Q J Med 2006; 99:431–436

doi:10.1093/qjmed/hcl059

Review

Antihypertensive treatment with beta-blockers and

the spectrum of glycaemic control
P.A. SARAFIDIS and G.L. BAKRIS
From the Hypertension/Clinical Research Center, Departments of Preventive and Internal Medicine,
Rush University Medical Center, Chicago, USA

Summary
Hypertension and type 2 diabetes mellitus (DM) In contrast, the newer vasodilating b-blockers
are major cardiovascular risk factors, and often appear to be free of adverse effects on the above
cluster in the same individual in the context of metabolic parameters, and could be a valuable
the metabolic syndrome. Management of hyper- tool for hypertension treatment in patients with DM
tension in the diabetic patient is extremely impor- or the metabolic syndrome. This review summarizes
tant, and agents from all major antihypertensive the evidence on the effects of antihypertensive
classes are effective towards this goal. Conventional treatment with both traditional and vasodilating
b-blockers are associated with detrimental b-blockers on parameters related to carbohydrate
effects on insulin sensitivity, glycaemic control, metabolism, and discuss the pathophysiological
and the incidence of type 2 DM and thus are mechanisms that may be responsible.
less often used in hypertensive patients with DM.

Introduction
Hypertension and diabetes mellitus (DM) represent morbidity and mortality.4,5 In diabetic patients,
two of the major risk factors for cardiovascular management of hypertension is of great impor-
disease (CVD).1 In many individuals, hypertension tance,6 and current guidelines recommend that
and type 2 DM accompany other CVD risk factors to achieve a goal of 130/80 mmHg, agents from
such as visceral adiposity and dyslipidaemia, in the all antihypertensive classes can be used, usually
so-called Metabolic or Insulin Resistance Syndrome, in combination.4,5 However, previous studies
for which insulin resistance and compensatory have suggested that antihypertensive agents from
hyperinsulinaemia have been proposed as the different classes may exert different effects on
underlying disorders.2 This combination appears glucose tolerance. In general, angiotensin-
to accelerate the development of atherosclerosis, converting-enzyme (ACE) inhibitors and calcium-
adding substantial cardiovascular risk beyond that of channel blockers (CCBs) were associated with
the individual risk factors.3 neutral or beneficial effects on carbohydrate and
Treatment of CVD risk factors such as hyper- lipid metabolism, but thiazide diuretics and
tension aims primarily to reduce cardiovascular b-blockers with adverse effects.7,8 Therefore, although

Address correspondence to Dr P.A. Sarafidis, Hypertension/Clinical Research Center, Department of Preventive

Medicine, Rush University Medical Center, 1700 West Van Buren, Suite 470, Chicago, IL 60612, USA.
email: psarafidis11@yahoo.gr
! The Author 2006. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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 432 P.A. Sarafidis and G.L. Bakris

conventional b-blockers reduce cardiovascular hypertension and type 2 DM. On the other hand,
risk in diabetic individuals,6,9 they are not recom- in patients without type 2 DM, the concept of the
mended as first-line antihypertensive therapy in metabolic syndrome suggests that a decrease in
patients with DM.4,5 However, there are data insulin sensitivity would not result in elevation
suggesting that newer b-blockers with vasodilating of blood glucose levels, as long as the pancreatic
properties have a different metabolic profile b-cells could secrete the necessary amounts of
from traditional ones,10–13 and could therefore be insulin. However, after a certain period of time,
of particular benefit for patients with type 2 DM. b-cells would no longer be able to compensate
This review summarizes the clinical evidence on for the increasing insulin resistance and type 2 DM
the effects of antihypertensive treatment with both would appear.17
conventional and vasodilating b-blockers on param- The importance of this detrimental effect of
eters related to carbohydrate metabolism, such as b-blockers on insulin sensitivity can be seen from
glycaemic control, insulin sensitivity and type 2 DM studies examining their effect on the incidence of
incidence, providing also some potential patho- DM, which represents a more definite outcome.
physiological explanations for these effects. For this Most of these data suggest that use of conventional
purpose, a systematic literature search of MEDLINE/ b-blockers, such as atenolol or metoprolol,
PubMed database was performed to identify English- increases the propensity of patients with hyperten-
language articles published until October 2005 that sion to develop type 2 DM. For example, in the large
reported data on the effects of antihypertensive prospective Atherosclerosis Risk in Communities
treatment with b-blockers on glycaemic control, (ARIC) cohort study, of 3804 hypertensive subjects,
insulin sensitivity and incidence of DM. Search representing a subgroup of the original study cohort,
terms used were: ’b-blocker’, ’antihypertensive after appropriate adjustment for all potentially
treatment’, ’diabetes’, ’glucose’, ’glycated hemo- important confounders those treated with b-blockers
globin’, ’glycemic control’, ’insulin sensitivity’ and had a 28% higher risk of type 2 DM, compared
’insulin resistance’. Reference lists of identified to those taking no medication (RR 1.28, 95%CI
articles were also evaluated for additional relevant 1.04–1.57), whereas users of thiazide diuretics, ACE
papers and information. Clinical studies providing inhibitors or CCBs were not at significantly higher or
adequate information on effects of b-blockers on the lower risk for subsequent type 2 DM than untreated
above parameters, as well as background studies hypertensives.18
providing mechanistic explanations for these effects, In the Captopril Prevention Project (CAPPP) trial,
were included. in which 10 985 hypertensive subjects were
The text that follows is divided in four sections: randomized to captopril or conventional treatment
the effects of conventional b-blockers on insulin consisting of a diuretic, b-blockers or both, the
sensitivity and the risk of new onset type 2 DM; captopril-based regimen was associated with a
potential mechanisms for these effects of conven- lower incidence of type 2 DM compared to the
tional b-blockers; the effects of vasodilating conventional regimen, in both intention-to-treat
b-blockers on insulin sensitivity and glycaemic (RR 0.86, 95%CI 0.74–0.99) and on-treatment
control; and potential mechanisms for these effects (RR 0.79, 95%CI 0.67–0.94) analyses.19 In the
of vasodilating b-blockers. Losartan Intervention For Endpoint reduction
(LIFE) study, 9193 patients with hypertension and
left ventricular hypertrophy were randomized to
losartan-based or atenolol-based antihypertensive
Effects of conventional b-blockers treatment for at least 4 years. In patients without
on insulin sensitivity and the risk of diabetes in randomization, the risk of subsequent
DM was 25% lower for those on losartan-based
new-onset type 2 diabetes mellitus compared with those on atenolol-based therapy
In clinical studies that used the euglycaemic (RR 0.75, 95%CI 0.63–0.88).20
hyperinsulinaemic clamp technique (the most In the International Verapamil-Trandorapril Study
reliable available method of estimating insulin (INVEST) trial, 22 576 patients with hypertension
sensitivity), treatment with conventional b-blockers and coronary artery disease were randomized to
(either non-selective, e.g. propranolol,14 or b1- verapamil-based or atenolol-based antihypertensive
selective, e.g. atenolol,15,16 metoprolol,11,16) signifi- therapy. Among patients without DM at entry, those
cantly decreased insulin sensitivity in hypertensive in the verapamil group had a 15% lower incidence
patients. This deterioration of insulin sensitivity with of new onset diabetes than subjects in the atenolol
b-blockers is expected to have a direct negative group (RR 0.85, 95%CI 0.77–0.95).21 In contrast
effect on glycaemic control in patients with both to the above data, in the Swedish Trial in Old

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 Beta-blockers and glycaemic control 433

Patients with Hypertension 2 (STOP-Hypertension 2) endothelium-dependent insulin-mediated vasodila-

study, there was no difference in diabetes incidence tation is seriously impaired, and it is considered an
between conventional treatment (b-blockers or important cause of reduction of insulin-stimulated
diuretics) and either ACE-inhibitor based or glucose uptake in the periphery.23,24 On the other
CCB-based treatment.22 hand, acute sympathetic nervous system (SNS)
Most of the above studies suggest that type 2 DM stimulation in normal individuals lowers insulin-
incidence is increased in subjects receiving stimulated glucose uptake in muscles through
b-blockers. However, a number of methodological vasoconstriction and blood flow reduction.25,26
issues limit the conclusions that can be drawn This effect is mediated via a1-adrenergic pathways,
from these studies. For example, none of those as evident from studies with direct a- and
studies,18–22 nor any randomized controlled trial b-blockade,27 and further supported by the vasodi-
with antihypertensive agents published so far, latating and insulin-sensitizing properties of
examined diabetes incidence as a primary end- a-adrenergic blockers.28 During treatment with
point. In some of the above mentioned randomized conventional b-blockers, unopposed a1-activity
trials, a large proportion of patients in the various would cause vasoconstriction and decreased blood
groups were receiving second-line agents that flow to muscles.29,30 According to the above logic,
could influence glycaemic control in the opposite this effect will result in reduced insulin-stimulated
direction from the main agent.19,21,22 In some of glucose uptake: in other words, insulin resistance.
these studies, an ACE inhibitor19,22 or a CCB22 was Treatment with b-blockers can also interfere with
compared to conventional treatment consisting of insulin secretion from pancreatic b cells. In par-
diuretics or b-blockers in various combinations, and ticular, b-blockers may decrease the first phase of
thus the net effect of the latter cannot be easily insulin secretion, possibly through an impairment
assessed. Moreover, as these trials compared active of b2-mediated insulin release.14–16,31 In general,
regimens, the observed differences19–21 could be attenuation of the first phase of insulin secretion
attributed either to a negative effect of b-blockers represents a crucial step in the natural history of type
or to a beneficial effect of the other treatment 2 DM, and has been suggested as an important
compared, a fact not allowing firm conclusions to predictor of this disease.32 Thus, this action of
be drawn. Detection bias could have occurred in b-blockers could be another important contributor
those of the above studies that were open-label with towards the development of type 2 DM.
blinded end-point evaluation,19,21,22 as diabetes may Weight gain is another proposed mechanism of
have been more intensively sought in patients receiving insulin sensitivity deterioration with b-blockers, as
b-blockers. Therefore to have a definite answer in those agents have been associated with an impor-
this field, it seems that we still need randomized, tant increase in body weight in various studies9,33
double-blind controlled trials examining diabetes and weight gain is closely connected to insulin
incidence as a primary end-point, preferably comparing sensitivity reduction.34 However, this mechanism
a b-blocker to placebo and having the same proportion does not seem to be of primary importance, since
of second-line agents in the groups compared. in the above mentioned studies decreased insulin
sensitivity was also observed in subjects without
weight gain,14–16 and in the ARIC study, weight
increase in patients treated with b-blockers
Potential mechanisms of the was identical to that of participants receiving no
effects of conventional b-blockers medication.18
on insulin sensitivity and glycaemic In addition to the above, in insulin-resistant states,
one of the main problems at the level of the liver is
control the inability of insulin to suppress hepatic glucose
Although the actions through which conventional production, which leads to elevated hepatic glucose
b-blocking agents influence insulin sensitivity and production after meals, a disorder also contributing
glycaemic control are not fully clarified, several to loss of glycaemic control.32,35 Sympathetic
mechanisms have been described that may be activation stimulates glyconeogenesis and glyco-
responsible. The most important are the haemo- genolysis and inhibits glycogen synthesis in the
dynamic effects of these agents. Under normal liver. Although the relative importance of a- and
conditions, insulin promotes vasodilatation and b-adrenergic receptors in mediating catecholamine-
increases blood flow in the skeletal muscles, an induced hepatic glucose production in humans
action tightly coupled with an increase of glucose in vivo remains to be resolved, in rats a2-receptors
disposal in the same tissue.23 In contrast, in insulin- are involved.36 If a-receptors play the major role in
resistant states such as type 2 DM and obesity, humans, unopposed a-activity in the presence of

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 434 P.A. Sarafidis and G.L. Bakris

b-blockade, as in the case of haemodynamic effects, pressure control was similar in the two groups,
could result in enhanced hepatic glucose output, HbA1c increased in the metoprolol (mean
SD
increasing the risk for type 2 DM. Other mechanisms 0.15%
0.04%, p < 0.001) but not in the
responsible for this detrimental effect of b-blockers carvedilol group (0.02%
0.04%, p ¼ 0.65), result-
on glycaemic control have been also speculated ing in a difference between the two groups of
upon, but not extensively studied, such as changes 0.13%
0.05% (95%CI –0.22% to –0.04%,
in the capacity of aerobic exercise, or changes in the p ¼ 0.004) in the modified intention-to-treat
cellular actions of insulin.8 analysis. Insulin resistance, as assessed by the
Homeostasis Model Assessment-Insulin Resistance
(HOMA-IR) index was significantly decreased with
Effects of vasodilating b-blockers carvedilol (–9.1%, p ¼ 0.004) but not metoprolol
(–2.0%, p ¼ 0.48) and the between-group difference
on insulin sensitivity and was –7.2% (95%CI –13.8% to –0.2%; p ¼ 0.04). In
glycaemic control addition, among patients with normal urine albumin
excretion in baseline, fewer progressed to micro-
In contrast to the effect described above, some
albuminuria in the carvedilol than in the metoprolol
studies suggest that newer b-blockers with vasodi-
group (6.4% vs. 10.3%, respectively; OR 0.60,
lating properties can have beneficial effects on
95%CI 0.36–0.97, ¼ 0.04). These findings support
parameters such as glycaemic control and insulin
a less detrimental effect of vasodilating compared
sensitivity. Several years ago, delivalol, a
to older b-blockers on glycaemic control and insulin
b1-selective b-blocker with a b2-agonistic action
sensitivity and suggest that among b-blockers,
was found to improve insulin sensitivity by about
vasodilating agents should be preferred in subjects
10% in hypertensive patients,37 but was withdrawn
with type 2 DM or the metabolic syndrome.
from the market due to side-effects. In a subsequent
study, another b1-blocker with b2-agonistic effects,
celiprolol, was associated with a 35% increase
in insulin sensitivity after a treatment period of Potential mechanisms of the effects
12 months.10 of vasodilating b-blockers on insulin
Carvedilol, a non-selective b-blocker with
a1-blocking properties has been also found to
sensitivity and glycaemic control
improve insulin sensitivity. Jacob et al. compared These beneficial or at least neutral effects of newer
the effects of carvedilol and metoprolol in 72 b-blocking agents on glycaemic control and insulin
hypertensive patients without DM, and observed a sensitivity could be explained in terms of patho-
14% increase in insulin sensitivity estimated with physiology from positive actions on some of the
the clamp with carvedilol after 12 weeks of above adverse mechanisms of the conventional
treatment, whereas metoprolol was associated with b-blockers. For example, as far as the haemo-
a reduction in this parameter.11 In another study, dynamic effects are concerned, stimulation of
Giuglano et al. compared the effects of carvedilol b2-receptors causes vasodilatation,38 therefore non-
and atenolol in 45 patients with both hypertension selective b-blockade will also stop this b2-mediated
and type 2 DM. After 24 weeks of treatment, fasting increase in blood flow. This is probably why insulin
plasma glucose and HbA1c were decreased and sensitivity is relatively more decreased with propran-
insulin sensitivity measured with the clamp was olol than with b1-selective blockers.14–16 In addi-
increased with carvedilol, whereas atenolol had the tion, in a patient receiving a b-blocker that
opposite results.12 combines b1-selective and b2-agonistic action,
Some months ago, the results of the Glycemic vasodilatation will predominate and peripheral
Effects in Diabetes Mellitus: Carvedilol-Metoprolol blood flow will increase.38 Thus, the observed
Comparison in Hypertensives (GEMINI) trial were increases of insulin sensitivity with delivalol37 and
published.13 In this multicentre trial, 1235 subjects celiprolol10 could be attributed to the vasodilatation
with hypertension and type 2 DM who were already they cause. Moreover, it seems unlikely these
receiving an ACE inhibitor or an angiotensin- compounds impair first-phase insulin secretion,
receptor blocker (ARB) were randomized to receive which is b2-mediated31 and therefore they are not
6.25–25 mg of carvedilol or 50–200 mg of metopro- implicated in another important mechanism of
lol twice daily, to compare the effects of these deterioration in glycaemic control.
b-blockers on glycaemic and metabolic control. In the case of carvedilol, the a1-blocking property
After 5 months of maintenance therapy, although would be expected to oppose to the a1-mediated
both drugs were well-tolerated and blood vasoconstriction. Indeed, carvedilol has been

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 Beta-blockers and glycaemic control 435

known for several years to cause vasodilatation and 4. Chobanian A, Bakris GL, Black HR, et al. Seventh report
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5. European Society of Hypertension–European Society of
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such as postural hypotension and dizziness, than 2003; 21:1011–53.
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