Direct Renin Inhibition Effects on Atherosclerotic Biomarkers
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology, Diabetes |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 85 |
| Updated: | 12/7/2017 |
| Start Date: | January 2008 |
| End Date: | August 2011 |
Effects of Direct Renin Inhibition on Atherosclerotic Biomarkers in Patients With Stable Coronary Heart Disease and Type 2 Diabetes Mellitus
The investigators aim to assess if a new blood pressure medication, aliskiren, reduces
various biomarkers of heart disease found in the blood in patients with a history of both
heart disease and type 2 diabetes. The primary hypothesis is that aliskiren will reduce these
biomarkers compared to a calcium channel blocker.
various biomarkers of heart disease found in the blood in patients with a history of both
heart disease and type 2 diabetes. The primary hypothesis is that aliskiren will reduce these
biomarkers compared to a calcium channel blocker.
Agents that attenuate the renin angiotensin system (RAS), i.e. angiotensin converting enzyme
inhibitors (ACE-Is) and angiotensin receptor blockers (ARB), have shown to have therapeutic
benefit in a variety of cardiovascular disorders. ACE-Is are considered standard of care for
secondary prevention of CAD by the AHA/ACC. Based on the HOPE study, the beneficial effects
of ACE-Is in patients at high risk for cardiovascular outcomes may be beyond mere blood
pressure control. In addition to their effects on blood pressure, aldosterone, and sodium and
water absorption, blockade of the RAS with ACE-Is or ARBs alter key biomarkers of vascular
inflammation, vascular endothelial function, and fibrinolytic balance. These surrogate
biomarkers are thought to play a role in the progression of atherosclerosis. Biomarkers of
vascular inflammation include vascular and intracellular cell adhesion molecule (VCAM and
ICAM respectively) and c-reactive protein (CRP). Markers of endothelial function include
endothelin-1 (ET-1) and the vasodilator nitric oxide (NO). Plasminogen activator inhibitor-1
(PAI-1) is a prothrombotic marker associated with plaque proliferation and atherosclerosis
progression.
ACE-Is block the conversion of angiotensin 1 (Ang 1) to angiotensin 2 (Ang 2). "ACE escape"
may attenuate the influence of ACE-Is despite proven benefits in clinical trials.
Aliskiren is the first direct renin inhibitor approved by the FDA for the treatment of
hypertension. It is a very specific and potent inhibitor of human renin. As such it may offer
an advantage over ACE-I and ARB therapy as it blocks the rate limiting step of the RAS. It
does not show a compensatory increase in RAS activity noted with ARBs or non-ACE production
of Ang 2 as seen with ACE-Is. Aliskiren appears to have additive blood pressure lowering
effects when added to ACE-I or ARB therapy.
A very commonly prescribed antihypertensive, the dihydropyridine calcium channel blocker
amlodipine, has a synergistic effect on lowering BP when used with an ACE-I. It has been
shown to have mixed effects on atherosclerotic biomarkers in a variety of subjects. Type 2
diabetes affects many of the atherosclerotic markers described above and as such can be a
confounding variable in research involving these biomarkers.
With the addition of a new therapeutic agent that affects the RAS, its different
pharmacodynamic effects on the RAS compared to ACE-I and ARB therapy, and that Ang 2 levels
are not fully blocked by ACE-I therapy, it is critical to better understand how the new class
of direct renin inhibitors may influence atherosclerotic biomarkers in patients with a
variety of cardiovascular disorders. The objectives of this application are to determine
whether the direct renin inhibitor, aliskiren, affects atherosclerotic biomarkers in patients
with stable coronary artery disease and diabetes currently receiving standard ACE-I therapy
and if aliskiren has a more favorable effect on these markers compared to the calcium
antagonist amlodipine.
Large clinical trials have proven the benefit of RAS blockade in reducing cardiovascular
morbidity and mortality. The significance of this research is that more information is needed
to better understand how antihypertensive agents, particularly those that block the RAS,
reduce cardiovascular disease beyond blood pressure reduction alone. Research that elucidates
how agents may reduce atherosclerosis is very important to help better target drug therapy to
a condition that is the leading cause of death in this country.
inhibitors (ACE-Is) and angiotensin receptor blockers (ARB), have shown to have therapeutic
benefit in a variety of cardiovascular disorders. ACE-Is are considered standard of care for
secondary prevention of CAD by the AHA/ACC. Based on the HOPE study, the beneficial effects
of ACE-Is in patients at high risk for cardiovascular outcomes may be beyond mere blood
pressure control. In addition to their effects on blood pressure, aldosterone, and sodium and
water absorption, blockade of the RAS with ACE-Is or ARBs alter key biomarkers of vascular
inflammation, vascular endothelial function, and fibrinolytic balance. These surrogate
biomarkers are thought to play a role in the progression of atherosclerosis. Biomarkers of
vascular inflammation include vascular and intracellular cell adhesion molecule (VCAM and
ICAM respectively) and c-reactive protein (CRP). Markers of endothelial function include
endothelin-1 (ET-1) and the vasodilator nitric oxide (NO). Plasminogen activator inhibitor-1
(PAI-1) is a prothrombotic marker associated with plaque proliferation and atherosclerosis
progression.
ACE-Is block the conversion of angiotensin 1 (Ang 1) to angiotensin 2 (Ang 2). "ACE escape"
may attenuate the influence of ACE-Is despite proven benefits in clinical trials.
Aliskiren is the first direct renin inhibitor approved by the FDA for the treatment of
hypertension. It is a very specific and potent inhibitor of human renin. As such it may offer
an advantage over ACE-I and ARB therapy as it blocks the rate limiting step of the RAS. It
does not show a compensatory increase in RAS activity noted with ARBs or non-ACE production
of Ang 2 as seen with ACE-Is. Aliskiren appears to have additive blood pressure lowering
effects when added to ACE-I or ARB therapy.
A very commonly prescribed antihypertensive, the dihydropyridine calcium channel blocker
amlodipine, has a synergistic effect on lowering BP when used with an ACE-I. It has been
shown to have mixed effects on atherosclerotic biomarkers in a variety of subjects. Type 2
diabetes affects many of the atherosclerotic markers described above and as such can be a
confounding variable in research involving these biomarkers.
With the addition of a new therapeutic agent that affects the RAS, its different
pharmacodynamic effects on the RAS compared to ACE-I and ARB therapy, and that Ang 2 levels
are not fully blocked by ACE-I therapy, it is critical to better understand how the new class
of direct renin inhibitors may influence atherosclerotic biomarkers in patients with a
variety of cardiovascular disorders. The objectives of this application are to determine
whether the direct renin inhibitor, aliskiren, affects atherosclerotic biomarkers in patients
with stable coronary artery disease and diabetes currently receiving standard ACE-I therapy
and if aliskiren has a more favorable effect on these markers compared to the calcium
antagonist amlodipine.
Large clinical trials have proven the benefit of RAS blockade in reducing cardiovascular
morbidity and mortality. The significance of this research is that more information is needed
to better understand how antihypertensive agents, particularly those that block the RAS,
reduce cardiovascular disease beyond blood pressure reduction alone. Research that elucidates
how agents may reduce atherosclerosis is very important to help better target drug therapy to
a condition that is the leading cause of death in this country.
Inclusion Criteria:
- Diagnosis of type 2 diabetes
- Diagnosis of coronary artery disease
- Currently receiving therapy with an ACE-Inhibitor or Angiotensin Receptor Blocker
- Currently receiving antiplatelet therapy and statin therapy
- Baseline blood pressure > 100/75 mm Hg
- BMI 25-35 kg/m2
Exclusion Criteria:
- Concurrent calcium channel blocker therapy
- Documented peripheral edema
- Hyperkalemia
- Serum creatinine > 2.0
- Diagnosed with proteinuria
- Diagnosed with liver dysfunction or serious rheumatological disorder
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