SYSTEMATIC REVIEW AND META-ANALYSIS
Effects of Sodium-Glucose Cotransporter 2 Inhibitors on 24-Hour
Ambulatory Blood Pressure: A Systematic Review and Meta-Analysis
William L. Baker, PharmD; Leo F. Buckley, PharmD; Michael S. Kelly, PharmD; John D. Bucheit, PharmD; Eric D. Parod, PharmD;
Roy Brown, MLIS; Salvatore Carbone, MS; Antonio Abbate, MD, PhD; Dave L. Dixon, PharmD
Background-—Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of antihyperglycemic agents that improve
glycemic control by increasing glycosuria. Additional benefits beyond glucose lowering include significant improvements in seated
clinic blood pressure (BP), partly attributed to their diuretic-like actions. Less known are the effects of this class on 24-hour
ambulatory BP, which is a better predictor of cardiovascular risk than seated clinic BP.
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
Methods and Results-—We performed a meta-analysis of randomized, double-blind, placebo-controlled trials to investigate the
effects of SGLT2 inhibitors on 24-hour ambulatory BP. We searched all studies published before August 17, 2016, which reported
24-hour ambulatory BP data. Mean differences in 24-hour BP, daytime BP, and nighttime BP were calculated by a random-effects
model. SGLT2 inhibitors significantly reduce 24-hour ambulatory systolic and diastolic BP by 3.76 mm Hg (95% CI, 4.23 to
2.34; I2=0.99) and 1.83 mm Hg (95% CI, 2.35 to 1.31; I2=0.76), respectively. Significant reductions in daytime and
nighttime systolic and diastolic BP were also found. No association between baseline BP or change in body weight were observed.
Conclusions-—This meta-analysis shows that the reduction in 24-hour ambulatory BP observed with SGLT2 inhibitors is a class
effect. The diurnal effect of SGLT2 inhibitors on 24-hour ambulatory BP may contribute to their favorable effects on cardiovascular
outcomes. ( J Am Heart Assoc. 2017;6:e005686. DOI: 10.1161/JAHA.117.005686.)
Key Words: ambulatory blood pressure monitoring • diabetes mellitus • diabetic therapy/glitazones • high blood pressure •
hypertension • metformin • sodium-glucose cotransporter 2 inhibitors
S
odium-glucose cotransporter 2 (SGLT2) mediates glucose uptake in the early proximal tubule of the kidney
and is responsible for the majority (80–90%) of glucose
reabsorption at the glomerulus level.1 The remaining 10% to
20% is then reabsorbed by SGLT1. In patients with diabetes
mellitus, inhibitors of SGLT2 improve hyperglycemia by
increasing glycosuria. Currently, 3 SGLT2 inhibitors have
been approved by the US Food and Drug Administration for
the treatment of type 2 diabetes mellitus as adjuncts to diet
From the Department of Pharmacy Practice, University of Connecticut School of
Pharmacy, Storrs, CT (W.L.B.); Department of Pharmacotherapy & Outcomes
Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA
(L.F.B., J.D.B., E.D.P., D.L.D.); Department of Pharmacy Practice, Chapman
University School of Pharmacy, Irvine, CA (M.S.K.); School of Nursing (R.B.) and
VCU Pauley Heart Center (S.C., A.A.), Virginia Commonwealth University,
Richmond, VA; Department of Experimental Medicine, Sapienza University of
Rome, Rome, Italy (S.C.).
Correspondence to: Dave L. Dixon, PharmD, 410 N 12th St, P.O.
Box 980533, Richmond, VA 23298-0533. E-mail: [email protected]
Received January 27, 2017; accepted April 12, 2017.
ª 2017 The Authors. Published on behalf of the American Heart Association,
Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use
and distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are made.
DOI: 10.1161/JAHA.117.005686
and exercise to improve glycemic control: canagliflozin,
dapagliflozin, and empagliflozin. Notably, empagliflozin has
the highest selectivity for SGLT2 compared with canagliflozin
and dapagliflozin.2
In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial,3
empagliflozin reduced total and cardiovascular mortality in
patients with type 2 diabetes mellitus compared with placebo,
an effect that was mainly driven by the beneficial effects on
heart failure. These impressive data have recently resulted in
a label change for empagliflozin to highlight the reduction in
cardiovascular mortality risk.4 However, the cardiovascular
benefits of empagliflozin cannot be justified by the improvement in glycemic control alone, which suggests the presence
of non-glucose-lowering effects of empagliflozin.
One of the most consistently reported non-glucoselowering effects of SGLT2 inhibitors is the reduction of
systemic arterial blood pressure (BP). A recent meta-analysis
of 27 randomized controlled trials (RCTs) concluded that, in
patients with type 2 diabetes mellitus, SGLT2 inhibitors
improve systolic BP by 4 mm Hg (95% CI, 4.4 to 3.5)
and diastolic BP by 1.6 mm Hg (95% CI, 1.9 to 1.3).5
The exact BP reduction-related mechanisms of SGLT2
inhibitors have not been fully elucidated. However, it
Journal of the American Heart Association
1
Effects of SGLT2 Inhibitors on 24-Hour BP
Baker et al
What is New?
• This meta-analysis demonstrates that Sodium-glucose
cotransporter 2 inhibitors, as a class, significantly reduce
24-hour ambulatory blood pressure, which further supports
their favorable cardiovascular profile.
What are the Clinical Implications?
• The decrease in 24-hour ambulatory blood pressure
observed with Sodium-glucose cotransporter 2 inhibitors
further emphasizes the need for close monitoring of blood
pressure and volume status, especially in patients receiving
concomitant diuretic therapy.
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has been suggested that inhibition of glucose-sodium reabsorption in the proximal tubule results in an osmotic diuresis
and decreased BP.6
Additional studies have also observed that SGLT2 inhibitors improve 24-hour ambulatory BP. Importantly, 24-hour
ambulatory BP is a better predictor of cardiovascular risk and
mortality than seated clinic BP and therefore, possibly, a
more-appropriate therapeutic target.7 Moreover, 24-hour
ambulatory BP can identify subjects with masked hypertension, which is associated with increased cardiovascular risk
and is more prevalent in patients with diabetes mellitus.8,9
Data on the effects of SGLT2 inhibition on 24-hour ambulatory
BP are confined to relatively small studies. The purpose of this
meta-analysis was to determine the magnitude of the effect
SGLT2 inhibitors exert on 24-hour ambulatory BP.
Methods
This meta-analysis conforms to standard guidelines and was
written in accord with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses statement.10
Figure 1. PRISMA diagram of study selection process. ABPM indicates ambulatory blood pressure
monitoring; DM, type 2 diabetes mellitus; RCT, randomized, controlled trial; Tx, treatment.
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
2
SYSTEMATIC REVIEW AND META-ANALYSIS
Clinical Perspective
Effects of SGLT2 Inhibitors on 24-Hour BP
Baker et al
A systematic search of 3 databases was conducted along
with a search of the reference lists of the retrieved
publications, in order to identify published articles addressing the topic. Databases searched included PubMed/Medline, Web of Science, and The Cochrane Database of Clinical
Trials. The articles included were limited to the English
language and those published anytime from the inception of
each database to present. The search was broken into 3
concept groups. One group encompassed the terminology
used to describe “sodium-glucose cotransporter 2 inhibitors,” another covered the terms relevant to “blood
pressure,” and a third addressed “randomized controlled
trials.” Medical Subject Headings (MeSH) and equivalent
controlled vocabulary and keywords were utilized in each
database. The last search of the databases was conducted
on August 17, 2016.
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Study Selection
Three authors (D.L.D., W.L.B., and L.F.B.) reviewed all
potentially relevant articles in a parallel manner by using a
priori defined criteria. Studies were eligible for inclusion in the
meta-analysis if they met the following criteria: (1) RCT in
humans; (2) evaluated a SGLT2 inhibitor compared with either
placebo or an active control; and (3) reported data on changes
in 24-hour ambulatory BP from baseline in a form suitable for
pooling. Only data from peer-reviewed publications were
considered for inclusion in this analysis.
Data Abstraction and Validity Assessment
For each included study, 2 authors (D.L.D., L.F.B.) used a
standardized abstraction tool to extract data for the analysis,
with disagreements resolved by a third investigator (M.K.).
Information collected from each study included author, year of
publication, study design, duration of follow-up, population
and setting, sample size, SGLT2 inhibitor evaluated, and
concomitant antihyperglycemic therapies. Data on changes in
24-hour BP were obtained. Missing data were collected
through a search of the study results reported on clinicaltrials.gov. Two reviewers (D.L.D., L.F.B.) assessed the quality of
each study by answering “yes,” “no,” or “unclear” to 11
questions regarding similarity of baseline populations, randomization, allocation concealment, blinding of study participants and personnel, outcome adjudication, completeness of
follow-up, and conflicts of interest using the Methods Guide
for Comparative Effectiveness Reviews.11 Studies were given
an overall score of good, fair, or poor with disagreements
resolved through discussion.
Table 1. Baseline Characteristics of Trials Evaluating SGLT2 Inhibitors and 24-Hour Ambulatory Blood Pressure
Study Name
Study Design
SGLT2 Group
n
Duration
(Weeks)
Average
Age (Y)
Baseline
24-Hour SBP
Baseline
24-Hour DBP
Baseline
Daytime SBP
Baseline
Nighttime SBP
Lambers-Heerspink
et al (2013)16
R, DB, PC
DAPA 10 mg/d
24
12
52.79.4
13112
777
13812
12013
Placebo
25
58.09.5
12712
747
13112
11715
Amin
et al (2015)20
R, DB, PC
ERTU 1 mg/d
39
54.47.0
133.11.7
78.61.3
NR
NR
NR
NR
NR
NR
Tikkanen
et al (2015)19
Townsend
et al (2016)15
R, DB, PC
R, DB, PC
Weber
et al (2016)18
R, DB, PC
Weber
et al (2016)17
R, DB, PC
4
ERTU 5 mg/d
38
53.89.9
135.01.9
80.11.4
ERTU 25 mg/d
39
52.56.6
135.51.9
80.31.3
Placebo
38
55.16.7
136.12.5
81.81.5
EMPA 10 mg/d
276
60.68.5
131.313.0
75.18.3
EMPA 25 mg/d
276
12
59.99.7
131.212.1
74.67.5
Placebo
271
60.38.8
131.711.8
75.27.5
CANA 100 mg/d
57
57.88.7
136.511.5
78.08.1
CANA 300 mg/d
56
6
58.36.9
139.610.6
79.37.9
Placebo
56
59.69.5
136.710.3
78.47.3
DAPA 10 mg/d
187
56.0 (51–62)
146.510.4
NR
NR
NR
Placebo
186
57.0 (50–62)
149.212.7
DAPA 10 mg/d
267
55.68.4
145.911.7
87.06.9
149.111.6
139.714.7
Placebo
263
56.28.9
146.611.7
87.26.7
150.41.2
139.115.1
12
12
CANA indicates canagliflozin; DAPA, dapagliflozin; DB, double-blind; DBP, diastolic blood pressure; EMPA, empagliflozin; ERTU, ertugliflozin; NR, not reported; PC, placebo-controlled; R,
randomized; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2 inhibitor.
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
3
SYSTEMATIC REVIEW AND META-ANALYSIS
Literature Search
Effects of SGLT2 Inhibitors on 24-Hour BP
Baker et al
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Meta-analyses were performed on the mean changes from
baseline in 24-hour systolic and diastolic BP, daytime
systolic and diastolic BP, and nighttime systolic and
diastolic BP. All continuous data are reported as a mean
difference and accompanying 95% CI and was pooled using
a Hartung-Knapp method12 random-effects model using the
“meta” package in R (version 3.1.3; The R Project for
Statistical Computing). We reported doses for each drug,
regardless of its regulatory status. We assessed presence
of statistical heterogeneity using the Cochrane P value
(P<0.10 significant) and the degree of heterogeneity
using the I2 statistic with a value >50% considered
substantial.13 Contour plots were constructed as a visual
representation of bias in the main results (24-hour systolic
and diastolic BP), and we used Egger’s test of asymmetry
of the plots.14
Subgroup analyses were performed by pooling data for
each individual SGLT-2 inhibitor separately and assessing the
pooled between-group variance. We also conducted randomeffects metaregression to evaluate whether the BP effects
observed with the SGLT-2 inhibitors were associated with
either baseline 24-hour ambulatory BP or changes in body
weight during the trial. Additional variables, such as percent
patients with hypertension at baseline and urinary sodium
excretion, were not sufficiently reported to allow for metaregression to be performed.
Results
Study Selection and Characteristics
The literature search process and results are shown in
Figure 1. A total of 6 randomized, double-blind, placebocontrolled studies were included in the analysis (Table 1).15–20
Of these, 3 RCTs (n=952) evaluated dapagliflozin,16–18 1 RCT
(n=823) evaluated empagliflozin,19 1 RCT (n=169) evaluated
canagliflozin,15 and 1 RCT (n=154) evaluated ertugliflozin.20
The dose of dapagliflozin used in each study was 10 mg/day,
and sample sizes ranged from 49 to 530 participants.16–18
Doses of empagliflozin, canagliflozin, and ertugliflozin ranged
from 10 to 25, 100 to 300, and 1 to 25, respectively.15,19,20 Key
clinical data for each of the included studies are provided in
detail in Table 2.15–20 The quality of each study was determined to be “good” with no disagreements between the
reviewers.
Table 2. Reported Clinical End Point Data
Change in
24-Hour
SBP From
Baseline
Change in
24-Hour
DBP From
Baseline
Change in
Daytime
SBP From
Baseline
Change in
Daytime
DBP From
Baseline
Change in
Nighttime
SBP From
Baseline
Change in
Nighttime
DBP From
Baseline
Study Name
SGLT2 Group
n
LambersHeerspink
et al (2013)16
DAPA 10 mg/d
24
5.611.62
Placebo
25
0.79.18
Amin
et al (2015)20
ERTU 1 mg/d
39
2.974.62
1.93.03
2.94.78
2.13.19
2.65.89
1.64.3
ERTU 5 mg/d
38
44.87
2.33.15
3.65.35
1.93.46
3.66.45
2.64.72
ERTU 25 mg/d
39
3.694.62
1.53.03
4.24.64
1.73.19
2.46.05
0.94.46
Placebo
38
EMPA 10 mg/d
276
2.998.86
1.14.96
3.49.55
1.285.41
2.2210.21
0.86.21
EMPA 25 mg/d
276
3.599.30
1.324.96
4.129.55
1.585.35
2.4711.09
0.756.32
Placebo
271
CANA 100 mg/d
57
4.788.33
2.184.87
5.058.66
2.395.41
4.3311.51
1.736.48
CANA 300 mg/d
56
7.3111.41
3.276.46
7.3611.66
3.236.56
6.9812.88
3.428.06
Placebo
56
1.269.86
0.265.35
0.659.87
0.25.26
3.4912.47
0.987.75
DAPA 10 mg/d
187
11.3321.9
7.5613.95
Placebo
186
6.8821.5
5.5713.64
DAPA 10 mg/d
267
9.6220.1
6.1513.73
1020.43
Placebo
263
6.7320.1
5.5313.78
6.920.69
Tikkanen
et al (2015)19
Townsend
et al (2016)15
Weber
et al (2016)18
Weber
et al (2016)17
0.14.4
0.428.25
NR
8.812.25
NR
1.912.5
0.89.31
0.83.30
0.35.06
0.85.19
0.388.74
NR
NR
0.611.48
0.93.3
0.46.29
0.265.36
NR
NR
0.5110.22
NR
8.822.88
0.94.40
0.366.8
NR
NR
6.523.17
CANA indicates canagliflozin; DAPA, dapagliflozin; DBP, diastolic blood pressure; EMPA, empagliflozin; ERTU, ertugliflozin; NR, not reported; SBP, systolic blood pressure; SGLT2, sodiumglucose cotransporter 2 inhibitor.
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
4
SYSTEMATIC REVIEW AND META-ANALYSIS
Statistical Analysis
Effects of SGLT2 Inhibitors on 24-Hour BP
drug = CANA
Townsend, et al., 201615 (100mg)
Townsend, et al., 201615 (300mg)
Random effects model
Mean difference
SGLT-2
SD
Total Mean
Placebo
Total Mean
SD
-4.78 8.33
-7.31 11.41
28 -1.26 9.86
28 -1.26 9.86
56
-3.52 [ -7.76; 0.72]
-6.05 [-10.77; -1.33]
-4.65 [-20.63; 11.33]
24 -5.60 11.62
187 -11.33 21.90
267 -9.62 20.10
478
25 -0.70 9.18
186 -6.88 21.50
263 -6.73 20.10
474
-4.90 [-10.78; 0.98]
-4.45 [ -8.85; -0.05]
-2.89 [ -6.31; 0.53]
-3.73 [ -6.38; -1.07]
57
56
113
SYSTEMATIC REVIEW AND META-ANALYSIS
Study
Baker et al
MD
95%-CI
Heterogeneity: I-squared=0%, p=0.4346
drug = DAPA
Heerspink, et al., 201316 (10mg)
Weber, et al., 201618 (10mg)
Weber, et al., 201617 (10mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.7842
drug = EMPA
Tikkanen, et al., 201519 (10mg)
Tikkanen, et al., 201519 (25mg)
Random effects model
276
276
552
-2.99 8.86 135.50
-3.59 9.30 135.50
271
0.42
0.42
8.25
8.25
-3.41 [ -5.15; -1.67]
-4.01 [ -5.78; -2.24]
-3.70 [ -7.52; 0.11]
39
38
39
116
-2.97 4.62
-4.00 4.87
-3.69 4.62
12.67
12.67
12.67
38
0.10
0.10
0.10
4.40
4.40
4.40
-3.07 [ -5.89; -0.25]
-4.10 [ -6.98; -1.22]
-3.79 [ -6.61; -0.97]
-3.65 [ -4.96; -2.34]
Heterogeneity: I-squared=0%, p=0.6355
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
drug = ERTU
Amin, et al., 201520 (1mg)
Amin, et al., 201520 (5mg)
Amin, et al., 201520 (25mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.8756
Random effects model
1259
839
-3.76 [ -4.23; -3.30]
Heterogeneity: I-squared=0%, p=0.9927
-10
-5
0
5
10
24-hr SBP
Figure 2. Effect of SGLT2 inhibitors on 24-hour systolic blood pressure. CANA indicates canagliflozin; DAPA, dapagliflozin; EMPA,
empagliflozin; ERTU, ertugliflozin; MD, mean difference; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2 inhibitor.
Quantitative Data Synthesis
24-hour BP
When the 6 RCTs were pooled, SGLT2 inhibitor use was
associated with a statistically significant 3.76 mm Hg
reduction in 24-hour systolic BP when compared with placebo
(95% CI, 4.23 to 2.34; I2=0.99; Figure 2).15–20 The mean
differences observed with canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin were
4.65 mm Hg (95% CI,
20.63 to 11.33),
3.73 mm Hg (95% CI,
6.38 to
Figure 3. Contour-enhanced funnel plots of 24-hour systolic blood pressure.
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
5
Effects of SGLT2 Inhibitors on 24-Hour BP
Baker et al
drug = CANA
Townsend, et al., 201615 (100mg)
Townsend, et al., 201615 (300mg)
Random effects model
57 -2.18 4.87
56 -3.27 6.46
113
Mean difference
Placebo
SD
Total Mean
MD
95%-CI
5.35
5.35
-1.92 [-4.27; 0.43]
-3.01 [-5.62; -0.40]
-2.41 [-9.30; 4.48]
186 -5.57 13.64
263 -5.53 13.78
449
-1.99 [-4.79; 0.81]
-0.62 [-2.96; 1.72]
-1.18 [-9.75; 7.38]
276 -1.10 4.96 135.50
276 -1.32 4.96 135.50
552
271
0.30
0.30
5.06
5.06
-1.40 [-2.43; -0.37]
-1.62 [-2.65; -0.59]
-1.51 [-2.91; -0.11]
39 -1.90 3.03 12.67
38 -2.30 3.15 12.67
39 -1.50 3.03 12.67
116
38
0.80
0.80
0.80
3.30
3.30
3.30
-2.70 [-4.75; -0.65]
-3.10 [-5.17; -1.03]
-2.30 [-4.35; -0.25]
-2.70 [-3.69; -1.71]
28 -0.26
28 -0.26
56
SYSTEMATIC REVIEW AND META-ANALYSIS
SGLT-2
Total Mean
SD
Study
Heterogeneity: I-squared=0%, p=0.5427
drug = DAPA
Weber, et al., 201618 (10mg)
Weber, et al., 201617 (10mg)
Random effects model
187 -7.56 13.95
267 -6.15 13.73
454
Heterogeneity: I-squared=0%, p=0.462
drug = EMPA
Tikkanen, et al., 201519 (10mg)
Tikkanen, et al., 201519 (25mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.768
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
drug = ERTU
Amin, et al., 201520 (1mg)
Amin, et al., 201520 (5mg)
Amin, et al., 201520 (25mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.8655
Random effects model
1235
-1.83 [-2.35; -1.31]
814
Heterogeneity: I-squared=0%, p=0.759
-4
-2
0
2
4
24-hr DBP
Figure 4. Effect of SGLT2 inhibitors on 24-hour diastolic blood pressure. CANA indicates canagliflozin; DAPA, dapagliflozin; DBP,
diastolic blood pressure; EMPA, empagliflozin; ERTU, ertugliflozin; MD, mean difference; SGLT2, sodium-glucose cotransporter 2 inhibitor.
1.07),
3.70 mm Hg (95% CI,
7.52 to 0.11), and
3.65 mm Hg (95% CI, 4.96 to 2.34), respectively. No
significant difference between individual SGLT-2 inhibitors
was noted (P=0.90). There was also no strong evidence of
small-study effects (Egger’s test, P=0.25; Figure 3).
Only 4 of the 6 RCTs reported data for 24-hour diastolic
BP. SGLT2 inhibitor use was associated with a statistically
significant 1.83 mm Hg reduction in 24-hour diastolic BP
when compared with placebo (95% CI, 2.35 to 1.31;
I2=0.76; Figure 4).15,17–20 The mean differences observed
Figure 5. Contour-enhanced funnel plots of 24-hour diastolic blood pressure.
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
6
Effects of SGLT2 Inhibitors on 24-Hour BP
drug = CANA
Townsend, et al., 201615 (100mg)
Townsend, et al., 201615 (300mg)
Random effects model
SGLT-2
Total Mean
57
56
113
SD
-5.05 8.66
-7.36 11.66
Placebo
Total Mean
SD
Mean difference
MD
95%-CI
9.87
9.87
-4.40 [ -8.69; -0.11]
-6.71 [-11.47; -1.95]
-5.43 [-20.03; 9.16]
25 -0.80 9.31
263 -6.90 20.69
288
-8.00 [-14.11; -1.89]
-3.10 [ -6.60; 0.40]
-4.31 [-31.17; 22.55]
28 -0.65
28 -0.65
56
SYSTEMATIC REVIEW AND META-ANALYSIS
Study
Baker et al
Heterogeneity: I-squared=0%, p=0.4801
drug = DAPA
Heerspink, et al., 201316 (10mg)
Weber, et al., 201617 (10mg)
Random effects model
24 -8.80 12.25
267 -10.00 20.43
291
Heterogeneity: I-squared=46.2%, p=0.1727
drug = EMPA
Tikkanen, et al., 201519 (10mg)
Tikkanen, et al., 201519 (25mg)
Random effects model
276
276
552
-3.40
-4.12
9.55 135.50
9.55 135.50
271
0.38
0.38
8.74
8.74
-3.78 [ -5.63; -1.93]
-4.50 [ -6.35; -2.65]
-4.14 [ -8.71; 0.43]
39
38
39
116
-2.90
-3.60
-4.20
4.78
5.35
4.64
12.67
12.67
12.67
38
0.80
0.80
0.80
5.19
5.19
5.19
-3.70
-4.40
-5.00
-4.37
Heterogeneity: I-squared=0%, p=0.5903
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
drug = ERTU
Amin, et al., 201520 (1mg)
Amin, et al., 201520 (5mg)
Amin, et al., 201520 (25mg)
Random effects model
[ -6.93; -0.47]
[ -7.73; -1.07]
[ -8.21; -1.79]
[ -6.00; -2.74]
Heterogeneity: I-squared=0%, p=0.8547
Random effects model
1072
-4.34 [ -5.09; -3.58]
653
Heterogeneity: I-squared=0%, p=0.8987
-10
-5
0
5
10
Daytime SBP
Figure 6. Effect of SGLT2 inhibitors on daytime systolic blood pressure. CANA indicates canagliflozin; DAPA, dapagliflozin; EMPA,
empagliflozin; ERTU, ertugliflozin; MD, mean difference; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2 inhibitor.
with canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin were
2.41 mm Hg (95% CI,
9.30 to 4.48),
1.18 mm Hg (95% CI, 9.75 to 7.38), 1.51 mm Hg
(95% CI, 2.91 to 0.11), and 2.70 mm Hg (95% CI,
3.69 to
1.71), respectively. A significant difference
between individual SGLT-2 inhibitors was noted (P<0.0001).
No strong evidence of small-study effects was observed
(Egger’s test P=0.15; Figure 5).
a statistically significant 2.09 mm Hg reduction in daytime
diastolic BP when compared with placebo (95% CI, 2.63 to
1.54; I2=0.80; Figure 7).15,19,20 The mean differences
observed with canagliflozin, empagliflozin, and ertugliflozin
were 2.58 mm Hg (95% CI, 7.90 to 2.74), 1.69 mm Hg
(95% CI, 3.60 to 0.22), and 2.80 mm Hg (95% CI, 3.30
to 2.30), respectively. A significant difference between
individual SGLT-2 inhibitors was noted (P<0.0001).
Daytime BP
Nighttime BP
An analysis of the 5 RCTs that reported daytime systolic BP
showed that SGLT2 inhibitor use was associated with a
statistically significant 4.34 mm Hg reduction when
compared with placebo (95% CI, 5.09 to 3.58; I2=0.90;
Figure 6).15–17,19,20 The mean differences observed with
canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin were
5.43 mm Hg (95% CI, 20.03 to 9.16), 4.31 mm Hg (95%
CI, 31.17 to 22.55), 4.14 mm Hg (95% CI, 8.71 to 0.43),
and 4.37 mm Hg (95% CI, 6.00 to 2.74), respectively. No
significant difference between individual SGLT-2 inhibitors was
observed (P=0.75).
Only 3 RCTs reported data for daytime diastolic BP. We
found no studies that evaluated the effects of dapagliflozin on
daytime diastolic BP. SGLT2 inhibitor use was associated with
An analysis of the 5 RCTs that reported nighttime systolic BP
showed that SGLT2 inhibitor use was associated with a
statistically significant 2.61 mm Hg reduction when compared with placebo (95% CI, 3.08 to 2.14; I2=0.99;
Figure 8).15–17,19,20 The mean differences observed with
canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin were
2.11 mm Hg (95% CI, 18.94 to 14.71), 2.05 mm Hg (95%
CI, 7.58 to 3.48), 2.85 mm Hg (95% CI, 4.44 to 1.26),
and 2.46 mm Hg (95% CI, 4.04 to 0.87), respectively. No
significant difference between individual SGLT-2 inhibitors was
observed (P=0.25).
Only 3 RCTs reported data for nighttime diastolic BP. We
found no studies that evaluated the effects of dapagliflozin on
nighttime diastolic BP. SGLT2 inhibitor use was associated
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
7
Baker et al
Effects of SGLT2 Inhibitors on 24-Hour BP
SYSTEMATIC REVIEW AND META-ANALYSIS
Mean difference
SGLT-2
Total Mean SD
Placebo
Total Mean SD
drug = CANA
Townsend, et al., 201615 (100mg) 57 -2.39 5.41
Townsend, et al., 201615 (300mg) 56 -3.23 6.56
113
Random effects model
28 -0.20 5.26
28 -0.20 5.26
56
-2.19 [-4.59; 0.21]
-3.03 [-5.63; -0.43]
-2.58 [-7.90; 2.74]
276 -1.28 5.41 135.50 0.26 5.36
276 -1.58 5.35 135.50 0.26 5.36
271
552
-1.54 [-2.65; -0.43]
-1.84 [-2.94; -0.74]
-1.69 [-3.60; 0.22]
Study
MD
95%-CI
Heterogeneity: I-squared=0%, p=0.6417
drug = EMPA
Tikkanen, et al., 201519 (10mg)
Tikkanen, et al., 201519 (25mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.7063
drug = ERTU
Amin, et al., 201520 (1mg)
Amin, et al., 201520 (5mg)
Amin, et al., 201520 (25mg)
Random effects model
39 -2.10 3.19
38 -1.90 3.46
39 -1.70 3.19
116
-3.00 [-5.07; -0.93]
-2.80 [-4.92; -0.68]
-2.60 [-4.67; -0.53]
-2.80 [-3.30; -2.30]
12.67 0.90 3.30
12.67 0.90 3.30
12.67 0.90 3.30
38
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
Heterogeneity: I-squared=0%, p=0.9649
Random effects model
781
-2.09 [-2.63; -1.54]
365
Heterogeneity: I-squared=0%, p=0.8014
-4
-2
0
2
4
Daytime DBP
Figure 7. Effect of SGLT2 inhibitors on daytime diastolic blood pressure. CANA indicates canagliflozin; DAPA, dapagliflozin; DBP, diastolic
blood pressure; EMPA, empagliflozin; ERTU, ertugliflozin; MD, mean difference; SGLT2, sodium-glucose cotransporter 2 inhibitor.
with a statistically significant 1.49 mm Hg reduction in
nighttime diastolic BP when compared with placebo (95% CI,
2.20 to 0.78; I2=0.79; Figure 9).15,19,20 The mean differences observed with canagliflozin, empagliflozin, and ertugliflozin were
1.54 mm Hg (95% CI,
12.25 to 9.17),
1.14 mm Hg (95% CI, 1.45 to 0.82), and 2.49 mm Hg
(95% CI, 4.60 to 0.38), respectively. A significant difference between individual SGLT-2 inhibitors was observed
(P=0.02).
Metaregression
Random-effects metaregression analysis showed no significant association between the 24-hour ambulatory systolic or
diastolic BP and either baseline BP (P=0.96, P=0.69, respectively) or changes in body weight (P=0.44; P=0.88, respectively). Because relatively few studies for each drug reported
24-hour ambulatory BP data, we could not perform metaregression by individual drug dose.
Discussion
This meta-analysis involving 2098 participants showed that
SGLT2 inhibitors significantly reduce 24-hour ambulatory
DOI: 10.1161/JAHA.117.005686
systolic BP by
3.76 mm Hg and 24-hour ambulatory
diastolic BP by 1.83 mm Hg. These results are similar to
a previous meta-analysis of seated clinic BP, which showed a
reduction in systolic BP of 3.8 mm Hg and diastolic BP of
1.6 mm Hg.5 Additionally, our results show that SGLT2
inhibitors significantly reduce daytime systolic and diastolic
BP and, to a lesser extent, nighttime systolic and diastolic BP.
The effects of SGLT2 inhibitors on 24-hour ambulatory BP
were consistent across the doses used in clinical trials. No
association was found between baseline BP and change in
body weight. Because direct comparisons between individual
agents could not be made, the reduction in 24-hour ambulatory BP observed with SGLT2 inhibitors should be considered a class effect.
The exact mechanism(s) through which SGLT2 inhibitors
lower BP are not completely understood, but are likely
multifactorial. SGLT2 inhibitors induce volume contraction
because of natriuretic and osmotic diuretic effects.1 Because
of chronic caloric deficit as a result of glucose excretion in the
urine, SGLT2 inhibitors can also induce weight loss and, more
important, body composition improvements by reduction of
fat mass with minor changes in lean mass.1,21 Fat mass
reduction has been reported to improve BP, proposing this as
an additional mechanism of BP reduction with SGLT2
Journal of the American Heart Association
8
Effects of SGLT2 Inhibitors on 24-Hour BP
drug = CANA
Townsend, et al., 201615 (100mg)
Townsend, et al., 201615 (300mg)
Random effects model
SYSTEMATIC REVIEW AND META-ANALYSIS
Study
Baker et al
Mean difference
SGLT-2
Total Mean
SD
Placebo
SD
Total Mean
57 -4.33 11.51
56 -6.98 12.88
113
28 -3.49 12.47
28 -3.49 12.47
56
-0.84 [ -6.34; 4.66]
-3.49 [ -9.21; 2.23]
-2.11 [-18.94; 14.71]
24 -1.90 12.50
266 -8.80 22.88
290
25 -0.60 11.48
263 -6.50 23.17
288
-1.30 [ -8.03; 5.43]
-2.30 [ -6.22; 1.62]
-2.05 [ -7.58; 3.48]
MD
95%-CI
Heterogeneity: I-squared=0%, p=0.5128
drug = DAPA
Heerspink, et al., 201316 (10mg)
Weber, et al., 201617 (10mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.8013
drug = EMPA
Tikkanen, et al., 201519 (10mg)
Tikkanen, et al., 201519 (25mg)
Random effects model
276 -2.22 10.21 135.50
276 -2.47 11.09 135.50
552
271
-2.73 [ -4.83; -0.63]
-2.98 [ -5.14; -0.82]
-2.85 [ -4.44; -1.26]
0.51 10.22
0.51 10.22
Heterogeneity: I-squared=0%, p=0.8709
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
drug = ERTU
Amin, et al., 201520 (1mg)
Amin, et al., 201520 (5mg)
Amin, et al., 201520 (25mg)
Random effects model
39 -2.60
38 -3.60
39 -2.40
116
5.89
6.45
6.05
12.67 -0.40
12.67 -0.40
12.67 -0.40
38
-2.20 [ -6.13; 1.73]
-3.20 [ -7.23; 0.83]
-2.00 [ -5.95; 1.95]
-2.46 [ -4.04; -0.87]
6.29
6.29
6.29
Heterogeneity: I-squared=0%, p=0.9054
Random effects model
1071
-2.61 [ -3.08; -2.14]
653
Heterogeneity: I-squared=0%, p=0.9983
-5
0
5
Nighttime SBP
Figure 8. Effect of SGLT2 inhibitors on nighttime systolic blood pressure. CANA indicates canagliflozin; DAPA, dapagliflozin; EMPA,
empagliflozin; ERTU, ertugliflozin; MD, mean difference; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2 inhibitor.
inhibitors.1 Treatment with SGLT2 inhibitors also improves
arterial compliance, which is associated with improved BP.1
Furthermore, SGLT2 inhibitors reduce sympathetic nervous
system activity and, as recently suggested, renin-angiotensinaldosterone system activity by increasing sodium delivery at
the macula densa level in the kidney, both of which are
important determinants of BP.1,22 Further study is warranted
to identify the underlying mechanism(s) that contribute to the
apparent effects of SGLT2 inhibitors on BP.
In the current meta-analysis, it appears that the observed
BP reduction with SGLT2 inhibitors persists throughout a 24hour day with a greater percent reduction in BP during the
daytime compared with nighttime. This may be, in part,
attributed to the glucose-dependent nature of how SGLT2
inhibitors improve glycemic control, considering that osmotic
diuresis is likely increased during daytime periods of higher
caloric and fluid intake. Reduced urine production at night
attributed to circadian rhythms in kidney function may also
explain the reduced BP-lowering effect at nighttime. Of
course, the BP-lowering effect of SGLT2 inhibitors may also
be independent of diuresis, and differences in diurnal and
nocturnal BP regulation may reflect differences in sympathetic
tone.
DOI: 10.1161/JAHA.117.005686
The effects of other antihyperglycemic therapies on 24hour ambulatory BP have also been reported. In a study of
220 patients, metformin was shown to have no significant
effect on 24-hour ambulatory BP.23 Sitagliptin, at doses of
50 mg twice-daily and 100 mg twice-daily, produced a small,
but significant, reduction in 24-hour ambulatory systolic and
diastolic BP of
2.0 to
2.2 mm Hg and
1.6 to
1.8 mm Hg, respectively, when compared with placebo.24
Twice-daily exenatide25 and once-daily liraglutide26 have not
been shown to significantly reduce 24-hour ambulatory BP,
whereas dulaglutide 1.5 mg once-weekly significantly reduced
24-hour systolic BP by 2.8 mm Hg (95% CI, 4.6 to 1.0,
P≤0.001) compared with placebo.27 Interestingly, rosiglitazone significantly reduced 24-hour ambulatory systolic BP
( 3.8 mm Hg) at both 6 and 12 months, when compared
with adding metformin ( 1.2 to 1.3 mm Hg; 6 months,
P=0.015; 12 months, P=0.031) to background sulfonylurea
therapy.28 Similar reductions with rosiglitazone were also
observed for 24-hour ambulatory diastolic BP. It is well
established that hyperinsulinemia resulting from insulin
resistance is associated with elevated BP; however, the
effects of exogenous insulin on BP are variable.29,30 Despite
the favorable effects of select antihyperglycemic therapies on
Journal of the American Heart Association
9
Effects of SGLT2 Inhibitors on 24-Hour BP
SGLT-2
Total Mean SD
drug = CANA
Townsend, et al., 201615 (100mg) 57 -1.73 6.48
Townsend, et al., 201615 (300mg) 56 -3.42 8.06
Random effects model
113
Placebo
Total Mean
SYSTEMATIC REVIEW AND META-ANALYSIS
Study
Baker et al
Mean difference
MD
SD
95%-CI
28 -0.98
28 -0.98
56
7.75
7.75
-0.75 [ -4.08; 2.58]
-2.44 [ -6.00; 1.12]
-1.54 [-12.25; 9.17]
276 -0.80 6.21 135.50 0.36
276 -0.75 6.32 135.50 0.36
271
552
6.80
6.80
-1.16 [ -2.52; 0.20]
-1.11 [ -2.48; 0.26]
-1.14 [ -1.45; -0.82]
4.40
4.40
4.40
-2.40
-3.40
-1.70
-2.49
Heterogeneity: I-squared=0%, p=0.4969
drug = EMPA
Tikkanen, et al., 201519 (10mg)
Tikkanen, et al., 201519 (25mg)
Random effects model
Heterogeneity: I-squared=0%, p=0.9594
drug = ERTU
Amin, et al., 201520 (1mg)
Amin, et al., 201520 (5mg)
Amin, et al., 201520 (25mg)
Random effects model
39 -1.60 4.30
38 -2.60 4.72
39 -0.90 4.46
116
12.67 0.80
12.67 0.80
12.67 0.80
38
[ -5.17; 0.37]
[ -6.25; -0.55]
[ -4.50; 1.10]
[ -4.60; -0.38]
Heterogeneity: I-squared=0%, p=0.704
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
Random effects model
781
-1.49 [ -2.20; -0.78]
365
Heterogeneity: I-squared=0%, p=0.7902
-6
-4
-2
0
2
4
6
Nighttime DBP
Figure 9. Effect of SGLT2 inhibitors on nighttime diastolic blood pressure. CANA indicates canagliflozin; DAPA, dapagliflozin; DBP, diastolic
blood pressure; EMPA, empagliflozin; ERTU, ertugliflozin; MD, mean difference; SGLT2, sodium-glucose cotransporter 2 inhibitor.
24-hour ambulatory BP, none have been shown to improve
cardiovascular outcomes. This is possibly attributed to other
deleterious effects that may offset any benefit from a
reduction in 24-hour ambulatory BP, such as the increase in
plasma volume observed with thiazolidinediones.31 Our analysis demonstrates that the SGLT2 inhibitors are the only
known class to have a consistent and significant reduction in
24-hour ambulatory BP regardless of which agent is used.
The EMPA-REG OUTCOME trial3 was the first study to
demonstrate that an antihyperglycemic therapy, empagliflozin, significantly reduces death from cardiovascular causes,
death from any cause, and hospitalization for heart failure.
Additionally, a prespecified analysis of the EMPA-REG
OUTCOME trial showed that empagliflozin also reduces
progression of diabetic nephropathy.32 In the EMPA-REG
OUTCOME study, empagliflozin reduced seated clinic systolic
BP by 4 to 6 mm Hg at week 16, whereas diastolic BP
was similar to placebo.3,33 Ongoing cardiovascular safety
trials with canagliflozin (CANVAS [CANagliflozin cardioVascular Assessment Study], NCT01032629) and dapagliflozin
DECLARE-TIMI 58 ([Dapagliflozin Effect on CardiovascuLAR
Events-TIMI 58], NCT01730534) will determine whether the
cardiovascular benefit of empagliflozin is a class effect. Much
remains to be determined regarding the specific mechanism
for how empagliflozin improves mortality and decreases heart
failure hospitalizations, yet it seems feasible that the reductions in BP would contribute.
DOI: 10.1161/JAHA.117.005686
It is important to note the limitations of this analysis. Study
protocols related to the measurement of 24-hour ambulatory
BP varied between studies, as did baseline BP. However,
metaregression showed no effects of SGLT2 inhibitors on BP
according to baseline BP. Additional heterogeneity in the
study populations also exists, such as presence or absence of
a hypertension diagnosis and use and duration of background
antihyperglycemic and antihypertensive therapies. Moreover,
we were unable to test whether the observed reduction in 24hour ambulatory BP would result in improvement in cardiovascular outcomes. The power of the statistical tests for
funnel plot symmetry is likely to be low because of less than
10 trials being included.
Conclusions
This meta-analysis shows that SGLT2 inhibitors significantly
improve overall 24-hour ambulatory BP and daytime and
nighttime BP in a diurnal fashion. The linear relationship
between 24-hour ambulatory BP and risk of cardiovascular
events, especially in patients with diabetes mellitus, suggests
that the favorable effects of SGLT2 inhibitors on 24-hour
ambulatory BP may, at least in part, contribute to a reduction in
cardiovascular risk.7,34,35 While additional study is warranted to
investigate mechanisms to describe the BP-lowering effects of
SGLT2 inhibitors and the impact of these effects on clinical
outcomes, these data highlight a unique characteristic of this
Journal of the American Heart Association
10
Effects of SGLT2 Inhibitors on 24-Hour BP
Baker et al
Sources of Funding
Mr Carbone, MS, is supported by a Mentored Clinical and
Population Research Award from the American Heart Association. Dr Abbate has received research support from
Janssen Pharmaceuticals.
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
Disclosures
Dr Abbate has served as a consultant for Janssen Pharmaceuticals. The other authors have no disclosures to report.
References
1. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular
considerations of SGLT2 inhibition. Nat Rev Nephrol. 2016;13:11–26.
2. Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a
sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014;53:213–225.
Research and Quality; 2014. Chapters Available at: www.effectivehealthcare.a
hrq.gov. Accessed April 12, 2017.
12. IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method
for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol.
2014;14:25. DOI: 10.1186/1471-2288-14-25.
13. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
meta-analyses. BMJ. 2003;327:557–560.
14. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis
detected by a simple, graphical test. BMJ. 1997;315:629–634.
15. Townsend RR, Machin I, Ren J, Trujillo A, Kawaguchi M, Vijapurkar U, Damaraju
CV, Pfeifer M. Reductions in mean 24-hour ambulatory blood pressure after 6week Treatment with canagliflozin in patients with type 2 diabetes mellitus and
hypertension. J Clin Hypertens (Greenwich). 2016;18:43–52.
16. Lambers-Heerspink HJ, De Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a
glucose-regulating drug with diuretic properties in subjects with type 2
diabetes. Diabetes Obes Metab. 2013;15:853–862.
17. Weber MA, Mansfield TA, Alessi F, Iqbal N, Parikh S, Ptaszynska A. Effects of
dapagliflozin on blood pressure in hypertensive diabetic patients on reninangiotensin system blockade. Blood Press. 2016;25:93–103.
18. 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.
19. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ.
Empagliflozin reduces blood pressure in patients with type 2 diabetes and
hypertension. Diabetes Care. 2015;38:420–428.
20. Amin NB, Wang X, Mitchell JR, Lee DS, Nucci G, Rusnak JM. Blood pressure
lowering effect of the sodium glucose co-transporter-2 inhibitor, ertugliflozin,
assessed via ambulatory blood pressure monitoring in patients with type 2
diabetes and hypertension. Diabetes Obes Metab. 2015;17:805–808.
21. Cefalu WT, Leiter LA, Yoon K-H, Arias P, Niskanen L, Xie J, Balis DA,
Canovatchel W, Meininger G. Efficacy and safety of canagliflozin versus
glimepiride in patients with type 2 diabetes inadequately controlled with
metformin (CANTATA-SU): 52 week results from a randomised, double-blind,
phase 3 non-inferiority trial. Lancet. 2013;382:941–950.
c M, Cherney DZI. Sodium–glucose cotransporter-2 inhibition and the
22. Skrti
potential for renal protection in diabetic nephropathy. Curr Opin Nephrol
Hypertens. 2015;24:96–103.
3. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M,
Devins T, Johansen OE, Woerle HJ, Broedi JC, Inzucchi SE. Empagliflozin,
cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med.
2015;373:2117–2128.
23. Wulffele MG, Kooy A, Lehert P, Betst D, Donker AJM, Stehouwer CD. Does
metformin decrease blood pressure in patients with type 2 diabetes
intensively treated with insulin? Diabet Med. 2005;22:907–913.
4. U.S. Food and Drug Administration. FDA approves Jardiance to reduce
cardiovascular death in adults with type 2 diabetes. Available at: http://
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.
htm. Accessed January 11, 2017.
24. Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA,
Herman GA. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood
pressure in nondiabetic patients with mild to moderate hypertension. J Clin
Pharmacol. 2008;48:592–598.
5. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB.
Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a
systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–275.
25. Gill A, Hoogwerf BJ, Burger J, Bruce S, Macconell L, Yan P, Braun D, Giaconia J,
Malone J. Effect of exenatide on heart rate and blood pressure in subjects with
type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot
study. Cardiovasc Diabetol. 2010;9:6. DOI: 10.1186/1475-2840-9-6.
6. Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium
glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus:
cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752–772.
7. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E,
McCormack P, Staessen JA, O’Brien E. Superiority of ambulatory over clinic
blood pressure measurement in predicting mortality: the Dublin outcome
study. Hypertension. 2005;46:156–161.
8. Franklin SS, Thijs L, Li Y, Hansen TW, Boggia J, Liu Y, Asayama K, BjorklundBodegard K, Ohkubo T, Jeppesen J, Torp-Pedersen C, Dolan E, Kuznetsova T,
Stolarz-Skrzypek K, Tikhonoff V, Malyutina S, Casiglia E, Nikitin Y, Lind L, Sandoya
E, Kawecka-Jaszcz K, Filipovsky J, Imai Y, Wang J, Ibsen H, O’Brien E, Staessen JA;
International Database on Ambulatory blood pressure in relation to Cardiovascular
Outcomes Investigators. Masked hypertension in diabetes mellitus: treatment
implications for clinical practice. Hypertension. 2013;61:964–971.
9. Schwartz JE, Burg MM, Shimbo D, Broderick JE, Stone AA, Ishikawa J, Sloan R,
Yurgel T, Grossman S, Pickering TG. Clinic blood pressure underestimates
ambulatory blood pressure in an untreated employer-based US population:
results from the Masked Hypertension Study. Circulation. 2016;134:1794–1807.
10. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P,
Stewart LA. Preferred reporting items for systematic review and meta-analysis
protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1. DOI: 10.1186/
2046-4053-4-1.
11. Methods guide for effectiveness and comparative effectiveness reviews. AHRQ
Publication No. 10(14)-EHC063-EF. Rockville, MD: Agency for Healthcare
DOI: 10.1161/JAHA.117.005686
26. Lovshin JA, Barnie A, DeAlmeida A, Logan A, Zinman B, Drucker DJ. Liraglutide
promotes natriuresis but does not increase circulating levels of atrial
natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes
Care. 2015;38:132–139.
27. Ferdinand KC, White WB, Calhoun DA, Lonn EM, Sager PT, Brunelle R, Jiang
HH, Threlkeld RJ, Robertson KE, Geiger MJ. Effects of the once-weekly
glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood
pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension. 2014;64:731–737.
28. Komajda M, Curtis P, Hanefeld M, Beck-Nielsen H, Pocock SJ, Zambanini A, Jones
NP, Gomis R, Home PD. Effect of the addition of rosiglitazone to metformin or
sulfonylureas versus metformin/sulfonylurea combination therapy on ambulatory
blood pressure in people with type 2 diabetes: a randomized controlled trial (the
RECORD study). Cardiovasc Diabetol. 2008;7:10. DOI: 10.1186/1475-2840-7-10.
29. Tiwari S, Riazi S, Ecelbarger CA. Insulin’s impact on renal sodium transport and
blood pressure in health, obesity, and diabetes. Am J Physiol Renal Physiol.
2007;293:974–984.
30. Heise T, Magnusson K, Heinemann L, Sawicki PT. Insulin resistance and the
effect of insulin on blood pressure in essential hypertension. Hypertension.
1998;32:243–248.
31. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M,
Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. Thiazolidinedione use,
fluid retention, and congestive heart failure. Circulation. 2003;108:2941–
2948.
Journal of the American Heart Association
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SYSTEMATIC REVIEW AND META-ANALYSIS
class. It also emphasizes the need for monitoring BP outside of
the clinic through the use of home BP monitoring or 24-hour
ambulatory BP monitoring, when available, to better monitor for
hypotension. Caution is warranted in individuals with lower
baseline BP and/or those already receiving diuretic therapies,
whereas volume status should also be monitored closely.36
Together with cardiovascular outcomes data from EMPA-REG
and this meta-analysis on 24-hour ambulatory BP, the evidence
continues to suggest a favorable effect of SGLT2 inhibitors on
cardiovascular outcomes in patients with diabetes mellitus.
Effects of SGLT2 Inhibitors on 24-Hour BP
Baker et al
33. Perseghin G, Solini A. The EMPA-REG outcome study: critical appraisal and
potential clinical implications. Cardiovasc Diabetol. 2016;15:85. DOI: 10.
1186/s12933-016-0403-8.
34. Eguchi K, Pickering TG, Hoshide S, Ishikawa J, Schwartz JE, Shimada K, Kario K.
Ambulatory blood pressure is a better marker than clinic blood pressure in
predicting cardiovascular events in patients with/without type 2 diabetes. Am
J Hypertens. 2008;21:443–450.
35. Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De
Bacquer DA. Daytime and nighttime blood pressure as predictors of death and
cause-specific cardiovascular events in hypertension. Hypertension.
2008;51:55–61.
36. Cherney DZ, Udell JA. Use of Sodium Glucose Cotransporter 2 Inhibitors in the
Hands of Cardiologists: With Greater Power Comes Great Responsibility.
Circulation. 2016;134:1915–1917.
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
DOI: 10.1161/JAHA.117.005686
Journal of the American Heart Association
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SYSTEMATIC REVIEW AND META-ANALYSIS
32. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Matthewus
M, Johansen OE, Woerle HJ, Broedl UC, Zinman B. Empagliflozin and
progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:
323–334.
Effects of Sodium−Glucose Cotransporter 2 Inhibitors on 24−Hour Ambulatory Blood
Pressure: A Systematic Review and Meta−Analysis
William L. Baker, Leo F. Buckley, Michael S. Kelly, John D. Bucheit, Eric D. Parod, Roy Brown,
Salvatore Carbone, Antonio Abbate and Dave L. Dixon
Downloaded from http://jaha.ahajournals.org/ by guest on June 18, 2017
J Am Heart Assoc. 2017;6:e005686; originally published May 18, 2017;
doi: 10.1161/JAHA.117.005686
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