Expert Opinion on Pharmacotherapy

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Mechanisms of blood pressure reduction with

sodium-glucose co-transporter 2 (SGLT2) inhibitors

T. D. Filippatos, V. Tsimihodimos & M. S. Elisaf

To cite this article: T. D. Filippatos, V. Tsimihodimos & M. S. Elisaf (2016) Mechanisms of blood
pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors, Expert Opinion on
Pharmacotherapy, 17:12, 1581-1583, DOI: 10.1080/14656566.2016.1201073

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EXPERT OPINION ON PHARMACOTHERAPY, 2016
VOL. 17, NO. 12, 1581–1583
http://dx.doi.org/10.1080/14656566.2016.1201073
EDITORIAL
Mechanisms of blood pressure reduction with sodium-glucose co-transporter
2 (SGLT2) inhibitors
T. D. Filippatos , V. Tsimihodimos and M. S. Elisaf
Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
ARTICLE HISTORY Received 14 May 2016; Accepted 9 June 2016; Published online 24 June 2016
KEYWORDS Sodium-glucose co-transporter 2 inhibitors; arterial hypertension; blood pressure; uric acid; body weight
1. Introduction
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are asso-
ciated with a decrease in blood pressure (BP) levels. BP reduc-
tion was confirmed using 24-h ambulatory blood pressure
monitoring in the EMPA-REG BP (12 week efficacy and safety
study of empagliflozin in hypertensive patients with type 2
diabetes mellitus) trial, which showed that empagliflozin
administration in both the 10 and 25 mg/d doses resulted in
a decrease in 24-h systolic blood pressure (SBP) by 3.44 and
4.16 mmHg, respectively, and a smaller decrease in diastolic
blood pressure (DBP) by 1.36 and 1.72 mmHg, respectively [1].
The drug modestly decreased nighttime BP values and
seemed to beneficially affect surrogate markers of arterial
stiffness in patients with type 2 diabetes mellitus and hyper-
tension [2]. The SGLT2 inhibitor-induced decrease in BP seems
to be higher in patients with baseline SBP >140 mmHg and
may play a prominent role in the beneficial effects of empagli-
flozin in the EMPA-REG OUTCOME (empagliflozin cardiovascu-
lar outcome event trial in type 2 diabetes mellitus patients)
trial [3]. It has been shown that BP reduction is a class effect of
SGLT2 inhibitors, since they induce a considerable decrease in
SBP and a lesser decrease in DBP compared with other glu-
cose-lowering drugs, without any differences among the dif-
ferent agents within this group of antidiabetic drugs [4]. The
BP reduction with these drugs exhibited a statistically signifi-
cant dose dependency only for canagliflozin (−3.9 and
−5.3 mmHg with 100 and 300 mg/d, respectively, for SBP
and −2.1 and −2.5 mmHg with 100 and 300 mg/d, respec-
tively, for DBP) [4]. Additionally, a meta-analysis of studies with
empagliflozin, dapagliflozin, and canagliflozin showed a posi-
tive effect on sitting BP [5]. Importantly, although orthostatic
dizziness has been reported with these agents, it has been
emphasized that the SGLT2 inhibitor-induced BP reduction is
not associated with orthostatic hypotension (relative risk com-
pared with control treatment 0.72; 95% confidence interval
0.47–1.09) and this finding has been verified by the recent
results of the EMPA-REG OUTCOME trial [3,4].
A number of possible mechanisms, which may be interre-
lated, have been proposed for the BP reduction with SGLT2
inhibitors (Table 1).
CONTACT Moses S. Elisaf egepi@cc.uoi.gr; melisaf54@cc.uoi.gr
Ioannina, Greece.
© 2016 Informa UK Limited, trading as Taylor & Francis Group
1.1. Hemodynamic mechanisms
Drug-associated hemodynamic changes may, at least in part,
explain the decrease in BP. An approximate decrease in
plasma volume by 7.3% measured by 125I-labeled human
serum albumin, maintained after 8 weeks of therapy, was
found in patients treated with dapagliflozin. In fact, this
decrease in plasma volume was associated with an increase
in hematocrit by 2.2% [6]. Plasma volume reduction has been
ascribed to the drugs’ diuretic and mild natriuretic effects,
which are attributed to the inhibition of sodium reabsorption
in the proximal tubules but also to osmotic diuresis. However,
since the initial natriuresis can be compensated by a chronic
increased sodium re-absorption in the distal tubules, the con-
tribution of natriuresis may be small.
1.2. Loop diuretic-like effects
It has recently been suggested that SGLT2 inhibitors act as loop
diuretics. Since diabetes-induced hypertension is characterized
as salt-sensitive hypertension, with a prominent increase in SBP,
and commonly exhibits a non-dipper pattern, SGLT2 inhibitors
acting as diuretics could result in a decrease in BP and subse-
quently in a conversion of salt-sensitive profile of BP to a non-
salt-sensitive one [7]. Experimental data have clearly shown that
empagliflozin not only improved glucose metabolism but also
decreased salt loading-mediated BP elevation and normalized
abnormal diurnal BP profile to a dipper one through its ability to
increase sodium excretion [8]. In fact, these drugs despite their
diuretic ability and also the volume-depletion activation of renin-
angiotensin system are not followed by a decrease in serum
potassium, the most common and important side effect of the
commonly used diuretics. On the contrary, a mild increase in
serum potassium has been documented with canagliflozin [9]. It
is possible that the SGLT2 inhibitor-induced decrease in plasma
glucose levels could result in a reduction in insulin levels, leading
to a redistribution of potassium from the cells to the extracellular
compartment; this redistribution of potassium ions can counter-
balance the renal potassium wasting and thus potassium home-
ostasis is preserved [7]. The diuretic effect of SGLT2 inhibitors has
been highlighted in clinical studies. A recently published
Department of Internal Medicine, School of Medicine, University of Ioannina, 45 110
1582 T. D. FILIPPATOS ET AL.
Table 1. Possible interrelated mechanisms of blood pressure (BP) reduction with
sodium-glucose co-transporter 2 inhibitors.
● Volume depletion due to diuresis and natriuresis
● Loop-diuretic-like action leading to conversion of salt-sensitive profile of BP
to a non-salt-sensitive one
● Weight loss
● Improvement of arterial stiffness
● Uric acid reduction
● Inhibition of sympathetic nervous system activity
randomized double-blind placebo-controlled trial, which rando-
mized 449 patients with residual BP elevation despite treatment
with a renin-angiotensin system (RAS) blocker to dapagliflozin
10 mg/day or placebo, showed that dapagliflozin decreased
seated SBP by 4.3 mmHg (p = 0.002) [10]. Interestingly, a post
hoc analysis of this trial suggested that dapagliflozin can potenti-
ate the antihypertensive effects of calcium channel blockers (by
5.1 mmHg) and beta-blockers (by 5.7 mmHg) in patients already
receiving RAS blockers [10], a finding which suggests a diuretic-
like volume depleting antihypertensive mechanism of action and
also hints that these drugs could replace diuretics in the treat-
ment of hypertensive patients with type 2 diabetes mellitus.
Notably, no further reduction in BP was noticed in patients
already receiving diuretics [10].
Interestingly, it has been shown that urine volumes return
to baseline values a few weeks after the initiation of SGLT2
inhibitors, while their antihypertensive effects remain stable, a
finding indicating that increased diuresis and natriuresis are
not the only mechanisms underlying the BP-lowering effects
of these drugs [1]. In line with this observation are data
indicating that the antihypertensive effects of these com-
pounds persist even in patients with reduced estimated glo-
merular filtration rate and attenuated diuresis and
natriuresis [11].
1.3. Weight loss
Weight loss and visceral fat reduction related to increased diur-
esis and glucosuria-associated loss of calories may play a role in
BP decrease. A meta-analysis of 25 randomized controlled trials
showed that BP reductions expressed per kilogram of weight loss
averaged −1.05 and −0.92 mmHg for SBP and DBP, respectively
[12]. Thus, the reduction of body weight by approximately 2–3 kg
over 24–52 weeks with SGLT2 inhibitors results in a decrease in
BP; however, this BP reduction seems to be higher than that
expected due to body weight decrease. In fact, it has been
shown that only 40% of the SBP reduction observed with cana-
gliflozin could be ascribed to weight loss [13].
1.4. Arterial stiffness and endothelial function
improvement
A number of mechanisms including improved glycemic con-
trol and insulin sensitivity, decreased obesity and hyperglyce-
mia-related oxidative stress and inflammation of the vascular
wall, as well as improved endothelial function through protec-
tion of endothelial glucocalyx from sodium overload can lead
to an improvement in arterial stiffness and vascular resis-
tance [2,14].
1.5. Reduction of uric acid levels
SGLT2 inhibitors have been associated with a reduction of
serum uric acid levels, possibly attributed to glycosuria-
induced alteration of uric acid transport activity, which
involves glucose transporter 9 isoform 2, in renal tubule [15].
The decrease in serum uric acid may play a role in BP reduc-
tion, since short-term clinical trials have shown that treatment
of hyperuricemia is followed by a decrease in BP [16].
1.6. Inhibition of the sympathetic nervous system
activity
An inhibitory effect of SGLT2 inhibitors on the sympathetic
nervous system activity has been reported [17]. However,
other authors have not shown significant changes in sympa-
thetic nervous activity markers with empagliflozin in type 1
diabetic patients [18].
In conclusion, SGLT2 inhibitors decrease BP levels through
various possible mechanisms, including diuretic and natriure-
tic effects, weight loss, improvement in arterial stiffness and
vascular resistance.
2. Expert opinion
The decrease of BP levels with SGLT2 inhibitors, especially of SBP
(an effect that can be speculated to be due to the reduction of
blood volume and the decrease of pulse pressure and other
markers of arterial stiffness [2,18]), might have played a role in
the impressive cardiovascular results of the EMPA-REG OUTCOME.
However, it is obvious that the rapid onset of these beneficial
effects is not fully compatible with the BP decrease theory. The
decrease in BP may also play a role in the potential long-term
renoprotective effects of these drugs [8]. In this context, it has
recently been shown that dapagliflozin reduces albuminuria in
diabetic patients with hypertension receiving RAS blockers [19].
It should be mentioned that, despite the decrease in BP,
SGLT2 inhibitors do not increase heart rate [1,4]. It is possible
that this absence of an increase in heart rate is related to an
inhibitory effect of these compounds on the sympathetic
nervous system. However, the underlying mechanisms are
not clear yet. On the other hand, these drugs should be care-
fully administrated in patients treated with diuretics to avoid
hypovolemia and hypotension [7,20]. Interestingly, in the
EMPA-REG, in which 43.7% of the study population were on
diuretics, empagliflozin administration was associated with a
small (statistically insignificant) increase in stroke incidence,
which is speculated to be related to increase diuresis-asso-
ciated hypovolemia and compromised cerebral blood supply.
This possible association needs further investigation in future
outcome trials.
The BP-decreasing effects of SGLT2 inhibitors, combined
with the fact that they do not reduce serum potassium levels,
highlight SGLT2 inhibitors as unique diuretics. However, more
research is needed to clarify the implicated mechanisms as
well as the possible future glucose-lowering-independent indi-
cations of these drugs.

Declaration of interest
This editorial was written independently; no company or institution sup-
ported it financially. No competing financial interests exist. M.S. Elisaf has
received speaker honoraria, consulting fees, and research funding from
AstraZeneca, Schering Plough, Merck, Pfizer, Solvay, Abbott, Boehringer
Ingelheim and Fournier, and has participated in clinical trials with
AstraZeneca, Merck, Sanofi-Synthelabo, Solvay, GlaxoSmithKline, Novartis,
Pfizer and Fournier. TD Filippatos has given talks and attended conferences
sponsored by Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen,
AstraZeneca, Novartis, Vianex, Teva and Merck Sharp & Dohme. V.
Tsimihodimos has given talks and attended conferences sponsored by
Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis,
Vianex, Teva and Merck Sharp & Dohme. The authors have no other relevant
affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
ORCID
T. D. Filippatos http://orcid.org/0000-0002-1713-0923
M. S. Elisaf http://orcid.org/0000-0003-0505-078X
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