A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01421355
Recruitment Status : Completed
First Posted : August 22, 2011
Results First Posted : July 21, 2014
Last Update Posted : July 21, 2014
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Mark Alan Creager, MD, Brigham and Women's Hospital

Brief Summary:
Specific Aim: To establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes. Atazanavir, a drug that inhibits bilirubin conjugation, will be used to induce moderate hyperbilirubinemia. Endothelial function will be measured before and after atazanavir therapy. In addition, plasma markers of antioxidant capacity and oxidant stress will be measured as proof-of-concept that induced moderate hyperbilirubinemia has favorable effects on oxidative stress in type 1 diabetes.

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Drug: Atazanavir Phase 1

Detailed Description:

Diabetes mellitus (DM) is associated with a markedly increased risk of both macro- and microvascular disease. Excess pro-oxidants and insufficient antioxidants each contributes to oxidant stress in DM. Oxidant stress induces endothelial dysfunction, a major determinant of vascular damage. In DM, hyperglycemia and elevated free fatty acids (FFAs) induce generation of reactive oxygen species (ROS) by stimulating protein kinase C (PKC) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Figure 1). In addition, hyperglycemia activates the renin-angiotensin system, and angiotensin II (Ang II) additively stimulates PKC and NADPH oxidase.

Bilirubin, long regarded as metabolic waste, is, in fact, a potent antioxidant scavenger of ROS. It also directly inhibits both protein kinase C and the NADPH oxidase system, augmenting its antioxidant activity (Figure 1). Moreover, bilirubin inhibits Ang II-mediated vasoconstriction and ROS generation. Experimental models suggest that hyperbilirubinemia may preserve diabetes-associated endothelial function and prevent vasculopathy. Furthermore, epidemiological studies demonstrate that higher bilirubin levels are associated with a reduced risk of vascular disease in DM. Bilirubin therefore emerges as a potentially critical molecule to protect against diabetic vascular and renal damage. However, limited translational research has addressed raising bilirubin levels as a preventive therapy for vascular disease in DM.

Accordingly, the investigators seek to establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes. the investigators will take advantage of the recently described use of atazanavir to safely achieve moderate hyperbilirubinemia. Atazanavir is a protease inhibitor used to treat HIV infection that competitively inhibits hepatic 1A1 isoform of uridine diphosphoglucose glucuronosyltransferase (UGT1A1), limiting bilirubin clearance and inducing hyperbilirubinemia (Figure 2). This mimics Gilbert's syndrome, a benign unconjugated hyperbilirubinemia due to partial genetic deficiency of UGT1A1.

This work has the potential to identify iatrogenic moderate hyperbilirubinemia as a strategy to interrupt key mechanisms of type 1 diabetes-associated macro- and microvascular disease.

This is a physiologic study. The design is a single arm and open label. There are three study visits: a screening visit, a baseline visit, and a final visit. The treatment is atazanavir 300 mg PO bid. The treatment period is 4 days. The primary study outcome is forearm vascular function. The principal secondary outcomes are serum antioxidant defense capacity and measures of oxidant stress.

The investigators aim to study 20 subjects to completion over the 12 month funding period. The investigators anticipate enrolling 40 subjects before 20 complete the study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Official Title: A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus
Study Start Date : May 2012
Actual Primary Completion Date : February 2014
Actual Study Completion Date : February 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Atazanavir 300 mg BID
Atazanavir 300 mg BID for 4 days.
Drug: Atazanavir
The study design is a single arm, open label trial. Treatment is atazanavir 300 mg BID per day for 4 days. The Brigham and Women's Hospital Investigational Drug Service (IDS) will dispense study drug.

Primary Outcome Measures :
  1. Change in Brachial Artery Diameter [ Time Frame: Day 0 and Day 4 ]
    The primary endpoint is the difference in the change in brachial artery diameter in response to a flow stimulus at visit 2 and 3. It is anticipated that a response will occur following atazanavir therapy compared with baseline. The principal secondary endpoints are the serum measures of oxidant stress and antioxidant capacity.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dl (11.1 mmol/l), or;
  2. FPG ≥ 126 mg/dl (7.0 mmol/l), or;
  3. 2-h postload glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. In addition, subjects would be required to be at increased risk of cardiovascular events, defined as:

    • microalbuminuria, or;
    • T1DM duration of > 20 years.

Exclusion Criteria:

  1. HIV infection
  2. Gilbert's syndrome
  3. Hepatic failure or active hepatitis,
  4. Unstable cardiovascular disease, including angina, heart failure or arrhythmia
  5. drug abuse including alcoholism or addiction to cocaine, heroin or amphetamines
  6. Use of medications that significantly with atazanavir
  7. Pregnancy, or inability to practice adequate contraception

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01421355

United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
National Institutes of Health (NIH)
Principal Investigator: Joshua Beckman, MD Brigham and Women's Hospital

Responsible Party: Mark Alan Creager, MD, Mark A. Creager, MD, Brigham and Women's Hospital Identifier: NCT01421355     History of Changes
Other Study ID Numbers: 1R03DK094510-01 ( U.S. NIH Grant/Contract )
First Posted: August 22, 2011    Key Record Dates
Results First Posted: July 21, 2014
Last Update Posted: July 21, 2014
Last Verified: June 2014

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Atazanavir Sulfate
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents