REVIEWS

Blood pressure reduction in diabetes:

lessons from ACCORD, SPRINT and
EMPA-REG OUTCOME
Pantelis A.Sarafidis1, Antonios A.Lazaridis2,3, Gema Ruiz-Hurtado4 and
LuisM.Ruilope46
Abstract | In patients with diabetes mellitus, the presence of hypertension substantially increases
the risk of cardiovascular events, and reductions in blood pressure (BP) can reduce cardiovascular
morbidity and mortality. Following evidence from trials randomizing patients to diastolic BP
levels, previous guidelines recommended an office BP target of <130/80mmHg in individuals
with diabetes mellitus. However, the evidence for this systolic BP (SBP) target was derived from
observational studies. When the results of the ACCORDBP study showed that those individuals
with diabetes mellitus and a target BP of <120mmHg had a cardiovascular risk that is similar to
those with <140mmHg, all guidelines returned to a recommended SBP of <140mmHg. However,
the ACCORDBP trial was limited by the low number of cardiovascular events observed, whereas
the mean SBP in the conventional arm was 133mmHg. The SPRINT study, showing
cardiovascular benefits in hypertensive patients without diabetes mellitus randomized to SBP
<120mmHg versus those randomized to <140mmHg, came in contrast with the ACCORDBP, but
a detailed evaluation reveals many similarities between the two trials. Finally, the EMPA-REG
OUTCOME study, with impressive cardiovascular mortality reduction with empagliflozin,
suggested that reduction of SBP to around 130mmHg is safe and might explain part of these
beneficial results. In this Review, we evaluate the implications of the ACCORDBP, SPRINT and
EMPA-REG OUTCOME trials and previous studies for the optimal BP target in diabetes mellitus.

Correspondence to P.A.S.
psarafidis11@yahoo.gr
doi:10.1038/nrendo.2016.209
Published online 20 Jan 2017
Diabetes mellitus is a major issue of public health and a
leading cause of morbidity and mortality. The prevalence
of diabetes mellitus in the general adult population is
estimated at ~8%, a number that is predicted to dou-
ble by 2030. Type2 diabetes mellitus (T2DM) accounts
for >90% of these patients1. Diabetes mellitus is a major
cardiovascular risk factor, and patients have a risk of
death that is twice as high as the risk in those without
the disease and equal to those who have had a previ-
ous myocardial infarction2,3. The increased incidence
of macrovascular and microvascular complications in
diabetes mellitus leads to a huge economic burden for
health systems worldwide4. Hypertension is also a lead-
ing cause of death, affecting nearly 30% of the adult pop-
ulation in Western countries, and is responsible for 49%
of cases of ischaemic cardiac disease, 69% of cerebro-
vascular disease and 7.1million deaths per year world-
wide57. As the control of hypertension is very poor in
most countries, the effective management of high blood
pressure (BP) is a major target of public health strategies.
The coexistence of T2DM and hypertension has
been long documented in the context of the meta-
bolic syndrome8. More than 8090% of patients with
T2DM also have hypertension9. The coexistence of
diabetes mellitus and hypertension greatly increases
cardiovascular risk. In previous studies, the presence
of T2DM almost tripled the risk of developing cardio-
vascular disease at any level of systolic BP (SBP), starting
from pre-hypertensive levels, whereas the presence of
hypertension increases cardiovascular risk by a factor
of four in patients with diabetes mellitus10,11. Based on
such findings, diabetes mellitus was clearly indicated as
a condition that conveyed high cardiovascular risk in
hypertension guidelines12.
Accumulated evidence suggests that BP reduction
in patients who have hypertension and T2DM largely
improves cardiovascular outcomes13. Although the BP
level of 140/90mmHg for diagnosis and treatment of
hypertension in the general hypertensive population
met little criticism over the past 30years, the optimal

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Key points <150/90mmHg in patients older than 60years of age

In the 2000s, international guidelines suggested a goal blood pressure (BP) of
<130/80mmHg in patients with diabetes mellitus, based mostly on observational data
and trials randomizing to diastolic BP targets
The results of the ACCORDBP trial suggested no benefit in reducing cardiovascular
events in patients with type 2 diabetes mellitus (T2DM) randomly assigned to
a systolic BP (SBP) of <120mmHg compared with <140mmHg, with the exception of
stroke, but this trial might be limited by low statistical power
New guidelines have moved the target BP for patients with diabetes mellitus to a less
strict target of <140/85mmHg or <140/90mmHg. In the SPRINT trial of patients with
hypertension, lower cardiovascular events and mortality were seen in patients
randomized to SBP <120mmHg compared with <140mmHg, which questioned
appropriate BP targets
The EMPA-REG OUTCOME trial showed major reductions in cardiovascular events
and mortality in patients with T2DM who were treated with empagliflozin;
concomitant SBP reduction from 135.3mmHg to 131.3mmHg might also question
current guidelines
Author addresses
1
Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital.
2
2nd Propaedeutic Department of Internal Medicine, Aristotle University of
Thessaloniki, Hippokration Hospital, Konstantinoupoleos 49, 54642Thessaloniki,
Greece.
3
Department of Internal Medicine, Papageorgiou Hospital, 56429 Thessaloniki, Greece.
4
Institute of Investigation and Hypertension Unit, Hospital 12 de Octubre, Avenida de
Crdoba s/n, 28041Madrid, Spain.
5
Department of Preventive Medicine and Public Health, Universidad Autonoma,
CiudadUniversitaria de Cantoblanco, 28049Madrid, Spain.
6
School of Doctoral Studies and Research, Universidad Europea de Madrid,
28670Villaviciosa de Odn, Madrid, Spain.
level to which BP should be reduced in patients with
diabetes mellitus has been a matter of considerable
debate. Observational data from the UK Prospective
Diabetes Study (UKPDS) 36 trial13 suggested that SBP
levels of 120mmHg were associated with a contin-
uous increase in cardiovascular risk. Clinical trial
data from the UKPDS38 (REF.14) and Hypertension
Optimal Treatment (HOT)15 studies demonstrated a
cardiovascular benefit with diastolic BP (DBP) levels of
<85mmHg and <80mmHg, respectively. Based on these
data, hypertension and diabetes mellitus guidelines from
the late 1990s to early 2000s and on suggested a BP target
of <130/85mmHg and subsequently of <130/80mmHg
in those with diabetes mellitus5,12,1629 (TABLE1).
This 130/80mmHg target in diabetes mellitus was
revisited after the publication of the Action to Control
Cardiovascular Risk in Diabetes Blood Pressure
(ACCORDBP) trial30, which showed that a BP target
of <120mmHg did not overall reduce fatal and nonfatal
major cardiovascular events in patients with T2DM com-
pared with a BP target of <140mmHg. The 2013 European
Society of Hypertension/European Society of Cardiology
guidelines recommended a target of <140/85mmHg
for patients with diabetes mellitus5. The latest Joint
National Committee8 guidelines moved another step
back, suggesting a BP target of <140/90mmHg for
adult patients with diabetes mellitus, as well as targets
of <140/90mmHg in adults with hypertension and
without diabetes mellitus or chronic kidney disease
(CKD)29. However, the relevance of the ACCORDBP
results to the 130mmHg target was questioned in the
literature. The publication of the seminal Systolic Blood
Pressure Intervention Trial (SPRINT) on individuals
who did not have diabetes mellitus but hypertension and
high cardiovascular risk showed that reduction of SBP
to <120mmHg resulted in significant improvements in
the incidence of cardiovascular events and revived the
discussion for the optimal BP level in hypertension31.
Furthermore, in the Empagliflozin Cardiovascular
Outcomes and Mortality in Type2 Diabetes (EMPA-REG
OUTCOME) trial32, the sodium-glucose cotransporter 2
(SGLT2) inhibitor empagliflozin reduced cardiovascular
mortality in T2DM, a result that was attributed in part
to the small but sustained BP decrease throughout the
trial33. In this Review, we discuss the implications of
the SPRINT and EMPA-REG OUTCOME trials, and
compare their results with data from ACCORDBP
and other relevant analyses for the aggressive reduction
of BP in patients with diabetes mellitus.
BP targets before ACCORDBP
As discussed, guidelines before the ACCORDBP
trial recommended a BP target of <130/80mmHg for
patients with T2DM1626. The first evidence for strict
BP control came from the UKPDS38 and HOT trials.
In the UKPDS38 trial, 1,148 patients with hyperten-
sion and T2DM were randomly assigned to BP targets
of <150/85mmHg or <180/105mmHg and achieved
mean BPs of 144/82mmHg and 154/87mmHg, respec-
tively, during 8.4years followup; significant reduc-
tions in diabetes-related death and complications were
observed in the control group14. In the HOT study 15,
18,790 patients with hypertension were randomly
assigned to three DBP targets of 90mmHg, 85mmHg
or 80mmHg. Although no difference between groups
was observed in the total study population, a 51% reduc-
tion in incidence of cardiovascular events between the
80mmHg and 90mmHg was evident for the sub-
group of 1,501 patients with T2DM, in which average
achieved BP levels from 6months of followup to the
end of the study were 148/85mmHg, 146/83mmHg
and 144/81mmHg for the three BP target groups15.
Although this observation came from a subanalysis of
the main HOT trial results, the large number of indi-
viduals and the magnitude of effect led to the recom-
mendation of the <130/80mmHg BP target in patients
with diabetes mellitus.
The main problem with a target of <130/80mmHg
is that the clinical evidence for this SBP level was
derived only from studies in which patients were ran-
domly assigned to low DBP targets (of ~8085mmHg).
Moreover, in these studies, the 130mmHg SBP level was
not even close to the actual SBPs achieved as the tight BP
control arms in UKPDS38, and HOT had mean SBPs of
144mmHg (REFS14,15). In clinical practice, a target SBP
of <130mmHg is difficult to achieve and often requires
three or more antihypertensive drugs and multiple visits
to the clinician. However, observational data supported

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Table 1 | Target blood pressure for patients with diabetes mellitus in international guidelines since 1997
Organization Year Systolic BP (mmHg) Diastolic BP (mmHg)
JNC VI 1997 <130 <85
WHO/ISH 1999 <130 <85
British Hypertension Society 1999 <140 <80
Canadian Hypertension Society 1999 <130 <80
National Kidney Foundation 2000 <130 <80
ADA 20012012 <130 <80
ESH/ESC 2003 <130 <80
JNC VII 2003 <130 <80
British Hypertension Society 2004 <130 <80
ESH/ESC 2007 <130 <80
NICE 2008 <130 <80
KDIGO 2012 140 90
ADA 2013 <140 <80
ESH/ESC 2013 <140 <85
JNC VIII 2014 <140 <90
ADA, American Diabetes Association; BP, blood pressure; ESC, European Society of Cardiology; ESH, European Society of
Hypertension; ISH, International Society of Hypertension; JNC, Joint National Committee; KDIGO, Kidney Disease Improving
Global Outcomes; NICE, National Institute for Health and Care Excellence.

the notion that lowering SBP to <130mmHg would
improve cardiovascular outcomes13, and further trials have
attempted to provide evidence for this important clinical
question. The Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Controlled
Evaluation (ADVANCE) trial randomly assigned 11,140
patients with T2DM to receive a fixed combination of
perindoprilindapamide or placebo, in addition to back-
ground antihypertensive therapy. After followup of
4.3years, and with an average BP of 135/75mmHg in the
drug group compared with 140/77mmHg in those receiv-
ing placebo, significant improvements of 9% in major
macrovascular or microvascular events (hazard ratio
(HR) 0.91; 95%CI 0.831.00; P=0.04), 18% in cardio
vascular death (HR0.82; 95%CI 0.680.98; P=0.03) and
14% in all-cause mortality (HR0.86; 95%CI 0.750.98;
P=0.03) favouring perindoprilindapamide were seen34.
These results indicated a favourable effect of further
SBP lowering but should be interpreted with caution,
as the actual comparison involved a drug intervention.
Consequently, in a subgroup analysis of 6,400 patients
from the International Verapamil SR Trandolapril Study
(INVEST) who had diabetes mellitus, hypertension and
coronary heart disease, no additional benefit was seen
in those who achieved a SBP level <130mmHg (REF.35).
An elevated risk of cardiovascular events in patients with
SBP >140mmHg during followup compared with those
with an SBP between 130mmHg and140mmHg was seen
(HR1.46; 95%CI 1.251.71; P<0.001). Furthermore,
patients in this trial who achieved an SBP <130mmHg
had a risk of a cardiovascular event that was similar to
those achieving SBP between 130mmHg and 140mmHg,
whereas those achieving an SBP <115mmHg had a
significant further increase in therisk35.
The ACCORDBP trial
The ACCORD programme included a factorial design to
investigate the effect of intensive glucose lowering, inten-
sive BP control and combination lipid therapy on cardio
vascular outcomes in high-risk patients with T2DM30.
The ACCORDBP trial was the first to study a SBP tar-
get below 130mmHg. 4,733 individuals with T2DM were
randomly assigned to an intensive-therapy group with a
SBP target <120mmHg or a standard-therapy group with
a SBP target <140mmHg. After the first year of followup,
the mean SBP in the intensive group was 119.3mmHg
(95%CI 118.9119.7) and in the standard group was
133.5mmHg (95%CI 133.1133.8). The mean DBP
was 64.4mmHg (95%CI 64.164.7) and 70.5mmHg
(95%CI 70.270.8) in the intensive and standard groups,
respectively 30. After 4.7years of followup, the two treat-
ment arms had no significant differences in the primary
composite outcome (nonfatal myocardial infarction, non
fatal stroke, death from cardiovascular causes; HR0.88;
95%CI 0.731.06; P=0.20), cardiovascular mortality
(HR1.06; 95%CI 0.741.52; P=0.74) and all-cause mor-
tality (HR1.07; 95%CI 0.851.35; P=0.55). Patients who
received intensive therapy had significant reductions in
the rate of stroke (HR0.59; 95%CI 0.390.89; P=0.01)
and nonfatal stroke (HR0.63; 95%CI 0.410.96; P=0.03).
However, this benefit must be balanced against the higher
incidence of serious adverse effects in the intensive group
(3.3% versus 1.3%; P<0.001), which included hypoten-
sion, syncope, arrhythmias, hyperkalaemia, angioedema
and renal failure. Based on these results, the authors con-
cluded that a SBP goal of <120mmHg in patients with
T2DM did not reduce cardiovascular events and that
most of the benefit might be derived from a SBP target
of <140mmHg.

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These findings were considered by international
guideline committees as evidence against a target BP
of 130/80mmHg and led to a rapid modification of the
guideline recommendations5,28,29. However, a careful
interpretation of the ACCORDBP results suggests that
several important issues need to be taken into account.
First, the low SBP goal in ACCORDBP was <120mmHg
and not <130mmHg. Second, the mean SBPs that were
achieved were 119.3mmHg and 133.5mmHg, values that
are not even close to 140mmHg. Third, the low BPs and
the good concomitant treatment led to a much lower-
than-expected cardiovascular event rate and prevented
any strong conclusions. Therefore, the conclusion of
ACCORDBP was that the SBP target of <120mmHg for
patients with T2DM cannot be recommended as it confers
benefit only for stroke and is associated with increased
incidence of adverse effects. However, the issue of the
optimal SBP goal remained largely unresolved, as with
ACCORDBP it could not be excluded that a SBP target
of <125mmHg, <130mmHg or <135mmHg reduces
cardiovascular risk compared with <140mmHg (REF.36).
Interestingly, a post hoc analysis of the effects of
combined BP and glycaemia regimes on cardiovascular
outcomes in T2DM in the ACCORD-BP trial yielded
different conclusions compared with the original trial.
In this analysis, patients were allocated to four target
groups including an intensive BP/intensive glycaemia,
intensive BP/standard glycaemia, standard BP/intensive
glycaemia and standard BP/standard glycaemia group;
intensive BP was defined as <120mmHg, standard BP as
<140mmHg, intensive glycaemia as HbA1c levels <6.0%,
and standard glycaemia as HbA1c levels 7.07.9%. A
reduced rate of the primary outcome of major cardio-
vascular events was seen in the intensive BP/intensive
glycaemia (HR0.71; 95%CI 0.520.96; P=0.026), inten- meta-analysis published in 2013 (REF.79) searched for
sive BP/standard glycaemia (HR0.74; 95%CI 0.551.00;
P=0.049) and standard BP/intensive glycaemia groups
(HR0.67; 95%CI 0.500.91; P=0.011) compared with for cardiovascular events and mortality; this analysis also
the standard BP/standard glycaemia group. For second-
ary outcomes, both groups of intensive BP treatment had
lower rates of stroke than the standard BP/standard gly-
caemia group, and most other hazard ratios were neutral
or favoured the intensive-treatment groups37.
BP targets after ACCORDBP
After publication of the ACCORDBP results, the authors
of several meta-analyses tried to clarify the optimal tar-
get BP levels in diabetes mellitus. One meta-analysis
included studies that recruited patients with diabetes
mellitus or impaired fasting glucose and/or impaired
glucose tolerance with followup longer than 1year 38. Of
13 trials, which included a total of 37,736 participants
and examined either different BP targets or drug inter-
ventions, in those patients who received intensive BP
control, all-cause mortality was reduced by 10% and
stroke by 17%30,34,3950. Meta-regression analysis suggested
a continued risk reduction in the incidence of stroke to
SBP <120mmHg; however, for BP levels <130mmHg, a
40% increase in serious adverse effects with no other ben-
efits was seen. The authors of a second meta-analysis51
included 31 studies with different BP target levels or
drug comparisons with a total of 73,913 patients with
diabetes mellitus7,30,49,5277. Patients who received a tight
BP control had a risk of stroke reduced by 39%, but the
incidence of myocardial infarction was not changed.
However, this analysis did not distinguish between dif-
ferent BP levels; thus, study arms with similar numer-
ical BP targets from different studies were grouped to
more-tight or less-tight groups depending on the BP of
the comparator. In a third meta-analysis78, with a total
of 7,312 individuals with diabetes mellitus, only five tri-
als were included, which had compared pre-specified
BP targets and had assessed at least one outcome of
mortality, myocardial infarction or stroke15,30,40,67,70. A
BP target of 130/80mmHg was associated with non
significant decreases in mortality (relative risk (RR)0.78;
95%CI 0.551.05) and myocardial infarction (RR0.93;
95%CI 0.801.08), and with a significant decrease in the
incidence of stroke (RR0.65; 95%CI 0.480.86) when
compared with 140160/85100mmHg. The strength
of this meta-analysis was the inclusion only of trials that
compared interventions to different BP goals; however,
four of five studies randomly assigned patients according
to DBP targets and two included patients who were nor-
motensive at baseline. Most importantly, in this analysis,
the ACCORDBP trial accounted for 65% of the total
population and, therefore, dominated the results. The
investigators acknowledged that from their results they
could not make any firm conclusion regarding a specific
BP target but could only comment on the comparative
effectiveness of intensive versus standard BPlowering
strategies. Furthermore, the difference between the tar-
get BPs and the actually achieved BPs in the stand-
ard treatment arms of some of these studies caused
problems similar to that of ACCORDBP. Finally, a
trials in people with diabetes mellitus randomized to
lower or to standard BP targets and reporting outcomes
included the same five studies15,30,40,67,70 of the previous
meta-analysis78. The investigators separately reported
studies that assigned patients to different SBP targets
(including only ACCORD-BP30 and providing similar
results to this trial) and those that assigned patients to
different DBP targets15,40,67,70, including 2,580 partici-
pants and showing a trend towards reduction in total
mortality in the group assigned to the tight DBP tar-
get (RR0.73; 95%CI 0.531.01) but no difference in
stroke (RR0.67; 95%CI 0.421.05), myocardial infarc-
tion (RR0.95; 95%CI 0.641.40) or in congestive heart
failure (RR1.06; 95%CI 0.581.92). An important fact
that has been overlooked is that in ACCORDBP and
subsequent meta-analyses, the RRs of all cardiovas-
cular outcomes studied pointed strongly towards an
improvement in outcomes with the intensive BP tar-
get. Consequently, one can assume that increased sta-
tistical power (for example, more cardiovascular events
in ACCORDBP) could have favoured the intensive
target groups. Based on all these data, a DBP target of
<80mmHg seems to be justified for all patients with
T2DM as, aside from the data from the HOT trial,
both study arms in ACCORDBP had DBPs below this

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level. However, whether the <130mmHg SBP target in
patients with T2DM is justified remained unanswered,
as this level was not studied in ACCORDBP. This could
be ideally answered by an adequately powered trial
comparing <130mmHg versus <140mmHg SBP goals,
in which the difference between the target BPs and the
actual BPs achieved is the same in both study arms, for
example, with actual BP within 23mmHg of the target
BP in each arm. It must be noted that, given the event
rate in the ACCORDBP study, such a trial would possi-
bly need to have a larger sample size, a longer followup
or a population with higher cardiovascular risk, or all of
them, and thus it could be more expensive to perform.
The SPRINT trial
The SPRINT trial31 attempted to identify the most
appropriate SBP target in patients with hypertension
but without diabetes mellitus. The investigators ran-
domly assigned 9,361 individuals with hypertension and
increased cardiovascular burden but not diabetes mel-
litus or prior stroke, with a baseline SBP 130mmHg,
to an intensive-treatment group with a SBP target of
<120mmHg or a standard-treatment group with a SBP
target of <140mmHg. In the standard-treatment group,
medications were adjusted to achieve an SBP between
135mmHg and 139mmHg. At baseline, patients in
both treatment arms had a mean SBP of 139.7mmHg.
At 1year followup, the mean SBP was 121.4mmHg in
the intensive-treatment group and 136.2mmHg in the
standard-treatment group; DBP was 68.7mmHg and
76.3mmHg, respectively. After 3.2years, the mean SBP
was 121.5mmHg in the intensive group and 134.6mmHg
in the standard group: a difference of 13.1mmHg.
The SPRINT trial was terminated earlier than sched-
uled owing to benefit in one treatment arm. Indeed, the
rate of the primary composite outcome (myocardial
infarction, acute coronary syndrome not resulting in
myocardial infarction, stroke, acute decompensated
heart failure or death from cardiovascular causes) was
significantly lower in the intensive-treatment group than
in the standard-treatment group (1.65% versus 2.19%
per year; HR0.75; 95%CI 0.640.89; P<0.001)31. For
secondary outcomes, patients in the intensive-treatment
group had a nonsignificant reduced risk of myocardial
infarction (HR0.83; 95%CI 0.641.09; P=0.19) and
stroke (HR0.89; 95%CI 0.631.25; P=0.50) and a signif-
icantly lower risk of heart failure (defined as hospitaliza-
tion or a visit to the emergency department that required
treatment; HR0.62; 95%CI 0.450.84; P=0.002). In
addition, patients in the intensive-treatment group had
a 27% lower risk of all-cause death (HR0.73; 95%CI
0.600.90; P=0.003) and a 43% lower risk of death
from cardiovascular causes (HR0.57; 95%CI 0.38
0.85; P=0.005). In the subpopulation of patients with
CKD, (defined as an estimated glomerular filtration rate
(eGFR) from 20ml/min/1.73m2 to <60ml/min/1.73m2),
which was considerably high (n=2,646; 28% of partici-
pants), no significant difference was seen between groups
for the composite renal outcome of a 50% decrease in
eGFR, development of end-stage renal disease or kidney
transplantation (HR0.89; 95%CI 0.421.87; P=0.76),
although the point estimate favoured the intensive group,
as the number of renal events was small following the
early termination of the trial. The overall rate of serious
adverse effects did not differ between the intensive-
treatment and standard-treatment groups (38.3% versus
37.1%; P=0.25). However, patients who received inten-
sive treatment more frequently developed hypotension
(2.4% versus 1.4%; P=0.001), syncope (2.3% versus 1.7%;
P=0.05), electrolyte abnormalities (3.1% versus 2.3%;
P<0.001) and acute kidney injury or failure (4.1% versus
2.5%; P<0.001), but not injurious falls or bradycardia.
The authors concluded that, in patients with high cardio
vascular risk but not diabetes mellitus, an SBP target of
<120mmHg versus <140mmHg resulted in reduced rates
of major cardiovascular events and all-cause death31.
Furthermore, the SPRINT trial added substantial credit
to the benefits of lowering SBP in elderly individuals with
hypertension to levels much lower than 150mmHg.
The SPRINT trial was limited by the exclusion of
specific patient populations (such as those with diabe-
tes mellitus, patients younger than 50years of age, those
with prior stroke or severe hypertension). This drawback
limits the generalizability of the study results. Moreover,
the effect of low BP on cognition and kidney function
could not be fully interpreted, as these outcomes usu-
ally require longer followup periods than those that
this trial permitted to be fully evaluated. However, some
issues relevant to the BP levels achieved in the SPRINT
trial raised important criticism. An important issue is the
way BP was measured. Patients sat in a quiet area with
no doctor present for 5minutes before measurement,
BP was then measured with an automated machine and
an average of three office BP readings was taken. The
criticism was that these measurements can result in BP
values that are lower than the values obtained by meas-
urements taken by a doctor; consequently, an automated
BP of 120mmHg could in fact correspond to an office BP
that is 10mmHg higher 80,81. However, at BPs as low as
120mmHg, the white-coat phenomenon is limited,
and office measurement closely reflects ambulatory
BP monitoring 82. Most importantly, even in the distinct
case that this mode of BP measurement effectively made
120mmHg mirror the 130mmHg level of routine clinical
practice, the 130mmHg level would still be better than
the currently recommended target of 140mmHg in the
general population5,28,29. Another issue that was discussed
is that the median SBP achieved in the SPRINT trial
throughout the 3.26years followup was 134.6mmHg
in the standard-treatment group and 121.5mmHg in the
intensive-treatment group. This observation indicates
that more than 50% of participants in the intensive-
treatment group had a SBP level above the predefined
target of the study. Therefore, it is not known whether
the outcomes would have been the same if the investiga-
tors had excluded the patients with BP levels above that
median83. However, a normal distribution of BPs around
the mean is a common phenomenon in such studies, but
this observation does not alter the validity of the results.
A point also can be made for the fact that participants in
SPRINT had an average SBP of 139.7mmHg at baseline
and patients with difficult-tocontrol BP were excluded;

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if patients with higher initial BP were included, they
would need more intensive drug therapy to achieve the
low BP target, which might increase the rate of adverse
effects84. However, even with some complications, any
potential for harm was completely offset by the lower
mortality and incidence of cardiovascular events that were
seen in the intensive-treatment group. In addition, investi-
gators in the SPRINT trial reported that the increased rate
of adverse effects might result from observation bias, as
these events were evaluated at every visit by non-blinded
clinical staff who could increasingly look for any minor
problem in the low BP arm. Moreover, patients in the
intensive-treatment group had a 30% increased rate of
unscheduled visits and consequently an opportunity to
report adverse effects more frequently than those receiving
standard treatment31.
Is the discrepancy between the results of the SPRINT
and ACCORDBP trials a true effect? And, if so, why?
For the primary outcome, the SPRINT trial had a signif-
icant 25% (P<0.001) reduction in the RR of the primary
outcome including myocardial infarction, acute coronary
syndrome, stroke, heart failure or death from cardiovas-
cular causes31, whereas in ACCORDBP a nonsignificant
12% (P=0.20) risk reduction in nonfatal myocardial
infarction, nonfatal stroke or death from cardiovascular
causes (but without heart failure) was seen30. Importantly,
the ACCORDBP trial had lower event rates than ini-
tially predicted because of a lower risk profile of the par-
ticipants included. Notably, the 95%CI for the primary
outcome in ACCORDBP (0.731.06) included the pos-
sibility of a 27% reduction, which is consistent with the
25% cardiovascular benefit observed in SPRINT. In
the SPRINT study, the intensive-treatment group had a
nonsignificant 11% reduction in the incidence of stroke,
whereas the corresponding group in the ACCORDBP
trial had a significant 41% reduction in outcome.
Furthermore, in the SPRINT trial, hospitalization or
emergency-department visit due to heart failure was
significantly reduced by 38% in the intensive-treatment
group (HR0.62; 95%CI 0.450.84; P=0.002), whereas cebo group32. Further to these data, in a 2016 analysis
a nonsignificant decrease of only 6% in hospitalization
or death from heart failure (HR0.94; 95%CI 0.701.26;
P=0.67) was seen in the ACCORDBP. The rate of myo-
cardial infarction had a nonsignificant reduction of 17%
(HR0.83; 95%CI 0.641.09; P=0.19) and 13% (HR0.87; macroalbuminuria, doubling of serum creatinine, initi-
95%CI 0.681.10; P=0.25) in the intensive-treatment ation of renal-replacement therapy or death from renal
groups of the SPRINT and ACCORDBP trials, respec-
tively. According to these data, the effects on individual
outcomes in the SPRINT and ACCORDBP trials are
generally similar and suggest a benefit of the <120mmHg
target, as it was highlighted in a meta-analysis that
included the SPRINT and ACCORDBP data85.
A reasonable question then is why did ACCORDBP
seemingly have different results from SPRINT? The
answer to this question is simple: statistical power.
The SPRINT trial had a much larger sample size than
ACCORDBP (9,361 versus 4,733) and, although prema-
turely terminated, a higher number of primary outcome
events (562 versus 445). The increased number of pri-
mary outcome events in SPRINT could be related to the
high number of other high-risk groups, apart from those
with T2DM, such as elderly individuals or patients with
CKD86. For example, in SPRINT, the average age was
higher than in ACCORDBP (68years versus 62years of
age), and patients with CKD constituted almost 28% of
the participants; in ACCORDBP, patients with a serum
creatinine level higher than 1.5mg/dl were excluded.
The results from SPRINT suggest a clinical benefit of
SBP <120mmHg in individuals older than 75years
and patients with CKD; consequently, the difference in
events in these subgroups might have enabled the study
to meet the primary outcome.
The EMPA-REG OUTCOME trial
The first trial to demonstrate cardiovascular risk reduc-
tion with an antidiabetic drug was the EMPA-REG
OUTCOME study 32. In this study, 7,028 patients with
T2DM and a high risk of cardiovascular disease were
randomly assigned to receive 10mg or 25mg of empag-
liflozin (an SGLT2 inhibitor) or placebo. After a median
observation period of 3.1years, the primary outcome
(which was nonfatal myocardial infarction, nonfatal
stroke or death from cardiovascular causes) occurred
in 10.5% of the patients in the pooled empagliflozin
group and in 12.1% of the patients in the placebo group
(HR0.86; 95%CI 0.740.99; P=0.04, for superiority).
No significant between-group difference was seen in the
secondary outcome (a composite of the primary outcome
plus hospitalization for unstable angina (P=0.08, for
superiority)). In addition, patients treated with empagli-
flozin had significantly lower rates of hospitalization for
heart failure (HR0.65; 95%CI 0.500.85; P=0.002), all-
cause mortality (HR0.68; 95%CI 0.570.82; P<0.001)
and death from cardiovascular causes (HR0.62; 95%CI
0.490.77; P<0.001). In the subgroup analysis, empag-
liflozin had a consistent benefit on cardiovascular mor-
tality across all subgroups. By contrast, no significant
difference was seen in the rate of fatal or nonfatal stroke
(HR1.18; 95%CI 0.891.56; P=0.26) between the two
groups, whereas the point estimate favoured the pla-
of the renal outcomes of the EMPA-REG OUTCOME
trial87, patients who were treated with empagliflozin had
reduced rates of the pre-specified outcome of incident
or worsening nephropathy constituted of progression to
disease (HR0.61; 95%CI 0.530.70; P<0.001). Patients
who were treated with empagliflozin also had reduced
incidence of a posthoc renal composite outcome of dou-
bling of serum creatinine, initiation of renal-replacement
therapy or death from renal disease (HR0.54; 95%CI
0.400.75; P<0.001), with significant differences existing
for all of the above-mentioned individual components
compared with placebo.
The authors of EMPA-REG OUTCOME have spec-
ulated that several mechanisms might underpin the
impressive reduction in cardiovascular events with
empagliflozin, such as decreases in HbA1c, body weight,
visceral adiposity, uric acid and albuminuria, among
others. However, the dissociation of the curves for the
outcomes that displayed the larger differences between

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groups, that is, hospitalization for heart failure and
death from cardiovascular causes, happened practi-
cally within weeks32. Consequently, the difference in
outcomes is very unlikely to be mediated by metabolic
effects, and a haemodynamic mechanism is much more
likely to be involved.
Although BP decrease cannot be the only factor
responsible for these favourable outcomes, this phe-
nomenon cannot be neglected33. All available SGLT2
inhibitors have, in randomized studies, consistently
been associated with decreases in office BP of between
35mmHg for SBP and 13mmHg for DBP, when com- effect of empagliflozin on BP, which might have been
pared with placebo or other antidiabetic agents during
followup periods of up to 208weeks88,89. This change in
BP is mainly the result of the mild natriuretic and diu-
retic effect of these drugs, resulting from a combination
of proximal tubule and osmotic diuresis, that is, through
inhibition of a small part of sodium reabsorption in the
proximal tubule and increased glycosuria, which exerts
a mild osmotic effect in the renal tubule. Other mech-
anisms, apart from BP decrease and enhanced natriu-
resis, might also be involved, including the inhibition
of renin secretion through mild increase of the tubular
sodium content in the macula densa area90, a reduction
in arterial stiffness, decreased sympathetic tone and a
shift from glucose to fatty acid oxidation resulting in
increased levels of ketones, such as hydroxybutyrate,
which might be a better fuel for the cardiac muscle9193.
Owing to the nonsignificant effect on incidence of
stroke, some investigators have questioned the benefit
of BP reduction in the EMPA-REG OUTCOME trial33.
However, empagliflozin treatment was, in fact, associ-
ated with an important rise in haematocrit levels of ~5%,
possibly due to haemoconcentration. Furthermore, the
increase in stroke incidence was also mainly a result of
events occurring after the drug treatment was stopped
and during the 4weeks of followup until study closure.
Consequently, the sustained, increased haematocrit and
the absence of empagliflozin protection might be partly
responsible for these strokeevents.
The EMPA-REG OUTCOME data confirmed previ-
ous observations on the effect of SGLT2 inhibitors on BP.
From the first weeks of treatment and until the end of the
study, patients receiving empagliflozin experienced mild
but sustained BP reduction, averaging 4mmHg for SBP
and 1.5mmHg for DBP, without increases in the heart
rate32. Notably, administration of all background anti-
hypertensive drugs could be modified upon investiga-
tor discretion. Consequently, although the number and
classes of antihypertensive drugs were similar between
the study arms at baseline, during followup, an increas-
ing number of patients in the placebo group received
antihypertensive agents of different classes (TABLE 2).
This change might have led to amelioration of the true
larger if the antihypertensive treatment had remained
constant. Importantly, the BP effect in the EMPA-REG
OUTCOME trial has been confirmed by a previous study
using ambulatory BP monitoring. In the EMPA-REG BP
study, 825 patients with diabetes mellitus and hyperten-
sion were randomly assigned to receive 10mg or 25mg
of empagliflozin or placebo for 12weeks. Patients in the
10mg and 25mg empagliflozin groups had an adjusted
mean difference of 3.44mmHg (95%CI from 4.78
to 2.09; P<0.001) and 4.16mmHg (95%CI from
5.50 to 2.83; P<0.001) in 24h SBP versus placebo,
respectively. The relevant differences in 24h DBP were
1.36mmHg (95%CI from 2.15 to 0.56; P<0.001)
and 1.72mmHg (95% CI from 2.51 to 0.93;
P<0.001), respectively. Empagliflozin significantly
reduced both daytime and night-time BP, and changes
in the office BP were consistent with the ambulatory
BP measurements94.
Of further interest are the actual BP level changes
in the EMPA-REG OUTCOME study. Individuals
with T2DM entering the study were, on average, very
well treated in terms of comorbidities32. Consequently,
patients in the pooled empagliflozin group had a mean
BP of 135.3/76.6mmHg at baseline, which was reduced
to 131.3/75.1mmHg by the end of the study. According to
all recent guidelines, such a reduction in BP should be
avoided, as it confers no additional clinical benefit for the
patient. According to those investigators who criticized
the SPRINT study, such reduction could be associated
with more serious adverse effects83,95. Given the effects
that SGLT2 inhibitors have on BP, one might think that

Table 2 | Baseline antihypertensive treatment and agents during followup in EMPA-REG OUTCOME
Antihypertensive therapy Baseline Introduction during followup
Placebo (%) Empagliflozin (%) Placebo (%) Empagliflozin (%)
ACE inhibitors/angiotensin 80.1 81 27.4 23.6
receptor blockers
-Blockers 64.2 65.2 18 15.9
Diuretics 42.3 43.7 22.7 16.2
Calcium channel blockers 33.8 32.6 18.3 12.6
Mineralocorticoid receptor 5.8 6.5 4.7 2.9
antagonists
Renin inhibitors 0.8 0.6 0.3 0.2
Other 8.2 8.2 5.9 5.0
ACE, angiotensin-converting enzyme; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcomes and Mortality in
Type2 Diabetes.

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Table 3 | Comparison of the ADVANCE and EMPA-REG OUTCOME trials
Characteristics
Mean follow-up (years)
Mean baseline SBP/DBP
(mmHg)
Mean end of study SBP/
DBP (mmHg)
Outcomes RR reduction versus placebo group (P value)
Primary outcome
Death from cardiovascular
causes
Death from any cause
Heart failure
Death due to CHD and
nonfatal MI
Fatal or nonfatal MI
excluding silent MI
Major cerebrovascular
events
Fatal or nonfatal stroke
Event (% of patients in trial)
Serious adverse effect
the EMPA-REG OUTCOME investigators should have
been particularly worried that this BP reduction would
ADVANCE EMPA-REG OUTCOME* lead to increased cardiovascular complications, but this
did not happen. Not only did empagliflozin significantly
4.3 3.1 reduce cardiovascular morbidity and mortality, but also
no difference in the number of adverse effects was seen
Placebo: 145.0/81.0 Placebo: 135.8/76.8 between empagliflozin and placebo (TABLE3).
Drug: 145.0/81.0 Drug: 135.3/76.6
Finally, the SBP level of ~130131mmHg achieved
Placebo: 140.0/77.0 NR in the EMPA-REG OUTCOME trial might indeed be
Drug: 135.0/75.0 Drug: 131.3/75.1 the one associated with the lowest incidence of cardio
vascular events in patients with T2DM. BP reduction in
9% (P=0.04) 14% (P=0.04, for patients with T2DM is well known to confer the largest
superiority) cardiovascular benefits compared with all other major
risk factors. In UKPDS38, a BP drop from a mean of
18% (P=0.03) 38% (P<0.001)
159/94mmHg to 144/82mmHg was associated with 32%
decrease in diabetes mellitus-related death (including
14% (P=0.03) 32% (P<0.001) death from cardiovascular causes)14. In the ADVANCE
2% (P=0.86) 35% (P=0.002) study, which started from lower baseline BP levels than
11% (Pvalue NR) NR UKPDS38, an SBP difference of 5mmHg and a DBP
difference of 2mmHg (that is 135/75mmHg versus
140/77mmHg between the active treatment and placebo
NR 13% (P=0.23)
groups) were associated with 14% reduction of all-cause
mortality (95%CI 225%; P=0.025), 18% risk reduction
2% (Pvalue NR) NR
of death from cardiovascular events (95%CI 232%;
P=0.02) and other benefits, which were demonstrated
NR 18% (P=0.26) clearly only after 1year of followup34. When compar-
ing the outcomes from the ADVANCE and EMPA-REG
Placebo: 1.2 Placebo: 42.3
OUTCOME trials, one can easily see important similar-
Active: 1.2 Active: 38.2 ities concerning the point estimates except from stroke
P<0.001 (TABLE3). Finally, the average SBP in the EMPA-REG

Acute renal failure NR Placebo: 6.6 OUTCOME during followup was 131133mmHg,
Active: 5.2 which was approximately the mean BP achieved in the
P<0.01 standardBP arm of the ACCORDBP trial (that is,
Acute kidney injury NR Placebo: 1.6 133mmHg)30. Consequently, even the harshest critics of a
Active: 1.0 SBP of <120mmHg could not deny that SBP levels of
P<0.05 ~130mmHg are associated with very low risk of cardio
Volume depletion NR Placebo: 4.9 vascular events and hypotensive-related complications.
Active: 5.1
Conclusions
Hypotension Placebo: 0.4 NR
Active: 1.2 After several years of recommendation of a target BP
<130/80mmHg in all major guidelines, the publication
Cough Placebo: 1.3 NR
of the ACCORDBP study led to conservative target SBP
Active: 3.3
suggestions of <140mmHg in individuals with diabe-
Bone fracture NR Placebo: 3.9 tes mellitus. However, looking closely at the data from
Active: 3.8
ACCORDBP, an objective reader would conclude that
Diabetic ketoacidosis NR Placebo: <0.1 the SBP level of 120mmHg did at least equally as well
Active: 0.1 as 133mmHg, with the level of 140mmHg being sim-
Thromboembolic event NR Placebo: 0.9 ply much above the actual BP achieved in the standard
Active: 0.6 BP group. The publication of the SPRINT trial, which
Urinary tract infection NR Placebo: 18.1 had a clear cardiovascular benefit conferred by a SBP
Active: 18.0 <120mmHg compared with <140mmHg, was surpris-
Genital infection NR Placebo: 1.8 ing, and several investigators tried to provide clues as to
Active: 6.4 why SPRINT and ACCORDBP had such contradictory
P<0.001 findings. Once again, a close look at these data suggests
*Pooled empagliflozin. ADVANCE (Action in Diabetes and Vascular Disease: Preterax and that these trials have more similarities than differences,
Diamicron Modified Release Controlled Evaluation): composite of death from cardiovascular and the low statistical power of the ACCORDBP trial
causes, nonfatal myocardial infarction (MI) or nonfatal stroke, and new or worsening
nephropathy or retinopathy; EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcomes
as a result of the low number of cardiovascular events
and Mortality in Type2 Diabetes): death from cardiovascular causes, nonfatal MI or nonfatal might explain the discrepancies. Finally, the EMPA-
stroke. ADVANCE: death or hospitalization due to heart failure, or worsening heart failure; REG OUTCOME trial with the impressive reduction
EMPA-REG OUTCOME: hospitalization for heart failure. Death due to cerebrovascular disease
or nonfatal stroke. CHD, coronary heart disease; DBP, diastolic blood pressure; NR, not in cardiovascular and total mortality in response to
reported; RR, relative risk; SBP, systolic blood pressure. empagliflozin indicates that a SBP reduction close

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to 130mmHg is safe and might partly explain these ben- data call for at least a careful reassessment of the recom-
eficial results. Importantly, the <140mmHg target in mended target of <140mmHg in diabetes mellitus until,
individuals with T2DM has as little support from direct and if, a properly designed trial comparing <130mmHg
evidence as <130mmHg or <120mmHg. Overall, these with <140mmHg thresholds is conducted.

1. World Health Organization. Global Report on Diabetes
(WHO, 2016).
2. IDF Diabetes Atlas Group. Update of mortality
attributable to diabetes for the IDF Diabetes Atlas:
estimates for the year 2013. Diabetes Res. Clin. Pract.
109, 461465 (2015).
3. Emerging Risk Factors Collaboration etal. Diabetes
mellitus, fasting blood glucose concentration, and risk
of vascular disease: a collaborative meta-analysis of
102 prospective studies. Lancet 375, 22152222
(2010).
4. Caro,J.J., Ward,A.J. & OBrien,J.A. Lifetime costs
of complications resulting from type2 diabetes in the
U.S. Diabetes Care 25, 476478 (2002).
5. Mancia,G. etal. 2013 ESH/ESC practice guidelines for
the management of arterial hypertension. Blood Press.
23, 316 (2014).
6. Perkovic,V., Huxley,R., Wu,Y., Prabhakaran,D. &
MacMahon,S. The burden of blood pressure-related
disease: a neglected priority for global health.
Hypertension 50, 991997 (2007).
7. Kearney,P.M. etal. Global burden of hypertension:
analysis of worldwide data. Lancet 365, 217223
(2005).
8. Sarafidis,P.A. & Nilsson,P.M. The metabolic
syndrome: a glance at its history. J.Hypertens. 24,
621626 (2006).
9. Kabakov,E. etal. Prevalence of hypertension in
type2 diabetes mellitus: impact of the tightening
definition of high blood pressure and association with
confounding risk factors. J.Cardiometab. Syndr. 1,
95101 (2006).
10. Stamler,J., Vaccaro,O., Neaton,J.D. & Wentworth,D.
Diabetes, other risk factors, and 12yr cardiovascular
mortality for men screened in the Multiple Risk Factor
Intervention Trial. Diabetes Care 16, 434444 (1993).
11. Haffner,S.M., Lehto,S., Rnnemaa,T., Pyrl,K. & 31. The SPRINT Research Group. A randomized trial of
Laakso,M. Mortality from coronary heart disease in
subjects with type2 diabetes and in nondiabetic
subjects with and without prior myocardial infarction.
N.Engl. J.Med. 339, 229234 (1998).
12. Mancia,G. etal. 2007 Guidelines for the management
of arterial hypertension: the Task Force for the
Management of Arterial Hypertension of the European
Society of Hypertension (ESH) and of the European
Society of Cardiology (ESC). Eur. Heart J. 28,
14621536 (2007).
13. Adler,A.I. etal. Association of systolic blood pressure
with macrovascular and microvascular complications of
type2 diabetes (UKPDS 36): prospective
observational study. BMJ 321, 412419 (2000).
14. UK Prospective Diabetes Study Group. Tight blood
pressure control and risk of macrovascular and
microvascular complications in type2 diabetes:
UKPDS 38.BMJ 317, 703713 (1998).
15. Hansson,L. etal. Effects of intensive blood-pressure
lowering and low-dose aspirin in patients with
hypertension: principal results of the Hypertension
Optimal Treatment (HOT) randomized trial. HOT
Study Group. Lancet. 351, 17551762 (1998).
16. [No authors listed.] The Sixth Report of the Joint
National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
Arch. Intern. Med. 157, 24132446 (1997).
17. Chalmers,J. etal. 1999 World Health Organization-
International Society of Hypertension Guidelines for
the management of hypertension. Clin. Exp.
Hypertens. 21, 10091060 (1999).
18. Ramsay,L. etal. Guidelines for management of
hypertension: report of the third working party of the
British Hypertension Society. J.Hum. Hypertens. 13,
569592 (1999).
19. Feldman,R.D. etal. 1999 Canadian recommendations
for the management of hypertension. Task Force for the
Development of the 1999 Canadian Recommendations
for the Management of Hypertension. CMAJ 161,
S1S17 (1999).
20. Bakris,G.L. etal. Preserving renal function in adults
with hypertension and diabetes: a consensus
approach. National Kidney Foundation Hypertension
and Diabetes Executive Committees Working Group.
Am. J.Kidney Dis. 36, 646661 (2000).
21. American Diabetes Association. Standards of medical
care for patients with diabetes mellitus. Diabetes Care
25, 213229 (2002).
22. American Diabetes Association. Executive summary:
standards of medical care in diabetes 2012.
Diabetes Care 35, S4S10 (2012).
23. Cifkova,R. etal. Practice guidelines for primary care
physicians: 2003 ESH/ESC hypertension guidelines.
J.Hypertens. 21, 17791786 (2003).
24. Chobanian,A.V. etal. The Seventh Report of the Joint
National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the
JNC 7 report. JAMA 289, 25602572 (2003).
25. Williams,B. etal. Guidelines for management of
hypertension: report of the fourth working party of the
British Hypertension Society, 2004BHS IV. J.Hum.
Hypertens. 18, 139185 (2004).
26. National Collaborating Centre for Chronic Conditions
(UK). Type2 Diabetes: National Clinical Guideline for
Management in Primary and Secondary Care
(Update) (Royal College of Physicians, 2008).
27. Taler,S.J. etal. KDOQI US commentary on the
2012 KDIGO clinical practice guideline for
management of blood pressure in CKD.
Am. J.Kidney Dis. 62, 201213 (2013).
28. [No authors listed.] Executive summary: standards of
medical care in diabetes 2013. Diabetes Care 36,
S4S10 (2013).
29. James,P.A. etal. 2014 evidence-based guideline for
the management of high blood pressure in adults:
report from the panel members appointed to the
Eighth Joint National Committee (JNC 8). JAMA 311,
507520 (2014).
30. Cushman,W.C. etal. Effects of intensive blood-
pressure control in type2 diabetes mellitus.
N.Engl. J.Med. 362, 15751585 (2010).
intensive versus standard blood-pressure control.
N.Engl. J.Med. 373, 21032116 (2015).
32. Zinman,B. etal. Empagliflozin, cardiovascular
outcomes, and mortality in type2 diabetes.
N.Engl. J.Med. 373, 21172128 (2015).
33. Sarafidis,P.A. & Tsapas,A. Empagliflozin,
cardiovascular outcomes, and mortality in
type2 diabetes. N.Engl. J.Med. 374, 1092 (2016).
34. Patel,A. etal. Effects of a fixed combination of
perindopril and indapamide on macrovascular and
microvascular outcomes in patients with
type2 diabetes mellitus (the ADVANCE trial):
a randomised controlled trial. Lancet 370, 829840
(2007).
35. Cooper-DeHoff,R.M. etal. Tight blood pressure
control and cardiovascular outcomes among
hypertensive patients with diabetes and coronary
artery disease. JAMA 304, 6168 (2010).
36. Sarafidis,P.A. & Ruilope,L.M. Aggressive blood
pressure reduction and renin-angiotensin system
blockade in chronic kidney disease: time for
reevaluation? Kidney Int. 85, 536546 (2014).
37. Margolis,K.L. etal. Outcomes of combined
cardiovascular risk factor management strategies in
type2 diabetes: the ACCORD randomized trial.
Diabetes Care 37, 17211728 (2014).
38. Bangalore,S., Kumar,S., Lobach,I. & Messerli,F.H.
Blood pressure targets in subjects with
type2 diabetes mellitus/impaired fasting glucose:
observations from traditional and bayesian random-
effects meta-analyses of randomized trials. Circulation
123, 27992810 (2011).
39. Schrier,R.W., Estacio,R.O., Mehler,P.S. &
Hiatt,W.R. Appropriate blood pressure control in
hypertensive and normotensive type2 diabetes
mellitus: a summary of the ABCD trial. Nat. Clin.
Pract. Nephrol. 3, 428438 (2007).
40. Estacio,R.O., Coll,J.R., Tran,Z.V. & Schrier,R.W.
Effect of intensive blood pressure control with
valsartan on urinary albumin excretion in
normotensive patients with type2 diabetes.
Am. J.Hypertens. 19, 12411248 (2006).
41. Chew,E.Y. etal. Effects of medical therapies on
retinopathy progression in type2 diabetes. N.Engl.
J.Med. 363, 233244 (2010).
42. Barzilay,J.I. etal. Cardiovascular outcomes using
doxazosin versus chlorthalidone for the treatment of
hypertension in older adults with and without
glucose disorders: a report from the ALLHAT study.
J.Clin. Hypertens. (Greenwich) 6, 116125 (2004).
43. Chan,J.C. etal. Long-term effects of angiotensin-
converting enzyme inhibition and metabolic control in
hypertensive type2 diabetic patients. Kidney Int. 57,
590600 (2000).
44. Bilous,R. etal. Effect of candesartan on
microalbuminuria and albumin excretion rate in
diabetes: three randomized trials. Ann. Intern. Med.
151, 1120 (2009).
45. Bosch,J. etal. Effect of ramipril on the incidence of
diabetes. N.Engl. J.Med. 355, 15511562
(2006).
46. Fogari,R. etal. Effects of amlodipine fosinopril
combination on microalbuminuria in hypertensive
type2 diabetic patients. Am. J.Hypertens. 15,
10421049 (2002).
47. Bakris,G.L. etal. Effects of different ACE inhibitor
combinations on albuminuria: results of the GUARD
study. Kidney Int. 73, 13031309 (2008).
48. McMurray,J.J. etal. Effect of valsartan on the
incidence of diabetes and cardiovascular events.
N.Engl. J.Med. 362, 14771490 (2010).
49. Daly,C.A. etal. The effect of perindopril on
cardiovascular morbidity and mortality in patients
with diabetes in the EUROPA study: results from the
PERSUADE substudy. Eur. Heart J. 26, 13691378
(2005).
50. Howard,B.V. etal. Effect of lower targets for blood
pressure and LDL cholesterol on atherosclerosis in
diabetes: the SANDS randomized trial. JAMA 299,
16781689 (2008).
51. Reboldi,G. etal. Effects of intensive blood pressure
reduction on myocardial infarction and stroke in
diabetes: a meta-analysis in 73,913 patients.
J.Hypertens. 29, 12531269 (2011).
52. Barnett,A.H. etal. Angiotensin-receptor blockade
versus converting-enzyme inhibition in type2 diabetes
and nephropathy. N.Engl. J.Med. 351, 19521961
(2004).
53. Marre,M. etal. Effects of low dose ramipril on
cardiovascular and renal outcomes in patients with
type2 diabetes and raised excretion of urinary
albumin: randomised, double blind, placebo
controlled trial (the DIABHYCAR study). BMJ 328,
495 (2004).
54. Tatti,P. etal. Outcome results of the Fosinopril Versus
Amlodipine Cardiovascular Events Randomized Trial
(FACET) in patients with hypertension and NIDDM.
Diabetes Care 21, 597603 (1998).
55. Brenner,B.M. etal. Effects of losartan on renal and
cardiovascular outcomes in patients with
type2 diabetes and nephropathy. N.Engl. J.Med.
345, 861869 (2001).
56. UK Prospective Diabetes Study Group. Efficacy of
atenolol and captopril in reducing risk of
macrovascular and microvascular complications in
type2 diabetes: UKPDS 39.BMJ 317, 713720
(1998).
57. Deedwania,P.C. etal. Efficacy, safety and tolerability
of metoprolol CR/XL in patients with diabetes and
chronic heart failure: experiences from MERITHF.
Am. Heart J. 149, 159167 (2005).
58. Heart Outcomes Prevention Evaluation (HOPE)
Study Investigators. Effects of ramipril on
cardiovascular and microvascular outcomes in
people with diabetes mellitus: results of the HOPE
study and MICRO-HOPE substudy. Lancet 355,
253259 (2000).
59. Ostergren,J. etal. The Anglo-Scandinavian Cardiac
Outcomes Trial: blood pressure-lowering limb: effects
in patients with typeII diabetes. J.Hypertens. 26,
21032111 (2008).
60. Niskanen,L. etal. Reduced cardiovascular morbidity
and mortality in hypertensive diabetic patients on
first-line therapy with an ACE inhibitor compared with
a diuretic/beta-blocker-based treatment regimen:
a subanalysis of the Captopril Prevention Project.
Diabetes Care 24, 20912096 (2001).

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REVIEWS

61. Yui,Y. etal. Nifedipine retard was as effective as
angiotensin converting enzyme inhibitors in
preventing cardiac events in high-risk hypertensive
patients with diabetes and coronary artery disease:
the Japan Multicenter Investigation for Cardiovascular
DiseasesB (JMICB) subgroup analysis. Hypertens.
Res. 27, 449456 (2004).
62. Hansson,L. etal. Randomised trial of effects of
calcium antagonists compared with diuretics and
-blockers on cardiovascular morbidity and mortality
in hypertension: the Nordic Diltiazem (NORDIL) study.
Lancet 356, 359365 (2000).
63. Curb,J.D. etal. Effect of diuretic-based
antihypertensive treatment on cardiovascular disease
risk in older diabetic patients with isolated systolic
hypertension. Systolic Hypertension in the Elderly
Program Cooperative Research Group. JAMA 276,
18861892 (1996).
64. Berthet,K. etal. Reductions in the risks of recurrent
stroke in patients with and without diabetes: the
PROGRESS Trial. Blood Press. 13, 713 (2004).
65. Black,H.R. etal. Principal results of the controlled
onset verapamil investigation of cardiovascular end
points (convince) trial. JAMA 289, 20732082
(2003).
66. Gasowski,J. etal. Systolic hypertension in Europe
(Syst-Eur) trial phase2: objectives, protocol, and
initial progress. J.Hum. Hypertens. 13, 135145
(1999).
67. Estacio,R.O., Jeffers,B.W., Gifford,N. &
Schrier,R.W. Effect of blood pressure control on
diabetic microvascular complications in patients with
hypertension and type2 diabetes. Diabetes Care 23
(Suppl. 2), B54B64 (2000).
68. OHare,P. etal. Low-dose ramipril reduces
microalbuminuria in type1 diabetic patients without
hypertension: results of a randomized controlled trial.
Diabetes Care 23, 18231829 (2000).
69. Dahlof,B. etal. Cardiovascular morbidity and
mortality in the losartan intervention for endpoint
reduction in hypertension study (life): a randomised
trial against atenolol. Lancet 359, 9951003
(2002).
70. Schrier,R.W., Estacio,R.O., Esler,A. & Mehler,P.
Effects of aggressive blood pressure control in
normotensive type2 diabetic patients on albuminuria,
retinopathy and strokes. Kidney Int. 61, 10861097
(2002).
71. Anker,S.D. etal. Prognostic importance of weight loss
in chronic heart failure and the effect of treatment with
angiotensin-converting-enzyme inhibitors: an
observational study. Lancet 361, 10771083 (2003).
72. Bath,P. etal. International Society of Hypertension
(ISH): statement on the management of blood
pressure in acute stroke. J.Hypertens. 21, 665672
(2003).
73. Bakris,G.L. etal. Metabolic effects of carvedilol
versus metoprolol in patients with type2 diabetes
mellitus and hypertension: a randomized controlled
trial. JAMA 292, 22272236 (2004).
74. Schrader,J. etal. Morbidity and mortality after stroke
in patients with diabetes subgroup analysis from
the moses-study. J.Clin. Basic Cardiol. 9 (Suppl. 1),
25 (2006).
75. Meredith,P.A. etal. Importance of sustained and
tight blood pressure control in patients with high
cardiovascular risk. Blood Press. 25, 7482
(2016).
76. Chalmers,J., Kengne,A.P., Joshi,R., Perkovic,V. &
Patel,A. New insights from ADVANCE. J.Hypertens.
Suppl. 25, S23S30 (2007).
77. Dagenais,G.R. etal. Effects of ramipril and
rosiglitazone on cardiovascular and renal outcomes in
people with impaired glucose tolerance or impaired
fasting glucose: results of the diabetes reduction
assessment with ramipril and rosiglitazone medication
(DREAM) trial. Diabetes Care 31, 10071014
(2008).
78. McBrien,K. etal. Intensive and standard blood
pressure targets in patients with type2 diabetes
mellitus: systematic review and meta-analysis. Arch.
Intern. Med. 172, 12961303 (2012).
79. Arguedas,J.A., Leiva,V. & Wright,J.M. Blood 93. Marx,N. & McGuire,D.K. Sodium-glucose
pressure targets for hypertension in people with
diabetes mellitus. Cochrane Database Syst. Rev. 10,
CD008277 (2013).
80. Cushman,W.C. etal. SPRINT trial results: latest news
in hypertension management. Hypertension 67,
263265 (2016).
81. Mancia,G. etal. Effects of blood-pressure
measurement by the doctor on patients blood
pressure and heart rate. Lancet 2, 695698
(1983).
82. Mancia,G. etal. Ambulatory blood pressure values in
the Ongoing Telmisartan Alone and in Combination
with Ramipril Global Endpoint Trial (ONTARGET). Author contributions
Hypertension 60, 14001406 (2012).
83. Pandit,J.A. & Batlle,D. Snapshot hemodynamics and
clinical outcomes in hypertension: precision in the
measurements is key. Hypertension 67, 270271
(2016).
84. Esler,M. SPRINT, or false start, toward a lower
universal treated blood pressure target in
hypertension. Hypertension 67, 266267 (2016).
85. Perkovic,V. & Rodgers,A. Redefining blood-pressure
targets SPRINT starts the marathon. N.Engl.
J.Med. 373, 21752178 (2015).
86. Tonelli,M. etal. Risk of coronary events in people with
chronic kidney disease compared with those with
diabetes: a population-level cohort study. Lancet 380,
807814 (2012).
87. Wanner,C. etal. Empagliflozin and progression of
kidney disease in type2 diabetes. N.Engl. J.Med.
375, 323334 (2016).
88. Imprialos,K.P., Sarafidis,P.A. & Karagiannis,A.I.
Sodium-glucose cotransporter -2 inhibitors and blood
pressure decrease: a valuable effect of a novel
antidiabetic class? J.Hypertens. 33, 21852197
(2015).
89. Vasilakou,D. etal. Sodium-glucose
cotransporter2 inhibitors for type2 diabetes:
a systematic review and meta-analysis. Ann. Intern.
Med. 159, 262274 (2013).
90. Gilbert,R.E. Sodium-glucose linked transporter2
inhibitors: potential for renoprotection beyond blood
glucose lowering? Kidney Int. 86, 693700 (2014).
91. Abdul-Ghani,M., Del Prato,S., Chilton,R. &
DeFronzo,R.A. SGLT2 inhibitors and cardiovascular
risk: lessons learned from the EMPA-REG OUTCOME
study. Diabetes Care 39, 717725 (2016).
92. Ferrannini,E., Mark,M. & Mayoux,E. CV protection
in the EMPA-REG OUTCOME trial: a thrifty
substrate hypothesis. Diabetes Care 39, 11081114
(2016).
cotransporter2 inhibition for the reduction of
cardiovascular events in high-risk patients with
diabetes mellitus. Eur. Heart J. 37, 31923200
(2016).
94. Tikkanen,I. etal. Empagliflozin reduces blood
pressure in patients with type2 diabetes and
hypertension. Diabetes Care 38, 420428
(2015).
95. Touyz,R.M. & Dominiczak,A.F. Successes of SPRINT,
but still some hurdles to cross. Hypertension 67,
268269 (2016).
All authors contributed equally to all aspects of the prepara-
tion of the article.
Competing interests statement
P.A.S. has received honoraria as an advisor for Boehringer
Ingelheim and AstraZeneca and research grants from
AstraZeneca. A.A.L., G.R.-H. and L.M.R. declare no competing
interests.

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