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

NCT02011620 | Withdrawn Phase 4 DMC

• 1 other identifier: D001
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Endothelial Dysfunction; Bone Disease

Outcome Measures

Primary Outcomes (1)

• Improvement in endothelial function as measured by laser doppler imaging.

  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).

  6 months

Secondary Outcomes (1)

• Improvement in bone metabolism

  6 months

Study Arms (2)

Isosorbide-5-mononitrate

ACTIVE COMPARATOR

Tablet Isosorbide mononitrate 20 mg; 1 tablet to be taken daily at night for a total duration of 6 months.

Other: Isosorbide-5-mononitrate

Standard care

NO INTERVENTION

Standard care - no intervention with nitrates

Interventions

Isosorbide-5-mononitrate OTHER

Tablet Isosorbide mononitrate 20 mg; 1 tablet to be taken daily at night for a total duration of 6 months.

Also known as: Name of the MA holder: TEVA UK LIMITED, MA number (if MA granted by a Member State): PL 0289/0287, UNITED KINGDOM

Isosorbide-5-mononitrate

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Tameside Hospital NHS Foundation Trust: lead

Study Sites (1)

Tameside General Hospital NHS Foundation Trust

Manchester, OL6 9RW, United Kingdom

Location

Related Publications (6)

• Wimalawansa SJ. Nitric oxide: new evidence for novel therapeutic indications. Expert Opin Pharmacother. 2008 Aug;9(11):1935-54. doi: 10.1517/14656566.9.11.1935.

  PMID: 18627331 BACKGROUND

• Veves A, Akbari CM, Primavera J, Donaghue VM, Zacharoulis D, Chrzan JS, DeGirolami U, LoGerfo FW, Freeman R. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes. 1998 Mar;47(3):457-63. doi: 10.2337/diabetes.47.3.457.

  PMID: 9519754 BACKGROUND

• Mascarenhas JV, Jude EB. Pathogenesis and medical management of diabetic Charcot neuroarthropathy. Med Clin North Am. 2013 Sep;97(5):857-72. doi: 10.1016/j.mcna.2013.05.002.

  PMID: 23992897 BACKGROUND

• Wimalawansa SJ. Rationale for using nitric oxide donor therapy for prevention of bone loss and treatment of osteoporosis in humans. Ann N Y Acad Sci. 2007 Nov;1117:283-97. doi: 10.1196/annals.1402.066.

  PMID: 18056048 BACKGROUND

• Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res. 2004 Sep;19(9):1512-7. doi: 10.1359/JBMR.040716. Epub 2004 Jul 26.

  PMID: 15312252 BACKGROUND

• Jamal SA, Goltzman D, Hanley DA, Papaioannou A, Prior JC, Josse RG. Nitrate use and changes in bone mineral density: the Canadian Multicentre Osteoporosis Study. Osteoporos Int. 2009 May;20(5):737-44. doi: 10.1007/s00198-008-0727-7. Epub 2008 Sep 18.

  PMID: 18800179 BACKGROUND

MeSH Terms

Conditions

Bone Diseases

Interventions

isosorbide-5-mononitrate

Condition Hierarchy (Ancestors)

Musculoskeletal Diseases

Study Officials

• Edward Jude, MD, MRCP

  Tameside General Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant Diabetologist and Endocrinologist

Study Record Dates

• First Submitted: November 26, 2013
• First Posted: December 13, 2013
• Study Start: October 1, 2014
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: September 11, 2019

Record last verified: 2019-09

Locations

GB (1)