Therapeutic Efficacy of Triple Combination in Drug-naïve Korean Type 2 Diabetic Patients

Study Overview
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Brief Summary
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Triple combination of metformin, DPP4 inhibitor and Thiazolidinedione would be a good option in the treatment of drug-naïve Korean type 2 diabetic patients.

Detailed Description
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Thiazolidionedione, a PPARgamman agonist, is an strong insulin sensitizer. It has shown that durable glucose lowering effect and beta cell preservation. It is an important treatment option in patients with type 2 diabetes. It has been well established that inhibition of dipeptidyl peptidase-4 (DPP-4) reduces blood glucose levels in both fasting and postprandial states, and preserves pancreatic β-cell function in patients with type 2 diabetes. The mechanism of action of DPP-4 inhibitors is to increase levels of active incretin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion as well as insulin biosynthesis while inhibiting glucagon release from pancreatic islets. DPP4 inhibitors also have better safety and tolerability profiles (e.g., weight neutrality and less hypoglycemia) compared to other hypoglycemic agents. When considering combination therapy with DPP-4 inhibitors, metformin is the most commonly used agent which has been shown to be effective and well tolerated from previous studies. Besides the glucose lowering effect by reducing hepatic glucose output and improving insulin resistance, metformin without inhibiting DPP-4 activity,also increases active GLP-1 concentrations by 1.5- to 2-fold following an oral glucose load in obese, nondiabetic subjects. Accordingly, this effect of metformin may provide a unique benefit when combined with DPP-4 inhibitors through a substantial enhancement of the incretin axis, which provides effective and potentially additive glycemic improvement. Because of its favorable pharmacological properties, combination of a DPP-4 inhibitor, metformin, and thiazolidinedione has been increasingly used to achieve rapid glycemic goal with low risk of hypoglycemia and no weight gain, and to delay the need for subsequent regimen changes. DPP-4 inhibitors block DPP-4 enzyme and preserve endogenous incretins whereas metformin increases the active form of GLP-1, both of which may enhance the secretory function of pancreas. However, the response to DPP-4 inhibitors and metformin combination therapy may be different in individuals according to their pancreatic function and insulin resistance status. In fact, previous studies with DPP-4 inhibitors showed different potency in glycemic controls depending on various patient characteristics including severity of diabetes and the use of other antidiabetic drug.Consequently, it would be clinically important to investigate effect of this triple combination therapy.

Official Title
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Therapeutic Efficacy of Triple Combination of Metformin, DPP4 Inhibitor and Thiazolidinedione in Drug-naïve Korean Type 2 Diabetic Patients

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Initial triple combination
* Drug: Conventional treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HbA1c 9-12% No treatment with insulin or oral agents for recent 6 months 20 ≤ Age < 80 years Exclusion Criteria: Contraindication to sitagliptin or metformin or thiazolidinedione Pregnant or breast feeding women Type 1 diabetes, gestational diabetes, or secondary forms of diabetes Not appropriate for oral antidiabetic agent Medication which affect glycemic control Disease which affect efficacy and safety of drugs Any major illness (Liver disease, Renal failure, Heart disease, Cancer, etc)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional treatment<br>Initial dual combination therapy with sulfonylurea and metfomin. Dose of sulfonylurea (glimepride 2-8 mg) and metfomin (500-2550 mg) can be ecalated at investigator's discreition at every visit. Insulin therpy can be added as a rescue therapy at investigator's discreition. | Drug: Conventional treatment<br>* Conventioanl treament with dose escalation<br>* Other names: metformin+sulfonylurea with dose escalation;|
| Experimental: Initial triple combination treatment<br>Initial dual combination therapy with metformin, sitagliptin (Januvia 100 mg), and lobeglitazone (Duvie 0.5 mg). Insulin therpy can be added as a rescue therapy at investigator's discreition. | Drug: Initial triple combination<br>* Initial triple combination arm<br>* Other names: metformin+sitagliptin (Januvia)+lobeglitazone (Duvie);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of HbA1c | Therapeutic efficacy of triple combination of metform, sitagliptin, and lobeglitazone compared with sulfonylurea and metformin in drug-naïve Korean type 2 diabetic patients | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| beta-cell function | Changes of beta-cell function after one year treatment | 12 months | 
| Insulin resistance | Changes of Insulin resistance after one year treatment | 12 months | 
| Glucose homeostasis | Changes in fasting glucose concentration | 12 months | 
| Glucose metabolism | Area under the curve of glucose during OGTT | 12 months | 
| Glucose metabolism | Area under the curve of insulin during OGTT | 12 months | 
| Microalbuminuria | urine microalbumin to creatinine ratio | 12 months | 
| Lipid profile | Changes in TG/HDL/LDL-concentrations | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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triple combination, metformin, sitagliptin, thiazolidinedione