Clin. Cardiol.
10, 561-566 (1987)
Review
The Effects of Beta-Adrenergic Blocking Agents on Blood Lipid Levels
H.WOLINSKY, M.D., Ph.D., F.A.C.C.
Department of Medicine,Mt. Sinai School of Medicine, New York, New York,USA
Summary: This review examines the effects of beta-
adrenergic blocking agents on blood lipids. These agents
have been effective in the treatment of angina and hyper-
tension and in the reduction of recurrence of ischemic
cardiac disease, such as myocardial infarction. Many beta
blockers, however, have an adverse effect on blood lipids,
especially by reducing high-density lipoprotein (HDL)
cholesterol and increasing triglycerides. One result is an
unfavorable influence on the cholesterol ratio (expressed
either as low-density lipoprotein [LDL]/HDL or total
cholesterol/HDL).These cholesterol parameters have been
shown to have a strong influence on coronary heart dis-
ease (CHD) risk. Studies have shown that antihyperten-
sive therapy has reduced the incidence of cerebrovascular
disease but, in many instances, has not reduced the inci-
dence of CHD. A hypothesis for this lesser effect on corn-
nary disease is that antihypertensive agents may be ad-
versely affecting blood lipids. Thus, while one major risk
factor for CHD is reduced, another may be somewhat en-
hanced. Pharmacologic properties of some beta blockers
such as peripheral alpha blockade (e.g., with labetalol)
or intrinsic sympathomimetic activity (ISA) (e.g., with
pindolol) may counteract some of these negative lipid ef-
fects. An investigational beta blocker, bevantolol, which
will be marketed shortly in the United States, has been
effective in antihypertensivetherapy. Bevantolol has been
shown to lower LDL cholesterol and not adversely affect
HDL cholesterol; in this way, bevantolol favorably in-
fluences the serum lipoprotein profile. Whether this ef-
fect will have clinical significance remains to be seen.
Address for reprints:
Harvey Wolinsky, M.D.
Depaltment of Medicine
Mt. Sinai Hospital and Medical Center
New York, NY 10129, USA
Received: May 19, 1987
Accepted: July 24, 1987
Key words: beta-adrenergic blockers, atenolol, pro-
pranolol, metoprolol, pindolol, labetalol , sotalol, ox-
prenolol, bevantolol, cholesterol, highdensity lipoprotein,
low-density lipoprotein, very lowdensity lipoprotein,
coronary heart disease, alpha-adrenergic blockers
Introduction
Hypemwion is clearly associated with an increased risk
of cardiovascularmorbidity and mortality. Lowering blood
pressure, alone or in concert with reducing other risk fac-
tors, decreases morbidity and mortality. Given these clear
results, a new challenge for physicians is to select from
numerous effective antihypertensive medications that will
not adversely affect coexisting risk factors, especially se-
rum cholesterol. The use of diuretics in traditional step
1 therapy may, therefore, be questioned because of the
accumulated evidence that these agents adversely affect
blood lipids. Conversely, alpha blockers, which do not
appear to adversely affect the lipid profile, may sometimes
be more attractive.
Beta-adrenergicblocking agents have been used to treat
hypertension and angina and to prevent recurrence of
ischemic cardiac disease, such as myocardial infarction.
There are many differences among the beta blockers. The
presence or absence of properties such as beta, selectivity
or intrinsic sympathomimetic activity may account for the
various findings reported by a wide range of investiga-
tors concerning the side effects of these agents. A poten-
tially important side effect-certainly in terms of risk of
coronary heart disease (CHD)-is the effect of these agents
on blood lipid levels.
Although numerous studies have shown that beta block-
ers have an adverse effect on blood lipid
23.26.27.32.33.37.41 some investigators feel that there is no such
adverse e f f e ~ t . ' . ' ~These
, ~ ~ studies have been done primar-
ily in patients being treated for hypertension; thus, this
review will focus on the effect of these agents on blood
lipids in patients with hypertension and the subsequent im-
pact on CHD.

562 Clin. Cardiol. Vol. 10, October 1987
The Cholesterol Hypothesis
The major blood lipids include cholesterol and the tri-
glycerides. The cholesterol fractions include low-density
lipoprotein (LDL) cholesterol, very low-density lipo-
protein (VLDL) cholesterol, and high-density lipoprotein
(HDL) cholesterol. High-density lipoproteins can be sub-
divided: HDLz and the even denser HDL,. The Framing-
ham Study17firmly established elevated blood cholester-
ol along with hypertension and cigarette smoking as major
risk factors for CHD. Elevated levels of triglycerides have
been established as a secondary risk factor. In 1979, the
Framingham Group identified the LDL fraction as athero-
genic and the HDL fraction as protective against CHD.
Pathogenesis of Atherosclerotic Disease
The mechanisms responsible for the acceleration of
atherosclerosisand the subsequent risk of CHD in hyper-
tension are not entirely certain; however, the role of the
cholesterol fractions in cellular lipid metabolism is becom-
ing clearer. The lipoprotein fraction that carries most of
the cholesterol is LDL. Borne by the bloodstream, the en-
dogenous, cholesterol-richLDL fraction apparently enters
the artery wall. The cholesterol load is deposited in the
intima, where it may initiate or aggravate the process of
atherosclerotic plaque formation, both by intra- and ex-
tracellular accumulation. The HDL lipoprotein, on the
other hand, may protect against the development or
progression of atherosclerosis by serving as an acceptor
of excess cholesterol from arterial and other tissues and
returning it to the liver for further metabolism and even-
tual e x ~ r e t i o n . ~ ~
The Importance of HDL Cholesterol
A correlation between the severity of CHD and the
blood levels of both HDL and LDL cholesterol has been
consistently observed. A high level of HDL cholesterol
is associated with less severe and reduced risk of CHD;
the inverse is true for a low level of HDL cholesterol. Spe-
cifically, the HDLz cholesterol subfraction-rather than
HDL,-is more strongly associated with protection against
CHD.
The relationship of the HDL cholesterol level to the risk
of CHD has been confirmed by a number of studies,
among them the Cooperative Lipoprotein Phenotyping
Study,3the Framingham Study,I4and the Lipid Research
Clinics Coronary Primary Prevention Trial.24In addition
to HDL and LDL levels themselves, increases in both the
ratio of total cholesterol to HDL cholesterol and the ratio
of LDL to HDL cholesterol have been associated with an
increased risk of mortality.13Even small reductions in lipid
levels over 5 to 7 years have been shown to substantially
reduce the incidence of myocardial infarction and death.
In fact, these studies, some of which were conducted in
19328737, 1987, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960101010, Wiley Online Library on [02/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
high-risk individuals, indicate that a 1 % reduction in se-
rum cholesterol or LDL is associated with an approximate
2% reduction in risk of death from CHD.14.44
The Benefit of Antihypertensive Therapy
The Hypertension Detection and Follow-Up Program
demonstrated a 20.5% reduction in overall mortality in
patients with mild hypertension (initial diastolic blood
pressure 90-104 mmHg) and 26% fewer deaths from
cardiovascular causes among patients receiving stepped-
care antihypertensive therapy versus refed-care patients
who received less systematic t ~ e a t m e n t . ~However,
.’~ a
number of studies have shown that, while antihyperten-
sive therapy definitely reduces the incidence of stroke and
congestive heart failure, the incidence of CHD is not sig-
nificantly diminished.15.2831.38.40 There has been much
speculation as to why this has occurred. One hypothesis
is that antihypertensive agents themselves may alter
cholesterol and triglyceride concentrations; this might
negate the beneficial effect that reduced blood pressure
would otherwise have on CHD. Because of their
widespread use and importance in the treatment of hyper-
tension, the impact of beta blockers on serum lipids in
the cardiac patient should be considered when selecting
a therapeutic regimen.
Effect of Beta Blockers on Blood Lipids
The effects of beta blockers on blood lipids have been
studied extensively. The results of many of these studies
can be found in Table I. In general, beta blockers tend
to significantly increase serum triglycerides and decrease
HDL cholesterol. This trend proved to be true in short-
and long-term studies, in large and small patient popula-
tions. However, interstudy variability of results for a par-
ticular drug may still be due to differences in duration of
therapy, previous treatment, the number of study subjects,
pretreatment serum lipid levels, and concurrent antihyper-
tensive therapy (e.g., a diuretic).
Atenolol has been found to produce adverse effects on
lipid levels over the long as well as the short term in a
number of studies, the most dramatic being the 36% in-
crease in triglycerides (p<0.05) and 13% decrease in
HDL cholesterol (p<O.Ol) reported by Middeke et al.
after 42 weeks of therapye2’In a study by Day and co-
workers, atenolol was associated with a 24% increase in
total triglycerides (p < 0.05) and a 48 % increase in VLDL
triglycerides (p<0.05), after 12 months of treat men^^
Numerous investigators have reported similar statistically
significant increases in total triglycerides and decreases
in HDL cholestero1.5-7~18~20~33.39In one study, atenolol was
associated with greater increases in total triglycerides than
pindolol, propranolol, and metoprolol after four weeks of
therapy.37 Rouffy and Jaillard observed significant in-
creases in LDL cholesterol ( + 5 . 6 % , p<0.05), VLDL
 TABLEI Effects of beta blockers on lipid component
No. of
Agent Source subjects Duration TC HDL TG LDL

Metoprolol, Bielmann and Leduc (2) 6 8 wk NC M NC MI75 mgldlb M115 mgldl"

propranolol P16 mgldl P1 194 mg/dl" P128 mg/dl"
Atenolol, Day et al. (4) 53 3 mo-1 yr 10.06-0.36 mmolll 10.04-0.18 mmol/lc 0.30-0.67 mmol/ld 10.11-0.40 mmollld
propranolol,
metoprolol,
oxprenolol
Atenolol, Day et al. (5) 30 3-6 mo iO.11-0.40 mmolll At0.34 mmollld
propranolol P10.91 mmolll"
Atenolol Eliasson et al. (6) 15 2-15 mo NC NC 10.50 mmolllb 10.05 mmollld
Atenolol, England et al. (7) 34 3 mo A10.05 mmol/l A113 mmol/ld AtO.lld A10.07 g/l
metoprolol M10.06 mmol/l M 118 mmollld Mt0.18d M10.03 gll
Labetalo1 Frishman et al. (10) 35 12 wk NC NC NC NC
Propranolol Gemma et al. (11) 11 8 wk NC NC 137.3% NC
Oxprenolol, Kjeldsen et al. (18) 19 18 wk NC 010.13 mmollld 0114.9% NC
atenolol A10.20 mmol/lb A1 17.9%
Sotalol Lehtonen and Viikari (2 12 1 Yr 10.88 mmol/lb 10.39 mmolllb 10.75 mmoiiib 11.27 mmolll'
Pindolol Leren et al. (22) 10 10 wk NC NC NC -
Propranolol Leren et al. (23) 23 8 wk NC 113%' 124%' NC
propranolol Lowenstein and Neusy (25) 29 2 mo NC NC NC NC
Labetalo1 McGonigle et
al. (26) 33 1 Yr 10.24 mmolll 10.14 mmolll
Atenolol Middeke et al. (27) 9 42 wk 19 mgldl 15 mgldlb 156 mgldld
Labetalo1 Pagnen et al. (29) 8 12 wk NC NC NC
Atenolol Roum and Jaillad (33) 50 3 mo 10.18 mmol/lb 10.12 mmolllb 10.24 mmollld
Bevantolol , Salonen (35) 33 12 wk B 16 mgldl B13 mgldlb B128 mgldld
atenolol A f 9 mg/dl A14 mgldld A142 mg/dld
Atenolol, Shaw et al. (37) 17 4 wk NC 10.38-0.84 mmollld
pindolol,
propranolol,
metoprolol
Propranolol Tanaka et al. (39) 10 8 wk NC
Metoprolol Waal-Manning (41) 14 3 mo NC

"p<O.l, 'p<O.OI, 'p<O.OOl, dp<0.05 compared to baseline.

Abbreviations: TC =total cholesterol; HDL= high density lipoprotein; TG =triglyceride; LDL=low density lipoprotein; NC =no change.

19328737, 1987, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960101010, Wiley Online Library on [02/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

564 Clin. Cardiol. Vol. 10. October 1987
cholesterol (+20%, p <0.05), and total triglycerides
( + 18% , p < 0.001) after three months of atenolol thera-
py, as well as significant decreases in HDL cholesterol
(-10.2%, pcO.001) and HDLz cholesterol (-6.l%,
p < 0.05).33
Evidence that propranolol adversely affects lipid levels
is also considerable. Day et al. reported an increase of
65% (pcO.01) in total triglycerides after six months of
propranolol therapy .5 Other investigators have reported
statistically significant increases of 24-37 % in total
triglycerides and decreases of 13% in HDL cholesterol
after 4 to 8 weeks.4,23-37
Metoprolol has been associated with a 14% increase in
total triglycerides (p <0.05) and a 13% decrease in HDL
cholesterol (pcO.01) after 12 months in a study by Day
and co-wo~kers.~ Other investigators reported statistically
significant triglyceride increases of 10-34 % and HDL
decreases of 13% in studies lasting from 4 to 12
week^.^,^',^^
Study results indicate that several other beta blockers
are also associated with adverse effects on lipid levels.
Day et al. observed a 25 % increase in triglycerides after
12 months of oxprenolol therapy (p < 0.01) and an 11%
decrease in HDL cholesterol ( p ~ o . O l )Kjeldsen
.~ er al.
reported an 11% decrease in HDL cholesterol levels with
oxprenolol after 18 weeks (p<O.05).l8 Lehtonen and Vii-
kari reported a 66% increase in triglycerides after 12
months of sotalol therapy (p <0.01) and a 26% decrease
in HDL cholesterol ( ~ < 0 . 0 1 ) .Finally,
~~ Shaw et al.
reported a 28 % increase in triglycerides with pindolol af-
ter 4 weeks of therapy.37Other investigators have report-
ed no adverse effects with pindolol.20
In support of the claim that plasma lipid changes are
not merely transitory but persist during long-term treat-
ment, Day and co-workers observed that subjects ad-
ministered a variety of beta blockers (atenolol, metoprolol,
oxprenolol, and propranolol) sustained increased triglycer-
ide levels and decreased HDL cholesterol levels through
12 months of the rap^.^ Although there was some variance
in HDL cholesterol levels between the third and sixth
months of therapy, with a temporary return almost to base-
line, the lowest HDL levels were nevertheless found af-
ter 12 months of therapy.
In one study, when nonselective (e.g., propranolol and
oxprenolol) and cardioselective (e.g., atenolol and
metoprolol) beta blockers were compared, it was found
that the cardioselective drugs produced smaller increases
in triglyceride levels than did the nonselective drugs .4
However, all four agents produced significant increases
in VLDL levels (p <0.05) and significant decreases in the
antiatherogenic lipid HDL (p <0.05 to 0.01). According
to some studies, beta blockers with ISA may be less like-
ly to alter total cholesterol, HDL cholesterol, or triglycer-
ide level^.^^^^^
It has been postulated that beta-blocker-induced altera-
tions in lipid levels may result from interactions with
lipoprotein lipase (LL) or other metabolic
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Some investigators suggest that agents with peripheral
alpha-adrenergic activity appear not to affect the serum
lipid profile adversely.8,26Labetalol, which is a combined
alpha- and beta-adrenergic blocker, is the first of a new
group of adrenergic antagonists. Several studies have
shown that labetalol does not adversely affect lipid
parameters and may, in fact, demonstrate a positive
effect. 102629
Bevantolol, a cardioselective beta blocker, is an inves-
tigational agent that will be approved shortly in the Unit-
ed States for the treatment of hypertension. Bevantolol has
minimal membrane-stabilizing activity, is devoid of ISA,
and has mild peripheral alpha-adrenergic activity. One
would expect this last component to promote a favora-
ble, or at least negligible, effect on a patient’s serum lipid
profile. In fact, a study in rats compared prazosin,
propranolol, bevantolol, and a saline control. At 3 and
10 mg/kg per day doses that approximate the human ther-
apeutic dosage range, bevantolol and prazosin lowered se-
rum triglycerides, total cholesterol, and total VLDL +
LDL cholesterol. These results were significant at the
p<O.O5 or better level for both agents. In contrast,
propranolol tended to increase plasma levels of all lipids
studied (R. Goldberg, personal communication).
Salonen compared the effects of bevantolol and atenolol
on serum lipid levels.3sIn angina patients, bevantolol was
associated with a 10% reduction in LDL cholesterol lev-
els after 12 weeks of therapy (p<0.05), while atenolol
was associated with a trend toward increased LDL lev-
els. There was a favorable change in the bevantolol group
for both LDLlHDL (pc0.01) and LDL/HDLz (p c0.02)
cholesterol ratios, with virtually no change in the atenolol
group.35
Possible Mechanisms
That beta blockers influence plasma lipid levels is well
documented. What is not clear is the mechanism by which
this occurs. A number of observations can be made based
on the data provided by the aforementioned studies. In
some studies, noncardioselective drugs, such as oxprenolol
and propranolol, appear to have a greater adverse effect
on total and VLDL cholesterol and triglycerides than do
the more cardioselective agents, such as atenolol and
m e t ~ p r o l o l . ~However,
~ ~ . ~ , ~other
~ investigatorshave found
no consistent differences between cardioselectiveand non-
cardioselective agents. L8~20.37.42
A recent review of the potential mechanisms of altera-
tions in plasma lipoprotein metabolism discussed the rela-
tionship between extrahepatic lipoprotein lipase (LL) and
the various lipid types.34This enzyme appears to catabo-
lize chylomicrons and VLDL, the major triglyceride car-
riers in plasma. These lipoprotein components are, in turn,
incorporated into circulating HDL particles. It is known
that catecholamines may inactivate LL and that serum lev-
els of catecholamines may be increased during beta-

H. Wolinsky: 0-blocking agents and blood lipid levels
adrenergic bl~ckade.~’ Therefore, one hypothesis for the
effect of beta blockers on serum lipids is that their indirect
inhibition of LL may be involved in lowering HDL
cholesterol levels in the plasma.34 Lipoprotein lipase is
also involved in the metabolism of triglycerides to free
fatty acids. However, Day et al. reported that increases
in triglyceride concentration with beta blockers cannot be
related to changes in plasma insulin or glucose concen-
tration, or to any consistent decrease in free fatty acids.s
Thus, one hypothesis is that stimulation of alpha-
adrenergic receptors, which is unopposed during beta
blockade, plays the predominant role in inhibiting LL.4,8
Alpha-adrenergic blockade can stimulate LL, thereby
reducing serum triglyceride levels.4,8
Lipoprotein lipase also catalyzes the conversion of
VLDL to HDL.36This observation is consistent with the
notions that extrahepatic LL plays a major role in regulat-
ing lipid levels and that unopposed alpha stimulation dur-
ing beta-blocker therapy may result in inhibition of
lipase.4.8.34
There are conflicting reports regarding the relation be-
tween free fatty acids and the increased serum triglyceride
levels found during beta blockade. Tanaka and co-workers
observed increased VLDL and triglycerides concomitant
with increases in fasting free fatty acid levels during 8
weeks of propranolol therapy.39In contrast, Day et al.
reported that a variety of beta blockers reduced free fatty
acid concentrations by nearly 50% (p<O.OOOl) while in-
creasing triglyceride and VLDL levels, during 12 months
of the~apy.~ Other investigators found that propmolol had
opposite effects in hypertriglyceridemicsand normal con-
trols. Subjects with elevated fasting triglyceride levels
showed an enhanced postprandial lipemic response after
2 weeks of propranolol therapy; in controls, postprandial
lipemia was significantly reduced after propranolol treat-
ment.’ The paucity of negative lipid effects reported with
pindolol has led some researchers to suggest ISA as ex-
erting a potentially positive effect on lipid para-
meters.10.32.44 Lehtonen reported some data that seemed
to indicate that pindolol has a positive effect on HDL lev-
els.*ONevertheless, at least one study has shown pindolol
to increase triglyceride level^.^'
Another possible mechanism for the effect of beta block-
ers on serum lipids might be the peripheral vasoconstric-
tion induced by unopposed beta blockade and concomi-
tant stimulation of open alpha receptors. Reduction of
blood flow to peripheral beds may affect the rate of
chylomicron hydr~lysis.’~ This effect may be blocked by
agents with an alpha-adrenergic effect, such as labetalol
or prazosin.
Cardioselectivity is probably not the main factor in
differentiating the lipid level effects of beta blockers.
Atenolol, a cardioselectivebeta blocker, has been associat-
ed with negative lipid effects comparable to those found
with oxprenolol, a noncardioselective beta blocker, and
greater than those associated with pindolol, also noncadio-
elective.^^'^.^^^^'
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565
The presence of ISA may explain pindolol’s relatively
favorable lipid profile. There is also, as stated above, a
strong case for the beneficial role of alpha-adrenergic
blockade, either through increased levels of extrahepatic
LL or through improved peripheral flow. This is a possi-
ble explanation of why beta blockers with an alpha-
adrenergic blocking component, such as labetalol or
bevantolol, have not been associated with negative effects
on lipid levels.
Conclusions
This review has examined the effects of beta-adrenergic
blocking agents on blood lipids. Although several agents
have inconsequential effects on blood lipids, many beta
blockers show an adverse effect. The clinical significance
of these findings is unclear at present. With the necessity
for long-term treatment of hypertension, it is possible that
some of the unfavorable changes in blood lipids seen with
most beta blockers are deleterious to patients with CHD.
The question at hand is to what degree the benefits of
treatment of hypertensive patients-with respect to
CHD--are reduced by these lipid changes. Although the
clinical significance of drug-induced blood lipid changes
has not been demonstrated, it is certain that differences
exist between antihypertensive agents in different phar-
macologic classes and even among agents within the same
category, namely beta blockers, with respect to their ef-
fects on serum lipids. Given the epidemic proportions of
CHD and the huge segment of our population now receiv-
ing treatment for hypertension, the potential impact of
these differenceson long-term outcome merits concern and
consideration in treatment choices. Thus, beta blockers
with a moderating property, such as mild alpha activity,
that has been shown to exert a beneficial effect on a pa-
tient’s lipid profile may deserve special attention when
choosing among antihypertensive medications.
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