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Fracture Risk With Thiazolidinediones

This study has been completed.
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01055223
First received: January 21, 2010
Last updated: June 2, 2011
Last verified: June 2011
  Purpose

Treatment with thiazolidinediones (TZD) has recently been reported to possibly increase the risk of fractures in a randomized trial exploring the efficacy of rosiglitazone (RSG), metformin, or glyburide encompassing 4360 patients with type 2 diabetes.

It is hypothesized that spironolactone, a diuretic that is broadly used for the treatment of fluid retention and edema associated with TZD, has a potential protective effect against bone fractures. However, to our knowledge, this has not been tested in diabetic patients treated with TZD. Amiloride is another diuretic that shares with spironolactone the anti mineralocorticoid ion gated channels activity and will be analysed in this study with regard to possible protective effect against bone fracture in combination with TZD.

This study is a nested case-control study conducted among type 2 diabetes subjects exposed to TZD. The study aims to explore if the risk of fracture is reduced among type 2 diabetic subjects exposed to spironolactone and TZD. The study will compare the odds of any low impact fracture, and hand, foot, upper arm, wrist, and hip fracture incidence in subjects treated with TZD+spironolactone and TZD+amiloride compared to subjects treated with TZD only.

The study population will consist of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one International Classification of Disease (ICD)-9 code for type 2 diabetes and have at least 6 months or at least 12 months of exposure to TZD (rosiglitazone [RSG], pioglitazone [PIO] or troglitazone) during their follow-up time available in the database.


Condition Intervention
Fractures, Bone
Type II Diabetes
Drug: TZD only (RSG or PIO or troglitazone)
Drug: TZD + spironolactone
Drug: TZD + amiloride

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Retrospective
Official Title: The Association Between Exposure to Spironolactone or Amiloride and Fracture Risk Among Subjects Treated With Thiazolidinediones

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD [ Time Frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 and December 31, 2008 ] [ Designated as safety issue: No ]
    ICD-9 codes (805-807.4x, 808-810.xx, 812-829.xx) were captured from Uniform Billing-92 records and Health Care Finance Administration records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for any low impact fracture occurring after the study period begin date (earliest date of the first TZD prescription). For each subject defined as case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched to cases on age (+ 5 years), gender, and year of fracture diagnosis.

  • Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD [ Time Frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 ] [ Designated as safety issue: No ]
    ICD-9 codes (805-807.4x, 808-810.xx, 812-829.xx) were captured from Uniform Billing-92 records and Health Care Finance Administration records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for any low impact fracture occurring after the study period begin date (earliest date of the first TZD prescription). For each subject defined as case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched to cases on age (+ 5 years), gender, and year of fracture diagnosis.


Secondary Outcome Measures:
  • Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD [ Time Frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 ] [ Designated as safety issue: No ]
    ICD-9 codes (815.0x, 816.0x, 817.0x, 825.0x, 825.2x, 826.0x, 812.0x, 812.2x, 812.4x, 814.0x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hand, foot, upper arm, and wrist fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.

  • Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD [ Time Frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 ] [ Designated as safety issue: No ]
    ICD-9 codes (815.0x, 816.0x, 817.0x, 825.0x, 825.2x, 826.0x, 812.0x, 812.2x, 812.4x, 814.0x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hand, foot, upper arm, and wrist fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.

  • Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD [ Time Frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 ] [ Designated as safety issue: No ]
    ICD-9 codes (820.0x, 820.2x, 820.8x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hip fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.

  • Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD [ Time Frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 ] [ Designated as safety issue: No ]
    ICD-9 codes (820.0x, 820.2x, 820.8x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hip fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.


Enrollment: 98483
Study Start Date: May 2009
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Type 2 diabetes subjects
Type 2 diabetes subjects
Drug: TZD only (RSG or PIO or troglitazone)
Drug exposure will be inferred from prescription claims. Subjects who have been exposed to TZD for at least 6 months or at least 12 months will be considered for inclusion.
Drug: TZD + spironolactone

Subjects who have been exposed to TZD for at least 6 months or at least 12 months will be considered for inclusion.

In order to be eligible for inclusion in this category, the prescription days supply for TZD and spirinolactone must overlap by at least 30 days.

Drug: TZD + amiloride

Subjects who have been exposed to TZD for at least 6 months or at least 12 months will be considered for inclusion.

In order to be eligible for inclusion in this category, the prescription days supply for TZD and Amiloride must overlap by at least 30 days.


Detailed Description:

Patients were not recruited for nor enrolled in this study. This study is a retrospective observational study. Data from medical records or insurance claims databases are anonymised and used to develop a patient cohort. All diagnoses and treatment are recorded in the course of routine medical practice.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

The study population will consist of type 2 diabetes patients aged 18 -65 years old exposed to TZD for at least 6 months or at least 12 months. The study will use data from the US health claims database, the Ingenix Impact National Managed Care Database (Impact Database). The Impact Database system is a comprehensive, de-identified U.S. healthcare claims database that is representative of the non-elderly, insurance-carrying population. It includes 89.3 million lives from 1997 to 2008. Approximately 74 percent of all patients in the database have pharmacy benefits and, on average, 25 months of enrollment/claims information. The data are collected from over 46 different healthcare plans serving members across nine census regions.

Criteria

Inclusion Criteria:

  • At least one ICD-9 code for type 2 diabetes
  • At least 6 months or at least 12 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database (The subject's study period begin date will be defined as the earliest date of their first TZD prescription. Subjects included in the study are required to have at least six months of follow-up time in the database prior to their first TZD prescription)

Exclusion Criteria:

  • Subjects with a diagnosis of Paget's disease and osteomalacia
  • A history of fracture, osteoporosis or cancer prior to the first prescription of TZD (study begin date)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01055223

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT01055223     History of Changes
Other Study ID Numbers: 113332
Study First Received: January 21, 2010
Results First Received: December 16, 2010
Last Updated: June 2, 2011
Health Authority: United States: No Health Authority

Keywords provided by GlaxoSmithKline:
thiazolidinediones
rosiglitazone
amiloride
pioglitazone
fracture
Spironolactone

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Fractures, Bone
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Wounds and Injuries
2,4-thiazolidinedione
Amiloride
Spironolactone
Troglitazone
Acid Sensing Ion Channel Blockers
Cardiovascular Agents
Diuretics
Diuretics, Potassium Sparing
Epithelial Sodium Channel Blockers
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Membrane Transport Modulators
Mineralocorticoid Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sodium Channel Blockers
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014