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Incretin-based Drugs and the Risk of Heart Failure

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ClinicalTrials.gov Identifier: NCT02456428
Recruitment Status : Completed
First Posted : May 28, 2015
Last Update Posted : April 19, 2016
Sponsor:
Collaborators:
Drug Safety and Effectiveness Network, Canada
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Canadian Network for Observational Drug Effect Studies, CNODES

Tracking Information
First Submitted Date May 21, 2015
First Posted Date May 28, 2015
Last Update Posted Date April 19, 2016
Study Start Date March 2014
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 26, 2015)
Hospitalization for incident heart failure [ Time Frame: Patients were followed from the date of study cohort entry until hospitalization for incident heart failure, censoring, or for up to 87 months. ]
Patients hospitalized for incident heart failure (HF) recorded in either the discharge abstract or hospitalization record with the following ICD codes: ICD-9 code: 428.x ICD-10 code: I50.x For patients who had no history of prior HF, cases were identified by the presence of a HF diagnosis in any position (most responsible, primary, or secondary), while for patients with a history of established HF, the event definition was restricted to those with a HF diagnosis as the primary or most responsible reason for hospitalization.
Original Primary Outcome Measures Same as current
Change History Complete list of historical versions of study NCT02456428 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Incretin-based Drugs and the Risk of Heart Failure
Official Title Incretin-based Drugs and the Risk of Heart Failure: A Multi-center Network Observational Study
Brief Summary

The purpose of this study is to determine whether incretin-based drugs (used to treat type 2 diabetes) taken either alone or in combination with other anti-diabetic drugs are associated with an increased risk of heart failure (HF) compared to other combinations of oral hypoglycemic agents (OHA).

The investigators will carry out separate population based cohort studies using administrative health databases in six jurisdictions in Canada, the US and the UK. Cohorts will be defined by the initiation of a new anti-diabetic drug when incretin-based drugs entered the market, with follow-up until hospitalization for HF. Analyses will be done separately for groups of patients with and without prior HF. The results from the separate sites will be combined to provide an overall assessment of the risk of HF in users of incretin-based drugs and by class of incretin-based drugs.

Detailed Description

The study objective is to determine whether the use of incretin-based drugs, compared with the use of oral anti-diabetic drug combinations, is associated with an increased risk of heart failure (HF) in routine clinical practice. The investigators will use a common-protocol approach to conduct retrospective cohort studies using administrative health care data from six jurisdictions (the Canadian provinces of Alberta, Manitoba, Ontario, and Saskatchewan, as well as the United States (US) MarketScan and the United Kingdom (UK) Clinical Practice Research Datalink [CPRD]). Briefly, the Canadian databases include population-level data on physician billing, diagnoses and procedures from hospital discharge abstracts, and dispensations for prescription drugs. Ontario data will be restricted to patients aged 65 years and older as prescription data are not available for younger patients. The CPRD is a clinical database that is representative of the UK population and contains the records for patients seen at over 680 general practitioner practices in the UK; these data will be linked to the Hospital Episode Statistics (HES) database, which contains in-hospital diagnosis and procedure data. US MarketScan includes individuals and their dependents covered by large U.S. employer health insurance plans, and government and public organizations.

Study population

In each jurisdiction, the investigators will assemble a base cohort that includes all patients with a first-ever prescription for a non-insulin anti-diabetic drug, including biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogs, alpha-glucosidase inhibitors, meglitinides, or combinations of these drugs from the earliest availability of data at each site to the last date of availability of data. The date of prescription (for the CPRD) or dispensation (for all other sites) of the first-ever non-insulin anti-diabetic drug will define the date of base cohort entry.

From this base cohort, a study cohort will be created including all patients who initiated a new anti-diabetic drug class during the year in which incretin-based drugs entered the market in each jurisdiction or any time thereafter. These new users consist of both those who are newly-treated for diabetes, as well as those who switch to or add on a new anti-diabetic drug class not included as part of their previous treatment history. The date of study cohort entry is defined by the prescription date of the newly-prescribed drug class.

For the purpose of this study, two separate cohorts will be created based on the presence or absence of a history of HF at any time prior to and including the date of study cohort entry. Patients in each cohort will be followed from the date of study cohort entry until an event (defined below) or censoring due to death, departure from the database, loss of continuous health plan or drug plan enrolment, entry into a long-term care facility, an incident diagnosis of HIV or new prescription of HAART, or the end of the study period (June 30, 2014 or the last date of data availability at that site), whichever occurs first.

Case-control selection

The cohorts defined above will be analyzed using a nested case-control analysis, where cases are defined as a hospitalization for HF. Risk set sampling will be used to randomly select up to 20 controls for each case, matched on sex, age (± 365 days), date of study cohort entry (± 180 days), duration of treated diabetes (± 90 days), and duration of follow-up in days.

Exposure assessment

Current exposure to an anti-diabetic drug will be defined as any prescription whose duration plus a 30-day grace period overlaps with the index or event date. Current exposure will be classified hierarchically based on the following five mutually-exclusive categories: 1) incretin-based drugs; 2) insulin; 3) ≥2 oral anti-diabetic drugs used in combination therapy; 4) oral anti-diabetic drug monotherapy; and 5) no current exposure to an anti-diabetic drug. Oral anti-diabetic drugs used in combination will serve as the primary reference category as incretin-based drugs are second- to third-line therapy and thus used at a comparable point in the disease management.

Statistical analyses

All analyses will be conducted separately among patients with and without a history of HF. Conditional logistic regression will be used to estimate the odds ratios and corresponding 95% confidence intervals (CIs) of the association of hospitalization for HF, comparing current use of incretin-based drugs to oral anti-diabetic drug combinations. This is considered the primary analysis. Secondary analyses will include sub-classifying current users of incretin-based drugs by type (i.e., DPP-4 inhibitor vs GLP-1 analog) and duration of current use (≤ 365 days, 366-729 days, and ≥730 days). The potential presence of effect modification by a history of myocardial infarction (MI) will also be explored. In addition, seven sensitivity analyses will be conducted, all defined a priori, to assess the robustness of the results. Finally, all site-specific estimates will be meta-analyzed using random-effects models with inverse variance weighting, with fixed-effects analyses conducted in the sensitivity analyses. The amount of between-site heterogeneity will be estimated using the I square statistic.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Retrospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Probability Sample
Study Population In each jurisdiction, a base cohort will be assembled including all patients with a first-ever prescription for a non-insulin anti-diabetic drug. Base cohort entry is defined as the date of prescription or dispensation of a first-ever non-insulin anti-diabetic drug. From this base cohort, a study cohort will be formed consisting of all patients who initiated a new anti-diabetic drug class during the year in which incretin-based drugs entered the market in each jurisdiction or any time thereafter. Study cohort entry is defined by the prescription date of the newly-prescribed drug class. Two separate cohorts will be created based on the presence or absence of a history of HF prior to and including study cohort entry.
Condition Type 2 Diabetes Mellitus
Intervention
  • Drug: DPP-4 inhibitors
    Current exposure to DPP-4 inhibitors (ATC A10BH, A10BD07-A10BD13) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.
    Other Names:
    • incretin-based drugs
    • sitagliptin
    • vildagliptin
    • saxagliptin
  • Drug: GLP-1 analogs
    Current exposure to GLP-1 analogs (ATC A10BX04, A10BX07) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.
    Other Names:
    • incretin-based drugs
    • exenatide
    • liraglutide
  • Drug: Insulins
    Current exposure to insulin (ATC A10A) will be defined as any use of insulin between base cohort entry and the index day.
    Other Names:
    • insulins and analogues for injection, fast-acting
    • insulins and analogues for injection, intermediate-acting
    • insulins and analogues for injection, long-acting
    • insulins and analogues for inhalation
  • Drug: Biguanides
    Current exposure to biguanides (ATC A10BA) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.
    Other Names:
    • oral hypoglycemic agent
    • phenformin
    • metformin
    • buformin
  • Drug: Sulfonylureas
    Current exposure to sulfonylureas (ATC A10BB or A10BC) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.
    Other Names:
    • oral hypoglycemic agent
    • glibenclamide
    • chlorpropamide
    • tolbutamide
    • glibornuride
    • tolazamide
    • carbutamide
    • glipizide
    • gliquidone
    • gliclazide
    • metahexamide
    • glisoxepide
    • glimepiride
    • acetohexamide
    • glymidine
  • Drug: Thiazolidinediones
    Current exposure to thiazolidinediones (ATC A10BG) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.
    Other Names:
    • oral hypoglycemic agent
    • troglitazone
    • rosiglitazone
    • pioglitazone
  • Drug: Alpha-glucosidase inhibitors
    Current exposure to alpha-glucosidase inhibitors (ATC A10BF) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index day.
    Other Names:
    • oral hypoglycemic agent
    • acarbose
    • miglitol
    • voglibose
  • Drug: Meglitinides
    Current exposure to meglitinides (ATC A10BX02, A10BX03) will be defined as a prescription duration plus a 30-day grace period (to account for non-adherence and the biological half-lives of these drugs) that overlaps with the index (event)day.
    Other Names:
    • oral hypoglycemic agent
    • repaglinide
    • nateglinide
Study Groups/Cohorts
  • Treated with incretins
    Current use of incretin-based drugs ((DPP-4 inhibitors [sitagliptin, vildagliptin, and saxagliptin] or GLP-1 analogs [exenatide, liraglutide]) alone or in combination with other anti-diabetic drugs (if the prescription overlaps with the index or event day with a 30-day grace period).
    Interventions:
    • Drug: DPP-4 inhibitors
    • Drug: GLP-1 analogs
  • Treated with insulin
    Current use of insulins between base cohort entry and the index or event day (alone or in combination with other anti-diabetic drugs) and no current use of incretin-based drugs.
    Intervention: Drug: Insulins
  • Treated with ≥2 oral hypoglycemic agents
    Current use of 2 or more non-insulin anti-diabetic medications (biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides) (if the prescriptions overlap with the index or event day with a 30-day grace period), and no current use of incretin-based drugs or insulins.
    Interventions:
    • Drug: Biguanides
    • Drug: Sulfonylureas
    • Drug: Thiazolidinediones
    • Drug: Alpha-glucosidase inhibitors
    • Drug: Meglitinides
  • Treated with single oral agent
    Current use of any single non-insulin anti-diabetic medications (biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides) (if the prescription overlaps with the index or event day with a 30-day grace period) and no current use of more than 2 OHAs, incretin-based drugs, or insulins.
    Interventions:
    • Drug: Biguanides
    • Drug: Sulfonylureas
    • Drug: Thiazolidinediones
    • Drug: Alpha-glucosidase inhibitors
    • Drug: Meglitinides
  • Not currently exposed group
    All patients not currently exposed to: incretin-based drugs, insulins, ≥2 OHAs, or a single OHA.
Publications * Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, Hu N, Paterson JM, Targownik L, Turin TC, Udell JA, Ernst P; CNODES Investigators. A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. N Engl J Med. 2016 Mar 24;374(12):1145-54. doi: 10.1056/NEJMoa1506115.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: May 26, 2015)
1499650
Original Actual Enrollment Same as current
Actual Study Completion Date May 2015
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Patients with a first-ever prescription for a non-insulin anti-diabetic drug, including biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogs, alpha-glucosidase inhibitors, meglitinides, or combinations of these drugs from the earliest availability of data at each site to the last date of availability of data.
  • Patients with at least 1 year of history in the database.
  • Patients at least 18 years of age.

Exclusion Criteria:

  • Patients who died or left the cohort before the year the first incretin-based drug entered the market.
  • Patients who never added-on or switched to a new anti-diabetic drug after incretin-based drugs entered the market up until June 30, 2014.
  • Patients diagnosed with HIV or initiating HAART therapy before and at study cohort entry.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Canada
Removed Location Countries  
 
Administrative Information
NCT Number NCT02456428
Other Study ID Numbers Q13-06C
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Canadian Network for Observational Drug Effect Studies, CNODES
Study Sponsor Canadian Network for Observational Drug Effect Studies, CNODES
Collaborators
  • Drug Safety and Effectiveness Network, Canada
  • Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Pierre Ernst, MD, MSc Lady Davis Institute for Medical Research, Jewish General Hospital - McGill University
PRS Account Canadian Network for Observational Drug Effect Studies, CNODES
Verification Date April 2016