Type 2 Diabetes
Conditions
Keywords
vildagliptin, metformin
Brief summary
The purpose of this study is to compare the effect of 16 weeks treatment with vildagliptin to pioglitazone as add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.
Detailed description
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by hyperglycemia that result from pancreatic islet dysfunction. Presently available oral antihypoglycemic drug improves glycemic control over the short term, none has been shown to stop the progressive decline in beta cell function which contributes to the deterioration of glycemic control over time. Pathophysiology of T2DM is known as tissue resistance for insulin and progressive beta cell failure. Which one attributes first is unclear, but non-obese T2DM patients often show normal fasting plasma glucose (FPG) but postprandial plasma glucose (PPG) level is high and reduced or lacking normal compensatory insulin secretion. In Korea, more than 80% of T2DM are non-obese type (BMI \>= 27 ) and it was observed that basal insulin level and compensatory insulin secretion reaction were reduced in normal healthy population. Based on that, metformin is an established first line treatment for type 2 diabetes, acting primarily to enhance hepatic and peripheral insulin sensitivity. However, it has become increasingly apparent that many patients require a combination of agents to attain optimal glycemic control. Better understanding of incretin effect on the pathophysiology of T2DM has recently led to development of new oral hypoglycemic agents. Vildagliptin is a potent and highly selective dipeptidyl peptidase (DPP)-IV inhibitor that improves islet function by increasing pancreatic alpha and beta cell responsiveness to glucose. Studies in patients with T2DM have shown that vildagliptin significantly reduced HbA1c and FPG level from baseline and did not induce weight gain and the incidence of hypoglycemia was low. In addition, studies in rodents support an effort of vildagliptin on beta cell remodeling. The thiazolidinediones are effective in reducing HbA1C in obese T2DM patients and it is known that only thiazolidinedione can delay the beta cell failure . But recently, thiazolidinediones were found to be associated with a decrease in bone mineral density and to raise the risk of myocardial infarct and cardiovascular related mortality. Thus, there is a need for new classes of blood glucose lowering drug which has the potential to delay or prevent the progression of T2DM.
Interventions
DRUGvildagliptin
vildagliptin 50mg bid for 16 weeks
DRUGPioglitazone
Pioglitazone 15mg bid for 16 weeks
Sponsors
Pusan National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Age in the range of 18 to 80 years 2. HbA1c 7 to 11% 3. FPG \< 270 mg/dL (15 mmol/L); 4. Agreement to maintain prior diet & exercise 5. Written informed consent to participate in the study
Exclusion criteria
1. Type 1 diabetes or Any kind of secondary diabetes 2. Pregnant or lactating women 3. Acute infections which may affect blood glucose control within 4 weeks prior to visit 1. 4. Significant diabetes complications e.g., symptomatic autonomic neuropathy or gastroparesis 5. Previous history of severe cardiovascular disease such as 1. Torsades de Pointes, sustained and clinically relevant ventricular tachycardia, or ventricular fibrillation 2. Percutaneous coronary intervention within the past 3 months 6. Any of the following within the past 6 months 1. Myocardial infarction (MI) (if the visit 1 ECG reveals patterns consistent with an MI and the date of the event cannot be determined, then the patient can enter the study at the discretion of the investigator and the sponsor) 2. Coronary artery bypass surgery 3. Unstable angina 4. Stroke 7. Congestive heart failure (NYHA class I to IV) 8. Liver disease such as cirrhosis or chronic active hepatitis 9. Known sensitivity to pioglitazone, rosiglitazone, or similar drugs 10. Chronic insulin treatment (\> 4 weeks of treatment in the absence of an intercurrent illness) within the past 6 months 11. Chronic oral or parenteral corticosteroid treatment (\> 7 consecutive days of treatment) within 8 weeks prior to visit 1 12. Any of the following laboratory abnormalities 1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) greater than 2.5 times the upper limit of the normal range at visit 1 2. Direct bilirubin greater than 1.3 times the upper limit of the normal range at visit 1 3. Serum creatinine levels \> 2.5 mg/dL (220 μmol/L) at visit 1 4. Clinically significant thyroid-stimulating hormone (TSH) outside normal range at visit 1
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Non-inferiority of HbA1C Change From Baseline in Vildagliptin + Metformin Group Compared With Pioglitazone + Metformin Group | 16 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | 16 weeks , visit 5 | 1. After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Fasting Plasma Glucose (FPG) 2. After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Postprandial Glucose (PPG) |
| the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | 16 weeks, visit 5 | The Mean Changes of Lipid Profiles(Triglyceride, Total cholesterol, LDL, HDL, Non-HDL cholesterol) From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups after 16weeks |
| the Mean Changes of Body Weight From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | 16 weeks, visit 5 | — |
| the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | 16 weeks, visit 5 | — |
Other
| Measure | Time frame |
|---|---|
| the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | 16 weeks, visit 3,4,5 |
Countries
South Korea
Participant flow
Pre-assignment details
Total number of patients who were in screening is 287. However, 59 patients were excluded. 49 Patients didn't meet inclusion/exclusion criteria. 10 Patients didn't take investigational product. As a result, 228 patients took investigational product.
Participants by arm
| Arm | Count |
|---|---|
| Vildagliptin vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy
vildagliptin: vildagliptin 50mg bid for 16 weeks | 117 |
| Pioglitazone Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy
Pioglitazone: Pioglitazone 15mg bid for 16 weeks | 111 |
| Total | 228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lack of Efficacy | 0 | 3 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Protocol Violation | 10 | 14 |
| Overall Study | Withdrawal by Subject | 0 | 6 |
Baseline characteristics
| Characteristic | Pioglitazone | Total | Vildagliptin |
|---|---|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 9.1 | 54.5 years STANDARD_DEVIATION 9.5 | 55.2 years STANDARD_DEVIATION 9.8 |
| Body Mass Index | 25.0 Kg/m^2 STANDARD_DEVIATION 3.3 | 24.9 Kg/m^2 STANDARD_DEVIATION 3.3 | 24.9 Kg/m^2 STANDARD_DEVIATION 3.2 |
| Duration of diaebetes | 60.2 months STANDARD_DEVIATION 58.6 | 64.3 months STANDARD_DEVIATION 60.4 | 68.3 months STANDARD_DEVIATION 62 |
| Sex: Female, Male Female | 63 Participants | 130 Participants | 67 Participants |
| Sex: Female, Male Male | 48 Participants | 98 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 117 | 11 / 111 |
| serious Total, serious adverse events | 4 / 117 | 2 / 111 |
Outcome results
Primary
Non-inferiority of HbA1C Change From Baseline in Vildagliptin + Metformin Group Compared With Pioglitazone + Metformin Group
Time frame: 16 weeks
Population: This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin | Non-inferiority of HbA1C Change From Baseline in Vildagliptin + Metformin Group Compared With Pioglitazone + Metformin Group | -0.94 % (change of HbA1c) | Standard Deviation 0.79 |
| Pioglitazone | Non-inferiority of HbA1C Change From Baseline in Vildagliptin + Metformin Group Compared With Pioglitazone + Metformin Group | -0.60 % (change of HbA1c) | Standard Deviation 1.12 |
Secondary
the Mean Changes of Body Weight From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Time frame: 16 weeks, visit 5
Population: This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vildagliptin | the Mean Changes of Body Weight From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | -0.07 kg | Standard Deviation 1.53 |
| Pioglitazone | the Mean Changes of Body Weight From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | 0.69 kg | Standard Deviation 2.07 |
Secondary
the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
1. After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Fasting Plasma Glucose (FPG) 2. After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Postprandial Glucose (PPG)
Time frame: 16 weeks , visit 5
Population: This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vildagliptin | the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | FBG levels difference | -20.41 mg/dL | Standard Deviation 34.81 |
| Vildagliptin | the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | PPG levels difference | -60.23 mg/dL | Standard Deviation 75.48 |
| Pioglitazone | the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | FBG levels difference | -15.04 mg/dL | Standard Deviation 38.15 |
| Pioglitazone | the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | PPG levels difference | -38.19 mg/dL | Standard Deviation 83.79 |
Secondary
the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Time frame: 16 weeks, visit 5
Population: This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vildagliptin | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Insulin difference | 0.36 mcU/mL*mmol/L | Standard Deviation 6.95 |
| Vildagliptin | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | C-peptide difference | 0.07 mcU/mL*mmol/L | Standard Deviation 0.84 |
| Vildagliptin | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | HOMA-IR difference | -0.06 mcU/mL*mmol/L | Standard Deviation 2.92 |
| Vildagliptin | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | HOMA-beta difference | 9.77 mcU/mL*mmol/L | Standard Deviation 28.1 |
| Pioglitazone | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | HOMA-beta difference | -24.26 mcU/mL*mmol/L | Standard Deviation 294.88 |
| Pioglitazone | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Insulin difference | -8.21 mcU/mL*mmol/L | Standard Deviation 70.06 |
| Pioglitazone | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | HOMA-IR difference | -3.33 mcU/mL*mmol/L | Standard Deviation 25.16 |
| Pioglitazone | the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | C-peptide difference | -0.24 mcU/mL*mmol/L | Standard Deviation 1.14 |
Secondary
the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
The Mean Changes of Lipid Profiles(Triglyceride, Total cholesterol, LDL, HDL, Non-HDL cholesterol) From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups after 16weeks
Time frame: 16 weeks, visit 5
Population: This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vildagliptin | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | HDL | -0.34 mg/dL | Standard Deviation 8.57 |
| Vildagliptin | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Non-HDL cholesterol | -8.39 mg/dL | Standard Deviation 24.67 |
| Vildagliptin | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Triglyceride | -9.22 mg/dL | Standard Deviation 55.98 |
| Vildagliptin | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Total cholesterol | -6.45 mg/dL | Standard Deviation 25.1 |
| Vildagliptin | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | LDL | -6.03 mg/dL | Standard Deviation 21.2 |
| Pioglitazone | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | LDL | 5.38 mg/dL | Standard Deviation 30.37 |
| Pioglitazone | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Total cholesterol | 9.60 mg/dL | Standard Deviation 33.83 |
| Pioglitazone | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Non-HDL cholesterol | 5.79 mg/dL | Standard Deviation 32.72 |
| Pioglitazone | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | HDL | 3.69 mg/dL | Standard Deviation 10.33 |
| Pioglitazone | the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Triglyceride | -4.79 mg/dL | Standard Deviation 67.83 |
Other Pre-specified
the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Time frame: 16 weeks, visit 3,4,5
Population: This number is subject population who were exposure the drug(Vildagliptin group n=117, Pioglitazone group n=111). It is excluded the patients who are screening failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vildagliptin | the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Number of incidence | 27 participants |
| Vildagliptin | the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Number of adverse events | 48 participants |
| Pioglitazone | the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Number of adverse events | 37 participants |
| Pioglitazone | the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups | Number of incidence | 25 participants |