The Novel Beta Blocker for

Diabetic Hypertensives

The New Frontier

Why are we looking at this?
• According to IDF, In Pakistan It is estimated that over 07
Million patients are suffering from Diabetes.

• The projected estimates of IDF for 2035 shows an alarming

situation and Pakistan with an estimated prevalence of 12.8
million diabetics, will be ranked 8th among the world’s top 10
countries.

• Evidence showed that up to 80% of diabetic patients having a

problem of hypertension.

• All leading guidelines recommends RAAS inhibitors (ACE or

ARBs) as first line antihypertensive for the management of
hypertension with diabetes.
Why are we looking at this?

• Evidence showed that alone RAAS

inhibitors are not enough to treat diabetic
hypertensives.

• Uncontrolled hypertension with Diabetes

can cause Endothelial Dysfunction, Insulin
Resistance, Erectile Dysfunction and CVD.
 Current Treatment Options

• ACE/ARBs

• Calcium Channel Blockers

• Beta Blockers

• Diuretics
β-blockers……
BUT WHY IN DIABETIC
HYPERTENSIVES
The Logical Choice…..
• Evidence showed that diabetic hypertensive patients
are associated with increased risk of all cause
mortality and cardiovascular related mortality.

• β-blockers appears to be logical choice to add on with

ACEi or ARB to treat diabetic hypertensives.

• Conventional β-blockers are renowned to treat blood

pressure as well as effectively reduces CVD.

• But due to the side effects of conventional beta

blockers have restricted their usage in diabetic
hypertensive patients.
 Issues of Traditional Beta Blockers

• Peripheral arterial disease

• Sexual Dysfunction
• Disturb Glucose Profile
• Disturb Lipid Profile
• Decrease Exercise Tolerance
• Asthma
• Chronic obstructive pulmonary disease
 Incident Diabetes in Clinical Trials of
Antihypertensive Drugs – A Network Meta-analysis

ARBs 0.57 (0.46-0.72) p<0.0001

ACE Inhibitors 0.67 (0.56-0.80) p<0.0001

CCBs 0.75 (0.62-0.90) p=0.002

Placebo 0.77 (0.63-0.94) p=0.009

Β blockers 0.90 (0.75-1.09) p=0.30

Diuretics Referent

0.50 0.70 0.90 1.26

Odds ratio of incident diabetes Incoherence=0.000017

Elliott WJ, Meyer PM. Lancet. 2007;369:201–207.

But All β-Blockers are not
Same……….
 Vasodilating Beta blockers

• Better side effect profile

• Better Tolerability

• Better efficacy
Similarly Vasodialating β-Blockers
are not Same……….
 Comparison between Byscard vs Carvedilol

Parameters Nebivolol Carvedilol

β-1 Selectivity 1:321 1:1

Improvement in EF Yes No

Direct NO Production Yes No

Disturb Lipid Profile No Yes

Disturb Glucose No Yes

Profile
Bronco Constriction No Yes
What we need…..
An antihypertensive drug which not only provides
good blood pressure reduction but also significantly
improves….

1. Erectile function

2. Endothelial function

3. Insulin sensitivity

4. Reduces cardiovascular diseases

Nebivolol is the novel β-Blocker for
Diabetic Hypertensive without β-
Blocker like side effects
 Nebivolol

• Nebivolol is approved in hypertension

and heart failure by US-FDA and ESC
Nebivolol Pharmacology
Ultra Selectivity to β-1 Receptor
Cardiovascular
Mortality
Benefits Beyond
B.P. Reduction
Better Blood Pressure Reduction
Nebivolol and Metoprolol: Effect on BP at 3 Months
 Nebivolol in Hypertensive Patients

Nebivolol when added to ACEi or ARBs

provides additional blood pressure
reduction with no side effects of
conventional beta blockers.

The Journal of Clinical Hypertension 2013

 Sexual Dysfunction

Conventional β-Blockers
Decreased blood flow in the
Corpora Cavernosa due to
Vasoconstriction
Nebivolol improves erectile function by increasing perfusion in small and
microvessels. Similar effects have been described for Sildenafil
Diabetes
 Lipid Metabolism

Conventional β-Blockers Decreased

Lipoprotein Lipase activity results in
Increased LDL and Triglyceride levels,
and decreased HDL.
Effects on Lipid Levels
 Pulmonary Effects of Nebivolol

• Nebivolol confirmed a very good safety

profile when regularly administered to
hypertensive subjects with obstructive
respiratory Comorbidities.

• Nebivolol seems to be a safe and effective

in treatment asthmatic hypertensive
patients.
Ther Adv Cardiovasc Dis 2009 3: 329
The Journal of Allergy and Clinical Immunology Volume 113, Issue 2, Supplement , Page S277, February 2004
 Improves Endothelial Function

• Nebivolol improves endothelial function

• Unlike Carvedilol, which are mediated

by α-adrenergic receptor blockade,
these hemodynamic effects are in the
case of nebivolol primarily mediated by
a direct stimulatory effect on the
endothelial nitric oxide synthase (eNOS)

• Nebivolol treatment led to a significant

improvement in endothelial function
compared with bisoprolol treatment

• Atenolol had no effect on endothelial

function, whereas nebivolol led to a
statistically significant increase in FMD
values.

• Nebivolol, but not metoprolol,

normalizes endothelial function,
reduces superoxide formation,
increases NO bioavailability

Exp Clin Cardiol Vol 14 No 4 2009 J. Am. Coll. Cardiol. 2009

Effect of Nebivolol on Endothelial Function
 Nebivolol Reduces Peripheral Vascular
Resistance in Patients with Hypertension
0

-2
Percent change vs baseline

-4

-6

-8

-10

-12

-14 -13.2
Peripheral resistance
(dyne/cm5)

At 2 weeks; *P<0.05 vs pretreatment. Change in SBP/DBP was -19/12 mm Hg for nebivolol

Adapted from Kamp O et al. Am J Cardiol. 2003;92:344-348
Vasodilating Beta Blockers

Improved Efficacy

in CHF
in Elderly and Obese Patients
 Study of Effects of Nebivolol
Intervention on Outcomes and
Rehospitalization in Seniors
with Heart Failure (SENIORS)

European Society of Cardiology

Congress
SENIORS- Key Inclusion Criteria

• Multicenter double blind placebo controlled

trial.
• Patients ≥ 70 years
• Clinical history of chronic heart failure with at
least one of the following:
– Documented hospital admission within the
previous 12 months with discharge diagnosis of
congestive heart failure
– Documented LVEF ≤ 35% within previous 6
months
Patients Disposition
 SENIOR Trial
Nebivolol Placebo
(n=1067) (n=1061)
Mean Age, years [range] 76.1 [70-93] 76.1 [69-95]
Male 657 (62%) 686 (65%)
Female 410 (38%) 375 (35%)
NYHA Classification
Patients from NYHA I, II, III & IV were included in this trial
Ischemic Etiology of CHF 797 (75%) 785 (74%)
Duration of CHF, Mean Years (SD) 2.8 (3.5) 3.0 (3.8)
 Baseline Concomitant Medication

Medication Nebivolol Placebo

(n=1067) (n=1061)
ACE Inhibitor 872 (82%) 876 (83%)
Angiotensin Receptor Blocker 66 (6%) 75 (7%)
Diuretic 915 (86%) 907 (86%)
Aldosterone Antagonist 307 (29%) 280 (26%)
Calcium Antagonist 114 (11%) 122 (12%)
Cardiac Glycoside 415 (39%) 422 (40%)
Lipid Lowering 217 (20%) 238 (22%)
Antiarrhythmics 122 (11%) 145 (14%)
Asprin 456 (43%) 441 (42%)
Vitamin K Antagonist 149 (14%) 164 (16%)
 Comorbidities at Baseline
Diagnosis, n (%) Nebivolol Placebo
(n=1067) (n=1061)

Coronary Artery Disease 735 (69%) 717 (68%)

Arrhythima 578 (54%) 606 (57%)

Hyperlipidemia 490 (46%) 484 (46%)

Hypertension 652 (61%) 660 (62%)

Myocardial Infarction 467 (44%) 463 (44%)

Prior Percutaneous Coronary Intervention 47 (4%) 34 (3%)

Prior Coronary Artery Bypass Surgery 101 (10%) 94 (9%)

Atrial Fibrillation 361 (34%) 377 (36%)

Diabetes Mellitus 287 (27%) 268 (25%)

SENIOR Trial
 Hazard Ratio Plots for Total Mortality for
Comparable Patient Subgroups

ß-Blocker Trials

Nebivolol

Carvedilol

Metoprolol

Bisoprolol

0 0.5 1 1.5 2
Hazard Ratio

Nebivolol. Marit D. Moen and Antona J. Wagstaff. Drugs 2006;66(10):1389–1409

SENIORS Sub Study

33%

One-third reduction in the risk of

ischemic events
SENIORS Trial
• We undertook a sub-analysis which was not pre-
specified (age less than median and ejection fraction
35%) in order to determine the result for patients most
similar to those recruited in previous trials.

• The findings were similar to the results from previous

trials, with significant 27 and 38% reductions in the
primary composite endpoint and all cause mortality,
respectively, indicating that nebivolol has beneficial
effects of a magnitude similar to those of other beta-
blockers proved to have major outcome benefits in
heart failure.
 Elderly Patients

• Decreased density of Beta receptors

results in decreased efficacy in the
elderly.

• Vasodilating BB do not just work by

blocking the Beta Receptors.
 Nebivolol
• For the treatment of hypertension, the
recommended starting dose is 5 mg to 10mg
once daily in combination with ACEi/ARB for
effective blood pressure control.

• The recommended starting dose of Nebivolol

in patients with CHF is 1.25 mg once daily. The
dose should be doubled at 1 to 2 week to 2.5
mg, 5 mg, and up to the intervals to 2.5 mg, 5
mg, and up to the maximum dose of 10 mg
once daily
Thank You