Articles

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
Michael A Weber, Traci A Mansfield, Valerie A Cain, Nayyar Iqbal, Shamik Parikh, Agata Ptaszynska

Summary
Background Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor Lancet Diabetes Endocrinol 2015
for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium–glucose Published Online
cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients November 24, 2015
http://dx.doi.org/10.1016/
already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2
S2213-8587(15)00417-9
inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension.
This online publication has
been corrected.
Methods In this double-blind, placebo-controlled, phase 3 study we enrolled patients from 311 centres in 16 countries The corrected version first
across five continents. Patients had uncontrolled type 2 diabetes (HbA1c 7·0%–10·5%; 53–91 mmol/mol) and appeared at thelancet.com/
diabetes-endocrinology on
hypertension (systolic 140–165 mm Hg and diastolic 85–105 mm Hg at both enrolment and randomisation, and a mean
November 27, 2015
24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of randomisation) and were receiving
See Online/Comment
oral antihyperglycaemic drugs, insulin, or both, plus a renin–angiotensin system blocker and an additional http://dx.doi.org/10.1016/
antihypertensive drug. Using an interactive voice-response system, we randomly assigned (1:1) patients to S2213-8587(15)00457-X
dapagliflozin 10 mg once a day or to placebo, with randomisation stratified by additional antihypertensive drug use SUNY Downstate College of
and insulin use at baseline, in a block size of two. The co-primary endpoints were changes in seated systolic blood Medicine, Brooklyn, NY, USA
pressure and HbA1c measured in the full analysis set, which included all patients who received at least one dose of (M A Weber MD); AstraZeneca,
Fort Washington, PA, USA
study drug and had both a baseline and at least one post-baseline measurement of efficacy. This trial is registered with (T A Mansfield PhD);
ClinicalTrials.gov, number NCT01195662. AstraZeneca, Wilmington, DE,
USA (V A Cain MSc);
Findings Between Oct 29, 2010, and Oct 4, 2012, we randomly assigned 225 patients to dapagliflozin and 224 to placebo. AstraZeneca, Gaithersburg,
MD, USA (N Iqbal MD,
Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin (adjusted mean change S Parikh MD); and Bristol-Myers
from baseline –11·90 mm Hg [95% CI –13·97 to –9·82]) compared with those assigned to placebo (–7·62 mm Hg Squibb, Princeton, NJ, USA
[–9·72 to –5·51]; placebo-adjusted difference for dapagliflozin −4·28 mm Hg [–6·54 to –2·02]; p=0·0002). Reductions (A Ptaszynska MD)
in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin (adjusted mean change Correspondence to:
from baseline –0·63% [95% CI –0·76 to –0·50]) than in those assigned to placebo (–0·02% [–0·15 to 0·12]; placebo- Dr Michael A Weber, SUNY
Downstate College of Medicine,
adjusted difference –0·61% [–0·76 to –0·46,]; p<0·0001). In a post-hoc analysis, we found difference in blood pressure New York, NY 10021, USA
versus placebo was greater in patients receiving a β blocker (−5·76 mm Hg [95% CI −10·28 to −1·23]) or a calcium- michaelwebermd@cs.com
channel blocker (−5·13 mm Hg, [−9·47 to −0·79]) as their additional antihypertensive drug than in those receiving a
thiazide diuretic (–2·38 mm Hg [–6·16 to 1·40]). Adverse events were similar in the dapagliflozin and placebo groups
(98 [44%] patients vs 93 [42%], respectively, had at least one adverse event), with few adverse events related to renal
function (1% vs <1%) or volume depletion (<1% vs 0%).

Interpretation Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to
placebo. Its blood pressure-lowering properties were particularly favourable in patients already receiving a β blocker
or calcium-channel blocker. Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to
optimise control of blood pressure, adding meaningful efficacy to antihypertensive drug regimens.

Funding Bristol-Myers Squibb, AstraZeneca.

Introduction achieve blood pressure goals (mostly defined as

Hypertension is a common comorbidity that affects most
patients with type 2 diabetes and contributes to the risk of
cardiovascular disease and microvascular complications.1
Guidelines recommend that people with diabetes and
hypertension be treated with an angiotensin-converting
enzyme (ACE) inhibitor or angiotensin II receptor blocker
and indicate that multidrug therapy is often needed to
<140/90 mm Hg).1 Some glucose-lowering drugs are
known to affect blood pressure—eg, glucagon-like
peptide-1 (GLP-1) receptor agonists, thiazolidinediones,
and (in some studies) dipeptidyl peptidase 4 (DPP-4)
inhibitors produce small reductions in blood pressure.2
The most commonly prescribed classes of anti-
hypertensive drugs are ACE inhibitors, angiotensin II

www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9 1

 Articles
Research in context
Evidence before this study
On Aug 11, 2015, we searched PubMed for articles with the
search terms “SGLT2”, “T2DM”, and either “blood pressure” or
“hypertension”, to identify reports of randomised controlled
trials published in English with no date restrictions. We
identified 143 articles, 23 of which were randomised trials. All
studies reported reductions in blood pressure with
dapagliflozin, canagliflozin, empagliflozin, ipragliflozin,
remogliflozin, or sotagliflozin, with many studies reporting
statistically significant decreases. Only three study protocols
mandated that background drugs for blood pressure should be
stable during the study treatment period. Most studies
reported blood pressure as an efficacy endpoint (either as a
co-primary endpoint [n=1], secondary endpoint [n=11], or
exploratory endpoint [n=7]), although four trials included
blood pressure as a safety outcome. For most trials, the primary
endpoint was change from baseline in HbA₁C, with no other
dapagliflozin studies and only one empagliflozin study
(EMPA-REG BP) reporting change from baseline in blood
pressure as a co-primary outcome. The EMPA-REG BP study,
which was also the only other dedicated randomised trial in
patients with type 2 diabetes and hypertension, showed
significant reductions at week 12 in ambulatory 24 h systolic
blood pressure (difference vs placebo −3·44 and −4·16 mm Hg
with empagliflozin 10 mg and 25 mg, respectively; p<0·001 for
both) and seated systolic blood pressure (difference vs placebo
receptor blockers, thiazide diuretics, calcium-channel
blockers, and β adrenergic blocking agents (β blockers),
each of which lowers blood pressure via distinct
mechanisms.3
Sodium–glucose cotransporter 2 (SGLT2) inhibitors
reduce glucose reabsorption in the proximal renal tubule,
lowering blood glucose via an insulin-independent
mechanism.4 Dapagliflozin is an orally-active, highly-
selective SGLT2 inhibitor,5 which improves glycaemic
control and is well tolerated, with a favourable safety
profile in patients with type 2 diabetes.6–9 Dapagliflozin
reduces blood pressure in patients with type 2 diabetes
mellitus;10–13 an effect that has been attributed to osmotic
diuresis, mild natriuresis, and weight loss.14 Furthermore,
despite its diuretic effect, dapagliflozin decreases rather
than increases serum uric acid12 and has not been
associated with potassium abnormalities.15
Although the blood pressure-lowering effects of SGLT2
inhibitors are already established,10–13 guidance is needed
on how to use these agents in patients already receiving
the most commonly prescribed antihypertensive
regimens; most typically comprising a renin-angiotensin
system blocker plus either a diuretic, a calcium channel
blocker, or a β blocker. In this phase 3 trial, we
investigated the hypothesis that the blood pressure-
lowering and glucose-lowering effects of dapagliflozin
10 mg once a day would be superior to placebo in
2 www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9
−3·92 mm Hg and −4·80 mm Hg, respectively; p<0·001 for
both), although no information was provided about what type
or dose of antihypertensive drugs were taken by patients.
Additionally, the results of a systematic review in which data
were pooled from 27 randomised controlled trials of SGLT2
inhibitors (n=12 960) showed reductions in systolic blood
pressure of 4·0 mm Hg (95% CI 3·5–4·4) relative to control.
Added value of this study
Dapagliflozin produced clinically meaningful reductions in
blood pressure in patients with type 2 diabetes and
hypertension, irrespective of the type of concomitant
antihypertensive therapy, albeit with a smaller
placebo-adjusted reduction in patients already receiving a
thiazide diuretic. To the best of our knowledge, no previous
study with an SGLT2 inhibitor has measured blood pressure
reductions on the basis of underlying antihypertensive drugs.
Implications of all the available evidence
Our findings suggest a possible approach to identify patients with
diabetes and hypertension most likely to benefit from blood
pressure-lowering effects of SGLT2 inhibitor therapy.
Dapagliflozin might be beneficial in patients with type 2 diabetes
who require additional control of blood pressure. Further studies
are needed to elucidate long-term outcomes with dapagliflozin in
patients with type 2 diabetes and hypertension.
combination regimens of antihyperglycaemic and
antihypertensive drugs in patients with inadequately
controlled type 2 diabetes mellitus and hypertension.
Methods
Study design and participants
In this multicentre, randomised, double-blind, placebo-
controlled, phase 3 trial, we enrolled patients at 311 centres
in Australia, Canada, Colombia, Czech Republic, Denmark,
Finland, Germany, Hungary, India, Ireland, Mexico,
Poland, Puerto Rico, Romania, UK, and the USA. Eligible
patients were those with type 2 diabetes, inadequate
glycaemic control (HbA1c 7·0%–10·5%; 53–91 mmol/mol),
and inadequately controlled hypertension (systolic
140–165 mm Hg and diastolic 85–105 mm Hg at both
enrolment and randomisation, and a mean 24 h blood
pressure of ≥130/80 mm Hg by ambulatory monitoring
within 1 week of randomisation).16,17 Participants were
required to be on a stable dose of at least one oral
antihyperglycaemic drug for 6 weeks or more (≥12 weeks if
thiazolidinedione) or a stable daily dose of insulin (as
monotherapy or in combination with another oral
antihyperglycaemic drug) for 8 weeks before enrolment,
plus a stable, effective, therapeutic dose of a renin-
angiotensin system blocker (ACE inhibitor or angiotensin
II receptor blockers) and an additional antihypertensive
drug for 4 weeks or longer. The types of additional

antihypertensive drugs permitted during the study were
pre-specified as a thiazide diuretic, a thiazide-like diuretic,
a calcium-channel blocker, a β blocker, an α adrenergic
blocker, or a central α adrenergic agonist. Key exclusion
criteria included serum creatinine of 177 μmol/L or lower
(unless the patient was taking metformin, in which case
exclusionary limits were serum creatinine ≥133 μmol/L for
men and ≥124 μmol/L for women); estimated creatinine
clearance of less than 60 mL per min, and significant
hepatic disease. Full inclusion and exclusion criteria are
listed in the appendix.
The study protocol was approved by the institutional
review board or independent ethics committee at each
site and all patients provided written informed consent.
Randomisation and masking
Patients were randomly assigned (1:1) to receive
dapagliflozin 10 mg once daily or matched placebo.
Randomisation was stratified by type of additional
antihypertensive medication use and insulin use (yes vs
no) at baseline in block sizes of two. An exploratory
treatment arm in which 133 patients were randomised to
dapagliflozin 5 mg was also included in the study, and
patients continued treatment for the full study period
(data not presented here). However, during the course of
the trial, while the study was still blinded, a protocol
amendment was initiated stipulating that patients would
no longer be enrolled to the 5 mg arm. Randomisation
was done by interactive voice response system.
Randomisation codes were kept centrally at a Bristol-
Myers Squibb facility in Lawrenceville, NJ, USA.
Investigators and patients were masked to treatment
allocation throughout the treatment period, after which
the data were unmasked for reporting purposes. Masking
was done through the identical appearance of the tablets,
pill bottles, and labels.
Procedures
The trial consisted of a qualification period (14 days or
less after enrolment), a lead-in period (4 weeks), a double-
blind treatment period (12 weeks), and a follow-up period
(1 week). During the qualification period, patients were
given a baseline examination to determine eligibility.
During the lead-in period, seated blood pressure and
heart rate were measured 28 days, 14 days, and 1 day
before the treatment period. Ambulatory blood pressure
was assessed 1 day before treatment begun with
Spacelabs model 90207 ambulatory blood pressure
monitoring device (Spacelabs Healthcare, Snoqualmie,
WA, USA).
During the 12 week treatment period, patients were
dispensed 10 mg of dapagliflozin or placebo tablets to be
taken at home orally once a day in the morning. All
antihyperglycaemic and antihypertensive drugs that
participants were taking before enrolment were continued
at the same dose throughout the study, with no new drugs
permitted. Seated systolic blood pressure was measured at
www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9
Articles
each study visit (weeks 1, 2, 4, 8, and 12 after randomisation)
between 0600 h and 1100 h after an initial resting period of
10 min. The mean was determined from three replicate
measurements obtained at least 1 min apart. Patients had
fasted for 8 h or longer and had last taken their
antihypertensive and study drugs the previous day.
Patients taking insulin who had an HbA1c value at
enrolment of 7·0–7·4% had to reduce their daily insulin
dose by 25% at randomisation and maintain this reduction
throughout the treatment period to avoid hypoglycaemia
and ensure patient safety. Any patients with a greater than For the protocol see http://
10% change in mean daily insulin dose after day 1 was astrazenecagrouptrials.
pharmacm.com
discontinued. Rescue treatment for hyperglycaemia was
not permitted. Any patient with inadequate glycaemic
control (defined as a confirmed fasting plasma glucose
>15·0 mmol/L) at any time after randomisation was
discontinued. Open-label antihypertensive rescue treat-
ment was available for severe (>180/110 mm Hg) or
sustained (>165/105 and <180/110 mm Hg on two
occasions) hypertension. Adverse events and laboratory
values were assessed at every study visit, including at the
follow-up visit 1 week after treatment. Adverse events were
either volunteered by the patient or obtained through
general questioning and examination at each study visit.
Systolic blood pressure was also assessed for a final time
at the end of the follow-up period (1 week after treatment
with the study drug ended).
Outcomes
The co-primary endpoints were changes from baseline to
week 12 in seated systolic blood pressure and HbA1c.
Secondary endpoints included change from baseline to
week 12 in 24 h ambulatory systolic blood pressure,
seated diastolic blood pressure, and serum uric acid.
Exploratory endpoints included the proportion of patients
with improved blood pressure control (defined as <140/90
and <130/80 mm Hg); change from baseline to week 12
in ambulatory daytime, night-time, and trough systolic
and diastolic blood pressures; and change from baseline
to week 12 in fasting plasma glucose and bodyweight.
To assess safety, we recorded the number of patients who
had at least one adverse event, serious adverse event
(defined as those events meeting the International
Conference on Harmonisation Good Clinical Practice
criteria7), and adverse event of special interest. The
intensity of adverse events was classified according to the
investigators’ judgment. We also assessed heart rate,
measured orthostatic hypotension (defined as a decrease
of >20 mm Hg in systolic blood pressure or >10 mm Hg in
diastolic blood pressure from a supine to a standing
position) and the proportion of patients receiving rescue
treatment for severe or sustained hypertension, and took
laboratory findings (serum concentrations of potassium,
sodium, calcium, magnesium, phosphorous, chloride,
bicarbonate and creatinine, estimated glomerular filtration
rate [eGFR], haematocrit, aspartate aminotransferase,
alanine aminotransferase, alkaline phosphatase, total
3
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provided the best efficacy. On Aug 28, 2012, the protocol

2245 patients enrolled was also amended further to specify use a longitudinal
repeated measures analysis instead of an ANCOVA model
1032 did not complete the enrolment period to account for missing data in the primary efficacy analysis.
934 did not meet eligibility criteria Due to these changes, 408 patients (204 in each group;
65 withdrew consent assuming 5% do not have a post-baseline assessment)
7 lost to follow-up
2 poor or no compliance were needed for at least 80% power to detect a difference of
2 administrative reason by sponsor 4 mm Hg in mean change from baseline in seated systolic
21 other
1 adverse event blood pressure between the active and control group at a
significance level of 0·05, assuming an SD of 14 mm Hg;
and at least 94% power to detect a difference of 0·4% in
1213 completed the enrolment period
mean change from baseline in HbA1c between the groups
at significance level of 0·05, assuming an SD of 1·1%.
625 not randomised Efficacy was assessed in the full analysis set, which
497 did not meet eligibility criteria included all patients who received at least one dose of
69 withdrew consent
13 lost to follow-up study medication and had both a baseline and at least one
11 poor or no compliance post-baseline efficacy measurement. Data for patients after
8 administrative reason by sponsor
6 adverse event
rescue for severe or sustained hypertension were excluded
2 patient request to discontinue study treatment from blood pressure analyses from after the rescue date,
19 other but all data were included in analyses for change in HbA1c,
serum uric acid, fasting plasma glucose, and bodyweight.
588 randomised to treatment The safety analysis set included all patients who received at
least one dose of study drug, irrespective of rescue
treatment.
139 not analysed A hierarchical closed testing procedure was done
133 randomised to dapagliflozin 5 mg
6 no longer met eligibility criteria across the primary and subsequent secondary endpoints
to control family-wise type 1 error rate at a two-sided
significance level of 0·05. For the primary efficacy
analysis, we used a longitudinal repeated measures
224 randomly assigned to placebo 225 randomly assigned to dapagliflozin 10 mg
analysis using the direct likelihood method with fixed
categorical effects of treatment, week, treatment-by-week
22 not completed 14 not completed interaction, and randomisation strata, and continuous
6 withdrew consent 4 withdrew consent fixed covariates of baseline seated systolic blood pressure
3 lost to follow-up 5 no longer met study criteria
2 administrative reason by sponsor 2 lost to follow-up value and baseline seated systolic blood pressure value-
2 lack of efficacy 1 adverse event by-week interaction. If this primary analysis was
4 adverse events 1 administrative reason by
3 other sponsor
statistically significant at the 0·05 level, the statistical test
1 request to discontinue study 1 other* for the second co-primary endpoint (change from
1 no longer met study criteria baseline in HbA1c) was done. This analysis used a similar
longitudinal repeated measures analysis except that the
202 completed study 211 completed study continuous fixed covariates were baseline HbA1c and
baseline HbA1c-by-week interaction. If the comparisons
Figure 1: Trial profile
between the dapagliflozin 10 mg treatment group and
*Site disbanded before patient discontinuation information was obtained. the placebo group were significant at the 0·05 level for
both co-primary endpoints, then the statistical tests for
the secondary efficacy endpoints were done. All other
bilirubin, urine albumin to creatinine ratio [UACR]). efficacy outcomes were assessed by use of longitudinal
repeated measures analyses, apart from 24 h ambulatory
Statistical analysis systolic blood pressure and daytime ambulatory systolic
This trial (MB102077) was originally planned as a four-arm, blood pressure, for which an ANCOVA model was used,
parallel-group trial to compare the addition of the following with treatment group as an effect and baseline value and
to patients regimens: dapagliflozin 2·5 mg, dapagliflozin randomisation strata as covariates. All analyses were
5 mg, dapagliflozin 10 mg, and placebo. The protocol done with SAS/STAT version 8.2 or higher.
specified that 1104 patients should be assigned into the This study is registered with ClinicalTrials.gov, number
four groups (276 in each) in a 1:1:1:1 ratio. On Aug 18, 2010, NCT01195662.
the protocol was amended to remove the 2·5 mg treatment
arm. On Nov 1, 2011, enrolment to the 5 mg arm was Role of the funding source
discontinued when it became clear that the 10 mg dose The study funders were involved in the study design;

4 www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9

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Overall population Additional antihypertensive subgroup

Thiazide diuretic* Calcium-channel blocker* β blocker*
Placebo (n=224) Dapagliflozin Placebo (n=77) Dapagliflozin Placebo (n=61) Dapagliflozin Placebo (n=59) Dapagliflozin
(n=225) (n=92) (n=60) (n=57)
Age (years) 57·0 56·0 56·0 54·0 59·0 55·5 57·0 60·0
(51·0–62·0) (50·0–62·0) (51·0–61·0) (48·5–61·0) (51·0–62·0) (49·0–60·0) (51·0–62·0) (52·0–64·0)
Sex
Men 129 (58%) 118 (52%) 42 (55%) 50 (54%) 34 (56%) 30 (50%) 38 (64%) 30 (53%)
Women 95 (42%) 107 (48%) 35 (46%) 42 (46%) 27 (44%) 30 (50%) 21 (36%) 27 (47%)
Ethnic origin
White 157 (70%) 160 (71%) 56 (73%) 68 (74%) 36 (59%) 33 (55%) 43 (72·9) 46 (81%)
Black 17 (8%) 19 (8%) 9 (12%) 7 (8%) 6 (10%) 9 (15%) 0 2 (4%)
Asian 38 (17%) 34 (15%) 8 (10%) 11 (12%) 15 (27%) 15 (25%) 12 (20%) 6 (11%)
Other 12 (5%) 12 (5%) 4 (5%) 6 (7%) 4 (7%) 3 (5%) 4 (7%) 3 (5%)
Bodyweight (kg) 89·9 (18·4) 88·0 (20·5) 89·0 (17·7) 89·3 (22·4) 87·8 (17·4) 87·5 (21·0) 92·0 (20·1) 87·8 (17·5)
Duration of type 2 diabetes (years) 7·3 (5·0) 7·7 (5·9) 6·5 (4·6) 7·5 (6·5) 7·0 (5·6) 7·0 (5·3) 8·1 (5·1) 8·1 (5·3)
HbA₁C (%; mmol/mol) 8·0% (1·0); 64 8·1% (0·9) 65 8·0% (1·0); 8·2% (1·0); 7·8% (1·0); 8·1% (1·0); 8·2% (0·9); 8·0% (0·8);
(10·6) (10·1) 64 (11·3) 66 (10·7) 62 (11·4) 65 (10·7) 66 (9·9) 64 (8·3)
Fasting plasma glucose (mmol/L) 8·9 (2·4) 9·0 (2·5) 9·0 (2·4) 9·5 (2·5) 8·3 (2·4) 8·4 (2·3) 9·4 (2·5) 8·9 (2·5)
Participants taking insulin 16 (7·1) 18 (8·0) 4 (5·2) 5 (5·4) 3 (4·9) 7 (11·7) 7 (11·9) 4 (7·0)
Duration of hypertension (years) 9·3 (7·7) 9·4 (7·8) 8·7 (7·4) 8·5 (8·2) 9·1 (7·8) 8·5 (6·6) 9·3 (7·0) 10·6 (8·0)
Systolic blood pressure (mm Hg) 151·3 (6·7) 151·0 (7·9) 151·8 (6·9) 151·1 (8·6) 150·0 (6·4) 150·1 (7·4) 151·4 (6·9) 152·6 (7·3)
Diastolic blood pressure (mm Hg) 91·4 (4·8) 91·2 (4·8) 91·9 (5·0) 91·5 (4·7) 90·7 (4·8) 91·6 (4·9) 91·1 (4·3) 90·6 (4·8)
Selective vascular history
Coronary artery disease 10 (5%) 12 (5%) 4 (5%) 3 (3%) 2 (3%) 1 (2%) 2 (3%) 7 (12%)
Stable angina 4 (2%) 4 (2%) 2 (3%) 0 0 1 (2%) 2 (3%) 3 (5%)
Peripheral vascular disease 8 (4%) 1 (<1%) 3 (4%) 0 1 (2%) 0 2 (3%) 1 (2%)
Carotid artery disease 2 (1%) 2 (1%) 2 (3%) 0 0 1 (2%) 0 1 (2%)
Amputation 1 (<1%) 0 1 (1%) 0 0 0 0 0
History of dyslipidaemia 113 (50·4) 112 (49·8) 31 (40·3) 37 (40%) 34 (56%) 32 (53%) 32 (54%) 33 (58%)
Recent cardiovascular event† 19 (9%) 21 (9%) 8 (10%) 6 (7%) 4 (7%) 2 (3%) 5 (9%) 12 (21%)
eGFR (mL/min per 1·73 m²) 87·0 (19·5) 84·8 (19·7) 86·7 (21·3) 85·1 (21·6) 84·4 (19·3) 86·9 (17·8) 90·9 (18·7) 83·1 (18·8)

Data are median (IQR), mean (SD), or n (%). ACE=angiotensin-converting enzyme. eGFR=estimated glomerular filtration rate. *Patients who did not take an additional antihypertensive drug from any of the
three subgroups or who received drugs from more than one subgroup were excluded from subgroup analysis. †Previous myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft,
carotid endarterectomy or stenting, peripheral vascular surgery, cerebrovascular accident, transient ischaemic attack, congestive heart failure, or hospitalisation for unstable angina.

Table 1: Baseline demographics and disease characteristics, overall and by additional antihypertensive drug treatment

collection, analysis, and interpretation of data; and the
decision to submit for publication. The corresponding
author had full access to all the data in the study and had
final responsibility for the decision to submit for
publication.
Results
Between Oct 29, 2010, to Oct 4, 2012, we enrolled 1213
patients (figure 1). Of 449 patients in the full analysis set,
225 were randomly assigned to receive dapagliflozin
10 mg and 224 to receive placebo. Before protocol
amendment, 133 patients were originally assigned to
dapagliflozin 5 mg a day and continued this treatment
for the full study period (data not shown).
About 55% of participants received a stable dose of an
ACE inhibitor (126 patients assigned to dapagliflozin vs
124 assigned to placebo) and about 45% received an
angiotensin II receptor blocker (99 vs 99), in addition to a
thiazide diuretic, a thiazide-like diuretic, a calcium-
channel blocker, a β blocker, or an α adrenergic blocker.
No participants received a central α adrenergic agonist.
Antihyperglycaemic drugs included metformin
(203 [90%] of 225 assigned to dapagliflozin vs 206 [92%]
of 224 assigned to placebo), sulfonylurea (105 [47%] vs 105
[47%]), DPP-4 inhibitors (16 [7%] vs 20 [9%]),
thiazolidinedione (eight [4%] vs nine [4%]), insulin
(18 [8%] vs 16 [7%]), acarbose (five [2%] vs three [1%]), and
meglitinides (three [1%] vs none). Baseline demographics
and disease characteristics were generally well balanced
between treatment groups and additional antihyper-
tensive subgroups (table 1), although history of
cardiovascular diseases differed slightly between
additional antihypertensive drug subgroups. Most
patients had normal renal function or mild renal
impairment, and less than a tenth of patients had an
eGFR less than 60 mL/min per 1·73 m² at baseline.

www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9 5

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A Seated systolic blood pressure B HbA1C

0 0·2
Placebo 0·1
–2
Adjusted mean change from

Adjusted mean change from

Dapagliflozin 0
–4 –0·1
baseline (mm Hg)

baseline (%)
–6 –0·2
–0·3
–8 –0·4
–10 –0·5
–0·6
–12
–0·7
–14 –0·8
Baseline 2 4 8 12 Baseline 4 8 12
Time (weeks) Time (weeks)
Number at risk Number at risk
Placebo 219 218 213 205 199 Placebo 217 214 207 197
Dapagliflozin 224 221 220 212 205 Dapagliflozin 220 219 211 204

C Ambulatory systolic blood pressure* D Serum uric acid

0 20
–2 10
Adjusted mean change from

Adjusted mean change from

–4
baseline (mm Hg)

baseline (μmol/L)
0
–6
–10
–8
–20
–10
–30
–12
–14 –40

–16 –50
0 2 4 6 8 10 12 14 16 18 20 22 24 Baseline 4 8 12
Time since recording initiated (h) Time (weeks)
Number at risk Number at risk
Placebo 176 178 181 184 184 184 182 183 184 184 185 151 Placebo 217 214 207 198
Dapagliflozin 175 181 182 184 184 185 185 184 185 185 183 158 Dapagliflozin 220 219 212 204

Figure 2: Change over 12 weeks in seated systolic blood pressure (A), HbA₁C (B), 24 h ambulatory systolic blood pressure (C), and serum uric acid (D) in the full
analysis set
Error bars show 95% CIs. Blood pressure data excluded data after antihypertensive rescue treatment; data for HbA₁C and serum uric acid included data after
antihypertensive rescue treatment. *24 h ambulatory monitoring was initiated between 0600 h and 1100 h for 24 h during week 12.

Patients assigned to dapagliflozin 10 mg had
significantly greater reductions in mean seated systolic
blood pressure from baseline to week 12 than did those
assigned to placebo (adjusted mean change from
baseline –11·90 mm Hg [95% CI –13·97 to –9·82] vs
–7·62 mm Hg [–9·72 to –5·51], respectively; placebo-
adjusted difference −4·28 mm Hg [–6·54 to –2·02];
p=0·0002; figure 2A). At week 13, 1 week after the study
drug was stopped, systolic blood pressure did not differ
between the dapagliflozin and placebo groups (adjusted
mean change from baseline –10·13 mm Hg [95% CI
–12·26 to –8·01] vs –8·93 mm Hg [–11·08 to –6·78],
respectively; placebo-adjusted difference −1·20 mm Hg
[95% CI −3·56 to 1·15]).
Reductions inHbA1c concentrations were significantly
greater in patients assigned to dapagliflozin 10 mg than
in those assigned to placebo (adjusted mean change
from baseline –0·63% [95% CI –0·76 to –0·50] vs –0·02%
[–0·15 to 0·12], respectively; placebo-adjusted difference
–0·61% [–0·76 to –0·46], p<0·0001; figure 2B).
Mean reductions from baseline values of 24 h
ambulatory systolic blood pressure at week 12 were more
pronounced in patients in the dapagliflozin group than in
those in the placebo group (placebo-adjusted difference
−4·45 mm Hg [95% CI –7·14 to –1·76]; p=0·0012;
figure 2C). At 12 weeks, dapagliflozin was associated with
consistently greater reductions in ambulatory systolic
blood pressure versus placebo at every timepoint assessed
over a 24 h period. Mean seated diastolic blood pressure
fell by 6·30 mm Hg in those assigned to dapagliflozin
(95% CI 5·06 to 7·54) versus 5·33 mm Hg (4·08 to 6·59)
in those assigned to placebo, respectively (placebo-
adjusted difference −0·97 mm Hg [95% CI –2·32 to
0·39]; p=0·16). The mean change from baseline to
week 12 in fasting plasma glucose was −1·0 mmol/L
(95% CI –1·4 to −0·6) in the dapagliflozin group
compared with 0·2 mmol/L (–0·2 to 0·6) in the placebo
group, with a placebo-adjusted difference of –1·2 mmol/L
(–1·7 to –0·8). The change from baseline in serum uric
acid at week 12 was –25·39 μmol/L (95% CI −35·71 to
−15·07) in those assigned to dapagliflozin compared with
–1·72 μmol/L (−12·12 to 8·69) in those assigned to
placebo (placebo-adjusted difference −23·67 μmol/L
[95% CI –33·70 to –13·64; figure 2D).

6 www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9

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A B
n Baseline mean Difference vs placebo n Baseline mean Difference vs placebo
seated SBP, mm Hg (SD) (95% CI) HbA1C, % (SD) (95% CI)

Overall population Overall population

Placebo 199 151·3 (6·8) –4·28 (–6·54 to –2·02) Placebo 197 8·00 (0·96) –0·61 (–0·76 to –0·46)
Dapagliflozin 205 151·0 (7·9) Dapagliflozin 204 8·09 (0·91)
β blocker subgroup β blocker subgroup
Placebo 52 151·4 (6·9) –5·76 (–10·28 to –1·23) Placebo 51 8·15 (0·92) –0·80 (–1·10 to –0·50)
Dapagliflozin 51 152·6 (7·3) Dapagliflozin 51 8·01 (0·79)
Calcium-channel blocker subgroup Calcium-channel blocker subgroup
Placebo 56 150·0 (6·4) –5·13 (–9·47 to –0·79) Placebo 54 7·87 (1·02) –0·65 (–0·94 to –0·35)
Dapagliflozin 58 150·1 (7·4) Dapagliflozin 58 8·13 (0·97)
Diuretic subgroup Diuretic subgroup
Placebo 69 151·8 (6·9) –2·38 (–6·16 to –1·40) Placebo 70 8·00 (1·01) –0·45 (–0·70 to –0·19)
Dapagliflozin 80 151·1 (8·6) Dapagliflozin 79 8·18 (0·98)

–20 –10 0 –1·0 –0·5 0 0·5

Adjusted mean change (mm Hg) Adjusted mean change (%)

C D
n Baseline mean Difference vs placebo n Baseline mean Difference vs placebo
ambulatory SBP, mm Hg (SD)* (95% CI) serum uric acid, μmol/L (SD) (95% CI)

Overall population Overall population

Placebo 186 149·2 (12·7) –4·45 (–7·14 to 1·76) Placebo 198 325·28 (78·92) –23·67 (–33·70 to –13·64)
Dapagliflozin 187 146·5 (10·4) Dapagliflozin 204 334·95 (92·59)
β blocker subgroup β blocker subgroup
Placebo 46 149·8 (11·6) –6·16 (–11·70 to –0·62) Placebo 51 313·46 (71·97) –36·88 (–56·51 to –17·25)
Dapagliflozin 47 146·1 (11·1) Dapagliflozin 51 333·68 (88·03)
Calcium-channel blocker subgroup Calcium-channel blocker subgroup
Placebo 52 149·3 (13·3) –4·45 (–9·30 to 0·39) Placebo 54 318·81 (75·53) –19·63 (–38·66 to –0·59)
Dapagliflozin 50 146·3 (9·6) Dapagliflozin 58 332·49 (86·84)
Diuretic subgroup Diuretic subgroup
Placebo 67 148·8 (13·8) –4·92 (–9·42 to –0·43) Placebo 70 336·06 (87·43) –13·09 (–29·15 to 2·97)
Dapagliflozin 75 146·9 (9·5) Dapagliflozin 79 331·30 (100·52)

–20 –15 –10 –5 0 –60 –40 –20 0 20 40

Adjusted mean change (mm Hg) Adjusted mean change (μmol/L)

Figure 3: Baseline and placebo-adjusted 12 week difference in seated SBP (A), HbA₁C (B), 24 h ambulatory SBP (C), and serum uric acid (D) by additional antihypertensive drug type, in the full
analysis set
Error bars show 95% CIs. Blood pressure data excluded data after antihypertensive rescue treatment; data for HbA₁C and serum uric acid included data after antihypertensive rescue treatment. Numbers
in antihypertensive subgroups are only those with baseline and week 12 values available.*24 h ambulatory monitoring was initiated between 0600 h and 1100 h for 24 h on day 0 (baseline)
and week 12. SBP=systolic blood pressure.

We did post-hoc subgroup analyses to assess efficacy
variables by the class of additional antihypertensive drug
received by patients during the treatment period (table 1).
These analyses included only data from patients in the
thiazide diuretic, calcium-channel blocker, and β blocker
subgroups because the numbers of patients in the other
subgroups were too small to make meaningful conclusions
(<10 patients in either treatment group); patients who did
not take an additional antihypertensive drug from any of
these three subgroups or who took drugs from more than
one subgroup were excluded from this subgroup analysis.
Seated systolic blood pressure was reduced with
dapagliflozin versus placebo to a greater extent in the
β blocker subgroup and the calcium-channel blocker
subgroup than in the thiazide diuretic subgroup
(figure 3A). This difference in systolic blood pressure
between the antihypertensive subgroups was reduced
when measured with 24 h ambulatory blood pressure
monitoring (figure 3C). Seated diastolic blood pressure
showed no relevant differences between the
antihypertensive subgroups. The proportion of patients
with improved blood pressure control (<140/90 mm Hg)
was 38% (85 of 224) assigned to dapagliflozin versus 33%
(72 of 219) assigned to placebo. The proportion of patients
with improved blood pressure control (<130/80 mm Hg)
was 8% (18 of 224) assigned to dapagliflozin versus 5%
(12 of 219) assigned to placebo. Change from baseline in
ambulatory daytime, night-time and trough systolic and
diastolic blood pressures are shown in the appendix.
Slightly greater reductions in daytime ambulatory
systolic blood pressure were noted in patients assigned to
dapagliflozin versus placebo (appendix), with greater
reductions in the β blocker subgroup than in the calcium-
channel blocker or thiazide diuretic subgroups.

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Overall population Additional antihypertensive subgroup

Thiazide diuretic Calcium-channel blocker β blocker
Placebo Dapagliflozin Placebo Dapagliflozin Placebo Dapagliflozin Placebo Dapagliflozin
(n=224) (n=225) (n=77) (n=92) (n=61) (n=60) (n=59) (n=57)
One or more adverse event 93 (42%) 98 (44%) 27 (35%) 46 (50%) 26 (43%) 21 (35%) 27 (46%) 24 (42%)
Adverse events that occurred in at least 10% of participants in either treatment group
Infections and infestations 32 (14%) 44 (20%) 7 (9%) 20 (22%) 13 (21%) 8 (13%) 7 (12%) 12 (21%)
Adverse event leading to discontinuation 4 (2%) 1 (<1%) 0 1 (1%) 2 (3%) 0 1 (2%) 0
One or more serious adverse event 2 (1%) 6 (3%) 1 (1%) 2 (2%) 1 (2%) 0 0 2 (4%)
Special interest categories
Hypoglycaemia* 6 (3%) 13 (6%) 1 (1%) 2 (2%) 1 (2%) 6 (10%) 4 (7%) 5 (9%)
Renal function† 1 (<1%) 3 (1%) 0 2 (2%) 0 0 0 1 (2%)
Volume depletion†‡ 0 1 (<1%) 0 1 (1%) 0 0 0 0
Genital infection† 4 (2%) 6 (3%) 1 (1%) 4 (4%) 3 (5%) 0 0 1 (2%)
Urinary tract infection† 2 (1%) 4 (2%) 0 3 (3%) 1 (2%) 0 0 1 (2%)

Includes data after antihypertensive rescue. No deaths or malignancies were reported in the study. *We noted no major episodes of hypoglycaemia, defined as symptomatic episodes requiring external assistance
with a capillary or plasma glucose value of less than 3 mmol/L and prompt recovery after glucose or glucagon administration; minor episodes of hypoglycaemia were defined as any symptomatic or
non-symptomatic episode with a capillary or plasma glucose measurement of less than 3·5 mmol/L that did not qualify as a major episode; other episodes of hypoglycaemia were defined as investigator-reported
episodes suggestive of hypoglycaemia that did not meet these criteria. †Based on a predefined list of preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 15.1. ‡Defined as
hypotension, dehydration, or hypovolaemia.

Table 2: Summary of adverse events for the 12 week treatment period

The effect of dapagliflozin on HbA1c concentrations was
marginally more pronounced in the β blocker and
calcium-channel blocker subgroups than in the thiazide
diuretic subgroup (figure 3B). There were no clinically
relevant differences in mean change from baseline in
mean fasting plasma glucose between the additional
antihypertensive subgroups (placebo-adjusted difference
for thiazide diuretics –1·1 mmol/L [95% CI –1·9 to –0·4];
calcium-channel blocker –1·4 mmol/L [–2·3 to –0·5]; and
β blockers –0·9 mmol/L [–1·8 to 0·0]). Reductions in
serum uric acid were greater in the β blocker subgroup
than the calcium-channel blocker or thiazide diuretic
subgroups (figure 3D).
The mean change in bodyweight from baseline to
week 12 was −1·44 kg (95% CI −1·95 to −0·92) in patients
assigned to dapagliflozin versus −0·59 kg (95% CI −1·11 to
−0·07) in those assigned to placebo (placebo-adjusted
difference −0·85 kg [−1·39 to −0·31]). The timecourse for
bodyweight reduction seemed similar to that of systolic
blood pressure reduction (appendix). Bodyweight was
reduced with dapagliflozin compared with placebo to a
greater extent in the β blocker subgroup (placebo-adjusted
difference −1·51 kg [95% CI −2·64 to −0·39]) than in the
calcium-channel blocker subgroup (−0·67 kg [−1·77, 0·43])
or thiazide diuretic subgroup (−0·49 kg [−1·43 to 0·44]).
The incidence of adverse events was similar between the
dapagliflozin (98 [44%] of 225 in the safety set) and placebo
(93 [42%] of 224) group, with few events leading to
discontinuation (table 2). Adverse events were more
common in those taking dapagliflozin (n=46; 50%) than
in those taking placebo (n=37; 35%) in the thiazide diuretic
subgroup (table 2), whereas events were less common in
those taking dapagliflozin in the other subgroups. More
patients had infections with dapagliflozin than with
placebo in the thiazide diuretic subgroup (namely
asymptomatic bacteriuria, urinary tract infection,
influenza, and nasopharyngitis) and the β blocker
subgroup (namely asymptomatic bacteriuria and
nasopharyngitis), whereas these were less common with
dapagliflozin than with placebo in the calcium-channel
blocker subgroup. Few serious adverse events occurred
during the study, but more patients in the dapagliflozin
group (n=6; 3%) than in the placebo group (two [1%]) had
a serious adverse event. Only one serious adverse event (in
the placebo group) led to discontinuation.
Hypoglycaemia was uncommon in both groups, but
affected slightly more patients assigned to dapagliflozin
than those assigned to placebo (table 2). No cases of major
hypoglycaemia were reported. The incidence of
hypoglycaemia was higher in patients assigned to
dapagliflozin than in those assigned to placebo in the
calcium-channel blocker subgroup whereas it was lower
in patients in the thiazide diuretic or β blocker subgroups,
although this effect might be due to higher insulin use in
the calcium-channel blocker subgroup (table 1). Renal
function-related adverse events were low in both treatment
groups and across all antihypertensive subgroups (table 2).
All renal events were mild or moderate in intensity and
were mostly due to small changes in creatinine
concentration. Renal function in the dapagliflozin 10 mg
group remained stable over 12 weeks, with no clinically
meaningful change in mean eGFR or urinary albumin-to-
creatinine ratio (appendix). Laboratory values did not
differ between the dapagliflozin and placebo groups at
week 12 (appendix) and mean potassium and sodium
concentrations remained stable in both groups.

8 www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9


At baseline, measured orthostatic hypotension was
reported in two patients in each treatment group. At
week 12, measured orthostatic hypotension was noted in
seven (3%) patients in the dapagliflozin 10 mg group and
four (2%) in the placebo group, but no patients reported it
as an adverse event. Only two patients (both in the placebo
group) received rescue medication for severe or sustained
hypertension. Seated heart rate at 12 weeks did not
meaningfully differ from that at baseline for either group
(−1·4 beats per min [bpm] with dapagliflozin 10 mg [baseline
77·1] vs −0·5 bpm with placebo [baseline 77·0]).
Discussion
In this study, the addition of dapagliflozin to treatment
regimens for 12 weeks was associated with lowered blood
pressure and improved glycaemic control in patients with
type 2 diabetes and hypertension inadequately controlled
with up to two antihyperglycaemic drugs, a renin-
angiotensin system blocker, and an additional anti-
hypertensive drug.
Despite the concurrent antihypertensive treatments,
the observed blood pressure effects of dapagliflozin seem
potentially clinically relevant. However, for patients
already receiving a renin–angiotensin system blocker
plus a thiazide diuretic, dapagliflozin produced a rather
small reduction in placebo-adjusted systolic blood
pressure compared with those receiving a renin-
angiotensin system blocker plus a β blocker or calcium-
channel blocker. This finding is not wholly unexpected,
since adding a drug with a predominantly diuretic-
dependent antihypertensive action14 to patients already
receiving a thiazide drug might be less likely to have a
major additive effect. This explanation is supported by
our finding that the weight loss produced by dapagliflozin
in the diuretic subgroup was less than that in the
β blocker and calcium-channel blocker subgroups. Still,
we cannot exclude the possibility that the slight placebo-
subtracted effect of dapagliflozin in the diuretic group
might have been affected by the chance occurrence of a
relatively large placebo effect.
Our results show clinically meaningful, placebo-adjusted,
decreases in systolic blood pressure of 5·1 mm Hg and
5·8 mm Hg in patients treated with a β blocker or calcium-
channel blocker, respectively, which are of a similar scale to
that which might be anticipated with a conventional
diuretic added to ongoing dual antihypertensive therapy.
For example, in an authoritative trial in patients with stage 2
hypertension (>160/100 mm Hg) receiving a renin-
angiotensin system blocker plus a calcium-channel blocker,
the addition of hydrochlorothiazide 25 mg decreased
systolic blood pressure by 6·2 mm Hg and diastolic
blood pressure by 3·3 mm Hg compared with a renin–
angiotensin system blocker plus calcium-channel blocker
alone,18 an effect only marginally greater than we recorded
in the present study despite the fact that the baseline blood
pressure in the stage 2 patients was clearly higher than in
our study population.
www.thelancet.com/diabetes-endocrinology Published online November 24, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00417-9
Articles
Dapagliflozin also significantly reduced 24 h ambulatory
systolic blood pressure compared with placebo, with no
difference between the three antihypertensive subgroups
at 12 weeks. Since ambulatory blood pressure is regarded
as a highly reliable basis for assessing hypertension,19 these
results further corroborate the clinical benefits of
dapagliflozin for patients with hypertension and type 2
diabetes. Dapagliflozin was not associated with significant
reductions in diastolic blood pressure. However, systolic
blood pressure is regarded as a stronger indicator of
cardiovascular risk than is diastolic blood pressure,20 which
has led to an increased emphasis on systolic blood pressure
control in recent guidelines.3,21
Blood pressure-lowering effects have been reported for
dapagliflozin in other clinical trials10–12 and in trials of other
SGLT2 inhibitors.22,23 Furthermore, we have previously
reported that dapagliflozin treatment is complementary to
the use of renin–angiotensin system inhibitors.24 The
results of the present study expand further our
understanding of dapagliflozin and suggest that reduction
of blood pressure is maintained irrespective of the class of
additional antihypertensive drug, with a slightly greater
effect in patients already receiving a β blocker or calcium-
channel blocker than in patients already on a thiazide
diuretic. Moreover, this trial is the first with dapagliflozin
in which blood pressure was measured as a co-primary
endpoint in patients with inadequately controlled
hypertension and type 2 diabetes, with no changes or
additions of background antihypertensive drugs allowed.
We also note that patients in this study had a fairly long
duration of hypertension (mean 9·4 years) and were
uncontrolled despite dual combination therapy, suggesting
that dapagliflozin might provide beneficial blood pressure
effects in this setting. Moreover, dapagliflozin 10 mg was
generally well tolerated and, unlike conventional thiazide
diuretics,25 did not cause hypokalaemia.
The glucose-lowering actions of dapagliflozin seen in
this study have also been well documented in previous
trials.7–9 The effects of dapagliflozin were similar across
the antihypertensive subgroups, although variations in
the effects of placebo meant that the placebo-adjusted
reductions in HbA1c were slightly less substantial in the
thiazide diuretic subgroup than in the β blocker or
calcium-channel blocker subgroups.
Reductions in serum uric acid with dapagliflozin have
been reported previously,12,24 but our results confirm
decreases with dapagliflozin in all antihypertensive
subgroups (including the thiazide diuretic subgroup, in
which there might be some concern about diuretic-
induced increases in uric acid25). Dapagliflozin was also
associated with small reductions in bodyweight and,
although it is unclear whether this effect contributed to
the reduction in blood pressure, the timecourse for blood
pressure reduction followed that of bodyweight
reduction. Weight loss was slightly more pronounced
among patients in the β blocker subgroup, although this
result could have been affected by low patient numbers.
9
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Data from previous studies suggest that β blockers might
be associated with weight gain.26
Our study had some limitations. Because of the strict
criteria for enrolment, we had to include many study
sites to recruit enough patients. However, protocol
compliance and data accuracy were ensured by rigorous
monitoring. Another possible limitation, as indicated
earlier, is that the attenuated antihypertensive efficacy of
dapagliflozin in patients already receiving a thiazide
diuretic might have resulted simply from a relatively
large placebo effect, although a smaller reduction in
bodyweight seemed to confirm a lesser diuretic action of
dapagliflozin in these thiazide-treated patients. A further
limitation of the study was that very few patients with
moderate renal impairment were included because
SGLT2 inhibitors have a lower efficacy in this population.6
Additionally, despite the useful reductions in blood
pressure, our study was not designed to measure major
cardiovascular endpoints. However, an outcomes trial
with dapagliflozin is currently in progress (Dapagliflozin
Effect on CardiovascuLAR Events [DECLARE TIMI-58];
NCT01730534). Furthermore, in the recent EMPA-REG
OUTCOME trial in patients with type 2 diabetes at high
risk of cardiovascular events, the SGLT2 inhibitor
empagliflozin reduced the risk of major cardiovascular
events compared with placebo.27
Contributors
All authors contributed to the conception and design of the study, the
acquisition and interpretation of the data, and the drafting and critical
revision of this report.
Declaration of interests
MAW received research funding from Bristol-Myers Squibb, and has been
a consultant to AstraZeneca, Novartis, and Forest Pharmaceuticals. TAM is
an employee of AstraZeneca and a shareholder of AstraZeneca and
Bristol-Myers Squibb. VAC, NI, and SP are employees and shareholders of
AstraZeneca. AP is an employee and shareholder of Bristol-Myers Squibb.
Acknowledgments
This study was funded by Bristol-Myers Squibb and AstraZeneca.
Editorial assistance was provided by Helen Brereton inScience
Communications, Springer Healthcare, London, UK, funding support
for which was provided by AstraZeneca.
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