Primary objective: to study whether pyridoxamine supplementation in type 2 diabetes improves microvascular function in the eye, kidney and skin, and reduces markers of endothelial dysfunction and glycation.Secondary objective: to study whether…
ID
Source
Brief title
Condition
- Diabetic complications
- Vascular injuries
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameter is the central retinal arteriolar diameter (CRAE)
as measured with retinal funduscopy.
Secondary outcome
Sensitivity analyses of the primary study parameter are:
• Microvascular function measured in the eyes with retinal funduscopy, adaptive
optics funduscopy, optical coherence tomography angiography (OCT-A) and dynamic
vascular analysis
• Microvascular function measured in the skin with laser Doppler flowmetry.
• Microvascular function measured as plasma markers of endothelial dysfunction
and glycation.
• Microvascular function measured in kidneys by urine albumin and estimated
glomerular filtration rate.
Other study parameters
• age,
• sex,
• alcohol use,
• lipid profile,
• immunological profile,
• baseline fasting glucose,
• HbA1c,
• glucose metabolism and β-cell function,
• AGE measurements in skin and blood plasma,
• concentration of MGO,
• glyoxal and 3-deoxyglucose in blood plasma,
• adipokine and inflammatory marker levels in blood plasma,
• markers of dicarbonyl stress and oxidative stress in urine,
• hepatic fat content,
• blood pressure,
• heart rate/ECG,
• anthropometric measurements,
• medical history,
• medication use, and
• potential (serious) adverse effects.
• For monitoring the compliance, the vitamers pyridoxamine, pyridoxal,
pyridoxine, and their phosphorylated derivatives will be measured in plasma by
UPLC-MS/MS.
Background summary
People with diabetes have an increased risk of malfunctioning of the small
blood vessels, e.g. in the eye and kidney, which can lead to blindness and
kidney failure. These are serious complications, but to date there are no
options to improve specifically the function of the small blood vessels.
But why do diabetics have such an increased risk of dysfunction of the small
blood vessels? We have shown that a high glucose concentration in the blood
plays an important role in the dysfunction of, particularly, the small blood
vessels. A possible explanation for this dysfunction is an increased production
of methylglyoxal, which arises from the breakdown of glucose. Methylglyoxal is
a small but highly reactive molecule that can damage various organs and
tissues. In several studies, we found that methylglyoxal is increased in type 1
and type 2 diabetes and that methylglyoxal is associated with dysfunction of
the smaller blood vessels. In our previous research in small laboratory
animals, we have shown that methylglyoxal directly causes damage of the small
blood vessels. Because of these potentially harmful effects of methylglyoxal,
we have tried to reduce methylglyoxal. In small laboratory animals, we have
found that the vitamin B6 isoform pyridoxamine inhibits the formation and
accumulation of methylglyoxal, and improves vascular function. In a clinical
trial in overweight people, we found that supplementation of pyridoxamine is
safe and that methylglyoxal levels can be reduced, and we found indications of
an improvement in vascular function.
Study objective
Primary objective: to study whether pyridoxamine supplementation in type 2
diabetes improves microvascular function in the eye, kidney and skin, and
reduces markers of endothelial dysfunction and glycation.
Secondary objective: to study whether pyridoxamine supplementation in type 2
diabetes improves glucose metabolism and beta cel function, methylglyoxal,
glyoxal and 3-deoxyglucose concentrations in blood plasma, advanced glycation
endproduct (AGE) concentrations in blood plasma and skin, adipokines and
inflammation markers in plasma, liver fat, blood pressure and heart rate/ECG,
and anthropometric measurements.
Study design
The study will be conducted in a randomized, double blind, placebo-controlled
manner. This intervention study includes two intervention periods of 8 weeks in
a crossover design with a washout period of 4 weeks.
Intervention
Pyridoxamine, a vitamin B6 vitamer (Supersmart, Luxembourg). Placebo, capsule
identical to pyridoxamine but without the active substance (i.e. pyridoxamine)
(Supersmart, Luxembourg).
The daily dosage (300 mg) pyridoxamine or placebo will be supplied as three
capsules of 100mg each per day, and are taken shortly before or during the
meal.
Study burden and risks
Benefit: the potential benefit of participating in this study is directly
related to the (possible) beneficiary effects of pyridoxamine. Pyridoxamine is
able to effectively inhibit the formation of advanced glycation endproducts
(AGEs). Regarding the negative effects of AGE accumulation in the body, e.g.
vascular damage, this counteractive effect of pyridoxamine on its own could be
considered beneficial. Considering the significant burden of diabetes-related
vascular damage and the lack of effective treatment options, it is of
importance to investigate new potential medications to tackle these morbidities.
The intervention, pyridoxamine, has been used in clinical trials before. With a
dose of 300mg pyridoxamine daily, the adverse event rate did not differ from
placebo intervention.
Although the number of tests performed on visiting days (4) is considerable,
the burden associated with participation in this research is thought to be
acceptable, because of the merely non-invasive character of the tests. Solely
getting IV access is invasive and carries a small risk of hematoma, infection
or collapse. This procedure is performed by experienced staff. The use of
mydriatic eye drops holds a small risk (<0.1%) of adverse events. This risk is
further minimized by obtaining information on medical history and by measuring
intraocular pressure. This protocol is extensively applied in The Maastricht
Study.
Universiteitssingel 50
Maastricht 6229ER
NL
Universiteitssingel 50
Maastricht 6229ER
NL
Listed location countries
Age
Inclusion criteria
- Age >= 18 years,
- Diagnosis of type 2 diabetes,
- Generalized microvascular dysfunction, i.e.
o eGFR 30-60 mL/min/1.73m2, and/or
o Microalbuminuria albumin/creatinine ratio 3-30 mg/mmol, and/or
o Retinopathy (not proliferative), and/or
o Neuropathy (any).
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
- Uncontrolled diabetes (i.e., hypoglycaemia >2 times/week and/or unstable
HbA1c >9%),
- Intraocular pressure >=30 mmHg,
- History of glaucoma,
- Diagnosis of proliferative diabetic retinopathy,
- Diagnosis of diabetic macula edema,
- Albumine-creatinine ratio >30 mg/mmol,
- eGFR <30 mL/min/1.73m2,
- Diagnosis of epilepsy,
- Active cardiovascular disease (e.g. stroke, coronary artery disease,
congestive heart failure, cardiac shunts, history of cardiac surgery, pulmonary
hypertension, cardiac arrhythmias, family history of ventricular arrhythmias or
sudden cardiac death),
- Alcohol usage >4 U/day,
- Drugs abuse,
- Use of systemic glucocorticosteroids,
- Higher grade hypertension (> 179 mmHg SBP and/or > 109 mmHg DBP),
- Diagnosis of inflammatory disease,
- Use of an investigational product within the previous month,
- Unstable body weight (no drastic changes in lifestyle before or during the
intervention are allowed, this means no weight gain or loss >3 kg in the last
two months),
- Pregnancy or lactation,
- Change in use of oral contraceptives or IUD (12 weeks prior of during the
intervention),
- Unwillingness to give up being a blood donor (or having donated blood) from 8
weeks prior to the start of the study to end of study,
- Insufficient knowledge of the Dutch language,
- Inability to provide written informed consent.
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| CCMO | NL85203.068.23 |