Clinical trial NCT01867502: Effects of Vildagliptin Versus Glibenclamide on Glycemia After Exercise in Patients With Type 2 Diabetes
Official title: A 12-week Study to Compare the Effects of Vildagliptin Versus Glibenclamide on Glycemic Variability After a Sub Maximal Exercise Test in Patients With Type 2 Diabetes Inadequately Controlled With Metformin.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Hypoglycemic Agents
Diabetic Blood Glucose Monitoring
Exercise
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
First posted: 2013-06-04
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Exercise is considered a way to benefit the health of unhealthy and healthy individuals. This is confirmed by different scientific researches, in which people who participated improve their health. The present study will be conducted to test the hypothesis that vildagliptin associated with metformin may have more impact in improving glucose variability after a sub-maximal exercise test, as compared to glibenclamide. Our general aim will be to evaluate glucose variability after the submaximal exercise test under the treatment with vildagliptin or glibenclamide. The specific aims of this study are to evaluate the oxidative stress, endothelial function, metabolic and cardiovascular responses to exercise under the treatment with vildagliptin or glibenclamide. All these responses are important in patients with Diabetes Mellitus type II. Allied to the patient's routine treatment (metformin), they will receive orally a second drug, to take in 12 weeks. The patients will be raffled to take one of the two drugs that act on glycemia, that are called vildagliptin (50 mg of this drug twice a day) and glibenclamide (5 mg once a day during the first week and later you will increase to 5 mg twice a day). The metformin drug will continue be used.

Patients who meet the eligible criteria for the study will first make the test of the maximum effort, to determination of peak oxygen consumption (VO2peak) and ventilatory thresholds. Forty eight hours after this test, patients will be allowed to do the pre-drugs protocol that will be given in three consecutive days as explained below.

* Day 1: Begin a 24-hour urinary collection, perform vascular doppler ultrasound to evaluate endothelial function and then the glucose sensor will be inserted subcutaneously (begin continuous glucose monitoring system - CGMS evaluation);
* Day 2: End the 24-hour urinary collection, submit to the submaximal test (blood collection at baseline, 15 and 30 min of the session, and 60 min after recovery). On the same day, the patients will begin 24h ambulatory blood pressure monitoring (24h-ABPM).
* Day 3: Removal of the glucose sensor; end of the 24h ABPM, randomization. This same protocol, except the randomization will be repeated at the end of the 12 week treatment.

Detailed description: The main procedures will occur during three consecutive days, before randomization and 3 days before 12 weeks. In the first day, the patients will begin the 24hour urinary collection; the ultrasonography will be made in fasting state and they will place the sensors (CGMS and MAPA). In the second day, the blood samples will be collected and the patients will undergo sub-maximal exercise test; in the third day the sensors will be removed. The sub-maximal exercise test will occur on day 2 after a standard breakfast (500 kcal; 60% carbohydrate, 30% fat and 10% protein) after 8 hours overnight fast. After the three days of the first assessments, the selected patients will be divided into two groups, the group 1 receiving vildagliptin and the group 2 receiving glibenclamide for 12 weeks. There will be follow up visits on week 4 and 8. The variables in response to exercise (sub-maximal test) will be compared between the groups after 12 weeks.

The sample estimated will be 20 patients (10% drop out included) with DM2, from outpatient clinics of Serviço de Endocrinologia do Hospital de Clínicas de Porto Alegre (HCPA) or from public health. Patients will be randomized to metformin plus vildagliptin (MET + vilda), which will receive an additional vidagliptin dose of 50 mg twice a day and metformin plus glibenclamide group (MET + gliben) that will receive an additional glibenclamide dose of 5 - 20 mg once a day. Based on Marfella et al (13) study on the evaluation of the efficacy of treatment with Vildagliptin or Sitagliptin on blood glucose in patients with DM2 inadequately controlled with Metformin, a sample size with a 90% power and one alpha (α) of 0, 01 was calculated. Vidagliptin had a serious effect (51% reduction in MAGE), since the average difference was 25mg/dl with a 16 and 7mg/dl SD. After 20 subjects were analyzed, the calculated sample will be redone for confirming the sample efficacy for evidence of the expected effect evidence.

Adverse events, including serious adverse events or pregnancies will be collected and reported in the medical report of the study (Annex IV).

The reports containing serious adverse events or pregnancies will be forwarded to the respective manufacturer laboratory within 24 hrs after their knowledge, and the health authority according to the local law.

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes (fasting glucose ≥ 126 mg/dl or 7.0 mmol/l)(25);
* Recent HbA1C determination (between 7, 5 and 10%);
* Not involved in regular physical exercise;
* Older than 18 years;
* In use of Metformin.

Exclusion Criteria:

* Smoker and use of analgesic or anti-inflammatory drugs during the week of the study
* BMI \> 40 kg/m²;
* Proliferative retinopathy;
* Ischemic cardiomyopathy;
* Peripheral vascular disease;
* Blood Aspartate transaminase (AST) and Alanine transaminase (ALT) 2.5 times higher the normal concentration before screening visit
* Lactose intolerance;
* Renal insufficiency (creatinine clearance \<60ml/min);
* Blood pressure more than 180/100mmHg at rest (3 consecutive measures).

Primary outcomes:
measure: Change in Glycemic variability
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Change in Hemodynamic response to exercise: Cardiac output (Q), Stroke Volume (SV) and blood pressure (BP)
timeFrame: Each 2 minutes during exercise and until 60 min post in baseline and 12 weeks
Other outcomes:
measure: Change in Flow Mediated Dilatation (FMD)
timeFrame: Baseline and 12 weeks
measure: Change in Blood pressure variability
timeFrame: Baseline and 12 weeks
measure: Change in Plasma glucagon concentration on exercise
timeFrame: -1h, 0, 15min, 30 min (end), 60min post exercise in baseline and 12 weeks
measure: Change in Oxidative stress (F2 isoprostane 8-iso prostaglandin F2α);
timeFrame: Baseline and 12 weeks.
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre Porto Alegre
state: Rio Grande do Sul
Study officials:
affiliation: Federal University of Rio Grande do Sul
name: Beatriz BS Schaan, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Federal University of Rio Grande do Sul
name: Aline AF Fofonka, MSc
role: STUDY_CHAIR
References:
citation: Fofonka A, Ribeiro JP, Casali KR, Schaan BD. Effects of vildagliptin compared with glibenclamide on glucose variability after a submaximal exercise test in patients with type 2 diabetes: study protocol for a randomized controlled trial, DIABEX VILDA. Trials. 2014 Nov 4;15:424. doi: 10.1186/1745-6215-15-424.