This study will be performed only at the Jewish General Hospital. It will investigate the
effect of treatment with aliskiren, an inhibitor of renin, a substance produced by the
kidney that constricts arteries and raises blood pressure, on the blood vessels,
specifically the arteries, of subjects who have diabetes and elevated blood pressure
To investigate blood vessels, different techniques will be used. For large arteries, these
will be studied by non invasive methods using detection of the pulse wave or using
ultrasound over the skin of the neck, the wrist and the groin. To study small vessels, the
investigators will perform a biopsy on the buttock, under local anesthesia, and obtain a
small sample of tissue from under the skin, from which the vessels will be dissected. The
investigators have performed many hundreds of these small biopsies over the past 20 years
for similar studies without any complications. The biopsies are very well tolerated. From
this research the investigators will thus be able to learn what the structure and function
of these vessels is in these patients, in comparison to a normal healthy group.
The hypertensive diabetic subjects will then be assigned by chance (randomized trial) to
treatment with the renin inhibitor aliskiren or a comparator, the diuretic
hydrochlorothiazide. Aliskiren is a relatively new drug used to treat hypertension that is
very well tolerated and is now being evaluated in numerous trials in hypertensive diabetic
individuals. The diuretic is a well-know agent used to treat high blood pressure now for
many years, and which is very well tolerated. Physicians, nurses and scientists involved in
the study will be unaware of who is receiving which drug, as will be the patients (this is
the meaning of double-blind trial). However, if there is any problem, the secret code will
be broken and the individual withdrawn from the study. Subjects will be treated for a year,
and the study procedures (non invasive and the biopsy) repeated at 6 months and after one
year of treatment. During the study, blood samples will be drawn and urine collected at
certain intervals to ensure safety of the treatment.
Once tissues are obtained they will be studied in the laboratory. The study of the vessels
will allow treatment us to determine how the treatment with the renin inhibitor aliskiren
affects the structure and function as well as cellular and molecular aspects of arteries of
hypertensive diabetic persons. The investigators expect these studies to provide us
knowledge on mechanisms and perhaps new targets for future therapies of cardiovascular
disease and hypertension.
Minimum age: 30 Years.
Maximum age: 70 Years.
- Diabetes mellitus (diagnosed for at least 6 months) will be defined by usual criteria
based on basal glycemia or glucose tolerance test . Diabetes must be well controlled,
with glycosylated hemoglobin below 0. 08 (8%).
- Hypertension is defined as a mean SiSBP > 130 mmHg or SiDBP of 85-115mmHg at the
screening visit, and after two weeks of placebo therapy. (Hypertension will be
considered essential if there is no evidence of an underlying treatable cause after
suitable clinical and laboratory assessment. Hypertensive patients may be taking any
antihypertensive agent except a renin inhibitor. They may be taking an ACE inhibitor
or an ARB, which will not be discontinued. If they have been on HCTZ, they are
eligible to participate.
- Subjects are 30-70 years old
- Informed Consent obtained by patient
Criteria for inclusion: Control Group
- Diabetic defined as: hemoglobin A1C < 0. 06 ( 6%) and / or fasting glycemia <
- Hypertensive defined as : SiSBP ≤120 mmHg and/or SiDBP ≤80mmHg
- Subjects are 30-70 years old
- Informed Consent obtained by patient
- Uncontrolled diabetes ( defined as: preprandial glycemia usually above 10 mmol/L and
glycosylated hemoglobin above 0. 08).
- Renovascular hypertension
- History of malignant hypertension
- Sitting systolic blood pressure > 210 mmHg
- Cerebrovascular accident within the past year, or current transient ischemic attacks
- History of myocardial infarction, percutaneous coronary angioplasty or coronary
artery bypass surgery
- Clinically significant AV conduction disturbances and/or arrhythmias (e. g. second- or
third-degree AV block; Sick-sinus syndrome or clinically significant bradycardia-
resting heart rate < 45 beats/minute).
- Tachyarrhythmias; clinically significant arrhythmias
- Presence of an accessory bypass tract (e. g. Wolff-Parkinson-White syndrome)
- Angina pectoris
- Current or prior history of heart failure or known left ventricular ejection fraction
- History of unexplained syncope or a known syncopal disorder (e. g., Stokes-Adams
- Presence or known history of hemodynamically significant obstructive valvular disease
or hypertrophic cardiomyopathy
- Hypertensive patients already taking a renin inhibitor.
- Psychotropic or Antidepressant Agents
- Major psychotropic agents such as phenothiazines are not permitted. Chronic doses of
antidepressants are not permitted.
- Oral Contraceptives are not allowed if the patient's hypertension was induced by this
- Regular use of NSAID is permitted if taken regularly on a stable regimen. Aspirin in
small doses (≤ 1 g/day) as a cardioprotective agent is permitted. Acetaminophen is
- Other Drugs
- Concomitant use of oral or inhaled steroids, ACTH, immunosuppressants or lithium are
not allowed, nor are cyclosporine, quinidine, aliskiren available from the market.
- Glycosylated hemoglobin above 0. 08 (8%).
- Plasma creatinine concentration ≥ 200 μmol/L (adjusted for age and weight).
- Prior to patient entry, any hematuria should be evaluated, the etiology
established/documented, and treatment rendered as appropriate.
- Off-treatment serum potassium concentration ≥ 5. 5 mmol/L or ≤ 3. 5 mmol/L
- AST (SGOT) or ALT (SGPT) > 2 x normal upper limit, and if clinically significant
- Clinically significant laboratory values outside of the established normal range
including but not limited to any of the following parameters: hematocrit, hemoglobin,
platelet count or white blood cell count
- Allergies/Hypersensitivity /Pulmonary
- Known hypersensitivity or contraindication to aliskiren or thiazide diuretics.
- History of clinically important malabsorption or gastrointestinal resection.
- Smoking of 10 cigarettes or more is excluded. Also excluded are co-existent
conditions which could independently affect the histology of resistance vessels
except for diabetes (e. g. any disease which may be associated with vasculitides:
collagen-vascular diseases, chronic hepatitis B antigenemia, circulating immune
complexes, complement disorders, amyloidosis, scleroderma, etc.).
- Pregnancy or lactating females. Females of childbearing age who are not surgically
sterilized and who are using effective contraception may enter only if an
exclusionary pregnancy test is done within 72 hours of the first double-blind dose of
test agent. Pregnancy tests will then be done monthly throughout the study in women
capable of conception.
- Other concurrent severe disease which could preclude participation or survival, such
as neoplasm or Acquired Immunodeficiency Syndrome (AIDS), or patients known to be HIV
- Any known bleeding or platelet disorder.
- The known absence of one kidney.
- Patients who are currently abusing or previously abused alcohol or other drug
substances (within past two years).
- Mentally or legally incapacitated patients.
- Patients who have participated in another investigational drug trial, including those
using marketed drugs (i. e. patient has signed a consent form), within the 28 days
prior to start of placebo therapy.
- Patients who, in the opinion of the investigator, will not cooperate fully, keep
appointments or are generally unreliable.
- Inability or unwillingness on the part of the patient to sign the Patient Consent
- Phase V of Korotkoff sounds cannot be detected.
Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000 Apr 11;101(14):1653-9.
Savoia C, Touyz RM, Endemann DH, Pu Q, Ko EA, De Ciuceis C, Schiffrin EL. Angiotensin receptor blocker added to previous antihypertensive agents on arteries of diabetic hypertensive patients. Hypertension. 2006 Aug;48(2):271-7. Epub 2006 Jun 19.
Savoia C, Touyz RM, Amiri F, Schiffrin EL. Selective mineralocorticoid receptor blocker eplerenone reduces resistance artery stiffness in hypertensive patients. Hypertension. 2008 Feb;51(2):432-9. doi: 10.1161/HYPERTENSIONAHA.107.103267. Epub 2008 Jan 14.