Thiazolidinedione (TZD) on the Diabetic Retinopathy and Nephropathy

The Effects of Thiazolidinedione on the Diabetic Retinopathy and Nephropathy

Objectives:

Thiazolidinediones (TZDs) are insulin sensitizers that decrease plasma glucose in type 2 diabetic patients. Thiazolidinediones can cause fluid retention and peripheral edema in diabetic patients, and the systematic fluid retention can be manifested as diabetic macular edema (DME). The overall goal of this study is to examine the effects of thiazolidinediones on the diabetic retinopathy and nephropathy.

Study design:

This is a prospective, randomized, open-labeled, controlled design to assess the effects thiozolidinediones on the diabetic retinopathy and nephropathy. The investigators will recruit 300 type 2 diabetic patients without significant retinopathy, nephropathy and cardiovascular disease. Inclusion criteria are type 2 diabetes, age between 30-80 years old, with microabluminuria, no significant retinopathy, on submaximal dose of sulphonylureas and metformin treatment, and A1C between 7-9%. Exclusion criteria are on insulin treatment, significant retinopathy and significant nephropathy. Patients with cardiovascular diseases, malignancy, pregnancy, in acute intercurrent illness, congestive heart failure, myocardial infarction, received PCI or CABG. All subjects will receive EKG and CXR before randomization.

These subjects will be randomized equally to 3 groups: acarbose, rosiglitazone and pioglitazone. The investigators will follow up for 6 months to investigate the short-term effects and 5 years to evaluate the long-term outcomes. The primary study end point of short-term study will be the macular thickness changes measured by optical coherence tomography, the changes in the level of urinary albumin-to-creatinine ratio, circulating metabolic parameters and adipocytokines during thiozolidinediones treatment. Secondary end point will be fasting blood glucose, A1C levels, development of clinically significant macular edema, serum creatinine change in patients with no history of diabetic retinopathy and nephropathy at baseline.

The primary study end point of long-term study will be the development of clinically significant macular edema and the time from the base-line visit to the first detection of overt nephropathy. Secondary end points include the development of greater than moderate NPDR, the time to the first event of the time from the base-line visit to a doubling of the serum creatinine concentration, end-stage renal disease, or death.

Study Overview

• Status: Unknown
• Conditions: Diabetes
• Intervention / Treatment: Drug: Actos (Pioglitazone); Drug: Acarbose

Detailed Description

The effects of thiazolidinedione on the diabetic retinopathy and nephropathy:

Overall Goal and Specific Aims

The overall goal of this study is to examine the effects of thiazolidinediones on the diabetic retinopathy and nephropathy.

The specific aims are:

1. To investigate the short-term effects of thiazolidinediones on the macular thickness measured by optical coherence tomography and the long-term effects of thiazolidinediones on the clinically significant macular edema and diabetic retinopathy documented by color photography and fluoroscein angiography.
2. Short-term effects of thiazolidinediones on the change of urine albumin excretion and serum cardiovascular risk profiles and long-term effects of thiazolidinediones on the estimated GFR change and progression to overt diabetic nephropathy.

Objectives

Thiazolidinediones (TZDs) are insulin sensitizers that decrease plasma glucose in type 2 diabetic patients. Thiazolidinediones can cause fluid retention and peripheral edema in diabetic patients, and the systematic fluid retention can be manifested as diabetic macular edema (DME). The overall goal of this study is to examine the effects of thiazolidinediones on the diabetic retinopathy and nephropathy.

Study design

This is a prospective, randomized, open-labeled, controlled design to assess the effects thiozolidinediones on the diabetic retinopathy and nephropathy. The investigators will recruit 300 type 2 diabetic patients without significant retinopathy, nephropathy and cardiovascular disease. Inclusion criteria are type 2 diabetes, age between 30-80 years old, with microabluminuria, no significant retinopathy, on submaximal dose of sulphonylureas and metformin treatment, and A1C between 7-9%. Exclusion criteria are on insulin treatment, significant retinopathy and significant nephropathy. Patients with cardiovascular diseases, malignancy, pregnancy, in acute intercurrent illness, congestive heart failure, myocardial infarction, received PCI or CABG. All subjects will receive EKG and CXR before randomization.

These subjects will be randomized equally to 3 groups: acarbose, rosiglitazone and pioglitazone. The investigators will follow up for 6 months to investigate the short-term effects and 5 years to evaluate the long-term outcomes. The primary study end point of short-term study will be the macular thickness changes measured by optical coherence tomography, the changes in the level of urinary albumin-to-creatinine ratio, circulating metabolic parameters and adipocytokines during thiozolidinediones treatment. Secondary end point will be fasting blood glucose, A1C levels, development of clinically significant macular edema, serum creatinine change in patients with no history of diabetic retinopathy and nephropathy at baseline.

The primary study end point of long-term study will be the development of clinically significant macular edema and the time from the base-line visit to the first detection of overt nephropathy. Secondary end points include the development of greater than moderate NPDR, the time to the first event of the time from the base-line visit to a doubling of the serum creatinine concentration, end-stage renal disease, or death.

The investigators also monitor the long-term safety issue, such as congestive heart failure, myocardial infarction, any cardiovascular event, and fracture.

Expected Results

TZDs can decrease plasma glucose in type 2 diabetic patients, but the major side effects are able to cause fluid retention. This prospective study will be able to test whether thiozolidinediones causes macular edema and to evaluate whether thiozolidinediones delays onset of diabetic retinopathy. The investigators also will be able to find the changes in the level of urinary albumin-to-creatinine ratio, circulating metabolic parameters and adipocytokines between the treatment of TZDs and Acrbose. The investigators can compare the time from the base-line visit to the first detection of overt nephropathy, the time to the first event of the composite end point of the time from the base-line visit to a doubling of the serum creatinine concentration, end-stage renal disease, or death.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • Taipei Veterans General Hospital, Taiwan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 26 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes
• Age between 30-80 years old
• No significant nephropathy
• No significant retinopathy
• On submaximal dose of sulphonylureas and metformin treatment
• A1C between 7-9%

Exclusion Criteria:

• On insulin treatment
• Significant retinopathy (greater than moderate non-proliferative retinopathy)
• Significant nephropathy (overt proteinuria or serum Cr >1.50 mg/dL)
• Malignancy
• Pregnancy
• Acute intercurrent illness
• Congestive heart failure (CHF, according to New York heart Association, NYHA functional class III to IV)
• Myocardial infarction, received PCI or CABG or liver cirrhosis

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: Actos; Actos 30 mg for 6 months	Drug: Actos (Pioglitazone); Actos 30 mg for 6 months; Other Names: Pioglitazone
Active Comparator: Acarbose; Acarbose 50mg tid for 6 months	Drug: Acarbose; Acarbose 50 mg tid for 6 months; Other Names: Glucobay

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diabetic retinopathy	The macular thickness changes	6 months
Diabetic nephropathy	The changes in the level of urinary albumin-to-creatinine ratio	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diabetic retinopathy	Development of greater than moderate NPDR, clinically significant macular edema	3 years
Diabetic nephropathy	The change of urine albumin excretion, estimated GFR change, progression to overt diabetic nephropathy.	3 years

Collaborators and Investigators

• Sponsor: Taipei Veterans General Hospital, Taiwan

Publications and helpful links

General Publications

• Chen YH, Tarng DC, Chen HS. Renal Outcomes of Pioglitazone Compared with Acarbose in Diabetic Patients: A Randomized Controlled Study. PLoS One. 2016 Nov 3;11(11):e0165750. doi: 10.1371/journal.pone.0165750. eCollection 2016.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Anticipated): December 1, 2012
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: July 23, 2010
• First Submitted That Met QC Criteria: August 3, 2010
• First Posted (Estimate): August 4, 2010

Study Record Updates

• Last Update Posted (Estimate): January 5, 2011
• Last Update Submitted That Met QC Criteria: January 4, 2011
• Last Verified: June 1, 2010

More Information

Terms related to this study

• Keywords: diabetes; nephropathy; retinopathy; thiazolidinediones
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Urologic Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Kidney Diseases; Retinal Diseases; Diabetic Retinopathy; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Pioglitazone; Acarbose
• Other Study ID Numbers: 201004014IA