Article

Journal of Cardiovascular
Pharmacology and Therapeutics
Effects of Carvedilol Compared to Nebivolol 1-6
ª The Author(s) 2016
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on Insulin Resistance and Lipid Profile in sagepub.com/journalsPermissions.nav
DOI: 10.1177/1074248416644987
Patients With Essential Hypertension cpt.sagepub.com

Ali Gokhan Ozyıldız, MD1, Serpil Eroglu, MD1, Ugur Bal, MD1, Ilyas Atar, MD1,
Kaan Okyay, MD1, and Haldun Muderrisoglu, MD1

Abstract
Background and aim: Beta-blockers have unfavorable effects on metabolic parameters in hypertensive treatment. New
generation beta-blockers with vasodilatory capabilities are superior to traditional beta-blockers, but studies examining their
effects on metabolic parameters are still lacking. This study aimed to compare the effects of 2 new generation beta-blockers,
carvedilol and nebivolol, on insulin resistance (IR) and lipid profiles in patients with essential hypertension. Methods: This was a
prospective, randomized, open-label, single-center clinical trial. A total of 80 patients were randomized into 2 groups: the car-
vedilol group (n ¼ 40, 25 mg of carvedilol daily) and the nebivolol group (n ¼ 40, 5 mg of nebivolol daily). Follow-up was per-
formed for 4 months. Fasting plasma glucose, insulin levels, and the lipid profile (high-density lipoprotein [HDL], low-density
lipoprotein [LDL], total cholesterol, triglyceride, apolipoprotein AI, and apolipoprotein B levels) were measured and IR was
calculated by the homeostasis model assessment (HOMA) index. These variables were compared before and 4 months after
treatment. Results: Blood pressure and heart rate were significantly and similarly reduced in the carvedilol and nebivolol groups
after treatment compared to those before treatment (both P < .001). Serum glucose (P < .001), insulin (P < .01), HOMA-IR (P < .01),
HDL (P < .001), LDL (P < .001), total cholesterol (P < .001), and apolipoprotein B (P < .05) levels decreased in a similar manner in the
carvedilol and nebivolol groups after treatment compared to those before treatment. Serum triglyceride and apolipoprotein AI levels
did not change after treatment with both drugs. Conclusion: New generation beta-blockers, carvedilol and nebivolol, efficiently
and similarly decrease blood pressure. They have similar favorable effects on glucose, insulin, IR, and the lipid profile.

Keywords
hypertension, carvedilol, nebivolol, insulin resistance, dyslipidemia

Introduction oxide–induced benefits, such as reversal of endothelial dys-

function.4 Despite these differences of traditional and vasodi-
Beta-blocker drugs have been used to treat hypertension for 4
lating beta-blockers, almost all of the studies that led beta-
decades. Recently, use of beta-blockers in antihypertensive
blockers to the background were on traditional agents (eg,
treatment has been debated because of the lack of hemody-
propranolol, atenolol, and metoprolol).
namic and metabolic benefits compared to placebo and other
New generation beta-blockers have been shown to be super-
antihypertensive agents.1
ior to the traditional beta-blockers regarding hemodynamic and
However, beta-blockers are a group of drugs that show het-
metabolic parameters.1-4 However, direct comparison of the
erogeneity with physiological and pharmacological properties.
effect of 2 new generation beta-blockers, carvedilol and nebi-
Effects of new generation vasodilating beta-blockers on hemo- volol, on metabolic parameters is not well known. In this study,
dynamic and metabolic parameters differ from traditional beta-
we aimed to compare the effects of 2 new generation beta-
blockers. Traditional beta-blockers decrease cardiac output and
increase peripheral resistance. Therefore, they may cause an
increase in insulin resistance (IR), susceptibility to diabetes,
and impairment of the lipid profile by reducing the transport 1
Department of Cardiology, University of Baskent, Ankara, Turkey
of glucose into peripheral tissues. In contrast, vasodilating
beta-blockers remove negative effects on glucose and lipid Manuscript submitted: December 12, 2015; accepted: February 16, 2016.
metabolism by decreasing peripheral vascular resistance, with-
Corresponding Author:
out adverse effects on cardiac output.2,3 Along with this per- Serpil Eroglu, Department of Cardiology, University of Baskent, F. Cakmak
ipheral vasodilatation, new generation beta-blockers, such as Cad. 10. sok No: 45 Bahcelievler, 06490 Çankaya, Ankara, Turkey.
carvedilol and nebivolol, have antioxidant effects and nitric Email: serpileroglu@gmail.com

Downloaded from cpt.sagepub.com at TULANE UNIV on April 23, 2016

2 Journal of Cardiovascular Pharmacology and Therapeutics
blockers, carvedilol and nebivolol, on IR and lipid profiles in
patients with essential hypertension.
Materials and Methods
Study Population
A total of 107 newly diagnosed patients with hypertension,
who were admitted to the Department of Cardiology at Bask-
ent University Ankara Hospital, were enrolled in this study,
between August 2013 and April 2014. Systolic blood pres-
sure and diastolic blood pressure were measured in both arms
by the auscultatory method, using a standard mercury sphyg-
momanometer, after at least 10 minutes of rest in the sitting
position. The mean of 2 recordings of blood pressure was
taken by the same physician, and 140 mm Hg systolic and/
or 90 mm Hg diastolic pressure or higher was considered as
hypertension.5
Patients with secondary hypertension, diabetes mellitus,
heart failure, sick sinus syndrome, sinus bradycardia, second-
or third-degree heart block, coronary artery disease, severe
valvular disease, hypothyroidism or hyperthyroidism, preg-
nancy or lactation, cerebrovascular disease, liver or kidney
failure, or antihypertensive or antihyperlipidemic drug use
were excluded from this study.
Study Protocol
The present study was a randomized, open-label, single-center
trial. Among the 107 patients who were initially included, 27
patients were excluded after the screening phase. These
included 15 patients who declined to participate, 8 whose anti-
hypertensive treatment was changed by another physician, 1
who discontinued taking antihypertensive drugs, and 3 patients
were lost to follow-up. Eighty patients were randomly assigned
to a 25-mg daily dose of carvedilol (n ¼ 40) or 5-mg daily dose
of nebivolol (n ¼ 40). The dose was titrated at 1-week intervals.
At the third week of treatment, if blood pressure was not con-
trolled (<140/90 mm Hg), amlodipine (5 mg), which has neu-
tral metabolic effects, was added to the therapy. After
providing effective blood pressure control, we planned 4
months of follow-up period to assess the effects of the drugs
on IR and the lipid profile.
Lifestyle changes were proposed to all the patients in line
with the European Society of Cardiology 2013 guidelines for
the management of arterial hypertension.5
Biochemical Measurements
Fasting blood samples were withdrawn from patients after 12
hours of fasting for measurements of biochemical parameters.
Insulin was measured by the chemiluminescence method. Fast-
ing plasma glucose (FPG), high-density lipoprotein (HDL)
cholesterol, low-density lipoprotein (LDL) cholesterol, and tri-
glyceride levels were measured with enzymatic methods. Apo-
lipoprotein AI (apoAI) and apolipoprotein B (apoB) were
measured with immunoturbidimetric methods.
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Insulin resistance was determined by homeostasis model
assessment of IR (HOMA-IR). HOMA-IR was calculated using
the following formula: (fasting insulin [mU/mL]  FPG
[mg/dL]/405). An HOMA-IR  2.7 was accepted as IR.6 Total
cholesterol (TC) was calculated by the Friedewald formula: TC
¼ LDL þ HDL þ triglycerides/5
Waist circumference was measured. Body mass index (BMI)
was calculated using the Quetelet index (weight/height2, kg/m2).
Four months after therapy initiation, the patients’ blood
pressure, heart rate, BMI, waist circumference, and biochem-
ical parameters (FPG, insulin, HDL, LDL, triglyceride, apoAI,
and apoB levels) were measured. We compared changes in
blood pressure, IR, and the lipid profile between the 2 drugs,
before and 4 months after treatment.
All of the participants provided written informed consent.
This study was approved by the Baskent University institu-
tional review board and ethics committee and Turkey Pharma-
ceuticals and Medical Devices Agency.
Statistical Analysis
The sample size was determined by power analysis done by
‘‘repeated measures analysis of variance for factorial design’’
(80% power). At the end of the study, we performed statistical
analysis of patients who received 4 months of treatment. When the
assumptions of parametric tests were fulfilled, the Student t test
was used to compare the 2 independent groups. The Mann-
Whitney U test was used when these conditions did not occur.
After control of the preconditions of sphericity and homogeneity
of variance, variables were tested by repeated measures analysis of
variance in a factorial design. The statistical significance level was
a ¼ .05. Continuous variables are expressed as mean + standard
deviation. Categorical variables are summarized as n (%). The
SPSS 17.0 statistical software package was used for analysis.
Results
Baseline demographic, clinical, and laboratory characteristics
of the carvedilol and nebivolol treatment groups are shown in
Table 1. Blood pressure and heart rate reduced significantly
and similarly (no significant difference between the groups)
in the carvedilol and nebivolol groups after 4 months of treat-
ment compared to before treatment (both P < .001). After 4
months of therapy, FPG (P < .001), insulin (P < .01), HOMA-
IR (P < .01), HDL cholesterol (P < .001), LDL cholesterol
(P < .001), TC (P < .001), and apoB (P < .05) levels decreased
in a similar manner (no significant difference between the
groups) in the carvedilol and nebivolol groups compared to
those before treatment. Interestingly, at the end of the treat-
ment, there were no significant differences in triglyceride and
apoAI levels in both the groups (Table 2).
Although 25 patients had IR (11 patients in the carvedilol
group and 14 patients in the nebivolol group) before treatment,
only 12 patients had IR after 4 months of therapy (6 patients in
the carvedilol group and 6 patients in the nebivolol group). This
decline in IR was significant (P < .01). Of these 12 patients, the
Ozyıldız et al 3

Table 1. Baseline Demographic, Clinical, and Laboratory reduce peripheral resistance without affecting cardiac output.
Characteristics of Carvedilol and Nebivolol Treatment Groups.a Additionally, they do not have unfavorable effects on IR, glycemic
Carvedilol, Nebivolol,
control, or the lipid profile.7 The current study is important
Variable n ¼ 40 n ¼ 40 P because it directly compared the effect of 2 new generation beta-
blockers, carvedilol and nebivolol, on the lipid profile and IR.
Age, years 52.6 + 9.9 50.1 + 9.7 .283b The new generation vasodilating beta-blockers carvedilol
Sex, male/female 23/17 22/18 .824c and nebivolol lower blood pressure as effectively as other anti-
BMI, kg/m2 29.2 + 3.9 29.3 + 4.3 .934b
hypertensive drugs. Although effective blood pressure
Waist circumference, cm 97.2 + 9 .5 97.5 + 11.3 .897b
Smoking, n (%) 9 (22.5) 15 (37.5) .146c decreases, adverse hemodynamic and metabolic effects are less
Alcohol, n (%) 1 (2.5) 4 (10) .169c with new generation beta-blockers than with traditional beta-
CCB, n (%) 11 (27.5) 6 (15) .174c blockers.8 After 4 months of therapy, we found that carvedilol
SBP, mm Hg 156.6 + 15.3 154.1 + 12.9 .433b and nebivolol treatment significantly decreased systolic blood
DBP, mm Hg 95.2 + 8.9 95.6 + 7.9 .844b pressure and diastolic blood pressure and heart rate compared
Heart rate, bpm 79.1 + 10.6 78.8 + 11.6 .918b to baseline, and this decline was similar for both the drugs.
FPG, mg/dL 98.6 + 8.4 96.9 + 10.2 .421b
These findings are similar to those of a study by Erdogan
Insulin, mU/mL 9.87 + 7.95 10.75 + 6.64 .192d
HOMA-IR 2.38 + 1.93 2.64 + 1.78 .338d et al.2 They determined that carvedilol and nebivolol treatment
Total cholesterol, mg/dL 209.6 + 41.8 205.2 + 33.1 .601b led to a significant decrease in blood pressure and heart rate
HDL, mg/dL 45.9 + 10.5 45.1 + 11.8 .759b compared with placebo, but none of the drugs was superior.
LDL, mg/dL 135.4 +36.2 131.0 + 32.8 .546b Several mechanisms have been suggested for vasodilating
Triglycerides, mg/dL 148.6 + 74.6 154.9 + 85.3 .728b beta-blockers and their useful effects on insulin and lipid meta-
apoAI, mg/dL 148.2 + 31.0 142.3 + 26.9 .371b bolism. Alpha-1 adrenergic receptor blockade and vasodila-
apoB, mg/dL 112.1 + 29.0 110.0 + 31.2 .736b
tion, anti-inflammatory effects, decreased oxidative stress,
Abbreviations: apoA-I, apolipoprotein AI; apoB, apolipoprotein B; BMI, body and decreased weight gain are the main proposed mechanisms.7
mass index; CCB, calcium channel blocker; DBP, diastolic blood pressure; FPG, In our study, we found similar decrease in FPG with carve-
fasting plasma glucose; HDL, high-density lipoprotein; HOMA-IR, homeostatic dilol and nebivolol after 4 months of therapy. This finding can
model assessment of insulin resistance; LDL, low-density lipoprotein SBP,
systolic blood pressure; SD, standard deviation. be explained by positive effects of new generation vasodilating
a
Values are mean + SD or n (%). beta-blockers on glucose metabolism. Furthermore, lifestyle
b
Student t test. changes, which were started by treating hypertension, might
c
Chi-square test.
d have contributed to this result. In the Glycemic Effects in
Mann-Whitney U test.
Diabetes Mellitus: Carvedilol – Metoprolol Comparison in
Hypertensives (GEMINI) study, the vasodilating beta-blocker
decrease in the number of patients with IR was similar between carvedilol and traditional beta-blocker metoprolol were
the groups (Table 2). compared in diabetic patients with hypertension.9 Carvedilol
The ApoB/ApoAI ratio, a predictor of coronary artery dis- provided better results than metoprolol in glycemic control.
ease, was compared between the groups before and after treat- We also found that the decrease in insulin and HOMA-IR values
ment. After treatment, the apoB/apoAI ratio decreased was similar between the carvedilol and the nebivolol groups. This
significantly in a similar manner (no significant difference supports the results of a previous study by Yildiz et al who compared
between the groups) in both the groups compared to before the effect of carvedilol and nebivolol on IR in diabetic patients.10
treatment (P < .001; Table 2). They found that there was also no superiority of the drug groups.
We observed that in the carvedilol and nebivolol groups, Dyslipidemia (ie, IR) is a strong and independent predictor of
BMI (P < .05) and waist circumference (P < .001) decreased hypertension for cardiovascular morbidity and mortality.11 Previ-
significantly at the fourth month of treatment compared to ous studies have shown that traditional beta-blockers may have
those before treatment (Table 2). All patients in the current harmful effects (eg, increase the triglyceride levels and decrease
study completed the follow-up of 4 months, and they tolerated the HDL levels) on the lipid profile.1 The activity of lipoprotein
the treatment well without any side effects. lipase is reduced in cases of hyperinsulinemia. Therefore, by
increasing the activity of lipoprotein lipase, vasodilating beta-
blockers can make a positive contribution to the lipid profile.12
Discussion Additionally, nitric oxide release and antioxidant properties of new
The current study demonstrated that new generation beta- generation beta-blockers may contribute to this positive effect.13
blockers, carvedilol and nebivolol, efficiently decreased blood In our study, both the new generation vasodilating beta-blockers
pressure, and they had similar favorable effects on glucose (carvedilol and nebivolol) significantly and similarly decreased
levels, insulin levels, IR, and the lipid profile. HDL, LDL, and TC values after treatment compared to those
Beta-blockers are the most diverse of the antihypertensives. before treatment. Triglyceride levels did not change in both the
Conventional beta-blockers have negative effects on the lipid groups. There was no significant difference in apoAI levels (main
profile, leading to a reduction in cardiac output and increase in lipoprotein of HDL cholesterol) between the groups. This finding
peripheral resistance. However, vasodilating beta-blockers does not explain the decrease in HDL levels but at least could

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4 Journal of Cardiovascular Pharmacology and Therapeutics

Table 2. Comparison of Hemodynamic and Metabolic Parameters Between Carvedilol and Nebivolol Treatment Before and After Treatment.

Carvedilol (n ¼ 40) Nebivolol (n ¼ 40) Pa Pb

SBP, mm Hg <.001 .708

Before 156.6 + 15.3 154.1 + 12.9
Fourth month 138.7 + 15.6 135.0 + 15.9
DBP, mm Hg <.001 .210
Before 95.2 + 8.9 95.6 + 7.9
Fourth month 87.7 + 9.4 85.3 + 10.9
Heart rate, bpm <.001 .100
Before 79.1 + 10.6 78.8 + 11.6
Fourth month 69.5 + 9.2 72.1 + 9.8
FPG, mg/dL <.001 .069
Before 98.6 + 8.4 96.9 + 10.2
Fourth month 88.8 + 14.9 93.1 + 17.4
Insulin, mU/mL <.01 .734
Before 9.87 + 7.95 10.75 + 6.64
Fourth month 7.68 + 6.65 9.01 + 6.63
HOMA-IR <.01 .461
Before 2.38 + 1.93 2.64 + 1.78
Fourth month 1.69 + 1.64 2.22 + 2.47
HOMA-IR  2.7, n (%) <.01 .472
Before 11 (44%) 14 (56%)
Fourth month 6 (50%) 6 (50%)
Total cholesterol, mg/dL <.001 .307
Before 209.6 + 41.8 205.2 + 33.1
Fourth month 176.0 + 44.7 179.1 + 33.7
HDL, mg/dL <.001 .647
Before 45.9 + 10.5 45.1 + 11.8
Fourth month 41.9 + 12.3 40.1 + 11.2
LDL, mg/dL <.001 .261
Before 135.4 + 36.2 131.0 + 32.8
Fourth month 105.0 + 32.8 109.0 + 25.8
Triglycerides, mg/dL .301 .353
Before 148.6 + 74.6 154.9 + 85.3
Fourth month 149.6 + 83.7 172.4 + 114.3
apoAI, mg/dL .926 .534
Before 148.2 + 31.0 142.3 + 26.9
Fourth month 150.0 + 26.6 140.0 + 27.6
apoB, mg/dL <.05 .733
Before 112.1 + 29.0 110.0 + 31.2
Fourth month 106.8 + 21.8 103.2 + 30.1
apoB/apoAI <.001 .859
Before 0.76 + 0.20 0.78 + 0.20
Fourth month 0.72 + 0.18 0.73 + 0.18
BMI, kg/m2 <.05 .635
Before 29.29 + 3.99 29.37 + 4.36
Fourth month 28.91 + 4.19 29.12 + 4.28
Waist circumference, cm <.001 .160
Before 97.2 + 9.5 97.5 + 11.3
Fourth month 94.6 + 9.7 96.3 + 11.6
Abbreviations: apoA-I, apolipoprotein AI; apoB, apolipoprotein B; BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high-
density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein; SBP, systolic blood pressure.
a
Comparison within the groups between before and after treatment
b
Comparison between the groups after treatment.

explain the lack of expected recovery. Levels of apoB (main lipo-
protein of LDL cholesterol) were significantly reduced after treat-
ment in both the groups. This finding could explain the decrease in
LDL cholesterol levels in our study. Although we expected a
decrease in triglyceride levels according to the decline in plasma
glucose levels and IR, there was no significant change in triglycer-
ide levels with treatment in both the groups. This finding is con-
sistent with a lack of an increase in triglyceride levels with
carvedilol in spite of metoprolol as observed in the GEMINI and
Extended-Release Carvedilol Trial Lipid studies.9,11

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Ozyıldız et al
However, in another randomized clinical trial, Studinger
et al compared carvedilol, nebivolol, and metoprolol on central
arterial pressure. After 3 months of therapy, they found no
differences in glucose and lipid parameters.14 The differences
between this study and ours might have resulted from the dif-
ferent treatment periods, therapeutic doses, but most likely the
lifestyle changes.
The apoB/apoAI ratio is an important indicator for assessing
the risk of vascular disease and treatment of atherosclerotic
vascular disease with statins. Some studies have suggested that
this ratio is superior to other lipoprotein and apolipoprotein
parameters for assessment of cardiovascular risk.15 In our study,
there was a significant reduction in apoB and the apoB/apoAI
ratio after treatment compared to those before treatment, but no
differences were observed between the groups. These findings
support that carvedilol and nebivolol could be used in patients
with hypertension and atherosclerotic vascular disease.
In the GEMINI study, there was significant weight gain with
metoprolol use, but this negative effect was not observed with
carvedilol.9 Although the reason for this disadvantage is not
clear with the use of traditional beta-blockers, it has been pro-
posed to result from insulin-evoked endothelial dysfunction.16
In our study, weight, BMI, and waist measurement values were
significantly decreased after treatment compared to that before
treatment, and these decreases were similar between the
groups. These findings are probably due to lifestyle changes,
activation of lipolysis, an increase in insulin sensitivity, and
reduction in weight, as expected from vasodilatory beta-
blocker therapy. Decrease in BMI (a strong predictor of IR)
shows a correlation with improvement in IR, which could be
another reason for choosing vasodilating beta-blockers.
Although renin–angiotensin–aldosterone system inhibitors are
recommended in patients with hypertension having metabolic
syndrome, an insufficient amount of studies have compared these
agents with carvedilol or nebivolol.1 In our study, positive and
similar results were obtained with 2 vasodilating beta-blockers.
Study Limitations
Because of ethical concerns, when antihypertensive treatment
began in all patients, an untreated control group could not be
used. The lack of blinding could pose potential weakness. Study
follow-up examinations of blood pressure and heart rate of
patients were performed with office and home measurements.
More information on blood pressure and heart rate could be
obtained with ambulatory measurements. Four months of treat-
ment was planned to evaluate effects of drugs on IR and the lipid
profile. A longer follow-up time could provide more accurate
metabolic values. Patients were recommended to perform life-
style changes along with the treatment of hypertension. Lifestyle
changes and their positive effects on metabolic parameters may
have contributed in part to the useful effects of the drugs.
Because of difficulties in standardizing lifestyle changes in
patients, the extent of this contribution is unknown. The present
study focused specifically on the comparison of the effects of
carvedilol and nebivolol on metabolic and lipid parameters.
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5
However, it is also recognized that carvedilol and nebiviolol are
known to provide benefit in terms of renal protection, reduction
in left ventricular hypertrophy, reduction in neointimal hyper-
plasia, and atherosclerosis regression, parameters that merit fur-
ther evaluation in additional comparative trials.1
Conclusion
New generation beta-blockers, carvedilol and nebivolol, effi-
ciently and similarly decrease blood pressure. These beta-
blockers also have similar favorable effects on glucose, insulin,
IR, and the lipid profile. Carvedilol and nebivolol could be
considered in the treatment of hypertension, with no superiority
with each other on hemodynamic and metabolic effects. Favor-
able effects on controlled blood pressure and metabolic para-
meters need to be investigated in large, randomized, placebo-
controlled studies.
Authors’ Contribution
Ozyildiz, A.G. contributed to conception or design, acquisition, anal-
ysis, or interpretation; drafted the manuscript; and agreed to be
accountable for all aspects of work ensuring integrity and accuracy.
Eroglu, S. contributed to conception or design, acquisition, analysis,
or interpretation; critically revised the manuscript; and agreed to be
accountable for all aspects of work ensuring integrity and accuracy.
Bal, U.A. agreed to be accountable for all aspects of work ensuring
integrity and accuracy. Atar, I._ contributed to acquisition, analysis, or
interpretation and agreed to be accountable for all aspects of work
ensuring integrity and accuracy. Okyay, K. agreed to be accountable
for all aspects of work ensuring integrity and accuracy. Muderrisoglu,
H. gave final approval and agreed to be accountable for all aspects of
work ensuring integrity and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: The current
study was supported by the Baskent University Research Fund.
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