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Influence of Nitrates on Bone Remodeling and Endothelial Function in Patients With Type 2 Diabetes Mellitus

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02011620
Recruitment Status : Withdrawn (The sponsor was no longer in a position to sponsor a CTIMP. Study did not open.)
First Posted : December 13, 2013
Last Update Posted : September 11, 2019
Information provided by (Responsible Party):
Dr Edward Jude, Tameside Hospital NHS Foundation Trust

Brief Summary:

Type 2 diabetes mellitus (DM) is becoming a leading global epidemic. DM affects several systems in the body. Most of the complications encountered in DM are attributed to uncontrolled hyperglycemia or poor glycemic control. Hyperglycemic stress tends to damage the inner lining of the small blood vessels (endothelium). Normally, the endothelium releases a chemical substance called nitric oxide (NO) which relaxes the blood vessels and also prevents blockade of these vessels. Therefore damage to the endothelium (endothelial dysfunction) results in diminished levels of NO which ultimately leads to occlusion of these small blood vessels (microvascular occlusion). Microvascular occlusion of vessels supplying the eyes, kidneys and nerves leads to serious complications like diabetic retinopathy, nephropathy and neuropathy.

Of late, the skeletal system has emerged as another vulnerable target of diabetic microvascular disease. Patients with DM have an increased risk of developing fractures. Certain predisposing factors like diabetic neuropathy and visual disturbances (retinopathy and cataract) increases the likelihood of fractures in DM. More recently, evolving research has demonstrated NO's prospective role in bone preservation. Earlier studies have also validated the use of nitrates (donor of NO) in improving bone strength and reducing the risk of fractures.

So far no study has investigated the effect of nitrates on endothelial function and bone microarchitecture in patients with diabetes. The investigators therefore propose to investigate the influence of nitrates on endothelial dysfunction and bone integrity in patients with type 2 diabetes. 40 patients with type 2 DM will be recruited into the study; 20 patients will receive 20 mg of oral isosorbide mononitrate daily and the other 20 will not receive the study drug. The investigators hope to demonstrate an improvement in endothelial function (by measuring skin blood flow) and bone integrity (by measuring markers of bone formation and bone resorption and bone mineral density - BMD) following 6 months of nitrate therapy.

Condition or disease Intervention/treatment Phase
Endothelial Dysfunction Bone Disease Other: Isosorbide-5-mononitrate Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: Influence of Nitrates on Bone Remodeling and Endothelial Function in Patients With Type 2 Diabetes Mellitus.
Estimated Study Start Date : October 2014
Actual Primary Completion Date : December 2014
Actual Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Isosorbide-5-mononitrate
Tablet Isosorbide mononitrate 20 mg; 1 tablet to be taken daily at night for a total duration of 6 months.
Other: Isosorbide-5-mononitrate
Tablet Isosorbide mononitrate 20 mg; 1 tablet to be taken daily at night for a total duration of 6 months.
Other Names:
  • Name of the MA holder: TEVA UK LIMITED
  • MA number (if MA granted by a Member State): PL 0289/0287

No Intervention: Standard care
Standard care - no intervention with nitrates

Primary Outcome Measures :
  1. Improvement in endothelial function as measured by laser doppler imaging. [ Time Frame: 6 months ]

    Assessment of the microcirculation with Laser Doppler Iontophoresis at baseline and 6 months

    A standard measurement of microcirculation is laser Doppler iontophoresis, which is used by several research institutes. In this trial the skin microcirculation will be measured on the ventral aspect of the forearm using a Perimed Laser Doppler imager and iontophoresis system.

    Endothelial-mediated vasodilation will be measured by the iontophoresis of acetylcholine, while sodium nitroprusside will be used to measure endothelium-independent vasodilation. The iontophoresis system consists of an ION chamber (iontophoresis delivery vehicle device) that sticks firmly to the skin and a reference electrode. The response in blood flow will be imaged and quantified using the Perimed Laser Doppler Imager (Sweden).

Secondary Outcome Measures :
  1. Improvement in bone metabolism [ Time Frame: 6 months ]
    1. An improvement in bone formation as measured by serum procollagen type 1 amino terminal propeptide (P1NP)
    2. Suppression of bone resorption as assessed by measurement of serum C-terminal crosslinked telopeptide of type 1 collagen (CTX)
    3. Improvement in calcaneal bone mineral density

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Females and males aged between 40-75 years
  • A diagnosis of type 2 DM based on one of the following criteria (ADA - 2010):
  • Fasting plasma glucose (FPG) >= 126 mg/dL (7.0 mmol/L) or
  • 2-h plasma glucose >= 200 mg/dl (11.1 mmol/L) during an OGTT or
  • Classic symptoms of hyperglycemia or hyperglycemic crisis with a random plasma glucose >= 200 mg/dL (11.1 mmol/L).
  • Known history of type 2 diabetes mellitus on treatment

Exclusion Criteria:

  • At screening, age below 40 years and above 75 years.
  • Pregnancy or lactation
  • Type 1 diabetes mellitus (patients with a history of ketoacidosis, age of onset of DM before 25 years of age, BMI <21 kg/m2 and use of insulin without a concomitant oral hypoglycemic agent)
  • Patients with uncontrolled hypertension (systolic blood pressure [SBP] > 160/90 mmHg) or hypotension (SBP of <=100 mm Hg) at screening.
  • History of hypersensitivity to nitrates
  • History of low blood pressure
  • History of raised intracranial pressure (from cerebral haemorrhage or head trauma)
  • History of cardiovascular disease (ischaemic heart disease, previous stroke and severe peripheral vascular disease [Ankle brachial pressure index - ABPI< 0.7])
  • History of acute circulatory failure (shock), circulatory collapse, cardiogenic shock
  • History of hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, aortic/ mitral valve stenosis
  • History of general systemic illness including cardiac, hepatic or renal insufficiency
  • Patients with clinical nephropathy (24 hour protein > 0.5g or dipstix protein +) or renal failure (serum creatinine > 130 µmol/l).
  • History of anaemia
  • History of closed angle glaucoma
  • History of migraine headaches
  • History of hypothyroidism
  • History of hypothermia
  • History of malnutrition
  • History of Paget's disease and other metabolic bone disorders
  • History of coeliac or inflammatory bowel disease
  • History of multiple myeloma or cancer
  • History of nitrate use for cardiac conditions
  • History of treatment with phosphodiesterase type-5 inhibitors
  • History of foot ulcers
  • History of active foot deformities e.g. Charcot foot
  • History of glucocorticoid intake within the last 3 months
  • History of hormone replacement therapy in the last 12 months
  • History of treatment with SERM (selective estrogen receptor modulator)
  • History of treatment with thiazolidinedione
  • History of anticonvulsant use
  • History of past or current treatment for osteoporosis
  • History of bisphosphonate therapy within the last 3 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02011620

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United Kingdom
Tameside General Hospital NHS Foundation Trust
Manchester, United Kingdom, OL6 9RW
Sponsors and Collaborators
Tameside Hospital NHS Foundation Trust
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Principal Investigator: Edward Jude, MD, MRCP Tameside General Hospital NHS Foundation Trust

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Responsible Party: Dr Edward Jude, Consultant Diabetologist and Endocrinologist, Tameside Hospital NHS Foundation Trust Identifier: NCT02011620     History of Changes
Other Study ID Numbers: D001
First Posted: December 13, 2013    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Bone Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Musculoskeletal Diseases
Isosorbide Dinitrate
Diuretics, Osmotic
Natriuretic Agents
Physiological Effects of Drugs
Vasodilator Agents
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action