1804 Chin Med J 2012;125(10):1804-1810

Meta analysis
Effect of angiotensin receptor blockers in the prevention of type 2
diabetes and cardiovascular events: a meta-analysis of
randomized trials
SONG Hui-fen, WANG Su and LI Hong-wei

Keywords: angiotensin receptor blockers; hypertension; diabetes mellitus; cardiovascular events

Background As the incidence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered
as a crucial objective in the near future. Several studies have shown angiotensin receptor blockers (ARBs) may
contribute to the prevention of new-onset type 2 diabetes. This study was conducted to determine if ARBs as
monotherapy or combination therapy may experience a decreased incidence of new-onset type 2 diabetes and prevent
cardiovascular events.
Methods Relevant experimental and clinical studies were identified by searching MEDLINE (1969 to May 30, 2011) to
extract a consensus of trial data involving the effect of ARBs on prevention of new-onset type 2 diabetes and
cardiovascular events. Studies were included if they were randomized controlled trials versus placebo/routine therapy. A
random-effects model was utilized. Subgroup and sensitivity analyses were conducted.
Results Eleven trials were identified, including 82 738 patients. ARBs prevented new-onset type 2 diabetes (odds ratio
0.8 (95% CI 0.76, 0.85)). Regardless of indication for use, essential hypertension (seven trials), impaired glucose
tolerance (one trial), cardiocerebrovascular disease (two trials) or heart failure (one trial), reductions in new-onset type 2
diabetes were maintained (0.75 (0.69, 0.82), 0.85 (0.78, 0.92), 0.80 (0.76, 0.85) and 0.80 (0.64, 0.99), respectively). No
statistical heterogeneity was observed for any evaluation. However, ARBs did not significantly reduce the odds of
all-cause mortality, myocardial infarction and heart failure versus control therapy among all of these studies. But ARBs
did reduce the odds of cardiac death and heart failure among the heart failure study versus control therapy.
Conclusion ARBs have significant ability to reduce risk of developing new-onset type 2 diabetes but does not improve
cardiovascular outcomes over the study follow-up periods among all of included studies.
Chin Med J 2012;125(10):1804-1810

T he incidence of type 2 diabetes is increasing

worldwide.1 In China, because of the rapid change
in lifestyle, prevalence of total diabetes and pre-diabetes
many clinical trials in patients with hypertension, high
risk of cardiovascular disease, heart failure and/or
impaired glucose tolerance. In pre-specified or post-hoc
have been 9.7% and 15.5%, respectively among Chinese analysis, the impact of ARBs usage on the incidence of
adults, accounting for 92.4 million adults with diabetes new-onset type 2 diabetes has been evaluated. Some trials
and 148.2 million adults with pre-diabetes.2 Type 2 found a benefit of ARBs, while many trials shown ARBs
diabetes is becoming a major health problem associated might contribute to the prevention of new-onset type 2
with excess morbidity and mortality and posing an diabetes, others trials did not found significant difference
enormous and escalating economic burden.1 The public between groups in terms of new-onset diabetes.4-14
health impact of type 2 diabetes makes it important to Moreover, if ARBs could provide cardiovascular events
continue efforts toward primary prevention of type 2 benefit in patients with hypertension especially combined
diabetes. with high risk factors is yet uncertain. There is an
increasing need to synthesize all the evidence. This
Type 2 diabetes which often occurs in association with meta-analysis aims to determine the effect of ARBs in
hypertension, accelerates the development of prevention of type 2 diabetes and cardiovascular events.
hypertension-induced cardiovascular disease and
hypertension is also a strong predictor of the development DOI: 10.3760/cma.j.issn.0366-6999.2012.10.022
Department of Cardiology, Beijing Friendship Hospital, Capital
of diabetes.3 Medical University, Beijing 100050, China (Song HF, Wang S and
Li HW)
Thus, the prevention of diabetes is important in the Correspondence to: LI Hong-wei, Department of Cardiology,
management of hypertension. Angiotensin receptor Beijing Friendship Hospital, Capital Medical University, Beijing
blockers (ARBs), as a new type of antihypertensive 100050, China (Tel: 86-10-63139780. Fax: 86-10-63023261.
Email: [email protected])
agents, enhance insulin sensitivity and therefore benefit This work was supported by a grant from the National Natural
patients at high risk of developing type 2 diabetes. ARBs Science Foundation of China (No. 30971240).
have been studied versus placebo or active therapy among The authors have no conflict of interest to declare.
Chinese Medical Journal 2012;125(10):1804-1810 1805

METHODS Statistical analyses

New-onset type 2 diabetes and cardiovascular events was
Selection criteria treated as a dichotomous variable and reported as odds
Studies were included in this meta-analysis if they were ratios (ORs) with 95% confidential intervals (CIs). Pooled
randomized controlled trials and met all the following ORs were calculated using the DerSimonian and Laird
criteria: (1) comparison between ARBs with placebo or random-effects model or the Mantel-Haenszel
routine treatment; (2) inclusion of individuals with fixed-effects model, depending on the existence or not of
hypertension or others high risk factors; (3) new-onset heterogeneity of treatment effects across studies.
type 2 diabetes and cardiovascular outcomes as primary
endpoint, a pre-specified end-point or as a part of The percentage variability of the pooled ORs attributable
post-hoc analysis; (4) median or average follow-up of at to heterogeneity among studies was quantified using the
least 1 year, recruiting more than 100 patients. Trials I2 statistic test.15 Typically, values above 50% are deemed
which did not meet the above requirements were to suggest large between-study heterogeneity, Sensitivity
excluded from the meta-analysis. analysis was performed by reanalyzing the data using the
fixed-effects model. Evidence of publication bias was
Search strategy examined by constructing funnel plots.16
Experimental and clinical studies of relevance to ARBs
and prevention of type 2 diabetes were identified by a Statistical analyses were performed using Review
search of MEDLINE (1969 to May 30, 2011). The search Manager (RevMan (Computer program), version 5.1 for
was limited to English-language articles in humans. Windows, Copenhagen: The Nordic Cochrane Centre,
Medical subject Search terms including ARBs, RAS The Cochrane Collaboration). A value of P <0.05 was
blockade/antagonist and individual drug names within considered statistically significant.
these classes were combined with “diabetes,”
“pre-diabetes,” “hypertension,” “high risk,” “coronary RESULTS
disease,” “cardiovascular outcome,” and “randomized,
controlled, trials’’. Reference lists of identified articles, Study selection
including previous meta-analyses and reviews on the Our search identified 11 randomized controlled trials for
field, were evaluated for additional relevant studies and inclusion.4-14 These trials enrolled 82 738 patients, of
information. whom 41 356 were randomized to ARBs therapy, while
the remainder received active control or placebo.
Data extraction and quality assessment
Titles and abstracts of the retrieved citations were Baseline characteristics
screened by one of the authors (Song) and full texts of the The baseline characteristics of patients are listed in Table
articles thought to be potentially eligible were retrieved. 1. Seven trials were performed in patients with essential
Two of the authors (Song and Wang) independently hypertension and one trial concerned patients with heart
reviewed these for eligibility. Data about characteristics failure,6 one trial in patients with impaired glucose
of the participants, interventions, comparisons, and tolerance,9 two trials performed in patients with
outcomes (new-onset type 2 diabetes and cardiovascular cardiocerebrovascular diseases.10,12
events) were extracted from each study. The
methodological quality of included randomized Five trials compared ARBs with placebo.6,7,10-12 While
controlled trials was assessed using standard criteria two trials included a diuretic and/or a beta-blocker as
(allocation concealment, intention-to-treat analysis, comparator4,8 and two trials used amlodipine as reference
blinding and completeness of follow-up). Disagreements drug,5,13 one trials used nateglinide or placebo as control,9
between the two authors were resolved by consensus. one study compared candesartan with non-ARBs.14

Table 1. Characteristics of studies included in the meta-analysis

Patients Mean age Male Mean follow-up
Studies Intervention Indication for use
(n) (years) (%) (years)
ALPINE (2003) Candesartan 196 HCTZ 196 392 55.0 48.0 1.0 Primary HTN
CASE-J (2008) Candesartan 2354 Amlodipine 2349 4728 63.8 55.2 3.2 HTN
CHARM (2003) Candesartan 3803 Placebo 3796 7599 66.0 68.4 3.1 HF
HIJ-CREATE (2009) Candesartan 1024 Non-ARB 1025 2049 64.8 80.2 4.2 HTN with CVD
KYOTO HEART (2009) Valsartan 1517 Placebo 1514 3031 66.0 57.0 3.3 HTN with high risk of cardiac events
LIFE (2002) Losartan 4605 Atenolol 4588 9193 66.9 46.0 4.8 essential HTN and LVH
NAVIGATOR (2010) Valsartan 4631 Nateglinide or placebo 4675 9306 63.7 49.4 5.0 IGT with CVD
PROFESS (2008) Telmisartan 10146 Placebo 10186 20332 66.1 64.0 2.5 ischemic storke
SCOPE (2003) Candesartan 2477 Placebo 2460 4937 76.4 35.5 3.7 HTN
TRANSCEND (2008) Telmisartan 2954 Placebo2972 5926 66.9 57.0 4.7 CVD or DM
VALUE (2004) Valsartan 7649 Amlodipine 7596 15245 67.2 57.5 4.2 HTN with high risk of cardiac events
HTN: hypertension; CVD: cardiovascular disease; HF: heart failure; ARBs: angiotensin receptor blockers; HCTZ: hydrochlorothiazide; IGT: Impaired glucose tolerance;
MI: myocardial infarction; DM: diabetes mellitus.
1806 Chin Med J 2012;125(10):1804-1810

3685 new cases (12.7%) in subjects

treated with placebo or other agents
(OR 0.8, 95% CI (0.76, 0.85)).
ARBs were associated with
significant reduction in the risk of
new-onset type 2 diabetes in
patients with primary hypertension
(OR 0.75, (0.69, 0.82)), heart failure
(OR 0.80, (0.64, 0.99)), cardiocere-
brovascular diseases (OR 0.84,
(0.72, 0.97)) or impaired glucose
tolerance (OR 0.85, (0.78, 0.92))
(Figure 1). There was no
heterogeneity and no evidence for
publication bias.

Incidence of cardiovascular events

ARBs were not associated with
significant reduction in the risk of
all-cause death in patients with
essential hypertension (OR 0.95,
(0.87, 1.05)), heart failure (OR 0.92,
(0.82, 1.04)), cardiocerebrovascular
diseases (OR 1.04, (0.95, 1.13)) or
Figure 1. Studies or subgroup analyses evaluating incidence of new-onset type 2 diabetes. impaired glucose tolerance (OR
0.90, (0.77, 1.06)), when compared
with controls (Figure 2). There was
low heterogeneity and no evidence
for publication bias.

Similarly, ARBs were not associated

with significant reduction in the risk
of cardiovascular death in patients
with essential hypertension (OR
0.94, (0.84, 1.04)), cardiocerebro-
vascular diseases (OR 0.93, (0.77,
1.12)) or impaired glucose tolerance
(OR 1.12, (0.87, 1.44)), when
compared with controls. Except
among patients with heart failure,
significant reduction in cardiac
death (OR 0.88 (0.78, 0.98))
occurred (Figure 3). There was no
heterogeneity and no evidence for
publication bias.

The results were similar when ARBs

were compared with either placebo
or with active treatment for the
outcome of myocardial infarction,
there were no significant deference
occurred in patients with heart
Figure 2. Effect of ARBs on all-cause death in patients with different baseline diseases. failure (OR 1.07, (0.75, 1.53)),
ARBs: angiotensin receptor blockers. cardiocerebrovascular diseases (OR
0.89, (0.71, 1.13)) or impaired
Incidence of new-onset type 2 diabetes glucose tolerance (OR 0.99, (0.78,
Overall, there were 3111 new cases of type 2 diabetes 1.26)), but in patients with primary hypertension, a
(10.7%) in patients treated with ARBs compared with significantly higher risk of myocardial infarction occurred
Chinese Medical Journal 2012;125(10):1804-1810 1807

For the outcome of heart failure,

among patients with primary
hypertension (OR 0.90, (0.80,
1.02)), heart failure (OR 0.78, (0.70,
0.87)), cardiocerebrovascular diseases
(OR 1.04, (0.87, 1.25)) or impaired
glucose tolerance (OR 0.98, (0.73,
1.31)), respectively (Figure 5).
There was moderate heterogeneity
and no evidence for publication
bias.

DISCUSSION

Our meta-analysis provides

evidence on the ability of ARBs to
reduce the incidence of new-onset
type 2 diabetes, when compared to
placebo in patients with essential
hypertension, impaired glucose
tolerance and/or high cardiovascular
risk. In this meta-analysis, 58 122
patients without diabetes were
evaluated for development of
new-onset type 2 diabetes.
Figure 3. Effect of ARBs on cardiovascular death in patients with different baseline Pharmacological treatment based on
diseases. ARBs: angiotensin receptor blockers. ARBs significantly reduced the
odds of new-onset type 2 diabetes
compared to control groups.

Although we found that ARBs can

help to prevent the incidence of
new-onset type 2 diabetes in
patients with aforementioned
diseases. The mechanisms
underlying the prevention of
new-onset type 2 diabetes by ARBs
are complex and not fully
elucidated. There are several
possible explanations for this effect.

It has been shown that the

antidiabetic effects of ARBs may be
due to vasodilatory actions that
increase skeletal muscle blood flow,
which are associated with increased
insulin sensitivity. This has been
supported by several studies in
patients and animals.17-19 Secondly,
the increased adiponectin levels
associated with ARBs therapy are
accompanied by reduced insulin
levels and improved insulin
sensitivity. Adiponectin is an
Figure 4. Effect of ARBs on myocardial infarction in patients with different baseline adipose-derived factor that
diseases. ARBs: angiotensin receptor blockers. augments and mimics metabolic
actions of insulin by increasing fatty
(OR 1.11, (1.00, 1.24)) (Figure 4). There was low acid oxidation and insulin-mediated glucose disposal in
heterogeneity and no evidence for publication bias. skeletal muscle as well as decreasing hepatic glucose
1808 Chin Med J 2012;125(10):1804-1810

KYOTO HEART study,7 the median

follow-up period was 3.27 years. In
both groups, blood pressure at
baseline was 157/88 and 133/76
mmHg at the end of study.
Compared with non-ARBs arm,
valsartan add-on arm had fewer
primary endpoints. Valsartan add-on
treatment to improve blood pressure
control prevented more
cardiovascular events than
conventional non-ARBs treatment
in high-risk hypertensive patients in
Japan. Moreover, these benefits
cannot be entirely explained by a
difference in blood pressure control.
In the LIFE study,8 despite similar
falls in blood pressure, losartan
appeared to be more effective in
reducing the primary endpoint, as
well as reducing death from
cardiovascular disease and all cause
mortality. However, the VALUE
study13 demonstrated no difference
in the cardiac outcomes between
Figure 5. Effect of ARBs on heart failure in patients with different baseline diseases. valsartan or amlodipine treatment
ARBs: angiotensin receptor blockers. despite better blood pressure control
in the amlodipine group. Although
there was a 23% lower incidence of
output.20 Thirdly, there may be direct effects of ARBs to new-onset type 2 diabetes in patients treated with
augment insulin-stimulated glucose uptake and promote valsartan compared to patients treated with amlodipine.
differentiation of adipocytes.21 Moreover, new-onset The recently published HIJ-CREATE study14 aimed to
diabetes could also be prevented through direct effects on test whether candesartan can reduce the incidence of
the pancreas by drugs that block the RAS. Animal studies cardiovascular events compared with non-ARBs-based
have found that RAS blockade is associated with standard pharmacotherapy in coronary artery disease
protection of the pancreatic islets from glucotoxicity and patients with hypertension. During a median follow-up of
restoration of beta-cell mass.22 In addition, some ARBs 4.2 years, candesartan showed no significant differences
have been reported to activate peroxisome in major adverse cardiovascular event (MACE) compared
proliferator-activated receptor receptor-γ activity, which with the non-ARBs treatment group. In the PRoFESS and
are contributing to improve insulin sensitivity.23 Finally, TRANSCEND study,10,12 therapy with telmisartan did not
ARBs therapy may reduce insulin resistance by other significantly lower the rate of major cardiovascular
mechanisms, such as inhibited NAD(P)H oxidase, the events.
consequent reduction in oxidative stress that also
contribute to nitric oxide bioavailability which might also There are several possible reasons that ARBs did not
contribute to improve glucose homeostasis. These improve cardiovascular outcomes. We limited our
mechanisms are not mutually exclusive and it is possible meta-analysis to studies that also evaluated new-onset
that several may combine to provide the beneficial effects type 2 diabetes. When evaluating the totality of data in
on metabolic function. heart failure, ARBs provide clear mortality benefit in
patients with heart failure.24 Our findings in heart failure
Since type 2 diabetes increase the risk of cardiovascular trial were also consistent with it. In addition, the benefit
events, it could be assumed that reducing the incidence of of ARBs has also been smaller in recent studies when
new-onset type 2 diabetes would result in fewer events. compared with observed historically, possibly because of
However, our findings demonstrated that among ARBs greater use of other effective therapies.9,10,13,25,26 These
trials evaluating new-onset type 2 diabetes, there were no factors may have diluted any potential benefit of ARBs.
significant differences in all-cause mortality, Furthermore, clinical studies failed to demonstrate any
cardiovascular end points versus control therapy. efficacy. This may be accountable by the relatively short
follow-up period, although long term trials might show
Effects of ARBs among involved trials in primary or that drugs to ARBs are more beneficial to cardiovascular
cardiovascular outcomes are controversial. In the prevention in hypertensive patients.27 Finally, lifestyle
Chinese Medical Journal 2012;125(10):1804-1810 1809

modification improves cardiovascular risk factors and candesartan antihypertensive survival evaluation in Japan
may also reduce the rate of cardiovascular events in the trial. Hypertension 2008; 51: 393-398.
long term.28,29 6. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ,
Michelson EL, et al. Effects of candesartan on mortality and
Study limitations morbidity in patients with chronic heart failure: the
It has to be appreciated that there are some limitations of CHARM-Overall programme. Lancet 2003; 362: 759-766.
our analysis with respect to new-onset type 2 diabetes and 7. Sawada T, Yamada H, Dahlof B, Matsubara H. Effects of
cardiovascular outcomes. First, it should be noted that valsartan on morbidity and mortality in uncontrolled
these are post-hoc analyses of these trials and none of the hypertensive patients with high cardiovascular risks: KYOTO
studies was primarily designed to address the issue of HEART Study. Eur Heart J 2009; 30: 2461-2469.
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for the definition of type 2 diabetes between studies. Faire U, et al. Cardiovascular morbidity and mortality in the
Thirdly, meta-analyses have intrinsic methodological Losartan Intervention For Endpoint reduction in hypertension
limitations related to combining trials with different study (LIFE): a randomised trial against atenolol. Lancet
designs, treatment strategies, and patient populations. For 2002; 359: 995-1003.
example, the present analysis combined trials in patients 9. McMurray JJ, Holman RR, Haffner SM, Bethel MA,
with and without heart failure. Moreover we limited our Holzhauer B, Hua TA, et al. Effect of valsartan on the
meta-analysis to studies that evaluated both new-onset incidence of diabetes and cardiovascular events. N Engl J
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outcomes were excluded, that might have affected the WA, et al. Telmisartan to prevent recurrent stroke and
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