Endothelial Dysfunction Clinical Trial
Official title:
Influence of Nitrates on Bone Remodeling and Endothelial Function in Patients With Type 2 Diabetes Mellitus.
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.
Diabetes mellitus (DM) is a chronic debilitating disease that affects almost all the systems
in the body with accompanying diabetic complications (neuropathy, retinopathy and
nephropathy) adding to the global burden of DM. These diabetic complications arise as a
manifestation of hyperglycaemic damage induced at the cellular level particularly the
endothelial cells (EC). Exposure to hyperglycaemic stress causes endothelial dysfunction,
which is the major perpetrator of microvascular disease. Disruption of endothelial function
also marks the advent of the subsequent development of cardiovascular disease (CVD) that
includes atherosclerosis and coronary artery disease (CAD). Microvascular disease occurs as a
result of deficiency of a potent endothelial vasodilator, nitric oxide (NO). NO plays a
fundamental role in vascular regulation which is mediated through vasodilation. Other
favourable characteristics of NO include antiplatelet activity and prevention of vascular
smooth muscle cell (VSMC) proliferation. Unsurprisingly, diminished NO levels in DM will
eventually lead to occlusion of the microvasculature in the retina, glomerulus and peripheral
nerve (vasa nervorum).
Of late, the skeletal system has also emerged as another vulnerable target of diabetic
microvascular disease. Certain predisposing factors like diabetic neuropathy (DN), visual
disturbances (retinopathy and cataract), gait abnormalities and hypoglycemia increase the
likelihood of fractures in DM. Among these factors DN contributes to a major extent in the
development of fractures especially fractures of the lower extremities.
Current antiresorptive therapies include estrogen/ HRT (Hormone replacement therapy),
bisphosphonates (BPP), selective estrogen receptor modulators (SERM) and denosumab (DMB).
These agents mainly retard bone resorption in the trabecular bone, with minimal effects on
cortical bone and are associated with only a 20-30% reduction in the risk of non-vertebral
fractures. Moreover, they decrease bone formation and are not devoid of adverse effects. Some
of these agents are also expensive and at times unavailable in some countries. All these
limitations challenge the discovery of an ideal agent that can prevent bone resorption,
increase bone formation and also reduce the risk of non-vertebral fractures.
Lately the therapeutic role of organic nitrates (source of NO) in bone metabolism has led to
a breakthrough in this field of research. Nitrates are commonly used in the treatment of
angina. Since nitrates are widely available, inexpensive and associated with limited side
effects, it would be practical to exploit these characteristic features in the treatment of
bone disease and endothelial dysfunction in DM.
AIMS
This pilot study aims to investigate the effect of Isosorbide mononitrate in patients with
type 2 DM with respect to:
- Its influence on bone remodelling by assessing the levels of bone markers and its
ability to improve BMD.
- Its role in modulating endothelial dysfunction.
HYPOTHESIS
In this randomised pilot study, patients with type 2 DM who receive 20 mg of Isosorbide
mononitrate will show:
- An improvement in bone formation as measured by serum procollagen type 1 amino terminal
propeptide (P1NP)
- Suppression of bone resorption as assessed by measurement of serum C-terminal
cross-linked telopeptide of type-I collagen (CTX)
- Improvement in calcaneal BMD
- Improvement in endothelial mediated vasodilation.
PATIENTS 40 female/ male subjects with type 2 DM will be considered eligible for the study.
They will be recruited from the Tameside Diabetes Centre and appropriate GP practices and a
written consent will be obtained from them prior to participation in the study.
Since there is no placebo in this study, the research fellow and research nurse will be
blinded to the treatment the patient is receiving. As it is known that the duration of
diabetes can affect microvascular circulation and possibly bone metabolism, the two groups
will be matched for the following variables: age, gender, duration of diabetes and severity
of neuropathy.
Diabetes self-education and management along with dietary advice will be provided to all the
participants in the study.
RANDOMISATION
With the help of a computer-generated program the study participants will be randomised into
2 groups:
- Group 1: 20 subjects will receive 20 mg/day of isosorbide mononitrate orally
- Group 2: 20 subjects will receive standard care
MEASUREMENTS Biochemical parameters at baseline and 6 months later
- Serum procollagen type 1 amino terminal propeptide (P1NP), a marker of bone formation
which indicates osteoblastic activity.
- Serum C-terminal cross-linked telopeptide of type-I collagen (CTX), a marker of bone
resorption Clinical parameters at baseline
- Laser Doppler imaging
- Calcaneal BMD (Sahara clinical bone sonometer; Hologic, Waltham, MA) Blood samples will
be obtained from the antecubital vein following an overnight fast and after resting for
15 minutes in the supine position.
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).
Assessment of calcaneal BMD at baseline and at 6 months This is a simple and convenient
method to assess peripheral BMD and assess fracture risk. The device used is a quantitative
ultrasound called Sahara Clinical Bone Sonometer (Sahara Clinical Bone Sonometer; Hologic,
Waltham, MA). The calcaneus is the preferred peripheral site to assess fracture risk. This
device uses ultrasound waves to determine the BMD of the calcaneus. In this procedure, once
the bare heel is placed in the device, the BMD is calculated within 30 seconds and the
results are then generated on paper by the device.
STATISTICAL ANALYSIS The results obtained from this study will be reported as a difference
between the baseline and 6 months later following a single daily oral dose of 20 mg
isosorbide mononitrate. The difference between the 2 groups will also be inferred at the end
of 6 months. The changes in skeletal parameters (serum P1NP and CTX) and microcirculation
will be compared between the 2 groups using t-tests to determine post hoc differences. A
p-value of < 0.05 will be considered significant. All analyses will be conducted using the
Statistical Package for Social Sciences (SPSS Inc., Chicago, Illinois, USA).
DURATION OF THE STUDY The estimated time for enrolment of patients will be within 6 months.
The duration of the study is 6 months and the last follow up will be at the end of 12 months.
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