CLINICAL IMPLICATIONS
Hypertension  ■ Vol.
Downloaded from http://ahajournals.org by on May 15, 2019
73  ■ No. 6  ■ June 2019
Outcomes of Blood Pressure Lowering
in Diabetes Mellitus (page 1291)
The blood pressure (BP) threshold for initi-
ation of antihypertensive treatment among
patients with diabetes mellitus remains
controversial, complicating their manage-
ment. Results from SPRINT (Systolic Blood
Pressure Intervention Trial) in patients
without diabetes mellitus provided persua-
sive evidence to support systolic BP targets
lower than <140 mm Hg. This contrasts with
the results from the ACCORD trial (Action
to Control Cardiovascular Risk in Diabetes),
where intensive BP therapy did not reduce
adverse cardiovascular outcomes compared
with the standard target of systolic BP <140
mm Hg. The benefit for intensive BP therapy
in patients without diabetes mellitus seems
to be associated with baseline risk, and the
same may be the case for those with dia-
betes mellitus. Thus, we examined whether
the effects of intensification of BP therapy in
the ADVANCE trial (Action in Diabetes and
Vascular Disease: Preterax and Diamicron
Modified Release Controlled Evaluation)
were also modified by baseline BP and esti-
mated atherosclerotic cardiovascular disease
risk. Intensification of BP therapy with addi-
tion of perindopril-indapamide versus pla-
cebo reduced mortality and major vascular
events regardless of baseline systolic (≥140
or <140 mm Hg) or diastolic BP (≥90 or <90
mm Hg). Similarly, the benefit of intensifi-
cation of treatment on all-cause mortality or
major vascular events was not affected by
10-year atherosclerotic cardiovascular di-
sease risk (≥20% or <20%). The results of our
study support intensive BP treatment among
individuals with diabetes mellitus. This is
consistent with recent recommendations
from the 2017 American Heart Association/
American College of Cardiology guidelines,
which recommend a BP target of <130/80
mm Hg in these patients.
(Hypertension. 2019;73:1137. DOI: 10.1161/HYPERTENSIONAHA.119.13158.)
© 2019 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp
Mortality and Intensive Blood
Pressure Targets in Chronic Kidney
Disease (page 1275)
In our study, we compare the effect of an inten-
sive blood pressure target of <130 mm Hg systolic
blood pressure versus a standard target of <140
mm Hg systolic blood pressure on clinical out-
comes in patients with chronic kidney disease. Our
analysis pools individual patient data from 4 large
randomized trials of intensive versus standard
blood pressure targets: AASK (African American
Study of Kidney Disease and Hypertension),
ACCORD (Action to Control Cardiovascular
Risk in Diabetes), MDRD (Modification of Diet
in Renal Disease), and SPRINT (Systolic Blood
Pressure Intervention Trial). In our primary anal-
ysis of 4983 patients with chronic kidney disease,
intensive targeting demonstrated a statistically
nonsignificant trend towards decreased all-cause
mortality rates (hazard ratio, 0.87 [0.69–1.08];
P=0.21). The average achieved systolic blood
pressure was 125.0 mm Hg in the intensive group
and 136.9 mm Hg in the standard group. After
excluding patients who were in the ACCORD in-
tensive glycemic group and those with glomerular
filtration rate ≥60 mL/min per 1.73 m2, we found
that patients with chronic kidney disease had a
statistically significant decrease in all-cause mor-
tality rates with intensive targeting (hazard ratio,
0.79 [0.63–1.00]; P=0.048). Additional analyses
evaluated composite cardiovascular outcomes and
found a statistically nonsignificant trend towards
improved outcomes both before and after remov-
ing patients with glomerular filtration rate ≥60
mL/min per 1.73 m2 and in the ACCORD inten-
sive glycemic group (hazard ratio, 0.87 [0.72–
1.05]; P=0.15 and hazard ratio, 0.82 [0.67–1.01];
P=0.060, respectively). Our results suggest
that controlling patients with chronic kidney
disease and hypertension to a target of <130
mm Hg systolic blood pressure may decrease
all-cause mortality rates.
DOI: 10.1161/HYPERTENSIONAHA.119.13158
1137
NI956/QGC006, a Novel
Antihypertensive Drug (page 1300)
Hyperactivity of the brain renin-angiotensin
system is involved in the development and
maintenance of hypertension. Brain angiotensin
III, generated by APA (aminopeptidase A), is
one of the main effector peptides of the brain
renin-angiotensin system which exerts a tonic
stimulatory control over blood pressure in hy-
pertensive rats. Brain APA, therefore, constitutes
a promising target for hypertension treatment.
We designed NI956/QGC006, a novel APA
inhibitor prodrug obtained by disulfide bridge-
mediated dimerization of NI929 ([3S,4S]-3-
amino-4-mercapto-6-phenyl-hexane-1-sulfonic
acid). NI929, which interacts with both the S1
and S′1 subsites of the APA active site, is 10×
more potent (30 nmol/L) than the first-in-class
APA inhibitor, EC33 ([3S]-3-amino-4-sulfanyl-
butane-1-sulfonic acid), interacting only with
the S1 subsite. We demonstrated that oral NI956/
QGC006 administration (4 mg/kg) inhibited
brain APA activity, normalizing blood pressure
for several hours in an experimental salt-depen-
dent model of hypertension, the deoxycorticos-
terone acetate (DOCA)-salt rat, at a dose 10×
weaker than that used for the first-in-class EC33
prodrug, RB150 (4,4-dithio [bis{(3S)-3-amino-
butyl sulfonic acid}]),/firibastat. NI956/QGC006
decreased plasma arginine-vasopressin levels
and increased diuresis and natriuresis without
affecting plasma sodium and potassium concen-
trations. Efficacy and safety of RB150/firibastat
in lowering blood pressure was demonstrated in
overweight hypertensive patients in the NEW-
HOPE trial (Novel Evaluation With QGC001 in
Hypertensive Overweight Patients of Multiple
Ethnic Origins;URL: http://www.clinicaltrials.
gov. Unique identifier: NCT03198793), in whom
50% were self-identified blacks and Hispanics
exhibiting high-salt-sensitivity and resistant to
systemic renin-angiotensin system blockers. Our
results for DOCA-salt rats illustrated that NI956/
QGC006 is a best-in-class central-acting APA in-
hibitor prodrug, belonging to the same drug class
as RB150/firibastat, supporting the development
of hypertension treatments targeting brain APA,
especially in patients for whom optimal blood
pressure control is difficult to obtain with cur-
rently available antihypertensive treatments.