors for the prevention of heart failure cular death and HHF) observed with empagliflozin in the EMPA-REG
OUTCOME trial and canagliflozin in the CANVAS Program were ap-
[16–18]. Indeed, this proposition is supported by a sub- parent in participants with and without a history of heart failure [5, 6]. The
group analysis of the CANVAS Program, which demonstrated forest plot is drawn on a logarithmic (log10) scale. This figure is available
a similar relative risk reduction for HHF in the so-called as part of a downloadable slideset
2110 Diabetologia (2018) 61:2108–2117

Fig. 2 Diabetes-associated ventricular remodelling (a) is characterised by of the fundamental molecular and cellular pathways involved in the de-
left ventricular hypertrophy, inflammation, increased extracellular matrix velopment and natural history of cardiac failure in diabetes (as illustrated
(ECM) production, impaired cardiac metabolism and cardiomyocyte by a healthy heart in b). © G. Oomen 2018. This figure is available as part
(CMC) apoptosis. SGLT2 inhibitors may offer salutary effects on several of a downloadable slideset

Before delving into these in detail, it is worth noting that with dapagliflozin (ClinicalTrial.gov registration no.
these salient effects appear to have little impact on conven- NCT03036124) and empagliflozin (ClinicalTrial.gov
tional risk factors. First, baseline and time-dependent registration no. NCT03057951 and NCT03057977). In
changes in HbA1c, blood pressure and cholesterol do not the section below, we highlight some of the key
seem to determine the overall benefit of SGLT2 inhibitors mechanistic themes that have emerged to explain the
on cardiovascular outcomes [22]. Second, their benefits on cardiorenal benefits of SGLT2 inhibitors.
HHF/cardiovascular death have been observed across the
spectrum of renal disease, with a similar magnitude of risk
reduction being seen in those with eGFRs of 30– Putative mechanisms underlying SGLT2
60 ml min−1 [1.73 m]−2, 60–90 ml min−1 [1.73 m]−2and inhibitor-associated cardiovascular benefits
>90 ml min −1 [1.73 m]−2 [23]. Although the glucose-
lowering efficacy of SGLT2 inhibitors declines at the low- 1. Improvement in ventricular loading conditions
through a reduction in preload (secondary to
er eGFR range, the cardiovascular benefits are remarkably
natriuresis, osmotic diuresis) and afterload
preserved, suggesting that the mechanism(s) involved in (reduction in blood pressure and improvement in
glycaemic control and cardiovascular risk reduction may vascular function) [7, 20, 21, 30–38]
be dissociated and/or follow a different dose–response
curve. Third, it is worth noting that the metabolic finger- 2. Improvement in cardiac metabolism and bioener-
print of these agents appears to be consistent among getics [39, 40, 44, 45]
those with and without diabetes. Studies suggest that
3. Myocardial Na+/H+ exchange inhibition [46–48]
SGLT2 inhibition exerts glucosuria and natriuresis, while
increasing glucagon and ketones even in individuals who 4. Reduction of necrosis and cardiac fibrosis [51,
do not have diabetes [24–26]. These data, therefore, argue 52, 60]
that the benefits noted may be observed even in those
without diabetes, a concept that has been borne out in 5. Alteration in adipokines, cytokine production and
preclinical experiments [27, 28] and which is being epicardial adipose tissue mass [55–57]
explored in ongoing heart failure treatment studies [29]
Diabetologia (2018) 61:2108–2117 2111

Fig. 3 Diabetes is associated with afferent arteriolar dilatation, which vasoconstriction. This in turn serves as a mechanism to reduce
leads to high intraglomerular pressure and hyperfiltration. Ongoing baro- intraglomerular hypertension and provide nephroprotection (b). © G.
trauma to the glomerulus may lead to proteinuria (a). SGLT2 inhibitors, Oomen 2018. This figure is available as part of a downloadable slideset
through tubuloglomerular feedback, promote afferent arteriolar

SGLT2 inhibitors improve ventricular loading conditions It also point towards volume contraction as being a key de-
has been proposed that one of the main mechanisms by terminant of benefit noted within the trial. In fact, approx-
which SGLT2 inhibitors exert their beneficial actions is imately 50% of the cardiovascular benefit observed within
via improvement of ventricular loading conditions, t h e tr i al w a s a s c r i b ed to e m pa gl i f l o zi n - i n du ce d
secondary to a reduction in preload primarily due to the haemoconcentration [31]. An early haemodynamic benefit
diuretic and natriuretic effects [7, 20]. SGLT2 inhibition would go hand in hand with the observed early separation
in the proximal tubule results in natriuresis and of the Kaplan–Meier curves noted within the clinical trials
glucosuria, and the ensuing osmotic diuresis may be when comparing empagliflozin or canagliflozin treatment
favourable, particularly in the heart of an individual with with placebo. Could diuresis really explain these benefits
diabetes, which functions on a steep Frank–Starling curve. when other diuretics have not changed prognosis in heart
SGLT2 inhibitors are unique among the diuretics available failure? Recent studies point to important differences be-
clinically in that they modulate the function of the tween SGLT2 inhibitors and classical diuretics. For exam-
proximal tubule. The natriuretic response is also a ple, in a comparative study of dapagliflozin and hydrochlo-
stimulus for tubuloglomerular feedback, which in turn rothiazide (a classical diuretic), a reduction in plasma vol-
results in afferent arteriolar vasoconstriction with ume and increase in erythrocyte mass was noted with
resultant reductions in intraglomerular hypertension (Fig. dapagliflozin but not with hydrochlorothiazide over a
3). This process may explain the significant long-term re- 12 week period of treatment [32]. In another study compar-
nal preservation noted with SGLT2 inhibitors. Of note, ing dapagliflozin with the loop diuretic bumetanide, though
angiotensin converting enzyme inhibitors and angiotensin both agents were associated with a reduction in sodium and
receptor blockers cause efferent arteriolar vasodilatation interstitial fluid, dapagliflozin afforded these effects with little
and, when used in combination with SGLT2 inhibitors, or no change in blood volume whereas bumetanide was asso-
will likely co-impact on intraglomerular pressure and ciated with greater reductions in intravascular volume [33]. A
may account for the initial drop in eGFR observed in pa- differential effect in regulating interstitial fluid (vs intravascular
tients, which is followed by a plateau over time. volume) may be particularly important in patients with heart
Individuals with diabetes are known to have an increase failure in whom, in many instances, intravascular contraction
in whole-body sodium content and, in recently completed is present and often aggravated by diuresis. The ability to se-
translational studies in humans, the SGLT2 inhibitor lectively reduce interstitial fluid may be a unique feature of
dapagliflozin has been demonstrated to reduce tissue SGLT2 inhibitors vs other diuretics (Fig. 4) and this may limit
sodium content in people with type 2 diabetes [30]. the reflex neurohumoral stimulation that occurs in response to
Mediation analyses from the EMPA-REG OUTCOME trial intravascular volume contraction with traditional diuretics.
2112 Diabetologia (2018) 61:2108–2117

Fig. 4 SGLT2 inhibitors may differentially regulate the interstitial vs in both interstitial and intravascular volume (c). It has been postulated that
intravascular compartment when compared with loop diuretics. In indi- this differential volume regulation by SGLT2 inhibitors (interstitial >
viduals with congestive heart failure, interstitial oedema is evident (a). intravascular) may limit the aberrant reflex neurohumoral stimulation that
SGLT2 inhibitors may selectively reduce interstitial volume with minimal occurs in the setting of intravascular depletion. © G. Oomen 2018. This
change in blood volume (b) whereas loop diuretics may cause a reduction figure is available as part of a downloadable slideset

However, this thesis requires further data. Another difference and promote the development of diastolic dysfunction [41].
between conventional diuretics and SGLT2 inhibitors relates to SGLT2 inhibitors are known to slightly increase the pro-
their effects on serum uric acid levels. Whereas SGLT2 inhib- duction of the ketone body β-hydroxybutyrate (βOHB),
itors are uricosuric, loop diuretics are associated with an in- and it is hypothesised that this may offer an alternative
crease in uric acid levels, possibly mediating differences in and less expensive myocardial fuel source in those with
cardiovascular outcomes [34]. diabetes [39, 42]. The elevation in ketone levels has been
In addition to volume changes, SGLT2 inhibitors may suggested to arise from an effort to raise glucagon levels
optimise loading conditions through reducing blood pres- and possibly through a reduction in ketone body excretion
sure and altering vascular function. In a recent study, via the kidneys. The underlying concept is that βOHB is a
empagliflozin was shown to reduce central and 24 h sys- ‘superfuel’ that is oxidised by the heart in preference to
tolic and diastolic blood pressure, central pulse pressure NEFAs and glucose, and that ketones not only improve
and forward wave amplitude in individuals with type 2 cardiac function in the failing heart, but also increase me-
diabetes [35]. Other studies have demonstrated that chanical efficiency [43]. This is an interesting postulate but
SGLT2 inhibitors improve endothelial function and aortic cogent data to support this thesis are scarce. Some support,
stiffness indices, and may potentially induce vasodilatation however, has been provided by preliminary studies carried
through activation of voltage-gated potassium (Kv) chan- out in pigs following myocardial infarction, which demon-
nels and protein kinase G [36–38]. strate that empagliflozin increases myocardial ketone con-
sumption, and reduces cardiac glucose consumption and
SGLT2 inhibitors improve cardiac metabolism and bioener- lactate production [44]. Others have postulated that
getics It has been postulated that SGLT2 inhibitors may SGLT2 inhibitor-induced increases in βOHB levels may
improve and/or optimise cardiac energy metabolism and inhibit histone deacetylase and prevent prohypertrophic
that by improving myocardial energetics and substrate ef- transcription pathways [40]. It is also possible that a de-
ficiency these agents may improve cardiac efficiency and crease in βOHB oxidation results in decreased acetyl-
cardiac output [39, 40]. It is well established that under CoA derived from ketone oxidation, thereby increasing
conditions of diabetes and/or heart failure, the metabolic the oxidation of glucose-derived pyruvate (i.e. improving
flexibility of the heart, as it relates to substrate utilisation, myocardial glucose metabolism). A decrease in acetyl-CoA
is impaired. Accordingly, an over-reliance on NEFAs as a supply may also decrease harmful hyperacetylation of mi-
substrate for ATP generation may result in a build-up of tochondrial enzymes, thereby improving mitochondrial en-
free fatty intermediates that may in turn promote ergy production [40]. Using an elegant untargeted metabo-
lipotoxicity, impair sarcoplasmic reticulum calcium uptake lomics strategy, SGLT2 inhibition was suggested to
Diabetologia (2018) 61:2108–2117 2113

Fig. 5 (a) Diabetes-associated heart failure is characterised by an increase block NHEs, consequently reducing cytoplasmic sodium and calcium,
in myocardial expression of NHEs. This can lead to elevations in cyto- thus offering cardioprotection. Ca2+M, mitochondrial calcium; MCU, mi-
plasmic sodium and calcium levels, which may contribute to the path- tochondrial Ca2+ uniporter. © G. Oomen 2018. This figure is available as
ology of heart failure. (b) Recent data suggest that SGLT2 inhibitors part of a downloadable slideset

promote branched-chain amino acid (BCAA) degradation, SGLT2 inhibition and cardiac fibrosis Cardiac fibrosis is widely
thereby providing an alternative fuel source for the failing regarded as a common final pathway through which heart fail-
myocardium. BCAA degradation is known to be impaired ure develops. This universally involves cardiac structural re-
in heart failure and may contribute to aberrant myocardial modelling due to deposition of extracellular matrix proteins
bioenergetics [45]. Although the findings described above laid down by cardiac fibroblasts, resulting in impeded ventric-
are intriguing, it is important to emphasise that we still lack ular compliance and accelerated development of heart failure
definitive evidence linking myocardial energetics to the [50]. Recent experimental data in rat models of post-
beneficial effects of SGLT2 inhibition. myocardial infarction demonstrate that dapagliflozin exhibits
marked cardiac antifibrotic effects by suppressing collagen
SGLT2 inhibition and direct effects on Na+/H+ exchange in the synthesis via increasing the activation of M2 macrophages
myocardium An emerging and tantalising hypothesis is and inhibiting myofibroblast differentiation [51]. Other prelim-
that SGLT2 inhibitors may directly inhibit the Na+/H+ inary studies, using human cardiac fibroblasts, have demon-
exchanger (NHE) 1 isoform in the myocardium [46, 47]. strated that empagliflozin significantly attenuates TGF-β1-
Activation of NHE1 results in increased cytosolic sodium induced fibroblast activation and reduces cell-mediated extra-
and calcium and has been demonstrated to occur in exper- cellular matrix remodelling as measured by the collagen fibre
imental models of heart failure (Fig. 5). Recently, alignment index [52]. In the same series of studies, the authors
Baartscheer et al showed that the SGLT2 inhibitor demonstrated that empagliflozin suppressed expression of key
empagliflozin inhibited cardiomyocyte NHE and, through pro-fibrotic markers, including type I collagen, α-smooth mus-
this mechanism, reduced cytoplasmic sodium and calcium cle actin, connective tissue growth factor and matrix metallo-
levels, while increasing mitochondrial calcium levels [48]. proteinase 2. Therefore, an emerging postulate is that SGLT2
Since SGLT2 receptors are not expressed in the heart, the inhibition, independent of hyperglycaemia, may have direct
mechanism by which these effects on cardiomyocyte NHE and favourable effects on cardiac fibroblast phenotype and
occur remains elusive. Of note, it has been postulated that function, one of the most important factors of heart failure.
SGLT2 inhibitors promote natriuresis by downregulating
the activity of NHE3 in the proximal tubule [49]. The SGLT2 inhibition and adipokines Altered adipokine produc-
expression of NHE3, known to mediate tubular sodium tion and/or action has been proposed as a common mechanism
reuptake, is increased in heart failure, and an inhibitory through which cardiovascular disease and insulin resistance
effect on NHE3 may serve as an additional mechanism to develops, particularly in states of obesity [53]. Ectopic fat
restore whole-body sodium homeostasis and reduce car- deposition in the form of perivascular and epicardial fat has
diac failure. Hence, inhibition of NHE1 and NHE3 may been implicated in the genesis of heart failure, in part through
be a common cardio–renal mechanism through which altered paracrine regulation of adipokines on the myocardium
these agents prevent and/or treat heart failure [46]. [54]. It has been suggested that SGLT2 inhibitors may mediate
2114 Diabetologia (2018) 61:2108–2117

their benefit, in part, by restoring the balance between pro- and function. As such, the causal relationship between SGLT2
anti-inflammatory adipokines. Recently, SGLT2 inhibitors inhibition and adipose tissue inflammatory cytokines should,
were postulated to reduce the levels of the adipokine leptin, for now, be considered hypothesis-generating.
which may have a pathophysiological role in sodium regula-
tion as well as cardiac inflammation and fibrosis [55]. Indeed,
in a 52 week clinical study, canagliflozin reduced serum leptin Unanswered mechanistic and translational
levels by 25% and increased the levels of the anti- themes
inflammatory adipokine adiponectin by 17%, when compared
with the sulfonylurea glimepiride [56]. A marked reduction in Despite the growing interest in the cardiovascular and renal
the inflammatory cytokine IL-6, but not TNF-α, was also protective biology of SGLT2 inhibitors, unanswered questions
observed in this study. Other studies have demonstrated that remain. For example, do SGLT2 inhibitors reverse pathological
dapagliflozin reduces epicardial adipose tissue volume, which cardiac remodelling in humans with diabetes? Although prelim-
has been implicated in the development and natural history of inary and uncontrolled case series suggest that empagliflozin
heart failure [57]. The independent changes that SGLT2 in- may be associated with a reduction in left ventricular mass and
hibitors appear to exert on adipokines need to be interpreted an improvement in diastolic function (as assessed by echocar-
with caution and it is imperative that we work towards diography) [58], persuasive data to support this important ques-
distinguishing between the secondary effects that arise from tion are pending. The ongoing randomised Effects of
fat mass loss and the direct effects that regulate adipose tissue Empagliflozin on Cardiac Structure in Patients with Type 2

Table 1 Completed and ongoing SGLT2 inhibitor-focused trials

Trial [reference/ClinicalTrial.gov Inclusion criteria Primary outcomes

registration no.]

Type 2 diabetes + CV disease and/or CV risk factors

EMPA-REG OUTCOME [2] Type 2 diabetes and high cardiovascular risk CV death, non-fatal MI and non-fatal stroke
CANVAS Program [2] Inadequately controlled type 2 diabetes with a history, CV death, non-fatal MI and non-fatal stroke
or high risk, of CV events Progression of albuminuria
DECLARE-TIMI 58a [65] Type 2 diabetes with a history, or high risk, of CV events CV death, non-fatal MI and non-fatal stroke
CV death or HHF
SCOREDa [NCT03315143] Type 2 diabetes, CV risk factors and moderately CV death, non-fatal MI and non-fatal stroke
impaired renal function CV death or HHF
VERTIS CVa [NCT01986881] Type 2 diabetes and established vascular disease CV death, non-fatal MI and non-fatal stroke
CKD ± type 2 diabetes
CREDENCE [66] Type 2 diabetes and moderately impaired renal function ESRD, doubling of serum creatinine, renal
or CV death
Dapa-CKDa [NCT03036150] CKD ≥50% sustained decline in eGFR, ESRD,
CV death or renal death
EMPA-Kidneya [NCT03594110] CKD ESRD, renal death, ≥40% sustained decline
in eGFR or CV death
Heart failure ± type 2 diabetes
Dapa-HFa [NCT03036124] Chronic heart failure, left ventricular ejection fraction CV death or HHF or an urgent heart failure
≤0.40% and elevated NT-proBNP clinic visit
EMPEROR-Reduceda [NCT03057977] Chronic heart failure, left ventricular ejection fraction CV death or HHF
≤0.40% and elevated NT-proBNP
EMPEROR-Preserveda [NCT03057951] Chronic HFpEF CV death or HHF
SOLOIST-WHFa [NCT03521934] Type 2 diabetes and prior heart failure and visit or CV death or HHF
hospitalisation for worsening heart failure
a
Ongoing trials
CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; CV,
cardiovascular; DECLARE-TIMI, Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction; eGFR, estimated glomer-
ular filtration rate; EMPEROR-Preserved, EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction;
EMPEROR-Reduced, EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction; ESRD, end-stage renal
disease; HHF, hospitalisation due to heart failure; MI, myocardial infarction; NT-proBNP, N-terminal of the prohormone brain natriuretic peptide;
SCORED, Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at
Cardiovascular Risk; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure
Diabetologia (2018) 61:2108–2117 2115

Diabetes (EMPA-HEART) trial (ClinicalTrial.gov registration may be observed across the spectrum of people with type 2
no. NCT02998970), evaluating the effects of empagliflozin on diabetes with and without established cardiovascular disease.
left ventricular mass by cardiac magnetic resonance imaging, The largest outcome study on the effects of SGLT2 inhibitors
represents an important step in understanding the effects of on cardiovascular disease, the Multicenter Trial to Evaluate the
SGLT2 inhibitors on ventricular remodelling. Other studies of Effect of Dapagliflozin on the Incidence of Cardiovascular
a similar nature are ongoing with empagliflozin (ClinicalTrial. Events (DECLARE-TIMI 58), which has enrolled about
gov registration no. NCT03198585) and dapagliflozin [59]. 10,000 participants within a so-called primary prevention co-
There is a paucity of data with respect to the effects of hort, will provide further insights in this regard [65]. A sum-
SGLT2 inhibitors on serum and renal biomarkers. Although mary of the reported and ongoing SGLT2 inhibitor trials is
initial studies have demonstrated that canagliflozin reduces provided in Table 1. In this review, we have outlined some of
levels of B-type natriuretic peptide and troponin [60], confir- the key mechanisms that may explain the notable
mation of this in larger studies with pathway-specific bio- cardioprotective benefits of SGLT2 inhibitors, including ef-
markers (e.g. renin–angiotensin–aldosterone, extracellular fects on volume and diuresis, myocardial metabolism and the
matrix markers and proximal tubule injury markers, such as potentially direct myocardial effects, with some preliminary
kidney injury molecule-1 [KIM-1]) are needed. In addition, observations suggesting an effect on myocardial metabolism
we would encourage further evaluation of uric acid reduction and adipokine kinetics. Whether these agents will emerge as
as a biomarker and/or mediator of SGLT2 inhibition, since treatment approaches in chronic HFpEF, HFrEF or acute heart
there is a large body of evidence suggesting that uric acid failure is an important question; the answer may be provided
levels are an important predictor of prognosis in heart failure. by trials that are currently underway.
It is also important to determine whether the effects of SGLT2
inhibitors are more pronounced in individuals with evidence Acknowledgements The authors thank H. Teoh, (St. Michael’s Hospital,
Toronto, ON, Canada) for editorial assistance.
of structural remodelling (such as left ventricular hypertrophy)
or in those with higher levels of natriuretic peptides.
Duality of interest SV reports receiving research grants and/or speaking
This area of research would also benefit from translational honoraria from Abbott, Amgen, AstraZeneca, Bayer, Boehringer
studies evaluating the effects of SGLT2 inhibitors on mecha- Ingelheim, Bristol-Myers Squibb-Pfizer, Eli Lilly, Janssen, Merck,
nisms of arrhythmias. Electrophysiological studies evaluating Novartis, Novo Nordisk, Sanofi and Valeant. JJVM reports that his em-
inducible ventricular arrhythmias, atrial tachyarrhythmias and ployer, the University of Glasgow, paid for his participation in clinical
trial committees by AbbVie, AstraZeneca, Amgen, Bayer, Bristol-Myers
corrected QT intervals would be insightful. Likewise, studies
Squibb, Dalcor, GlaxoSmithKline, Merck, Novartis, Resverlogix, Stealth
evaluating functional capacity in heart failure are needed; in and Theracos. In addition, his travel and accommodation costs for atten-
line with this, two studies investigating empagliflozin in dance at meetings related to some of the clinical trials have been funded
HFpEF and HFrEF, with the 6 min walk test being the primary by these sponsors. JJVM’s employer has also paid for his attendance at
endpoint, are currently underway (ClinicalTrial.gov advisory boards organised by Novartis and Sanofi-Aventis.
registration no. NCT03448406 and NCT03448419).
Contribution statement SV drafted the article. Both authors revised it
Physiological studies that evaluate the effects of SGLT2 critically for important intellectual content and approved the version to
inhibitors on the sympathetic nervous system and neuro- be published.
humoral activation are needed. It is also intriguing that, de-
spite volume loss and a decrease in blood pressure, no change
in heart rate has been observed with SGLT2 inhibitor therapy References
and this should be further investigated.
Mechanistic and functional studies that evaluate the effects 1. Neal B, Perkovic V, Mahaffey KW et al (2017) Canagliflozin and
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