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ARTICLES
Cardiovascular morbidity and mortality in patients with diabetes
in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): a randomised trial against atenolol
Lars H Lindholm, Hans Ibsen, Björn Dahlöf, Richard B Devereux, Gareth Beevers, Ulf de Faire, Frej Fyhrquist, Stevo Julius,
Sverre E Kjeldsen, Krister Kristiansson, Ole Lederballe-Pedersen, Markku S Nieminen, Per Omvik, Suzanne Oparil,
Hans Wedel, Peter Aurup, Jonathan Edelman, Steven Snapinn, for the LIFE study group*
Summary
Background The most suitable antihypertensive drug to reduce
the risk of cardiovascular disease in patients with hypertension
and diabetes is unclear. In prespecified analyses, we
compared the effects of losartan and atenolol on
cardiovascular morbidity and mortality in diabetic patients.
Methods As part of the LIFE study, in a double-masked,
randomised, parallel-group trial, we assigned a group of 1195
patients with diabetes, hypertension, and signs of leftventricular hypertrophy (LVH) on electrocardiograms losartanbased or atenolol-based treatment. Mean age of patients was
67 years (SD 7) and mean blood pressure 177/96 mm Hg
(14/10) after placebo run-in. We followed up patients for at
least 4 years (mean 4·7 years [1·1]). We used Cox regression
analysis with baseline Framingham risk score and
electrocardiogram-LVH as covariates to compare the effects of
the drugs on the primary composite endpoint of cardiovascular
morbidity and mortality (cardiovascular death, stroke, or
myocardial infarction).
Findings Mean blood pressure fell to 146/79 mm Hg (17/11)
in losartan patients and 148/79 mm Hg (19/11) in atenolol
patients. The primary endpoint occurred in 103 patients
assigned losartan (n=586) and 139 assigned atenolol
(n=609); relative risk 0·76 (95% CI 0·58–0·98), p=0·031. 38
and 61 patients in the losartan and atenolol groups,
respectively, died from cardiovascular disease; 0·63
(0·42–0·95), p=0·028. Mortality from all causes was 63 and
104 in losartan and atenolol groups, respectively; 0·61
(0·45–0·84), p=0·002.
*Members listed at end of reference 1
Umeå University Hospital, Sweden (Prof L H Lindholm MD); Glostrup
University Hospital, Denmark (H Ibsen MD); Sahlgrenska University
Hospital/Östra, Gothenburg, Sweden (B Dahlöf MD); Cornell Medical
Center, New York, NY, USA (Prof R B Devereux MD); City Hospital,
Birmingham, UK (Prof G Beevers MD); Karolinska University
Hospital, Stockholm, Sweden (Prof U de Faire MD); Helsinki
University Central Hospital, Finland (Prof F Fyhrquist MD,
Prof M S Nieminen MD); University of Michigan, Ann Arbor,
Michigan, MI, USA (Prof S Julius MD); Ullevaal University Hospital,
Oslo, Norway (S E Kjeldsen MD); Merck Research Laboratories
Scandinavia, Stockholm (K Kristiansson PhD); Viborg Hospital,
Denmark (O Lederballe-Pedersen MD); Haukeland University
Hospital, Bergen, Norway (Prof P Omvik MD); University of Alabama,
Birmingham, Alabama, AL, USA (Prof S Oparil MD); The Nordic
School of Public Health, Gothenburg (Prof H Wedel PhD); Merck
Research Laboratories, West Point, PA, USA (P Aurup MD,
J Edelman MD, S Snapinn PhD)
Correspondence to: Prof Lars H Lindholm, Department of Public
Health and Clinical Medicine, Umeå University Hospital, SE-901 85
Umeå, Sweden
(e-mail: [email protected])
1004
Interpretation Losartan was more effective than atenolol in
reducing cardiovascular morbidity and mortality as well as
mortality from all causes in patients with hypertension,
diabetes, and LVH. Losartan seems to have benefits beyond
blood pressure reduction.
Lancet 2002; 359: 1004–10
See Commentary page 990
Introduction
The Losartan Intervention For Endpoint reduction (LIFE)
study was designed in the early 1990s1–4 when no drug class
for the treatment of essential hypertension had been shown
to be more effective in prevention of cardiovascular
morbidity and mortality than -blockers and diuretics. The
main hypothesis of LIFE was that selective angiotensin-II
type-1-receptor antagonism with losartan would be more
effective than -blockade with atenolol in reducing
cardiovascular morbidity and mortality in patients with
essential hypertension and signs of left ventricular
hypertrophy (LVH) on electrocardiograms.
Diabetes mellitus doubles the risk of cardiovascular
disease,5 even in patients with hypertension who are already
at high risk because of their high blood pressure.6 Since
many patients with hypertension develop diabetes, this
combination of risk factors will account for a large
proportion of cardiovascular morbidity and mortality. The
frequency of diabetes mellitus is increasing rapidly
worldwide.7 In the LIFE study,1 we compared the long-term
effects of once-daily losartan-based with atenolol-based
antihypertensive treatment in patients with hypertension
and LVH on the frequency of cardiovascular morbidity and
mortality (a composite of cardiovascular mortality, stroke
and myocardial infarction). The most suitable drug to
prevent premature cardiovascular disease in diabetic
patients with high blood pressure is unclear. Therefore, we
analysed the outcome in the prespecified subgroup of
patients who had diabetes mellitus at the start of the LIFE
study.
Methods
Patients and procedures
The LIFE study1 was a double-masked, randomised,
parallel-group study with double dummy drugs. The main
outcome1 and the complete study protocol with study
design, organisation, clinical measures, endpoint
definitions, exclusion criteria, reasons for choice of
comparative agents, statistical power calculations, and
baseline characteristics have been published.2–4
We included patients aged 55−80 years with hypertension
(either treated or untreated) and signs of LVH on
electrocardiograms. We gave patients placebo drugs for 1–2
weeks after which we assigned them to treatment groups if
they had a sitting systolic blood pressure of
160–200 mm Hg, a diastolic pressure of 95−115 mm Hg, or
both. In both groups, we added hydrochlorothiazide and
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ARTICLES
10778 patients
assessed
for eligibility
1556 ineligible
1341 did not meet
protocol criteria
215 unwilling to
participate
9222 randomised
29 excluded for
irregularites
7998 without diabetes
at baseline
1195 with diabetes
at baseline
586 assigned
losartan
609 assigned
atenolol
32 dropped out
11 withdrew
consent
11 incomplete
follow-up
10 vital status
only
586 available for
intention-totreat analyses
36 dropped out
7 withdrew
consent
11 incomplete
follow-up
14 vital status
only
4 lost to
follow-up
609 available for
intention-totreat analyses
Figure 1: Trial profile
Losartan (n=586)
Demographic and clinical characteristics
Age (years)*
Women
Ethnic origin
White
Black
Hispanic
Asian
Other
Blood pressure (mm Hg)*
Heart rate (bpm)*
BMI (kg/m2)*
Cornell voltage-duration product (mmmsec)*
Sokolow-Lyon (mm)*
Framingham risk score*
Current smokers
Medical history
Any vascular diasease
Coronary heart disease
Cerebrovascular disease
Peripheral vascular disease
Atrial fibrillation
Isolated systolic hypertension†
67·4 (6·8)
302 (52%)
506 (86%)
62 (11%)
12 (2%)
5 (0·9%)
1 (0·2%)
176/97 (14/9)
76 (12)
30·0 (5·3)
2885 (988)
28·8 (10·3)
0·304 (0·084)
70 (12%)
206 (35%)
138 (24%)
69 (12%)
40 (7%)
32 (5%)
103 (18%)
other agents (but not -blockers, angiotensin-convertingenzyme inhibitors, or angiotensin-II antagonists) if blood
pressure remained high during follow-up.1 1195 (13%) of
9193 LIFE participants had a diagnosis of diabetes mellitus
(most likely of type-2) at baseline. We randomly assigned
586 participants to losartan and 609 to atenolol. Figure 1
shows the trial profile and table 1 shows baseline
characteristics. 767 (64%) participants came from the
Nordic countries, 365 (31%) from the USA, and 63 (5%)
from the UK. 86% were white. Before the start of the
study, 958 patients had been treated with antihypertensive
drugs, 472 (81%) in the losartan group and 486 (80%) in
the atenolol group.
At baseline, antidiabetic drugs, insulin, or both, had been
given to 669 (56%) patients: 323 in the losartan and 346 in
the atenolol group. 526 (44%) had received oral drugs
(sulphonylureas, biguanides, or both) and 186 (16%)
insulin (table 2). We gave all patients who were not on these
drugs non-pharmacological treatment during the study;
additionally, 139 of the remaining 263 losartan patients and
136 of the remaining 263 atenolol patients started taking
antidiabetic drugs during follow-up. 124 (21%) losartan
patients and 127 (21%) atenolol patients were not treated
with antidiabetic drugs or insulin during the trial. Groups
were also well balanced for treatment with lipid-lowering
drugs and aspirin during the study (table 2). Treatment for
diabetes was at the discretion of patients’ physicians.
We enrolled patients from June, 1995, to May, 1997, if a
screening electrocardiogram fulfilled criteria for LVH.1 We
followed up patients for at least 4 years with regular visits
and upward-titration of study drugs to reduce blood
pressure to below 140/90 mm Hg. We defined diabetes
mellitus according to the 1985 WHO criteria.8 After the
study end date in September, 2001, patients had a followup clinic visit or at least a vital status check within 6 weeks.
Tests were done at two laboratories that assured
comparability of measurements by crossvalidation, and all
electrocardiograms
were
coded
at
the
same
electrocardiogram core centre.1 We recorded sitting blood
pressure 24 h after study drug dose (range 22–26).
Statistical analysis
We assessed all endpoints by intention-to-treat analysis.
We included all randomised patients and all available
follow-up data from randomisation to the study end
Atenolol (n=609)
67·4 (7)
332 (55%)
519 (85%)
71 (12%)
13 (2%)
5 (0·8%)
1 (0·2%)
177/96 (14/10)
76 (11)
30·0 (5·6)
2926 (995)
28·3 (10·2)
0·312 (0·086)
92 (15%)
214 (35%)
145 (24%)
71 (12%)
49 (8%)
48 (8%)
132 (22%)
All with diabetes (n=1195)
67·4 (7)
634 (53%)
1025 (86%)
133 (11%)
25 (2%)
10 (0·8%)
2 (0·2%)
177/96 (14/10)
76 (12)
30·0 (5·5)
2906 (992)
28·5 (10·3)
0·308 (0·085)
162 (14%)
420 (35%)
283 (24%)
140 (12%)
89 (7%)
80 (7%)
235 (20%)
All without diabetes (n=7998)
66·9 (7)
4329 (54%)
7478 (94%)
400 (5%)
75 (0·9%)
33 (0·4%)
12 (0·2%)
174/98 (14/9)
74 (11)
27·7 (4·6)
2817 (1057)
30·2 (10·5)
0·212 (0·090)
1337 (17%)
1886 (24%)
1186 (15%)
588 (7%)
431 (5%)
244 (3%)
1091 (14%)
Bpm=beats per minute. BMI=body-mass index. Data are number (%) unless otherwise indicated. *Data are mean (SD). †Definition >160/90 mm Hg.
Table 1: Baseline characteristics
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1005
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ARTICLES
Losartan
Primary composite endpoint
Atenolol
24
Treatment
Antidiabetic
Sulfonylureas
Biguanides
Insulin
Lipid lowering
Statins*
Fibrates
Aspirin
During study
Baseline
Atenolol
Losartan
During study
223 (38%)
71 (12%)
96 (16%)
328 (56%)
218 (37%)
170 (29%)
260 (43%)
79 (13%)
90 (15%)
369 (61%)
243 (40%)
165 (27%)
54 (9%)
9 (2%)
158 (27%)
181 (31%)
19 (3%)
274 (47%)
48 (8%)
17 (3%)
166 (27%)
195 (32%)
28 (5%)
289 (47%)
Proportion of patients
with first event (%)
Baseline
Data are number (%). *Statins=3-hydroxy-3-methylglutaryl coenzyme A
(HMGC0-A) reductases.
20
16
12
8
4
ARR: 24·5%, p=0·031
URR: 26·7%, p=0·017
0
Table 2: Antidiabetic, lipid lowering, and aspirin treatment
0
6
12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
date. We included endpoints in analyses only if
confirmed by the endpoint committee. We classed
patients with more than one endpoint as having had an
event in all relevant endpoint analyses; however, we
counted only the first event in a specific category in
individual analyses. We assessed the difference between
treatment groups with respect to clinical events with a
Cox regression model with degree of LVH (measured by
Cornell voltage-duration product and Sokolow-Lyon
voltage) and the Framingham risk score9 at baseline as
covariates. We chose this adjusted analysis before the
trial to account for any difference in key risk predictors
at baseline. We also did a secondary unadjusted
analysis. We measured treatment effects by hazard ratios
(relative risks) and 95% CIs derived from Cox
regression models. We calculated the risk reduction for
losartan versus atenolol as 100(1–relative risk). We
adjusted results for blood pressure according to Cox
regression models with blood pressures throughout the
trial as time-varying covariates. We analysed differences
between groups in changes in electrocardiogram
measures of LVH with the Wilcoxon rank-sum test, and
the frequency of adverse experiences with Fisher’s exact
test. The level of two-sided significance was 5%.
586 569 558 548 532 520 513 501 484 459 237 127
Atenolol
609 588 562 552 540 527 507 486 472 434 204 99
Figure 2: Kaplan-Meier curves for primary composite endpoint
ARR=adjusted risk ratio. URR=unadjusted risk ratio.
participants without diabetes,1 patients with the disease
had higher body-mass index, higher Framingham risk
score, a higher prevalence of cardiovascular disease at
baseline (table 1), higher systolic blood pressure
(difference 3 mm Hg), lower diastolic pressure (2 mm
Hg), higher pulse pressure (5 mm Hg), and higher
serum glucose concentration (9·6 [SD 3·8] vs 5·5 [1·0]
mmol/L). Fewer patients with diabetes smoked than
other LIFE participants.1
Primary endpoints occurred in 242 (20%) patients
during 5596 patient-years of follow-up (table 3): 103 in
the losartan group (39·2 per 1000 patient-years) and
139 in the atenolol group (53·6), relative risk 0·76 (95%
CI 0·58–0·98), p=0·031. 63 losartan patients (22·5 per
1000 patient-years) and 104 in the atenolol group (37·2)
died from all causes (0·61, 0·45–0·84, p=0·002). 38
(13·6 per 1000 patient-years) and 61 patients (21·8) in
the losartan and atenolol groups, respectively, died from
cardiovascular disease (0·63, 0·42–0·95, p=0·028,
table 3). Stroke occurred in 51 losartan and 65 atenolol
patients (p=0·205), and myocardial infarction in 41 and
50 patients, respectively (p=0·373). 32 patients were
admitted to hospital for heart failure (11·8 per 1000
patient-years) in the losartan group and 55 (20·7) in the
atenolol group (0·59, 0·38–0·92, p=0·019). Figure 2
shows Kaplan-Meier curves for the primary composite
endpoint, and figures 3 and 4 show Kaplan-Meier
curves for individual endpoints and total mortality,
respectively. Adjustment for baseline Framingham risk
score and LVH had little effect on results (table 3).
There was no evidence of interaction between treatment
and sex for any of the endpoints.
Role of the funding source
Study data are in a Merck database. Merck provided the
study steering committee with free access to all data.
The steering committee was free to interpret data and
write the paper and the outcome was validated
independently by the steeering committee. Merck
reviewed the paper.
Results
Groups were closely matched in demographic
characteristics, severity of hypertension, prevalence of
coexisting cardiovascular conditions, Framingham risk
score, and electrocardiogram-based LVH criteria
(table 1). Compared with the remaining LIFE
Endpoint
Primary composite endpoint
Cardiovascular mortality
Stroke (all)
Myocardial infarction (all)
Other prespecified endpoints
Total mortality
Admitted to hospital for
Angina pectoris
Heart failure
Revascularisation
Losartan
Losartan (n=586)
Atenolol (n=609)
Unadjusted
hazard ratio (95% CI)
p
n
Adjusted†
p
hazard ratio (95% CI)
Rate*
n
Rate*
39·2
13·6
19·0
15·2
103 (18%)
38 (6%)
51 (9%)
41 (7%)
53·6
21·8
24·5
18·7
139 (23%)
61 (10%)
65 (11%)
50 (8%)
0·76 (0·58–0·98)
0·63 (0·42–0·95)
0·79 (0·55–1·14)
0·83 (0·55–1·25)
0·031
0·028
0·204
0·373
0·73 (0·57–0·95)
0·62 (0·41–0·92)
0·78 (0·54–1·13)
0·81 (0·54–1·22)
0·017
0·019
0·190
0·318
22·5
63 (11%)
37·2
104 (17%)
0·61 (0·45–0·84)
0·002
0·60 (0·44–0·82)
0·001
11·1
11·8
23·5
30 (5%)
32 (5%)
62 (11%)
11·1
20·7
26·6
30 (5%)
55 (9%)
70 (11%)
1·06 (0·64–1·76)
0·59 (0·38–0·92)
0·90 (0·64–1·26)
0·828
0·019
0·533
1·00 (0·60–1·66)
0·57 (0·37–0·89)
0·88 (0·63–1·24)
0·989
0·013
0·470
*Per 1000 patient-years of follow-up. †For degree of left-ventricular hypertrophy and Framingham risk score at randomisation.
Table 3: Endpoints
1006
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ARTICLES
Total mortality
Cardiovascular mortality
24
Atenolol
Losartan
10
8
6
4
2
ARR: 36·6%, p=0·028
URR: 38·4%, p=0·019
0
Proportion of patients (%)
Proporrtion of patients (%)
12
Atenolol
Losartan
20
16
12
8
4
ARR: 38·7%, p=0·002
URR: 40·1%, p=0·001
0
0
Number at risk
586 579 573 572 566 558 552 543 533 513 265 136
Losartan
6
12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Losartan
586 579 573 572 566 558 552 543 533 513 265 136
609 604 592 582 576 566 552 537 529 495 232 113
Atenolol
Atenolol
609 604 592 582 576 566 552 537 529 495 232 113
Myocardial infarction (fatal and non-fatal)
12
Proportion of patients
with first event (%)
Figure 4: Kaplan-Meier curves for total mortality
ARR=adjusted risk ratio. URR=unadjusted risk ratio.
10
8
6
4
2
ARR: 17·1%, p=0·373
URR: 19·0%, p=0·318
0
Number at risk
Losartan
586 570 563 559 550 540 532 519 504 484 248 129
609 593 576 567 556 544 526 504 494 456 216 107
Atenolol
Stroke (fatal and non-fatal)
Proportion of patients
with first event (%)
12
10
8
6
4
2
ARR: 21·2%, p=0·204
URR: 21·8%, p=0·190
0
0
6
12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
586 570 560 554 540 530 524 519 500 477 248 131
Losartan
Atenolol
609 590 572 561 549 537 521 515 494 456 211 101
to the study drug and hydrochlorothiazide did not differ
between groups. Table 4 shows that at the end of the
trial, more patients in the atenolol group than in the
losartan group had stopped taking the study drug
(p=0·076).
Systolic, diastolic, and mean blood pressures fell
substantially in both groups (figure 5). Mean blood
pressure at the last visit before a primary endpoint, or at
the end of follow-up, was 146/79 (17/11) and
148/79 mm Hg (19/11) in the losartan and atenolol
groups, reductions of 31/17 (19/11) and 28/17 mm Hg
(21/11), respectively. 499 (85%) losartan and 497
(82%) atenolol patients had diastolic blood pressure less
than 90 mm Hg at the end of the study. 220 (38%)
losartan and 205 (34%) atenolol patients had systolic
blood pressure below 140 mm Hg; these results were
not much different in LIFE patients without diabetes.
Mean arterial blood pressure at the end of the study was
101 (11) and 102 mm Hg (12) in losartan and atenolol
groups, respectively. Adjustment for blood pressure
during follow-up had little effect on the endpoint results
(data not shown).
Fewer patients in the losartan group (2 [0·3%])
stopped taking the study drug because of serious
drug-related adverse events than in the atenolol
group (9 [2%], p=0·065). Tables 5 and 6 show
results
for
selected
adverse
events
and
biochemical measurements, respectively. Albuminuria
was reported less frequently (p=0·002) as an adverse
event in the losartan than in the atenolol group
(table 5). Serum glucose concentrations remained
high throughout the study (figure 6, table 6),
Figure 3: Kaplan-Meier curves for individual endpoints
Losartan
ARR=adjusted risk ratio. URR=unadjusted risk ratio.
We assigned patients with diabetes and untreated
hypertension at baseline (n=237) to losartan (n=114) or
atenolol (n=123). In this subgroup, the primary
composite endpoint occurred in 17 (33·3 per 1000
patient-years) losartan and 34 atenolol patients (64·7),
four (7·2) and 15 (26·6) died from cardiovascular
disease, and five (9·1) and 24 (42·6) died from all
causes, respectively.
Mean follow-up from randomisation to death, loss to
follow-up, or end of the study was 4·7 years (1·1). The
proportion of patients who were given additional drugs
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
Drug doses
50 mg only
50 mg plus additional drugs*
100 mg with or without additional
drugs*
Alone
With HCTZ only
With other drugs only
With HCTZ and other drugs
Off study drugs
Atenolol
46 (8%)
81 (14%)
300 (51%)
32 (5%)
98 (16%)
285 (47%)
8 (1%)
96 (16%)
24 (4%)
172 (30%)
159 (27%)
7 (1%)
81 (13%)
36 (6%)
161 (27%)
194 (32%)
*Including hydrochlorothiazide (HCTZ).
Table 4: Number of participants on study drug at endpoint or
end of follow-up
1007
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Atenolol
Losartan
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
16
Serum glucose (mmol/L)
mm Hg
ARTICLES
Systolic
Mean arterial
Diastolic
14
12
10
8
6
4
Losartan
Atenolol
2
0
0
6
12
18 24 30 36
Time (months)
42
48
54
Figure 5: Blood pressure during follow-up
0
Number of
patients
Losartan 563
Atenolol 580
12
24
36
Time (months)
48
60
521
548
503
514
471
461
345
306
494
473
Data are derived from intention-to-treat analysis.
Figure 6: Non-fasting serum glucose concentrations
and did not differ significantly between the groups
(p=0·087). Table 7 shows serum creatinine concentrations and the number (%) of diabetic patients with
clinical albuminuria.
Mean Cornell voltage-duration product fell more
(p<0·0001) in the losartan group (8·4% reduction) than
in the atenolol group (0·6%), and Sokolow-Lyon voltage
decreased by 13·6% and 5·6%, respectively (p<0·0001,
figure 7).
Losartan
Atenolol
Prespecified adverse events
Angio-oedema
1 (0·2%)
Bradycardia
6 (1%)
Cancer
49 (8%)
Cold extremities
25 (4%)
Cough
24 (4%)
Dizziness
95 (16%)
Hypotension
12 (2%)
Sexual dysfunction
22 (4%)
Sleep disturbance
4 (0·7%)
Additional common* adverse events
Nausea
40 (7%)
Anaemia
41 (7%)
Hypokalaemia
22 (4%)
Headache
92 (16%)
Vertigo
68 (12%)
Dyspnoea
67 (11%)
Pneumonia
32 (6%)
Albuminuria
43 (7%)
Urinary tract infection
45 (8%)
Abdominal pain
42 (7%)
Asthenia/fatigue
94 (16%)
Chest pain
71 (12%)
Influenza-like disease 46 (8%)
3 (0·5%)
50 (8%)
37 (6%)
24 (4%)
15 (3%)
87 (14%)
7 (1%)
23 (4%)
8 (1%)
48 (8%)
31 (5%)
42 (7%)
87 (14%)
44 (7%)
88 (14%)
47 (8%)
79 (13%)
59 (10%)
37 (6%)
105 (17%)
51 (8%)
35 (6%)
p
0·625
<0·0001
0·146
0·884
0·142
0·376
0·251
1·000
0·386
0·508
0·182
0·020
0·517
0·010
0·122
0·130
0·002
0·260
0·486
0·588
0·036
0·167
*An incidence >5% in one of the treatment groups and a difference between
treatment groups >1%.
Table 5: Adverse events
Data are mean (SD).
Discussion
Our results show that losartan was better than atenolol in
reducing the risk of cardiovascular morbidity and mortality
in patients with diabetes and hypertension. Results were
especially marked in the small group (20%) of patients who
had not been treated for hypertension before the study. We
emphasise that we decided before the start of the study to
adjust results for the Framingham risk score and degree of
LVH to account for any difference in key risk predictors at
baseline and thus accounted for the baseline differences
between treatment groups. The LIFE study, although
designed as a trial in patients with hypertension and LVH,
was also a correctly randomised study with respect to the
prespecified subgroup of patients with diabetes.
In terms of achieving reductions in cardiovascular
morbidity and mortality, the benefits of treating
hypertension in middle-aged and elderly patients with
diabetes have been investigated mostly in subgroups of
patients in prospective trials.10–21 Although the importance
of effective blood pressure control in patients with
hypertension and diabetes has been shown in controlled
trials,10,15,16 the relative benefits of different antihypertensive
drugs on the frequency of cardiovascular disease in this
group of patients was not certain. Effective lowering of
blood pressure may be even more important than glucose
control in these patients.13 Angiotensin-II antagonists have
beneficial renal effects in patients with diabetes and
nephropathy.22,23 In our patients, albuminuria was reported
significantly less often in the losartan than in the atenolol
group.
Our results accord with those of CAPPP14 and to some
extent HOPE,17 but differ from those of UKPDS,13 STOP
Hypertension-2,18 NORDIL,19 and INSIGHT.20
Losartan (n=586)
Baseline*
Haemoglobin (g/L)
Sodium (mmol/L)
Potassium (mmol/L)
ALAT (IU/L)
Glucose (mmol/L)
Total cholesterol (mmol/L)
HDL (mmol/L)
Uric acid (mol/L)
Creatinine (mmol/L)
143·7 (12·9)
139·8 (2·7)
4·16 (0·38)
31·9 (22·6)
9·36 (3·54)
5·79 (1·11)
1·32 (0·35)
324·8 (76·1)
90·5 (20·2)
Atenolol (n=609)
Year 4
Change
Baseline*
Year 4
Change
137·5 (14·0)
139·6 (2·9)
4·22 (0·41)
27·2 (19·2)
9·41 (3·71)
5·38 (1·06)
1·32 (0·34)
352·8 (99·7)
102·2 (30·1)
–6·2 (11·4)
–0·2 (3·4)
0·05 (0·43)
–4·7 (18·3)
0·05 (4·44)
–0·41 (1·05)
0·01 (0·24)
28·0 (85·6)
11·8 (24·0)
143·8 (11·6)
139·8 (2·6)
4·15 (0·36)
31·0 (20·3)
9·47 (3·73)
5·83 (1·12)
1·29 (0·37)
336·0 (79·9)
88·2 (19·3)
139·1 (14·1)
139·8 (2·9)
4·15 (0·48)
27·6 (20·6)
9·52 (3·31)
5·43 (1·04)
1·25 (0·30)
383·4 (102·7)
100·2 (34·4)
–4·8 (10·6)
0·0 (3·4)
0·00 (0·49)
–3·4 (19·6)
0·05 (4·36)
–0·40 (1·11)
–0·04 (0·23)
47·4 (89·2)
12·1 (25·9)
ALAT=alanine aminotransferase. Data are mean (SD). *Among patients who also had a value at year 4.
Table 6: Biochemical variables
1008
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For personal use. Only reproduce with permission from The Lancet Publishing Group.
ARTICLES
Time
Baseline
Year 1
Year 2
Year 3
Year 4
Year 5
Losartan (n=586)
Atenolol (n=609)
Clinical
albuminuria*
Creatinine
(mmol/L)†
Clinical
Creatinine
albuminuria* (mmol/L)†
59 (11%)
29 (6%)
35 (7%)
27 (6%)
36 (8%)
27 (8%)
92·3 (20·8)
97·6 (24·6)
99·6 (24·5)
100·7 (26·5)
102·2 (30·1)
102·4 (29·8)
63 (12%)
48 (9%)
43 (9%)
36 (8%)
49 (11%)
31 (11%)
90·5 (20·8)
95·7 (24·2)
97·1 (23·6)
98·5 (26·9)
100·2 (34·3)
103·3 (43·7)
*Urine albumin to creatinine ratio 33·93 mg/mmol (300 mg/g).30 †Data are
mean (SD).
Table 7: Albuminuria and serum creatinine concentrations
As expected, the incidences of cardiovascular morbidity
and mortality in patients with diabetes were higher than in
the entire LIFE population.1 However, incidences of these
events in our study were lower than in patients with
diabetes in STOP Hypertension-218 (n=719, mean age
76 years), which shows the effect of age on cardiovascular
mortality risk.
Some limitations of the study need to be mentioned. The
study population was mainly white and was from western
countries. Moreover, the diabetic patients were derived
from a high-risk population of hypertensive patients with
LVH. The outcome should be interpreted in this context.
Diabetes is an independent stimulus for LVH,24 an effect
that is magnified by hypertension.25,26 Furthermore,
preliminary evidence suggests that LVH has predictive
value for cardiovascular events in patients with diabetes;27
thus, reversal of hypertensive LVH may be associated with
improved cardiovascular outcome in these patients. More
than half all diabetics have hypertension and LVH is very
frequent in this group.26
Despite the fact that more of our patients in the losartan
than in the atenolol group (p=0·076) remained on masked
treatment until the end of the study, this difference did not
contribute substantially to the effects of the drugs on the
composite and individual endpoints (confirmed by an ondrug analysis, data not shown). Since patients were treated
without restriction after study drug discontinuation, an
open-labelled angiotensin-II antagonist or an angiotensionconverting-enzyme inhibitor may have reduced the
difference between groups. Therefore, our estimation of
treatment differences is conservative.
Serum glucose was high at baseline and remained so in
both groups (figure 6). Total cholesterol fell by 0·4 mmol/L
in both groups (table 6). Other changes in biochemical
measurements were as expected with the drugs involved.
Fewer than 40% of all patients attained a systolic blood
Losartan
Atenolol
Cornell product
Sokolow-Lyon
Change from baseline (%)
0
–2
–4
–6
–8
–10
–12
p<0·0001
–14
–16
p<0·0001
Figure 7: Percentage reduction of Cornell voltage-duration
product and Sokolow-Lyon voltage
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
pressure below 140 mm Hg. The goal for systolic pressure
in patients with diabetes was set to below 130 mm Hg in
the 1999 WHO/International Society of Hypertension
guidelines.28 Thus, the potential for more aggressive
treatment to lower blood pressure remains for this group of
patients as well as the need for better metabolic control
(figure 6, table 7).
Systolic blood pressure during the trial was not
associated with any change in risk of the primary composite
endpoint and therefore adjustment for this factor had little
effect on the results. Thus, the greater cardiovascular
protective effect of losartan than atenolol could result from
more pronounced blockade of the detrimental effects of
angiotensin II. Losartan was more effective than atenolol in
reversing LVH (figure 7), which is likely to result from
more complete protection against angiotensin II with
losartan, whether generated by the circulating reninangiotensin system or other mechanisms, especially since
angiotensin II is a myocardial growth factor and an
independent risk factor for cardiovascular disease.29 Hence,
the general message to the practising physician is that
hypertensive diabetic patients with LVH benefit more from
losartan than atenolol.
Contributors
L H Lindholm and H Ibsen were the subcommittee on diabetes.
P Aurup, S Snapinn, and J Edelman are researchers at Merck. All other
authors were members of the LIFE steering committee and have
commented on the manuscript. A full list of the LIFE investigators and
committees is given in reference 1.
Conflict of interest statement
K Kristiansson is a Merck employee and was a non-voting member of the
steering committee. P Aurup, S Snapinn, and J Edelman are employees of
Merck.
Acknowledgments
We thank Sigrid Helle Berg for her dedicated work with the LIFE Study.
The trial was supported by an unrestricted grant from Merck.
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