Direct Renin Inhibition Effects on Atherosclerotic Biomarkers
Condition: Coronary Artery Disease; Type 2 Diabetes Mellitus
MeSH terms: Coronary Artery Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Aliskiren; Amlodipine
Intervention type(s): Drug; Drug
Intervention description(s): 150 - 300 mg once daily for 6 weeks; 5-10 mg once daily for 6 weeks
Other intervention name(s): Tekturna; Norvasc
Intervention MeSH terms: Amlodipine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: diabetes; heart disease; atherosclerosis