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

• ClinicalTrials.gov Identifier: NCT02188186
• Recruitment Status: Completed
• First Posted: July 11, 2014
• Last Update Posted: March 18, 2019
• Sponsor: Seoul National University Bundang Hospital
• Information provided by (Responsible Party): Soo Lim, Seoul National University Bundang Hospital

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes	Drug: Initial triple combination; Drug: Conventional treatment	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Therapeutic Efficacy of Triple Combination of Metformin, DPP4 Inhibitor and Thiazolidinedione in Drug-naïve Korean Type 2 Diabetic Patients
• Actual Study Start Date: July 2014
• Actual Primary Completion Date: September 2018
• Actual Study Completion Date: September 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Conventional treatment; 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; Conventioanl treament with dose escalation; Other Name: metformin+sulfonylurea with dose escalation
Experimental: Initial triple combination treatment; 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; Initial triple combination arm; Other Name: metformin+sitagliptin (Januvia)+lobeglitazone (Duvie)

Outcome Measures

Primary Outcome Measures :

1. Change of HbA1c [ Time Frame: 12 months ]
   Therapeutic efficacy of triple combination of metform, sitagliptin, and lobeglitazone compared with sulfonylurea and metformin in drug-naïve Korean type 2 diabetic patients

Secondary Outcome Measures :

1. beta-cell function [ Time Frame: 12 months ]
   Changes of beta-cell function after one year treatment
2. Insulin resistance [ Time Frame: 12 months ]
   Changes of Insulin resistance after one year treatment
3. Glucose homeostasis [ Time Frame: 12 months ]
   Changes in fasting glucose concentration
4. Glucose metabolism [ Time Frame: 12 months ]
   Area under the curve of glucose during OGTT
5. Glucose metabolism [ Time Frame: 12 months ]
   Area under the curve of insulin during OGTT
6. Microalbuminuria [ Time Frame: 12 months ]
   urine microalbumin to creatinine ratio
7. Lipid profile [ Time Frame: 12 months ]
   Changes in TG/HDL/LDL-concentrations

Other Outcome Measures:

1. Hypoglycemia [ Time Frame: 12 months ]
   Incidence of hypoglycemia during study period
2. Body weight [ Time Frame: 12 months ]
   Changes of body weight after one year treatment
3. Body composition [ Time Frame: 12 months ]
   Changes of body composition after one year treatment

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

Korea, Republic of

Seoul National University Bundang Hospital

Seongnam, Gyeonggi, Korea, Republic of, 463-707

Sponsors and Collaborators

Seoul National University Bundang Hospital

More Information

• Responsible Party: Soo Lim, Professor, Seoul National University Bundang Hospital
• ClinicalTrials.gov Identifier: NCT02188186
• Other Study ID Numbers: Triple
• First Posted: July 11, 2014
• Last Update Posted: March 18, 2019
• Last Verified: March 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Soo Lim, Seoul National University Bundang Hospital:

triple combination; metformin; sitagliptin; thiazolidinedione

Additional relevant MeSH terms:

Metformin; Sitagliptin Phosphate; Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action