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Impact of empagliflozin on BP in patients with
type 2 diabetes and hypertension
Comment by Jan N Basile
MD
T
he recently reported Empagliflozin,
Cardiovascular Outcomes, and
Mortality in Type 2 Diabetes (EMPA-
REG OUTCOME) trial (
N Engl J Med
2015;373:2117–2128) found that, in patients
with type 2 diabetes mellitus (T2DM) at
high-risk for cardiovascular (CV) disease,
empagliflozin when added to standard of
care reduced the 3-point composite of death
from CV causes, nonfatal MI, and nonfatal
stroke compared with placebo. Of note, only
the 38% relative risk (RR) reduction in death
from CV causes was significant. Furthermore,
a 35% RR reduction in first hospitalisation for
heart failure was also seen. Subsequently, the
phase 3, randomised, placebo-controlled 12-
week EMPA-REG hypertension trial (
Diabetes
Care
2015;38:420–428) investigated the
efficacy and safety of empagliflozin in patients
with T2DM and stage 1 hypertension receiving
either empagliflozin 10 mg (n=276) or 25 mg
(n=276) compared with placebo (n=271) for
change in blood pressure (BP) based on 24-
hour ambulatory BP monitoring (ABPM). This
smaller hypertension-specific trial from within
the overall study found that treatment with
empagliflozin was associated with significant
and clinically meaningful reductions in both
systolic BP (SBP) and diastolic BP (DBP)
throughout the 24-hour period compared
with placebo. In addition, like in the overall
trial, improvements in glucose control and
reductions in weight were also seen.
Now,inasubstudyoftheEMPA-REG hyperten-
sion trial (
Hypertension
http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07703
; published
online October 10, 2016), the BP-lowering
effects of empagliflozin in these patients with
T2DM and stage 1 hypertension taking 10 and
25 mg of active drug were analysed based on if
they were taking none, one, or two or more anti-
hypertensive medications and the effect on BP
specifically if they were or were not taking diu-
retics or angiotensin-converting enzyme (ACE)
inhibitor/angiotensin receptor blocker (ARB)
background therapy. The investigators found
that the favourable BP-lowering effect of empa-
gliflozin on 24-hour SBP and DBP compared
with placebo was irrespective of the number of
antihypertensives used at baseline and regard-
less of if they were or were not specifically on
a background of diuretics (all types pooled
together due to the small number of thiazide
vs loop users) and ACE inhibitor/ARB use.
In summary, empagliflozin reduces BP when
used alone or when combined with commonly
used antihypertensive agents, including both
diuretics and RAS-blocking drugs in those
with T2DM and stage 1 hypertension.
Dr Basile is from the Seinsheimer
Cardiovascular Health Program, Medical
University of South Carolina, Ralph H
Johnson VA Medical Center, Charleston,
and SC President-Elect American
Society of Hypertension 2018–2020.
Association of systolic BP variability with
mortality, coronary heart disease, stroke,
and renal disease
Comment by Jeffrey Whittle
MD, MPH
T
hese investigators examined the association of systolic blood
pressure variability (SBPV) with risk of mortality, incident coro-
nary heart disease, stroke, and end-stage renal disease in a large
cohort of US veterans. In each case, higher SBPV increased the risk
of the adverse event. This finding has been noted in multiple prior
studies, generally with more selected populations; but this study used
BP measures obtained during routine practice throughout the period of
follow-up. Rather than focus on methodological concerns, the reader
should recognise the growing weight of evidence that blood pressure
variability predicts adverse events, whether it is measured visit to visit
over years (as in this study), over the course of days to weeks of home
blood pressure measurements, or during a single 24-hour ambulatory
blood pressure recording. It is also clear that we don’t have much reason
to change our clinical practice in response to this information. Certainly,
the increased risk might be a cause for more aggressive treatment, but
this same variability might increase the risk of adverse events with treat-
ment. While some drug classes, in particular calcium channel blockers,
clearly are associated with less SBPV, they are not, on balance, more
protective against adverse outcomes than other drugs with the opposite
effect on SBPV, notably ACE inhibitors, when similar reductions in
SBP are achieved. This is a result that should stimulate research but
not change current clinical practice.
Dr Whittle is Director of Health Services Research,
Clement J Zablocki VA Medical Center in Wisconsin
and Professor, Division of General Internal Medicine,
Department of Medicine, Medical College of Wisconsin.
Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and
hypertension by background antihypertensive medication
Hypertension
Take-home message
•
This 12-week study evaluated the effect of empagliflozin 10 mg or 25 mg on systolic blood pressure and diastolic blood pressure readings over a
24-hour period in patients with type 2 diabetes mellitus. The results were analyzed based on co-treatment with other antihypertensives, specifically
diuretics or ACE inhibitors/ARBs. The results showed that empagliflozin at both treatment doses reduced systolic and diastolic blood pressure
regardless of number or type of co-treatment antihypertensive medications.
•
The researchers concluded that empagliflozin shows promise as an adjunct treatment option for reducing blood pressure in patients with
type 2 diabetes.
Abstract
In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg once daily reduced
glycohemoglobin, blood pressure (BP), and weight versus placebo in patients
with type 2 diabetes mellitus and hypertension. Patients received placebo (n=271),
empagliflozin 10 mg (n=276), or empagliflozin 25 mg (n=276) for 12 weeks (n=full
analysis set). This present analysis investigated changes from baseline to week
12 in mean 24-hour systolic BP (SBP) and diastolic BP (DBP) in patients receiving
0, 1, or ≥2 antihypertensive medications and patients receiving/not receiving
diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor
blockers. Compared with placebo, empagliflozin 10 mg and 25 mg reduced
mean 24-hour SBP/DBP in patients receiving 0 (10mg: −3.89/−2.58mmHg; 25mg:
−3.77/−2.45mmHg), 1 (10mg: −4.74/−1.97mmHg; 25mg: −4.27/−1.81 mmHg), or ≥2 (10
mg: −2.36/−0.68 mmHg; 25 mg: −4.17/−1.54 mmHg) antihypertensives. The effect
of empagliflozin was not significantly different between subgroups by number of
antihypertensives for changes in SBP (interaction P value 0.448) or DBP (interaction
P value 0.498). Empagliflozin reduced 24-hour mean SBP/DBP irrespective of
diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker
use, with no significant difference between subgroups by use/no use of diuretics
(interaction P values 0.380 [systolic]; 0.240 [diastolic]) or angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers (interaction P values 0.900
[systolic]; 0.359 [diastolic]). In conclusion, in patients with type 2 diabetes mellitus
and hypertension, empagliflozin for 12 weeks reduced SBP and DBP versus
placebo, irrespective of the number of antihypertensives and use of diuretics or
angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.
Hypertension
2016 Oct 10;[Epub ahead of print], Mancia G, Cannon CP,
Tikkanen I
Association of systolic blood pressure variability with
mortality, coronary heart disease, stroke, and renal
disease
Journal of the American College of Cardiology
Take-home message
•
The authors evaluated 2,865,157 US veterans to assess the association between
visit-to-visit systolic blood pressure variability (SBPV) and all-cause mortality,
cardiovascular events, and end-stage renal disease (ESRD).
•
Results showed that the higher the variability (measured in standard deviation quar-
tiles), the greater the association with all-cause mortality, CHD, stroke, and ERSD.
Abstract
BACKGROUND
Intraindividual blood pressure
(BP) fluctuates dynamically over time.
Previous studies suggested an adverse link
between greater visit-to-visit variability in
systolic blood pressure (SBP) and various
outcomes. However, these studies have
significant limitations, such as a small size,
inclusion of selected populations, and
restricted outcomes.
OBJECTIVES
This study investigated the
association of increased visit-to-visit variability
and all-cause mortality, cardiovascular
events, and end-stage renal disease (ESRD)
in a large cohort of U.S. veterans.
METHODS
From among 3,285,684 U.S.
veterans with and without hypertension
and normal estimated glomerular filtration
rates (eGFR) during 2005 and 2006, we
identified 2,865,157 patients who had 8
or more outpatient BP measurements.
Systolic blood pressure variability (SBPV)
was measured using the SD of all SBP
values (normally distributed) in 1 individual.
Associations of SD quartiles (<10.3, 10.3 to
12.7, 12.7 to 15.6, and ≥15.6 mmHg) with all-
cause mortality, incident coronary heart
disease (CHD), stroke, and ESRD was
examined using Cox models adjusted for
sociodemographic characteristics, baseline
eGFR, comorbidities, body mass index,
SBP, diastolic BP, and antihypertensive
medication use.
RESULTS
Several sociodemographic
variables (older age, male sex, African-
American race, divorced or widowed
status) and clinical characteristics (lower
baseline eGFR, higher SBP and diastolic BP),
and comorbidities (presence of diabetes,
hypertension, cardiovascular disease,
and lung disease) were all associated
with higher intraindividual SBPV. The
multivariable adjusted hazard ratios and
95% confidence intervals for SD quartiles
2 through 4 (compared with the first quartile)
associated with all-cause mortality, CHD,
stroke, and ESRDwere incrementally higher.
CONCLUSIONS
Higher SBPV in individuals
with and without hypertension was
associated with increased risks of all-
cause mortality, CHD, stroke, and ESRD.
Further studies are needed to determine
interventions that can lower SBPV and their
impact on adverse health outcomes.
J Am Coll Cardiol
2016 Sep 27;68:1375-
1386, Gosmanova EO, Mikkelsen MK,
Molnar MZ, et al.
HYPERTENSION
VOL. 1 • No. 3 • 2016
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