Nebivolol Versus Sustained Release Metoprolol Succinate in Patients With Chronic Kidney Disease

Patients with chronic kidney disease (CKD) are at an increased risk of mortality related to
cardiovascular (CV) disease compared with the general population. Furthermore, a reduced
glomerular filtration rate (GFR), defined as < 60 ml/min/1.73m², has been shown to be
associated with increased risk of hospitalization, death and cardiovascular events
independent of other known cardiovascular risk factors.

Albuminuria, a marker of endothelial dysfunction or kidney damage, or both, frequently
accompanies a reduction in GFR during the development of CKD, and is a well-recognized risk
factor for kidney disease progression. Importantly, the presence of albuminuria has also
been shown to be a powerful predictor of CV mortality independent of other risk factors.

Endothelial dysfunction has been implicated in the pathophysiology of progressive renal
disease and may be a link between CKD and CV mortality. Levels of asymmetric dimethyl
arginine (ADMA), a competitive inhibitor of nitric oxide synthase, are elevated in patients
with CKD. Elevated levels of ADMA have been shown to correlate with the presence of
endothelial dysfunction and to predict mortality in patients with CKD. In addition, ADMA has
been shown to be associated with progression of non-diabetic kidney disease and lowering
ADMA levels could potentially prevent progressive renal impairment.

Oxidative stress also plays a fundamental role in the development of endothelial function
and cardiovascular disease. While markers of oxidative stress are notoriously difficult to
measure, F2- isoprostanes are considered to be reliable biomarkers of in vivo lipid
peroxidation. F2-isoprostanes are a family of prostaglandin F2 isomers produced by free
radical peroxidation of arachidonic acid and have been used as end points in clinical
studies of anti-oxidant therapies.

Blood pressure control is an important factor in predicting CV mortality. However, in
patients with CKD, blood pressure is frequently difficult to control. Angiotensin converting
enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) with or without
diuretics, are the antihypertensive agents of choice in patients with CKD. More recently,
the combination of an ACEI and a dihydropyridine calcium channel blocker (CCB) have been
shown to be more effective than an ACEI and a thiazide diuretic in controlling blood
pressure in patients with essential hypertension including those with CKD or diabetes
mellitus. However, even with this combination of medications, blood pressure control in
patients with CKD is often difficult to achieve. The effect of beta adrenergic blocking
agents (BB) on lowering blood pressure has not been extensively investigated in patients
with CKD. A randomized control trial in hemodialysis patients from Italy showed that there
was a higher two-year survival in those receiving carvedilol. Beta blockers are not
routinely used to lower blood pressure in patients with CKD due to the possibility that
these medications may have a deleterious effect on insulin resistance, although this theory
has been disproved in a large clinical trial. A recent review points out that beta blockers
are underused in patients with CKD although they offer many potential benefits in this
patient population. This is not surprising, as sympathetic overactivity is an important
contributor to cardiovascular disease and propensity to sudden death in patients with CKD.
However, despite the potential benefits of BBs in patients with CKD their use remains
limited because of the potential for inducing a relatively high rate of adverse effects and
the lack of data in regard to their effectiveness in patients with CKD.

The recent availability of the third generation beta blocker nebivolol, known to improve the
availability of nitric oxide by reducing ADMA levels, thereby improving endothelial
function, provides an opportunity to more effectively control blood pressure, prevent the
progression of CKD, and also the occurrence of CV events. A reduction in the bioavailability
of nitric oxide (NO) has been shown to play a significant role in both endothelial
dysfunction and hypertension. Therefore, increasing the availability of nitric oxide can
potentially be very beneficial. In a comparative study in patients with diabetes mellitus a
trial of nebivolol versus metoprolol showed that metoprolol raised ADMA levels, suggesting a
worsening of endothelial function, whereas nebivolol did not have this effect. Thus,
nebivolol would appear to have a major advantage over other BBs in patients CKD due to
diabetes mellitus or hypertension although this has not yet been systematically studied.

Inclusion Criteria:

- Age > 18 years old and < 85 years old

- Willing and able to comply with all study procedures

- Blood pressure on standard antihypertensive therapy, which may include: a diuretic,
ACE-I, ARB, CCB, and/or an alpha adrenergic antagonist, and a blood pressure ≤ 180 mm
Hg systolic and ≥ 130 mm Hg systolic. The blood pressure will be taken after a period
of 15 minutes of resting in the sitting posture

- Clinically stable patients with CKD (GFR 20-60 ml/min/1.73 m²) by the abbreviated
MDRD equation and with a rate of decline of GFR no greater than 1 ml/min/1.73 m² per
month over the prior three months and with albuminuria (urine albumin:creatinine
ratio) in a spot urine sample of between 100-3000 mcg/g of creatinine). Albumin
excretion (i.e., urine albumin:creatinine ratio) will be checked prior to enrollment
in two separate (collected at least one week apart) spot early morning urine
specimens

- Females of child bearing potential must have a negative pregnancy test at screening.
Females considered not of childbearing potential include those who have been in
menopause at least 2 years, had tubal ligation at least 1 year prior to screening or
who have had a total hysterectomy

Exclusion Criteria:

- Use of a BB in the 3 months prior to study enrollment, other than atenolol or
metoprolol

- Uncontrolled hypertension with a blood pressure > 160/100 mm Hg or those with changes
to their antihypertensive regime during the last 2 months

- Concurrent disease or conditions that would interfere with study participation or
safety, such as bleeding disorders, history of syncope or vertigo, severe
gastrointestinal reflux (GERD) or gastric ulcers, heart failure, symptomatic coronary
or peripheral vascular disease, arrhythmia, serious neurological disorders including
seizures or organ transplantation

- Diabetics that are uncontrolled (HbA1c consistently > 9.0 g/dL), unstable, newly
diagnosed, or have undergone major changes in therapy within the last 2 months

- Any severe co-morbid condition that would limit life expectancy to < 6 months

- Advanced CKD with an eGFR < 20 ml/min/1.73 m²

- Patients with albuminuria due to causes other than diabetes mellitus or hypertension

- Hepatic enzyme concentrations > 2 times the upper limit of normal

- HIV infection, hepatic cirrhosis or other preexisting liver disease; or positive HIV,
Hepatitis B or C test at screening

- Use of any investigational product or investigational medical device within the last
60 days of screening

- History of alcohol and or drug abuse

- Any condition that in view of the investigators places the subject at high risk of
poor treatment or compliance or of not completing the study