OPEN

Journal of Human Hypertension (2016), 111

www.nature.com/jhh

ORIGINAL ARTICLE
Blood pressure-lowering effects of nifedipine/candesartan
combinations in high-risk individuals: subgroup analysis
of the DISTINCT randomised trial
G Mancia1, G Cha2, B Gil-Extremera3, P Harvey4, AJ Lewin5, G Villa6 and SE Kjeldsen7 for the DISTINCT Investigators

The DISTINCT study (reDening Intervention with Studies Testing Innovative Nifedipine GITSCandesartan Therapy) investigated
the efcacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients
with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including
those with renal impairment (estimated glomerular ltration rate o 90 ml min 1, n = 422), type 2 diabetes mellitus (n = 202),
hypercholesterolaemia (n = 206) and cardiovascular (CV) risk factors (n = 971), as well as the impact of gender, age and body mass
index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or
candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in
high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a
doseresponse effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C
combinations in each high-risk subgroup. The benets of combination therapy vs monotherapy were additionally observed in
patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the
pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study
outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with
respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy.

Journal of Human Hypertension advance online publication, 11 August 2016; doi:10.1038/jhh.2016.54

INTRODUCTION Although a number of angiotensin receptor blocker (ARB)CCB

Individuals with hypertension who have comorbidities such as xed-dose combinations are available, none have previously
diabetes mellitus, renal impairment or established cardiovascular contained the extended-release formulation of nifedipine GITS.
(CV) disease are at increased risk of future events and mortality.14 The potential benets of a nifedipine GITSARB combination
Prompt initiation of treatment is recommended in individuals in high-risk patients is, therefore, clinically interesting. DISTINCT
with grade 2 or 3 hypertension and any level of CV risk2,5 because (reDening Intervention with Studies Testing Innovative
a short time-to-effect has been demonstrated between increased Nifedipine GITSCandesartan Therapy) was an 8-week,
blood pressure (BP) control and reduction in CV risk.6 To achieve randomised, double-blind, placebo-controlled, parallel-group,
an optimal time-to-effect, many guidelines recommend initial multifactorial study that evaluated the efcacy and safety of dose
combination therapy using agents that have complementary combinations of nifedipine GITS and candesartan cilexetil,
mechanisms of action.2,7 compared with respective monotherapies and placebo, in patients
Angiotensin II is known to have a role in the progression of with grade 1 or 2 hypertension.11 In DISTINCT, the ARBCCB
diabetic nephropathy.8 Recent guidelines recommended combination was effective and well tolerated, with each
initiating therapy including a renin angiotensin system (RAS) component contributing independently to BP reductions; the
blocker in patients with chronic kidney disease (CKD) owing to combination also signicantly reduced vasodilatory side-effects
benecial renal outcomes.2,7 Unlike -blockers or diuretics, compared with nifedipine GITS monotherapy.
calcium channel blockers (CCB) are not associated with adverse The current descriptive subgroup analyses of DISTINCT inves-
effects on glucose and lipid metabolism7,9 and, thus, are not tigated the BP-lowering effects and tolerability of nifedipine
considered of concern in patients with diabetes or metabolic GITScandesartan cilexetil combinations in high-risk participants,
syndrome. Furthermore, the combination of a CCB with a RAS including those with renal impairment, type 2 diabetes mellitus
blocker has the potential for greater BP reductions compared with (T2DM), hypercholesterolaemia and an aggregate of CV risk factors
monotherapy, especially in high-risk patients in whom BP control (T2DM or body mass index (BMI) 30 kg m 2 or low-density
is more difcult,2 can reduce peripheral oedema (vs CCB lipoprotein (LDL) cholesterol 130 mg dl 1), as well as assessing
monotherapy)10,11 and attenuate renal hyperltration.12 the effects of gender, age and BMI.

1
Unit and Department of Clinical Medicine, University of Milano-Bicocca, IRCCS Istituto Auxologico Italiano, Milan, Italy; 2KRK Medical Research Institute, Dallas, TX, USA; 3Hospital
Universitario San Cecilio, Granada, Spain; 4Formerly in The Crouch Oak Family Practice, Addlestone, UK; 5National Research Institute, Los Angeles, CA, USA; 6Fondazione Salvatore
MaugeriIRCCS, Pavia, Italy and 7Oslo University Hospital Ullevaal, University of Oslo, Oslo, Norway. Correspondence: Professor G Mancia, Piazza dei Daini, 4, 20126 Milan, Italy.
E-mail: giuseppe.mancia@unimib.it
Received 7 October 2015; revised 2 March 2016; accepted 14 March 2016
 Combination therapy in high-risk hypertension
G Mancia et al
2
METHODS o60 ml min 1 (that is, moderate/severe) and o 90 ml min 1 (that is, any
Study design grade of renal impairment) at baseline.17,18 Hypercholesterolaemia was
dened as total cholesterol 4240 mg dl 1.2,19 CV risk factors were dened
Details of the DISTINCT study design have been reported previously11
as T2DM, BMI 30 kg m 2 (obesity), LDL cholesterol 130 mg dl 1 or any
(clinicaltrials.gov identier NCT01303783). In brief, DISTINCT was an
combination of these factors.20 The potential impacts of age and BMI were
8-week, multi-national, multi-centre, randomised, double-blind, placebo-
assessed by analysis of tertiles (age:o55, 5564 and 64 years; BMI:o25,
controlled, multifactorial study to determine the doseresponse of 16
2529 and 30 kg m 2). Analyses of specic high-risk groups (that is, renal
combinations of nifedipine GITS (N) 0, 20, 30 or 60 mg and/or candesartan
impairment and T2DM) were prespecied in the study protocol; additional
cilexetil (C) 0, 4, 8, 16 or 32 mg in participants with grade 1 and 2
analyses were performed post hoc.11
hypertension. Following a 2-week (3 days) screening/washout period and
a 24 week, single-blind, placebo run-in, participants were randomised in
equal ratios to one of the 16 treatment groups. For subjects randomised to Assessments
the highest dose (N60C32), there was a forced dose titration period of one Visits during the double-blind treatment period were at 1, 2, 4, 6 and
week, during which N30C16 was administered. Subjects were instructed to 8 weeks post-baseline. BP was measured between 08:00 and 09:00 h. BP
take their medication with water at the same time in the morning measurements were performed in both arms at rst visit and the arm with
(8:00 2 h), except on the day of a visit. highest BP reading was used for all subsequent measurements. At each
The study was conducted in accordance with the Declaration of Helsinki visit, patients were required to sit for at least 5 min, after which three
and the International Conference on Harmonization guidelines on good BP measurements were taken 2 min apart, always with the patient in
clinical practice. The study protocol was reviewed and approved by each the seated position. The arithmetic mean BP was considered to be the
centres independent ethics committee or institutional review board. All representative value of the visit.
participants provided written informed consent prior to study entry. The prespecied measurements of interest were: (1) Change from
Standardsation across investigator sites was maintained by establishment baseline in mean seated DBP and systolic BP (SBP) and (2) BP control rate
of a detailed clinical protocol and through monitoring adherence to the after 8 weeks of treatment. BP control was dened as the proportion of
protocol by COVANCE Inc. (Indianapolis, IN, USA). patients achieving a BP of o140/90 mm Hg, with the exception of
participants with T2DM in any high-risk group, whose control rate was
Population based on o 140/85 mm Hg to reect recommendations in the latest ESH/
ESC guidelines.2 Control rates are also presented based on BP o130-
DISTINCT included men and women aged 18 years or older with grade 1 or /80 mm Hg at 8 weeks in patients with renal impairment or T2DM, as
2 hypertension according to the World Health Organization/International recommended by ESH/ESC guidelines at the time of study.21
Society of Hypertension 2003 guidelines.13 Patients were recruited from Prespecied analyses of participants with renal impairment in
131 study centres in 12 countries (Argentina, Belgium, Canada, Italy, DISTINCT included a cutoff for eGFR of o60 ml min 1 (representing
Lithuania, Russia, South Africa, South Korea, Spain, Ukraine, UK and USA) moderate/severe renal impairment). Post hoc analyses in the current paper
between 28 April 2011 and 28 May 2012.11 BP was measured by a additionally include an eGFR cutoff of o 90 ml min 1 (that is, all grades of
calibrated electronic device (Model HEM-705CP; Omron Healthcare, Inc., renal impairment) to provide increased numbers of patients for analysis
Bannockburn, IL, USA), with a cuff of appropriate size, supplied with and greater scope for generalisation.
instructions for use by Bayer HealthCare AG (Berlin, Germany). Patients Treatment-emergent adverse events (AE) and their relationship to
were required to have a mean seated diastolic BP (DBP) 95 mm Hg and treatment were recorded in all groups. The occurrence and severity of
o110 mm Hg at randomisation, and an absolute difference in mean peripheral oedema were assessed at all scheduled visits. Incidences of
seated DBP of o10 mm Hg between screening and randomisation, headache were determined by participant self-reports.
consistent with the guidelines current at the time of study planning and
in agreement with other phase IIb dose-nding studies of CCB/ARB xed-
dose agents (for example, amlodipine/valsartan, amlodipine/olmesartan Statistical analyses
and amlodipine/telmisartan).1316 Inclusion and exclusion criteria have Efcacy analyses in the DISTINCT main study included all randomised
been described previously.11 subjects who received at least one dose of study medication and had a
The current subgroup analysis focuses on BP lowering in participants in baseline as well as at least one valid post-baseline BP measurement
DISTINCT with renal impairment, T2DM, hypercholesterolaemia and CV risk (full analysis set). The current efcacy analyses included all subjects in the
factors, as well as patients categorised by gender, age and BMI. Renal full analysis set who had the identied risk factors at baseline. Patients in
impairment was dened by an estimated glomerular ltration rate (eGFR) the full analysis set without these risk factors were also analysed for

Table 1. Baseline characteristics of high-risk and non-high-risk individuals (safety analysis set)

Characteristic Renal impairment of any T2DM Hypercholesterolaemia (total CV risk factor(s) (T2DM or BMI 30 kg m 2 or
grade (baseline cholesterol 4240 mg dl 1) LDL 130 mg dl 1)
eGFR o 90 ml min 1)

Yes No Yes No 4240 200240 o 200 13 12 1 None

(N = 426) (N = 955) (N = 205) (N = 1176) (N = 210) (N = 454) (N = 715) (N = 986) (N = 958) (N = 679) (N = 395)

Age, years, mean 61.6 50.6 56.8 53.5 55.2 54.0 53.7 53.7 53.7 53.4 54.8
Male, n (%) 232 (54.5%) 567 (59.4%) 116 (56.6%) 683 (58.1%) 110 (52.4%) 245 (54.0%) 442 (61.8%) 547 (55.5%) 534 (55.7%) 390 (57.4%) 252 (63.8%)

Ethnicity
White, n (%) 317 (74.4%) 685 (71.7%) 148 (72.2%) 854 (72.6%) 166 (79.0%) 353 (77.8%) 481 (67.3%) 730 (74.0%) 712 (74.3%) 494 (72.8%) 272 (68.9%)
Black, n (%) 46 (10.8%) 180 (18.8%) 33 (16.1%) 193 (16.4%) 25 (11.9%) 59 (13.0%) 142 (19.9%) 180 (18.3%) 173 (18.1%) 121 (17.8%) 46 (11.6%)
Asian, n (%) 55 (12.9%) 68 (7.1%) 11 (5.4%) 112 (9.5%) 14 (6.7%) 35 (7.7%) 74 (10.3%) 55 (5.6%) 53 (5.5%) 48 (7.1%) 68 (17.2%)

BMI, kg m 2, mean 27.4 32.6 32.3 30.8 30.4 31.2 31.1 32.9 32.8 32.2 26.2
Obesity 109 (25.6%) 619 (64.8%) 129 (62.9%) 599 (50.9%) 97 (46.2%) 242 (53.3%) 389 (54.4%) 728 (73.8%) 700 (73.1%) 437 (64.4%) 393 (99.5%)
2
(BMI 30 kg m ),
n (%)
SBP, mm Hg, mean 158.8 155.5 159.1 156.1 157.1 156.3 156.5 156.3 156.3 156.1 157.1
DBP, mm Hg, mean 99.3 99.7 99.3 99.6 99.2 99.9 99.4 99.5 99.5 99.5 99.6
Abbreviations: BMI, body mass index; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular ltration rate; LDL, low-density lipoprotein;
SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus.

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
Table 2. Least squares mean reduction in SBP/DBP (mm Hg) from baseline to week 8 (analysis of covariance) in high-risk and non-high-risk individuals treated with nifedipine GITS (N20, 30, 60) and/ 3

Abbreviations: BMI, body mass index; C, candesartan cilexetil; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular ltration rate; LDL, low-density lipoprotein; N, nifedipine GITS; SBP,
comparative purposes. Descriptive analyses were performed for the

None (N = 391)

10.6/ 11.0
16.3/ 10.8
16.8/ 14.8

15.8/ 12.0
16.2/ 12.0
17.9/ 15.2
21.0/ 14.1
14.6/ 14.3
21.4/ 14.6
21.2/ 16.2
22.8/ 18.7
25.0/ 18.0
10.1/ 9.5
change from baseline in mean SBP and DBP and for control rates utilising

7.0/ 9.5

8.2/ 7.8
1.2/ 3.1
the criteria described above. DBP and SBP changes from baseline are
presented as least squares means, calculated using analysis of covariance,
with treatment, (pooled) centres, BP and age at baseline as covariates.
Missing values are imputed by the last observation carried forward
approach.

12.3/ 10.4

15.5/ 12.3

14.9/ 10.4
16.7/ 12.7
17.9/ 14.3
19.3/ 14.3
20.8/ 15.1
21.6/ 14.4
17.7/ 14.4
19.8/ 16.0
19.1/ 14.5
21.6/ 15.4
10.8/ 8.6

11.2/ 8.9
(T2DM or BMI 30 kg m 2 or

5.7/ 6.3

9.8/ 8.2
Safety analyses include all randomised subjects who took at least one
(N = 669)

dose of study drug. Participants with treatment-emergent AEs are analysed

LDL 130 mg dl 1)

1
CV risk factor(s)

according to pooled treatment groups: nifedipine GITScandesartan

cilexetil combination, nifedipine GITS or candesartan cilexetil monother-
apy, or placebo, as in the main DISTINCT study.11
Analyses were performed using SAS software 9.2 (SAS Institute Inc., Cary,
13.5/ 10.1

15.5/ 11.8

14.7/ 10.5
16.4/ 11.9
18.9/ 14.1
19.6/ 13.6
19.7/ 14.2
21.6/ 14.4
17.7/ 13.9
21.3/ 15.4
19.8/ 14.3
21.9/ 15.1
13.0/ 8.9

10.9/ 8.0

11.7/ 9.3
6.4/ 7.2
(N = 943)

NC, USA).
12

RESULTS
Demographics
13.6/ 10.0

15.5/ 11.5

14.5/ 10.2
16.3/ 11.3
18.9/ 13.9
19.9/ 13.5
19.8/ 14.1
21.8/ 14.3
18.0/ 13.4
21.2/ 15.3
20.5/ 14.5
22.0/ 15.0
12.9/ 8.8

10.9/ 7.9

11.7/ 9.4
6.2/ 7.0

A total of 2817 patients were screened and 1381 (49.0%) were

(N = 971)
13

randomised to treatment in the main DISTINCT study

(Supplementary Materials Supplementary Figure 1).11 Of
these patients, 30.8% (n = 426) had renal impairment of any
grade (eGFRo 90 ml min 1), including 3.6% (n = 50) with
o200 (N = 704)

11.5/ 10.1

16.9/ 13.3

18.2/ 14.3
17.0/ 12.4
21.3/ 15.9
21.8/ 14.9
19.9/ 15.8
19.7/ 13.4
24.2/ 16.7
22.8/ 16.8
24.3/ 16.2

moderate/severe renal impairment (eGFR o60 ml min 1); 14.8%

11.7/ 9.9
13.4/ 9.7

10.9/ 8.8
13.3/ 9.3
6.6/ 5.8

(n = 205) had T2DM; 15.2% (n = 210) had hypercholesterolaemia

and 71.4% (n = 986) had CV risk factors. Baseline characteristics of
patients with renal impairment, T2DM, hypercholesterolaemia and
CV risk factors are provided in Table 1. Approximately one-half of
Hypercholesterolaemia

high-risk participants were male, with an age range of 53.761.6

200240 (N = 450)
(total cholesterol
4240 mg dl 1)

13.2/ 10.9

17.8/ 12.6
11.8/ 11.6
14.6/ 10.4

21.4/ 15.4
18.0/ 12.5
18.3/ 12.7
20.1/ 13.2
19.3/ 14.8
18.6/ 15.0
20.4/ 15.6
22.9/ 16.6
11.5/ 8.1

12.8/ 8.7

14.7/ 9.9

years and approximately one-half in each group were obese. The

4.4/ 7.4

high-risk populations were generally well matched in baseline

characteristics with the main DISTINCT study population11 and
with patient subgroups without the high-risk conditions, although
the subgroup with renal impairment was older (mean 62 vs 51
years), had lower BMI (27 vs 33 kg m 2) and included a larger
4240 (N = 206)

19.5/ 13.0
13.8/ 10.7
10.7/ 11.4
14.9/ 10.2
10.7/ 11.7

19.4/ 15.5
19.3/ 13.5
22.0/ 17.1
21.2/ 13.7
16.6/ 13.6
21.5/ 17.1
18.8/ 13.7
21.7/ 16.7
12.9/ 8.5

14.9/ 8.1
1.4/ 8.1

proportion of Asian and fewer Black participants than the

subgroup without renal impairment (Table 1).

Efcacy
The efcacy analysis set in the main DISTINCT study included 1362
14.1/ 10.5

17.3/ 12.7

16.9/ 11.4
19.7/ 13.2
20.7/ 13.7
21.3/ 13.6
20.1/ 13.9
19.7/ 14.3
21.7/ 15.5
23.4/ 15.9
24.4/ 16.4
11.7/ 8.7

14.0/ 9.1

12.0/ 9.2
13.1/ 9.7

individuals.11 Of this population, the high-risk participants

4.9/ 6.2
(N = 1160)

included 422 with renal impairment of any grade

No

(eGFRo 90 ml min 1), including 50 with moderate/severe renal

or candesartan cilexetil (C4, 8, 16, 32) or placebo (efcacy analysis set)

impairment (eGFRo 60 ml min 1), 202 with T2DM, 206 with

T2DM

hypercholesterolaemia and 971 with CV risk factors. These

15.7/ 10.8

14.0/ 10.1
15.8/ 12.6

19.5/ 12.6
12.4/ 15.0
21.0/ 15.9
21.5/ 17.3
27.0/ 18.5
23.3/ 11.4
29.0/ 17.8
17.8/ 14.0
22.0/ 14.9
11.3/ 6.9

13.8/ 9.4
14.2/ 8.8

19.0/ 9.6

subgroups were investigated for efcacy in the current analyses.

(N = 202)

Additional subgroup analyses according to gender (male, n = 788),

Yes

and tertiles of age (o 55 years, n = 701; 5564, n = 463; 65,

systolic blood pressure; T2DM, type 2 diabetes mellitus.

n = 198) and BMI (o 25 kg m 2, n = 172; 2529, n = 467; 30,

n = 719) are also included in the Supplementary Materials.
14.8/ 10.7

16.6/ 11.4

17.7/ 10.3
18.6/ 11.8
18.9/ 13.8
19.6/ 13.9
20.5/ 13.4
17.3/ 12.8
19.9/ 14.6
23.1/ 15.6
22.0/ 15.0
(baseline eGFR o 90 ml min 1)

12.8/ 9.7

12.6/ 8.0

11.1/ 8.4
12.6/ 9.2
5.7/ 6.3
(N = 940)

BP changes. As reported for the main DISTINCT study

No
Renal impairment

population,11 mean changes in SBP/DBP in high-risk participants

of any grade

were overall greater with combination therapy than respective

monotherapies or placebo, with indicators of a doseresponse
17.5/ 11.1
15.4/ 14.7
15.2/ 13.0
14.1/ 11.0
16.3/ 14.3
19.2/ 16.2
21.5/ 14.7
19.5/ 15.2
20.3/ 16.8
22.3/ 15.8
22.9/ 17.5
17.4/ 16.1
29.4/ 19.3

effect (Table 2). In general, consistent trends were observed

3.6/ 6.8
6.2/ 7.6
9.0/ 9.1
(N = 422)

between high-risk participants and respective non-high-risk

Yes

groups in terms of greater BP reduction in combination therapy

compared with the respective monotherapies or placebo (Table 2).
Pooled treatment analyses demonstrated that early SBP/DBP
reductions (that is, within the rst 2 weeks of treatment) were
Treatment group

superior for combination therapy vs each monotherapy in all

high-risk groups, including those with renal impairment of any
Placebo

N20C16

N30C16
N30C32
N60C16
N60C32

grade (Figure 1a), T2DM (Figure 1b), hypercholesterolaemia

N20C4
N20C8

N30C8
N20
N30
N60
C16
C32

(Figure 1c) and any CV risk factors (Figure 1d). These group
C4
C8

differences were sustained for the study duration.

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
4
l l

l l

l l

l l

l l

Figure 1. Least squares mean change in SBP/DBP (mm Hg) during 8 weeks of treatment with nifedipine GITS (N20, 30, 60) and/or candesartan
cilexetil (C4, 8, 16, 32) in individuals with (a) renal impairment (baseline eGFR o90 ml min 1), (b) T2DM, (c) hypercholesterolaemia (total
cholesterol4240 mg dl 1) or (d) any CV risk factors (T2DM or BMI 30 kg m 2 or LDL 130 mg dl 1). Abbreviations: BMI, body mass index;
BP, blood pressure; C, candesartan cilexetil; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular ltration rate;
LDL, low-density lipoprotein; N, nifedipine GITS; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus.

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
5
BP control rates. In all high-risk participants, 8-week BP control
Table 3. Stratied BP control rates (ESH/ESC 2013: o140/85 mm Hg for diabetes patients in each treatment group and 140/90 mm Hg for all other patients, n/N (%) at week 8 in high-risk and non-

Abbreviations: BMI, body mass index; BP, blood pressure; C, candesartan cilexetil; CV, cardiovascular; eGFR, estimated glomerular ltration rate; LDL, low-density lipoprotein; N, nifedipine GITS; T2DM, type 2
CV risk factor(s) (T2DM or BMI 30 kg m 2 or LDL 130 mg dl 1)

None (N = 391)

11/24 (45.8%)
10/29 (34.5%)
13/20 (65.0%)

11/25 (44.0%)
13/21 (61.9%)
16/21 (76.2%)
11/25 (44.0%)
17/29 (58.6%)
19/34 (55.9%)
15/21 (71.4%)
19/30 (63.3%)
6/28 (21.4%)
5/20 (25.0%)
9/21 (42.9%)
2/18 (11.1%)
6/25 (24.0%)
rates (using ESH/ESC 2013 guidelines) were generally higher with
combination therapy than monotherapies or placebo, with
indicators of a doseresponse effect (Table 3, Figure 2). Findings
were comparable using the stricter, prespecied denition for BP
control of o 130/80 mm Hg.

18/43 (41.9%)
10/37 (27.0%)
18/42 (42.9%)
13/41 (31.7%)
15/44 (34.1%)
18/44 (40.9%)
20/44 (45.5%)
24/44 (54.5%)
23/43 (53.5%)
19/40 (47.5%)
24/40 (60.0%)
27/37 (73.0%)
25/47 (53.2%)
26/41 (63.4%)
In pooled treatment analyses, combination therapy was
9/36 (25.0%)
3/46 (6.5%)
1 (N = 669)

associated with earlier BP control compared with monotherapies

in participants with renal impairment of any grade, T2DM,
hypercholesterolaemia and CV risk factors (Figure 3ad). These
improvements were maintained throughout the study, consistent
with the main outcomes.
(26.8%)
(43.5%)
(24.5%)
(41.3%)
(30.4%)
(35.0%)
(38.9%)
(44.3%)
(51.6%)
(50.8%)
(50.0%)
(56.1%)
(71.2%)
(52.5%)
(61.1%)
12 (N = 943)

(7.5%)

Descriptive subgroup analyses based on gender and tertiles of

both age and BMI demonstrated a similar greater treatment
5/67
15/56
27/62
13/53
26/63
17/56
21/60
21/54
27/61
33/64
33/65
30/60
32/57
37/52
31/59
33/54
effect for combination therapy vs placebo and respective
monotherapies for BP changes and BP control, as above, across
patient groups (Supplementary Materials Supplementary Tables 1
(27.1%)
(42.9%)
(25.5%)
(40.6%)
(29.8%)
(33.3%)
(37.3%)
(43.5%)
(52.2%)
(51.5%)
(50.8%)
(54.2%)
(69.8%)
(54.1%)
(61.1%)
13 (N = 971)

and 2).
(7.4%)
high-risk individuals treated with nifedipine GITS (N20, 30, 60) and/or candesartan cilexetil (C4, 8, 16, 32) or placebo (efcacy analysis set)

5/68
16/59
27/63
14/55
26/64
17/57
21/63
22/59
27/62
35/67
34/66
31/61
32/59
37/53
33/61
33/54

Safety
The safety analysis set in the main DISTINCT study included 1381
individuals.11 Of this population, 426 had renal impairment of any
o200 (N = 704)
Hypercholesterolaemia (total cholesterol4240 mg dl 1)

grade (eGFRo 90 ml min 1), including 50 with moderate/severe

13/51 (25.5%)
16/44 (36.4%)
13/46 (28.3%)
18/43 (41.9%)
12/42 (28.6%)
12/39 (30.8%)
20/43 (46.5%)
21/49 (42.9%)
25/44 (56.8%)
27/46 (58.7%)
18/48 (37.5%)
22/40 (55.0%)
28/39 (71.8%)
28/46 (60.9%)
23/40 (57.5%)
5/44 (11.4%)

renal impairment (eGFRo 60 ml min 1), 205 had T2DM, 210 had
hypercholesterolaemia and 986 had CV risk factors. These
subgroups were investigated for safety in the current analyses.
At least one treatment-emergent AE was reported in 141/426
participants (33.1%) with renal impairment of any grade, 61/205
200240 (N = 450)

(29.8%) with T2DM, 64/210 (30.5%) with hypercholesterolaemia

15/31 (48.4%)

16/28 (57.1%)
10/30 (33.3%)

15/31 (48.4%)
16/29 (55.2%)
15/25 (60.0%)
20/39 (51.3%)
17/32 (53.1%)
15/25 (60.0%)
21/33 (63.6%)
6/24 (25.0%)

4/20 (20.0%)

9/27 (33.3%)
9/25 (36.0%)
9/23 (39.1%)
2/28 (7.1%)

and 382/986 (38.7%) with CV risk factors (Table 4). The treatment-
emergent AEs led to discontinuation of study drug in 12 (2.8%)
participants with renal impairment of any grade, 4 (2.0%) with
T2DM, 5 (2.4%) with hypercholesterolaemia and 18 (1.8%) with CV
risk factors. In pooled treatment analyses, the highest rate of
4240 (N = 206)

treatment-emergent AEs was consistently in high-risk patients

3/9 (33.3%)
6/11 (54.5%)
7/18 (38.9%)
4/12 (33.3%)

5/17 (29.4%)
2/12 (16.7%)
8/15 (53.3%)
8/13 (61.5%)
7/12 (58.3%)
9/13 (69.2%)
7/9 (77.8%)
11/16 (68.8%)
5/11 (45.5%)
8/11 (72.7%)
1/13 (7.7%)

taking nifedipine GITS monotherapy compared with combination

0/14

therapy (40.2% vs 36.2% of those with renal impairment of any

grade, 34.9% vs 34.0% with T2DM, 34.9% vs 29.7% with
hypercholesterolaemia and 43.7% vs 41.9% with CV risk factors).
It is notable that treatment-emergent AEs in these subgroups
(17.4%)
(24.3%)
(26.8%)
(31.1%)
(18.7%)
(20.9%)
(31.3%)
(34.2%)
(41.9%)
(42.9%)
(41.0%)
(41.3%)
(47.4%)
(48.5%)
(52.1%)
No (N = 1160)

appeared to occur at generally similar or lower rates than in

(6.8%)

participants without the high-risk conditions (Table 4).

Vasodilatory treatment-emergent AEs occurred at a lower rate
5/73
12/69
18/74
19/71
23/74
14/75
14/67
20/64
27/79
31/74
30/70
32/78
31/75
37/78
32/66
38/73

with combination therapy vs nifedipine GITS monotherapy in all

T2DM

high-risk participants (renal impairment of any grade: 12.2% vs

23.0%; T2DM: 14.4% vs 18.6%; hypercholesterolaemia: 13.9% vs
2/13 (15.4%)
4/15 (26.7%)
4/13 (30.8%)
2/13 (15.4%)
3/10 (30.0%)
3/10 (30.0%)
3/16 (18.8%)
5/16 (31.3%)

6/14 (42.9%)
7/17 (41.2%)

5/13 (38.5%)

7/16 (43.8%)
6/11 (54.5%)
Yes (N = 202)

2/8 (25.0%)

3/8 (37.5%)

6/9 (66.7%)

18.6%; any CV risk factors: 20.3% vs 25.1%) (Table 4). These rates
were also, overall, lower among the high-risk participants
compared with the non-high-risk participants. Incidences of
oedema during 8-week treatment were consistently lower with
(27.9%)
(48.3%)
(22.4%)
(50.0%)
(27.6%)
(34.0%)
(39.2%)
(39.0%)
(52.9%)
(56.7%)
(47.3%)
(50.0%)
(63.3%)
(56.1%)
(62.7%)

combination therapy than nifedipine GITS monotherapy at all

Renal impairment of any grade
(baseline eGFR o 90 ml min 1)

No (N = 940)

(6.8%)

times for each high-risk subgroup (Figure 4ad).

Safety analyses based on gender, age and BMI demonstrated
17/61
28/58
11/49
28/56
16/58
18/53
20/51
23/59
37/70
34/60
26/55
33/66
38/60
37/66
37/59
4/59

similar rates of total treatment-emergent AEs and vasodilatory

treatment-emergent AEs in combination therapy, respective
monotherapies and placebo groups, when compared with the
10/29 (34.5%)
13/35 (37.1%)
11/28 (39.3%)

11/29 (37.9%)
15/28 (53.6%)
11/18 (61.1%)
16/27 (59.3%)
16/31 (51.6%)
16/22 (72.7%)
18/27 (66.7%)
11/16 (68.8%)
15/25 (60.0%)
3/27 (11.1%)
5/23 (21.7%)

7/27 (25.9%)
8/30 (26.7%)
Yes (N = 422)

main study population, without evident differences between

males or females, tertiles of age or BMI (Supplementary Materials
Supplementary Table 3).

DISCUSSION
diabetes mellitus.
Treatment group

These subgroup analyses of DISTINCT show that nifedipine GITS

candesartan cilexetil combinations are more effective than
Placebo

N20C16

N30C16
N30C32
N60C16
N60C32
N20C4
N20C8

N30C8

respective monotherapies or placebo for BP lowering in high-

N20
N30
N60
C16
C32

risk populations, including those with renal impairment, diabetes,

C4
C8

hypercholesterolaemia or CV risk factors. Combination therapy

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
6

l
l

l
l l l l
l

l
l

l l l l
Figure 2. Stratied BP control rates (ESH/ESC 2013: o140/85 mm Hg for diabetes patients in each treatment group and o140/90 mm Hg for
all other patients, (%) achieved at week 8 in high-risk individuals treated with nifedipine GITS (N20, 30, 60) and/or candesartan cilexetil (C4, 8,
16, 32) or placebo. (a) Renal impairment (baseline eGFR o90 ml min 1), (b) T2DM, (c) hypercholesterolaemia (total cholesterol 4240 mg dl 1)
or (d) any CV risk factors (T2DM or BMI 30 kg m 2 or LDL 130 mg dl 1). Arrow indicates dose group with highest BP control. Abbreviations:
BMI, body mass index; BP, blood pressure; C, candesartan cilexetil; CV, cardiovascular; eGFR, estimated glomerular ltration rate; LDL, low-
density lipoprotein; N, nifedipine GITS; T2DM, type 2 diabetes mellitus.

was associated with greater and earlier SBP/DBP reductions and CKD and diabetic nephropathy, have found a consistent reduction
increased BP control (regardless of the cutoff used) compared in urinary protein excretion endpoints associated with ARB
with respective monotherapies and these effects were sustained use.2325 Recent guidelines recommend combination therapy for
throughout the 8-week study. The magnitude of SBP/DBP high-risk patients to achieve target BP.2 Randomised, double-blind
lowering in these high-risk subgroups was broadly similar to the trials have demonstrated the antihypertensive efcacy of
reductions observed in the main DISTINCT study and in individuals candesartan cilexetil26 and CCBARB combination27 in diabetic
without these risk factors.11 These ndings also applied to populations. However, few randomised studies have investigated
subgroup analyses based on gender, age and BMI. the effects of nifedipine GITS in high-risk populations with renal
The presence of renal impairment, T2DM, hyper- impairment or diabetes.28,29 The positive ndings in this study of
cholesterolaemia and obesity elevates the risk for CV events and greater and earlier BP reductions in both high-risk groups
for further decline of renal function in hypertensive patients, supports the literature on the additive effects of combination
especially among older patients.2 Angiotensin-converting enzyme therapy for hypertension.
(ACE) inhibitors and ARBs are the preferred drug classes for A number of studies have also highlighted the CV benets of
antihypertensive therapy in patients with diabetes and renal CCB and RAS inhibitor therapy in high-risk patients. The INSIGHT
impairment, given their superior renoprotective effects study of 1302 individuals with hypertension and diabetes
compared to other antihypertensive classes.22 Several randomised found similar incidence rates of primary CV outcomes (CV death,
controlled trials have indicated more effective reductions in myocardial infarction, heart failure, stroke) and mean BP
microalbuminuria or proteinuria using RAS inhibitors compared reductions for CCB (nifedipine GITS) and thiazide (co-amilozide)
with other antihypertensive agents or placebo.12 Various studies treatment.29 However, composite secondary outcomes (all-cause
across different patient subgroups, including those with T2DM, death, vascular-related death and non-vascular-related death)

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
7

l
l l
l

l
l l

Figure 3. Stratied BP control rate (ESH/ESC 2013 guidelines: o 140/85 mm Hg for patients with diabetes in each treatment group,
o140/90 mm Hg for all other patients) during 8 weeks of treatment with nifedipine GITS (N20, 30, 60) and/or candesartan cilexetil (C4, 8, 16,
32) in individuals with (a) renal impairment of any grade (baseline eGFR o90 ml min 1), (b) T2DM, (c) hypercholesterolaemia (total
cholesterol4240 mg dl 1) or (d) any CV risk factors (T2DM or BMI 30 kg m 2 or LDL 130 mg dl 1. Abbreviations: BMI, body mass index;
BP, blood pressure; C, candesartan cilexetil; CV, cardiovascular; eGFR, estimated glomerular ltration rate; LDL, low-density lipoprotein;
N, nifedipine GITS; T2DM, type 2 diabetes mellitus.

were signicantly lower with nifedipine GITS than co-amilozide Nifedipine GITScandesartan cilexetil combination therapy was
(14.2% vs 18.7%; P = 0.03). A post hoc analysis of the ACTION trial associated in the current analyses with a lower incidence of
showed that adding nifedipine GITS to an existing antihyperten- vasodilatory treatmentemergent AEs compared with nifedipine
sive regimen reduced BP by an average of 6/ 3 mm Hg in GITS monotherapy, with an approximate halving of these
patients with diabetes and hypertension with controlled BP side-effects for participants with renal impairment and a reduction
(mean = 140.7/79.8 mm Hg) at baseline.30 The ACCOMPLISH trial of approximately one quarter for the diabetes, hypercholester-
compared the combination of an ACE inhibitor (benazepril) with olaemia and CV risk factor subgroups. These improvements
either a CCB (amlodipine) or thiazide diuretic (hydrochlorothia- were largely due to reductions in the incidence of headache in
zide) and found superior outcomes with the CCBACE inhibitor high-risk subgroups, except for patients with hypercholesterolae-
combination in terms of reduced CV deaths, nonfatal myocardial mia. The incidence of oedema was also lower with combination
infarction and nonfatal stroke31 and a signicant reduction in CKD therapy vs nifedipine GITS monotherapy in participants with
progression.32 A subgroup analysis also found a signicant renal impairment and hypercholesterolaemia, although not in
reduction in the risk of a composite of CV outcomes among those with diabetes or CV risk factors. CCB-associated oedema
patients with diabetes receiving CCBACE inhibitor treatment is a known side-effect of vasodilation, caused by increased
intracapillary pressure which results in leakage of uid into
(compared with diureticACE inhibitor).33
dependent soft tissue. This can be alleviated by concomitant use
Hypertension, glucose intolerance, central obesity and hyper-
of a RAS blocker, which induces post-capillary venular relaxation
cholesterolaemia are components of a risk factor cluster (termed
therefore reducing CCV-related intracapillary pressure and capil-
metabolic syndrome) for CV disease and T2DM.21 However, some
lary leakage.37 However, given the relatively common occurrence
of these risk factors have been found to impact differently of a persistent dry cough with ACE inhibitors, ARBs may present
according to gender, for example, greater CV heart disease a better tolerability prole with similar antihypertensive
mortality in women with diabetes compared to men.34 Given that effectiveness.38
more than a third of the DISTINCT study sample presented with at These analyses have some limitations. First, DISTINCT was not
least one CV risk factor, this supports the literature that most of powered to enable subgroup comparisons, precluding meaningful
the hypertensive population rarely presents with elevated BP in statistical analyses. Second, the denition of BP control in the
isolation.2 Recent ESC/EAS guidelines recommend LDL main DISTINCT study used a target of o 140/90 mm Hg for the
cholesterol-targeted interventions in hypertensive patients with overall population and o 130/80 mm Hg for those with renal
CV risks, that is, those with metabolic syndrome, as these impairment and/or diabetes.11 These denitions were included in
populations present a higher risk of CV diseases than the the study protocol ahead of updates in the ESH/ESC (2013)
general population.35 The ASCOT-LLA trial demonstrated guidelines, which now recommend a target of o 140/90 mm Hg
improved outcomes with the addition of a statin to the treatment in patients with renal dysfunction and o140/85 mm Hg in those
regime for an average of 3 years, including reductions in major CV with diabetes. (Notably, there remains a lack of agreement on
events and a lowering of total serum cholesterol.36 adopting less-aggressive BP targets, given the evidence from

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
8
Table 4. Treatment-emergent AEs, n/N (%) by pooled treatment with nifedipine GITS (N20, 30, 60 mg) and/or candesartan cilexetil (C4, 8, 16, 32 mg)
or placebo in high-risk and non-high-risk individuals treated for 8 weeks (safety analysis set)

Pooled Renal impairment (baseline T2DM Hypercholesterolaemia (total CV risk factor(s) (T2DM or BMI 30 kg m 2 or
treatment group eGFRo 90 ml min 1) cholesterol4240 mg dl 1) LDL 130 mg dl 1)

Yes (N = 426) No (N = 955) Yes (N = 205) No 4240 200240 o 200 13 (N = 986) 12 (N = 958) 1 (N = 679) None
(N = 1176) (N = 210) (N = 454) (N = 715) (N = 395)

Any treatment-emergent AE
Total 141 (33.1%) 395 (41.4%) 61 (29.8%) 475 64 (30.5%) 176 (38.8%) 296 (41.4%) 382 (38.7%) 375 (39.1%) 277 (40.8%) 154 (39.0%)
(40.4%)
Placebo 3/27 (11.1%) 22/61 (36.1%) 2/14 (14.3%) 23/74 3/14 5/28 (17.9%) 17/46 (37.0%) 19/70 (27.1%) 19/69 (27.5%) 13/47 (27.7%) 6/18
(31.1%) (21.4%) (33.3%)
C 32/116 78/230 11/51 99/295 16/52 33/104 61/188 79/246 77/239 53/162 31/100
(27.6%) (33.9%) (21.6%) (33.6%) (30.8%) (31.7%) (32.4%) (32.1%) (32.2%) (32.7%) (31.0%)
N 35/87 74/167 15/43 94/211 15/43 41/83 53/128 80/183 77/174 63/132 29/71
(40.2%) (44.3%) (34.9%) (44.5%) (34.9%) (49.4%) (41.4%) (43.7%) (44.3%) (47.7%) (40.8%)
NC 71/196 221/497 33/97 259/596 30/101 97/239 165/353 204/487 202/476 148/338 88/206
(36.2%) (44.5%) (34.0%) (43.5%) (29.7%) (40.6%) (46.7%) (41.9%) (42.4%) (43.8%) (42.7%)

Any study drug-related treatment-emergent AE

Placebo 2/27 7/61 1/14 8/74 1/14 0/28 8/46 5/70 5/69 3/47 4/18
(7.4%) (11.5%) (7.1%) (10.8%) (7.1%) (17.4%) (7.1%) (7.2%) (6.4%) (22.2%)
C 7/116 29/230 2/51 34/295 7/52 13/104 16/188 24/246 22/239 16/162 12/100
(6.0%) (12.6%) (3.9%) (11.5%) (13.5%) (12.5%) (8.5%) (9.8%) (9.2%) (9.9%) (12.0%)
N 19/87 33/167 5/43 (11.6%) 47/211 9/43 20/83 23/128 37/183 35/174 29/132 15/71
(21.8%) (19.8%) (22.3%) (20.9%) (24.1%) (18.0%) (20.2%) (20.1%) (22.0%) (21.1%)
NC 34/196 93/497 11/97 116/596 18/101 41/239 68/353 94/487 94/476 70/338 33/206
(17.3%) (18.7%) (11.3%) (19.5%) (17.8%) (17.2%) (19.3%) (19.3%) (19.7%) (20.7%) (16.0%)

Discontinuations due to treatment-emergent AEs

Placebo 0/27 1/61 (1.6%) 0/14 1/74 (1.4%) 0/14 0/28 1/46 0/70 0/69 0/47 1/18
(2.2%) (5.6%)
C 0/116 3/230 (1.3%) 0/51 3/295 1/52 0/104 2/188 3/246 3/239 3/162 0/100
(1.0%) (1.9%) (1.1%) (1.2%) (1.3%) (1.9%)
N 5/87 5/167 1/43 9/211 0/43 4/83 6/128 5/183 5/174 4/132 5/71
(5.7%) (3.0%) (2.3%) (4.3%) (4.8%) (4.7%) (2.7%) (2.9%) (3.0%) (7.0%)
NC 7/196 (3.6%) 13/497 (2.6%) 3/97 (3.1%) 17/596 4/101 7/239 9/353 10/487 10/476 9/338 10/206
(2.9%) (4.0%) (2.9%) (2.5%) (2.1%) (2.1%) (2.7%) (4.9%)

Any vasodilatory treatment-emergent AE

Placebo 1/27 9/61 2/14 8/74 2/14 1/28 7/46 7/70 7/69 3/47 3/18
(3.7%) (14.8%) (14.3%) (10.8%) (14.3%) (3.6%) (15.2%) (10.0%) (10.1%) (6.4%) (16.7%)
C 6/116 35/230 6/51 35/295 5/52 14/104 22/188 32/246 30/239 22/162 9/100
(5.2%) (15.2%) (11.8%) (11.9%) (9.6%) (13.5%) (11.7%) (13.0%) (12.6%) (13.6%) (9.0%)
N 20/87 40/167 8/43 52/211 8/43 28/83 24/128 46/183 44/174 35/132 14/71
(23.0%) (24.0%) (18.6%) (24.6%) (18.6%) (33.7%) (18.8%) (25.1%) (25.3%) (26.5%) (19.7%)
NC 24/196 103/497 14/97 113/596 14/101 38/239 75/353 99/487 99/476 72/338 28/206
(12.2%) (20.7%) (14.4%) (19.0%) (13.9%) (15.9%) (21.2%) (20.3%) (20.8%) (21.3%) (13.6%)

Flushing
Placebo 0/27 0/61 0/14 0/74 0/14 0/28 0/46 0/70 0/69 0/47 0/18
C 0/116 0/230 0/51 0/295 0/52 0/104 0/188 0/246 0/239 0/162 0/100
N 0/87 1/167 (0.6%) 0/43 1/211 0/43 1/83 (1.2%) 0/128 1/183 (0.5%) 1/174 (0.6%) 1/132 (0.8%) 0/71
(0.5%)
NC 0/196 6/497 (1.2%) 0/97 6/596 0/101 5/239 (2.1%) 1/353 (0.3%) 4/487 (0.8%) 4/476 (0.8%) 3/338 (0.9%) 2/206
(1.0%) (1.0%)

Headache
Placebo 1/27 (3.7%) 5/61 (8.2%) 1/14 (7.1%) 5/74 (6.8%) 1/14 1/28 (3.6%) 4/46 (8.7%) 3/70 (4.3%) 3/69 (4.3%) 1/47 (2.1%) 3/18
(7.1%) (16.7%)
C 0/116 12/230 (5.2%) 1/51 (2.0%) 11/295 0/52 6/104 (5.8%) 6/188 (3.2%) 9.246 (3.7%) 9/239 (3.8%) 8/162 (4.9%) 3/100
(3.7%) (3.0%)
N 8/87 20/167 4/43 24/211 2/43 14/83 12/128 20/183 20/174 14/132 8/71
(9.2%) (12.0%) (9.3%) (11.4%) (4.7%) (16.9%) (9.4%) (10.9%) (11.5%) (10.6%) (11.3%)
NC 6/196 32/497 2/97 36/596 5/101 35/454 19/353 27/487 27/476 22/338 11/206
(3.1%) (6.4%) (2.1%) (6.0%) (5.0%) (7.7%) (5.4%) (5.5%) (5.7%) (6.5%) (5.3%)

Oedema
Placebo 0/27 4/61 1/14 3/74 (4.1%) 1/14 0/28 3/46 4/70 4/69 2/47 0/18
(6.6%) (7.1%) (7.1%) (6.5%) (5.7%) (5.8%) (4.3%)
C 6/116 24/230 5/51 25/295 5/52 9/104 16/188 24/246 22/239 15/162 6/100
(5.2%) (10.4%) (9.8%) (8.5%) (9.6%) (8.7%) (8.5%) (9.8%) (9.2%) (9.3%) (6.0%)
N 14/87 22/167 5/43 (11.6%) 31/211 6/43 17/83 13/128 28/183 26/174 21/132 8/71
(16.1%) (13.2%) (14.7%) (14.0%) (20.5%) (10.2%) (15.3%) (14.9%) (15.9%) (11.3%)
NC 19/196 70/497 12/97 77/596 10/101 22/239 57/353 74/487 74/476 52/338 15/206
(9.7%) (14.1%) (12.4%) (12.9%) (9.9%) (9.2%) (16.1%) (15.2%) (15.5%) (15.4%) (7.3%)

Abbreviations: AE, adverse event; BMI, body mass index; C, candesartan cilexetil; CV, cardiovascular; eGFR, estimated glomerular ltration rate; LDL, low-density
lipoprotein; N, nifedipine GITS; T2DM, type 2 diabetes mellitus.

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
9

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Figure 4. Incidence rate of oedema during 8 weeks of treatment with nifedipine GITS (N20, 30, 60) and/or candesartan cilexetil (C4, 8, 16, 32) in
individuals with (a) renal impairment (baseline eGFRo 90 ml min 1), (b) T2DM, (c) hypercholesterolaemia (total cholesterol4240 mg dl 1)
or (d) any CV risk factors (T2DM or BMI 30 kg m 2 or LDL 130 mg dl 1). Abbreviations: BMI, body mass index; C, candesartan
cilexetil; CV, cardiovascular; eGFR, estimated glomerular ltration rate; LDL, low-density lipoprotein; N, nifedipine GITS; T2DM, type 2
diabetes mellitus.

clinical trials that renal and CV protection are increased by more subgroups. The combination therapy was well tolerated in
intensive BP lowering.7) For these reasons, the current analyses these high-risk groups, with a lower incidence of vasodilatory
include control rates using both the updated ESH/ESC side-effects than nifedipine GITS monotherapy.
recommendations (o 140/85 mm Hg for patients with diabetes
and o140/90 mm Hg for other high-risk groups) and the
prespecied target (o 130/80 mm Hg for patients with renal What is known about this topic?
failure and diabetes). The DISTINCT study had an 8-week duration Guidelines recommend initial combination therapy for individuals
and therefore does not provide information on long-term efcacy with hypertension and comorbidities with increased CV risks.
and safety. In addition, although analyses of specic high-risk RAS blockers and -blockers have shown benecial renal and
groups (that is, renal impairment and T2DM) were prespecied in metabolic outcomes.
the study protocol, the other subgroup analyses (hypercholester-
olaemia and presence of CV risk factors) were performed What this study adds?
This post hoc analysis of high-risk participants with hypertension in
post hoc.
In summary, this sub-analysis of DISTINCT is the rst study to the DISTINCT trial demonstrated the superior efcacy of nifedipine
GITSARB combination therapy, compared with respective
examine the effects of nifedipine GITScandesartan cilexetil in monotherapies and placebo.
various dose combinations in high-risk populations, including The nifedipine GITSARB combination therapy was well tolerated
those with renal impairment, T2DM, hypercholesterolaemia or CV with a better vasodilatory side-effect prole compared with
risk factors. Consistent with the main outcomes of DISTINCT, these nifedipine GITS monotherapy in high-risk participants, as in all
analyses demonstrate that combination therapy is associated with patients in the main DISTINCT trial.
greater reductions in BP and higher control rates in all high-risk

Journal of Human Hypertension (2016), 1 11

 Combination therapy in high-risk hypertension
G Mancia et al
10
CONFLICT OF INTEREST 7 Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG et al.
G Mancia has received speaker's or consultation fees in the last 2 years from Actavis, Clinical practice guidelines for the management of hypertension in the
Bayer, Bhringer Ingelheim, Covidien, CVRx, Daiichi Sankyo, Ferrer, Lilly, Medtronic community a statement by the American Society of Hypertension and the
Vascular Inc., Menarini Int., Merck Serono, MSD, Novartis, Recordati, Sano, Servier, International Society of Hypertension. J Hypertens 2014; 32: 315.
Takeda. AJ Lewin has received research grants in the last 2 years from Abbott 8 Huang XR, Chen WY, Truong LD, Lan HY. Chymase is upregulated in
Laboratories, AbbVie Inc., ActivX Biosciences Inc., Akros Pharma, Inc., Amarin Pharma, diabetic nephropathy: implications for an alternative pathway of angiotensin
Inc., Amgen Inc., Amylin Pharmaceuticals, AstraZeneca, Bavarian Nordic, Bayer, II-mediated diabetic renal and vascular disease. J Am Soc Nephrol 2003; 14:
17381747.
Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Catabasis, Daiichi
9 Sowers JR. Effects of calcium antagonists on insulin sensitivity and other
Sankyo, Elcelyx Therapeutics, Eli Lilly and Company, Esperion Therapeutics, Forest
metabolic parameters. Am J Cardiol 1997; 79: 2428.
Research Institute, Gilead Sciences, Inc., GlaxoSmithKline, F. Hoffmann-La Roche,
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