Incretin-based Drugs and the Risk of Heart Failure
Information source: Canadian Network for Observational Drug Effect Studies, CNODES
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Type 2 Diabetes Mellitus
Intervention: DPP-4 inhibitors (Drug); GLP-1 analogs (Drug); Insulins (Drug); Biguanides (Drug); Sulfonylureas (Drug); Thiazolidinediones (Drug); Alpha-glucosidase inhibitors (Drug); Meglitinides (Drug)
Phase: N/A
Status: Completed
Sponsored by: Canadian Network for Observational Drug Effect Studies, CNODES Official(s) and/or principal investigator(s): Pierre Ernst, MD, MSc, Principal Investigator, Affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital - McGill University
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.
Clinical Details
Official title: Incretin-based Drugs and the Risk of Heart Failure: A Multi-center Network Observational Study
Study design: Observational Model: Cohort, Time Perspective: Retrospective
Primary outcome: Hospitalization for incident heart failure
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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.
Locations and Contacts
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec H3T1E2, Canada
Additional Information
Starting date: March 2014
Last updated: June 16, 2015
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