Quadruple Oral Combination Therapy for Type 2 Diabetes Mellitus : Glycemic Control by Thiazolidinedione (TZD) or Sodium Glucose Co-transporter 2 (SGLT-2) Inhibitor as an add-on Therapy in Type 2 Diabetes Mellitus After Failure of an Oral Triple Antidiabetic Regimen

In the treatment of type 2 diabetes (T2D), the number of patients requiring combination therapy of oral antidiabetic agents (OADs) is more than 70%. Especially in Korea, the tendency to avoid insulin therapy is relatively higher than other countries, therefore, the need for combination therapy of OADs is quite high. However, according to the current guidelines, clinicians are recommended to prescribe three or fewer OADs as the combination therapy for T2D. Recently, various OADs have been developed, and it is expected that quadruple combination therapy of OADs would be quite effective to lower blood glucose levels. In the present study, the investigators designed the study to compare the efficacy and safety of quadruple combination therapy; thiazolidinedione (TZD) vs. SGLT-2 inhibitor as an add-on therapy to triple combination therapy (Metformin, Sulfonylurea, Dipeptidyl peptidase-4(DPP-4) inhibitors). Quadruple combination therapy group with the SGLT-2 inhibitor will be considered as active control group, because it have shown non-inferior glycemic efficacy to the conventional insulin conversion therapy in a previous clinical study. Patients who could not achieve the target blood glucose level (7% <HbA1c ≤ 10%) under the triple combination therapy (Metformin, Sulfonylurea, DPP-4 inhibitors) for more than 12 weeks will be enrolled in this prospective, open-label, randomized, parallel comparison, multicenter clinical trial. Subjects in each group (60 patients/group) will be treated with TZD-containing quadruple therapy or SGLT-2 inhibitor-containing quadruple therapy for 24 weeks. The investigators will evaluate the glycemic efficacy and safety of each group. Primary outcome is the 24 week-change of HbA1c from baseline levels.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: TZD group; Drug: SGLT-2 group

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. 19 ≤ age ≤ 80, male or female
• 2. Type 2 diabetes patients who have taken triple combination therapy of OADs as followed : Metformin (≥1000 mg/day), Sulfonylurea (Glimepiride ≥ 4 mg/day or Gliclazide ≥ 60 mg/day), DPP-4 inhibitor (Full dose) for over 12 weeks
• 3. At screening, 7% < HbA1c ≤ 10%
• 4. Patients who refused insulin therapy.
• 5. Subjects who understood the contents of the clinical trial and are cooperative in the trial progress, and are considered to be able to participate until the end of the trial.
• 6. Patients who have voluntarily agreed in writing to participate in the clinical trial after hearing the explanation of the trial.

Exclusion Criteria:

• 1. Type 1 diabetes, gestational diabetes, and other types of diabetes than type 2 diabetes mellitus.
• 2. Patients who have the history of allergy of hypersensitivity for the medication of the clinical trial.
• 3. Patients who have the history of taking TZDs or SGLT-2 inhibitors within a year prior to screening visit, or have the history of discontinuation of them due to severe side effects.
• 4. Patients who have the history of acute or chronic metabolic acidosis including diabetic ketoacidosis (with or without coma), or any kinds of ketosis within 12 weeks prior to screening visit.
• 5. Patients who have genetic metabolic diseases, such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• 6. Patients who have the history of taking steroids for more than 2 weeks, within 8 weeks prior to screening visit.
• 7. Patients who have the history of malignancy within 5 years prior to screening visit (In case of bladder cancer, subjects will be excluded regardless of the time of diagnosis)
• 8. Patients who have the history of coronary artery bypass surgery or percutaneous coronary intervention, or suffered from heart failure (NYHA class III, IV)
• 9. Patients who have the history of uncontrolled arrhythmia, unstable angina, myocardial infarction, stroke, transient ischemic attacks, and cerebral vascular disease within 24 weeks prior to the screening date.
• 10. Patients of chronic renal failure, chronic kidney disease stage 3~5 (estimated glomerular filtration rate calculated vial CKD-EPI <60 mL/min/1.73m2) or on dialysis therapy.
• 11. Elevated liver enzymes (AST, ALT, ALP ≥ 2.5*upper limit of normal (ULN) or Total bilirubin ≥ 2.5*ULN) or Child-Pugh class B or C (for the patients of liver cirrhosis)
• 12. Subjects who are pregnant or lactating
• 13. Perioperative patients, patients with severe infections or severe trauma
• 14. Patients with unexamined gross hematuria
• 15. Any other subjects who is determined to be ineligible for the clinical trials by researchers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TZD group; Pioglitazone added to Metformin, DPP-4 inhibitors, Sulfonylurea	Drug: TZD group; Pioglitazone 15mg (Acpio®, once daily, regardless of meal time, for 24 weeks) will be added for T2DM(type 2 diabetes mellitus) patients who had inadequate glycemic control (7%; Other Names: Acpio
Active Comparator: SGLT-2 inhibitor group; Empagliflozin added to Metformin, DPP-4 inhibitors, Sulfonylurea	Drug: SGLT-2 group; Empagliflozin 10mg (Jardiance®, once daily, regardless of meal time, for 24 weeks) will be added for T2DM patients who had inadequate glycemic control (7%; Other Names: Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of HbA1c		12 weeks
Change of HbA1c	Mean difference of HbA1c after 24 week-treatment	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
glucose	Percentage of patients who achieve target HbA1c (≤7% level)	12 weeks
glucose	Mean difference of fasting blood glucose after 24 week-treatment	24 weeks
Adverse events	Incidence of adverse events during treatment period	12 weeks
Adverse events	Incidence of adverse events during treatment period	24 weeks
Change of kidney function	Mean change of BUN and serum creatinine	12 weeks
Change of kidney function	Mean change of BUN and serum creatinine	24 weeks
Change of liver enzymes	Mean change of AST(Asparate aminotransferase)	12 weeks
Change of liver enzymes	Mean change of ALT(Alanine aminotransferase)	12 weeks
Change of liver enzymes	Mean change of Total bilirubin	12 weeks
Change of liver enzymes	Mean change of AST	24 weeks
Change of liver enzymes	Mean change of ALT	24 weeks
Change of liver enzymes	Mean change of Total bilirubin	24 weeks

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2019
• Primary Completion (Actual): May 13, 2020
• Study Completion (Actual): May 28, 2020

Study Registration Dates

• First Submitted: July 2, 2019
• First Submitted That Met QC Criteria: July 3, 2019
• First Posted (Actual): July 9, 2019

Study Record Updates

• Last Update Posted (Actual): May 4, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 4-2019-0393

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No