Metformin and Its Impact on the Substances Associated With NO Production in Prediabetes Patients.
Condition: PreDiabetes; Impaired Fasting Glucose (IFG); Impaired Glucose Tolerance (IGT)
MeSH terms: Prediabetic State; Glucose Intolerance
Study type: Interventional
Phase: Phase 4

Summary: 
      This study evaluates the effect of different doses of metformin on the function of
      endothelium in people with pre-diabetes. One group of the patients will receive metformin in
      dose: 1500 mg, the second one will receive 3000 mg/day.

      The parameters from healthy volunteers will be taken only at the study beginning to compare
      the test results with the parameters from patients with pre-diabetes. This group will be not
      treated with metformin (no intervention)
    

Detailed description: 
      In addition to exercise and diet, metformin is a medicine used to treat diabetes mellitus
      (DM) and pre-diabetic (pre-DM) conditions. This drug improves insulin sensitivity in both
      groups of patients (DM and pre-DM) and as a result gives a reduction in blood glucose.

      However, studies also confirm the effect of metformin on the reduction of cardiovascular risk
      in patients with diabetes (UKPDStudy), regardless of the hypoglycaemic effect.

      The precise mechanism of action of the drug in this field is not clear. There is also no data
      on whether similar effects apply to patients with pre-diabetes. Although we know that this
      group of patients is also characterized by increased cardiovascular risk.

      One of the most important substances that are involved in vasodilation is nitric oxide (NO).
      Impairment of its secretion is an important signal of endothelial damage and is connected
      with cardiovascular complications.

      The impact of metformin on endothelial function in pre-diabetes patients is not known. We do
      not know the effect of the drug dose and its different serum concentration on the secretion
      of the dilators of the vessels, which are associated with endothelial function.

      The study involves patients with pre-diabetes who meet the inclusion criteria, have no
      contraindication to participate in the study (see exclusion criteria), and give their written
      consent after reading "Information for the patient".

      The conditions (IFG, IGT) for participation in the study are confirmed by a diabetologist
      (principal investigator ) based on fasting glucose and OGTT (oral glucose tolerance test)
      with 75 mg of glucose.

      Metformin will be given in an increasing dose in accordance with the test protocol.

      After reaching a one-week treatment with a dose of 3 x 500 mg, patients will be assigned to
      group A -a continuation of a dose of 3 x 500 and group B- increase dose to 3 x 1000mg.
      Randomization depends on the identification number (ID). The patients with an even, second
      number in the PESEL (identification number) will be randomized to the A group, the patients
      with the second, odd number in the PESEL will be randomized to the group B. Here as an
      example: PESEL: 60010102823-" 0" is as an even number so the patient will be randomized to
      the group A; PESEL: 61010102823- "1" is an odd number- the patient will be randomized to the
      group B. This PESEL number (ID) in Poland is given to every person shortly after birth and
      the researchers have no influence on it.

      In the final stage also patients from group B (metformin: 3 x 1000 mg), will back to the
      treatment dose of metformin 3 x 500 mg- to show the relationship between the dose, serum
      concentration of the metformin and its effect on the secretion of the measured substances.

      The healthy volunteers will be not treated with metformin. Patients will be reminded by phone
      about the increase in metformin dose as well as on control visits.

      The lack of possible treatment with proper doses of metformin due to poor drug tolerance will
      move the patient from group B to group A if such dose (3 x 500 mg) is well tolerated. The
      patient will be excluded from the study if no compliance or lack of contact with the patient
      will be recorded during the treatment period or if metformin dose: 3 x 500 mg will be
      characterized with bad tolerance.

      Information about: age, gender, BMI, cardiovascular risk factors, the current basic
      lab-tests, and pharmacotherapy will be recorded.

      The blood samples for: plasma metformin level and listed substances will be collected for
      patients with pre-diabetes as described below (see diagram). The basic parameters as well as
      NO indirect products concentrations will be assessed for healthy volunteers only once-at the
      beginning of the study.

      Test 1: NO(0) (indirect products) for patients before treatment start

      3 weeks increasing dose of metformin to the final dose: 1500mg/day

      3 x 500 mg (1500/day)- the dose is reached

      3 weeks treatment 1500mg/day

      Tests 2: NO1(1500) and metformin concentration

      Randomization B:3 weeks increasing dose A: 6 weeks continuation with of metformin to the
      final a dose 3 x 500 mg

      dose 3 x 1000mg

      3 x 1000mg (3000mg/day)- the dose is reached 3 weeks treatment 3000mg/day Tests 3: NO2(1000)
      or NO3(500) and metformin concentration for both groups

      3 weeks treatment 1500mg/day for both groups

      Test 4: NO4 and metformin concentration

      Statistical analysis:

      For statistical analysis, the Statistica 12 program will be used (StatSoft Polska Sp. z o.o.
      www.statsoft.pl).

      The cut-off point for statistical significance (p) was determined at 0.05. To determine the
      statistical significance will be used tests compliant with the distribution of variables and
      data character (Student's t-test, Mann-Whitney test, chi-square test, Kruskal-Wallis ANOVA
      test). For analysis taking into account the duration of the study and determine the impact of
      relevant variables to achieve the appropriate concentration of nitric oxide will be used Cox
      proportional hazard regression. The goal of the optimal determination cut-off point for
      predictors will use ROC curves. Logistic regression was used to determine the independent
      predictors to obtain the desired concentration of nitric oxide. In order to determine the
      correlation, it will be used correlation of order Spearman's rank correlation coefficient or
      Pearson correlation coefficient.
    

Intervention name(s): Metformin
Intervention type(s): Drug
Intervention description(s): for group A: 12 weeks metformin treatment in a final dose 3 x 500 mg
for group B: 3 weeks metformin treatment in a dose 3 x 500 mg, next: 3 weeks metformin treatment in a final dose 3 x 1000mg, next: 3 weeks metformin treatment in a dose 3 x 500 mg.
Other intervention name(s): Metformax; Glucophage; Formetic; Siofor
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The group of patients taking the drug at the target dose of 3 x 1000 after 4 weeks returned to the dose of 3 x 500 mg. The group of patients taking the drug at the target dose 3 x 500 mg consequently had this dose during the whole study period.
The basic parameters and biochemical parameters from healthy individuals at the beginning of the study were assessed to compare with patients with pre-diabetes. This group did not take the metformin and thus did not have further examination and lab-tests during the study.
Masking: Single (Investigator)
Primary purpose: Basic Science
Keywords: prediabetes; impaired fasting glucose; impaired glucose tolerance; metformin; nitric oxide