Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes

Phase 3

Completed

Conditions: Type 2 Diabetes

Interventions: Drug: Vildagliptin
Drug: Glibenclamide
Drug: Metformin

Registration Number: NCT01822548

Lead Sponsor: Azienda Ospedaliero-Universitaria di Parma

Brief Summary: The purpose of this study is to evaluate the effect of Dipeptidyl peptidase (DPP) -IV inhibitor Vildagliptin vs. Glibenclamide on circulating endothelial progenitor cells (EPCs) number in type 2 diabetes patients in metformin failure. Subjects will be followed for 12 months after randomization.

Detailed Description: Diabetic patients show a higher cardiovascular risk compared with non-diabetic patients. It is therefore crucial that blood glucose lowering drugs reveal a favorable cardiovascular risk profile independently of metabolic control.

EPCs are a subset of circulating mononuclear cells derived from the bone marrow. EPCs play a fundamental role in the formation of new blood vessels (neo-endothelization) and repairing of existing blood vessels (re-endothelization) in order to maintain endothelial homeostasis and integrity. Endothelial damage and tissue ischemia, through the release of growth factors and cytokines, represent a strong stimulus for the mobilization of EPCs from the bone marrow. Reduced EPC number has been related to the presence of traditional risk factors for cardiovascular disease and to the development of atherosclerosis and has been shown to predict cardiovascular (CV)risk. Type 2 diabetes is known to be associated with an increased CV risk and a reduced EPC number. Recent data suggest that DPP-IV inhibitors might be involved in the mechanisms promoting bone-marrow EPC mobilization. This putative ancillary effect of DPP-IV might have a favorable impact on type 2 diabetes, a condition characterized by an increased CV risk.

This is a randomized, open-label, active-treatment-controlled, two parallel arm (2:1), intervention trial comparing DPP-IV inhibitor Vildagliptin (100 mg daily) with Glibenclamide (maximum daily dose of 10 mg). Treatment allocation and titration regimens are not blinded.

Primary end-point:Absolute change in the EPC number at visit: V0 (randomization), V2 (month 4), V3 (month 8) and V4 (month 12).

Secondary end-point: Absolute change in HbA1C compared to baseline.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

Inclusion Criteria

Age equal or above 35 years;
Diagnosis of type 2 diabetes mellitus as defined by the American Diabetes Association , with at least one year of disease duration at the time of the screening visit;
Blood glucose lowering treatment with Metformin alone (monotherapy) at a stable dose of at least 1.5 g/day (or maximum tolerated dose) in the 3 months prior to the screening visit;
Insufficient metabolic control as defined by recent (last six months) HbA1c ≥ 7% in any peripheral laboratory and confirmed at the time of the screening;
Absence of a recent clinically-relevant progression of micro- and macro-vascular complications (see exclusion criteria);
Written informed consent to participate to the study.

Exclusion criteria:

Age below 35 years
Type 1 diabetes or other causes of diabetes (pancreatectomy, gestational diabetes, etc.)
HbA1c < 7% or ≥ 9% at the screening visit
Treatment with any blood glucose lowering treatment other than Metformin in the six months before screening visit
BMI < 20 or ≥ 40 kg/m2, or current/ past history of clinically-relevant eating disorders (including -but no limited to- nervous anorexia, bulimia, binge-eating disorders, etc.)
Significant progression of diabetic macro-angiopathy or cardiovascular disease in the six months prior to study visit
Significant progression of diabetic micro-angiopathy in the six months prior to study visit
Organ failure or other severe diseases limiting life expectancy;
Beginning, in the three months before screening visit, of any kind of drug which can modify glycemic levels (beta-blockers, diuretics...), or acute disease (acute infection, urinary tract infection...) in three months before screening visit
History of inflammatory/infective/autoimmune chronic disease
History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, gastric surgery, inflammatory bowel disease;
Any clinically significant abnormality identified on physical examination, laboratory tests, ECG or vital signs at screening that in the judgment of the investigator would preclude safe completion of the study;
Uncontrolled or inadequately controlled hypertension at screening (Systolic Blood Pressure (SBP)>190 or Diastolic Blood Pressure (DBP) >100 mmHg)
Ongoing pregnancy or absence of effective contraception in women with childbearing potential
Contraindications to the maintenance of the background therapy (Metformin), including -but not limited to- chronic kidney failure or plasma creatinine concentrations > 1.5 mg/dL, severe respiratory failure, etc.;
Contraindications to the use of a Sulfonylurea;
Contraindications to the use of a DPP-IV Inhibitor;
Laboratory findings, or other disease conditions, at the screening visit that might interfere with study measurements:
1. Hemoglobinopathy known to affect HbA1c assays;
2. Known chronic liver diseases, including HBV (hepatitis B virus) and HCV (hepatitis C virus) infection;
3. Liver makers (aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), Gamma-glutamyltransferase (GGT) , bilirubin) above 2 times the upper normal limit;
4. Amylase and/or lipase above 2 times the upper normal limit;
Chronic use of systemic and/or inhaled corticosteroids (only topical corticosteroids are allowed);
History of low compliance, clinically-relevant psychiatric disorders or any current/ historical finding suggesting the patient as inappropriate to follow the study procedures.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vildagliptin & metformin	Vildagliptin	Vildagliptin 100 mg tablet and metformin (max dose=2500 mg) tablet daily oral administration
Vildagliptin & metformin	Metformin	Vildagliptin 100 mg tablet and metformin (max dose=2500 mg) tablet daily oral administration
Glibenclamide & metformin	Glibenclamide	Glibenclamide maximum dose of 10 mg tablet and metformin (max dose=2500 mg) tablet daily oral administration
Glibenclamide & metformin	Metformin	Glibenclamide maximum dose of 10 mg tablet and metformin (max dose=2500 mg) tablet daily oral administration

Primary Outcome Measures

Name	Time	Method
Absolute Change in the Endothelial Progenitor Cell (EPC) Number	V0, V2 (month 4), V4 (12 month)	The study primary endpoint was the change from baseline values of the EPC number in the Vildagliptin vs Glibenclamide arm at 4 and 12 months.

Secondary Outcome Measures

Name	Time	Method
Absolute Change in HbA1C Compared to Baseline	V0 (randomization), V2 (month4), V4 (month 12).	The secondary endpoint was the change from baseline values of HbA1C in the Vildagliptin vs Glibenclamide arm at 4 and 12 months