Diabetes Mellitus, Type 2 Clinical Trial
Official title:
Atypical Antipsychotics and Hyperglycemic Emergencies: Multicentre, Retrospective Cohort Study of Administrative Data
The purpose of this study is to determine whether the use of atypical antipsychotic
medication increases the risk of hospitalization for a hyperglycemic emergency.
The investigators will carry out separate population-based cohort studies using
administrative health databases in eight jurisdictions in Canada and the UK. Cohort entry
will be defined by the initiation of a new antipsychotic medication. Follow-up will continue
until hospitalization for a hyperglycemic emergency or the end of 365 days. The results from
the separate sites will be combined to provide an overall assessment of the risk of
hyperglycemic emergencies among new users of various antipsychotic drugs.
The objective of this study is to determine whether the use of atypical antipsychotics is
associated with an increased risk of hospitalization for hyperglycemic emergencies
(hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state).
A common-protocol approach will be used to conduct retrospective cohort studies using
administrative health care data from eight jurisdictions (the Canadian provinces of British
Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec, and Nova Scotia, as well as the
United Kingdom (UK) General Practice Research Database [GPRD]). Briefly, the Canadian
databases include population-level data on physician billing, diagnoses and procedures from
hospital discharge abstracts, and dispensations for prescription drugs. The data in Nova
Scotia, Ontario, and Alberta will be restricted to patients aged 65 years and older, as
prescription data are not available for younger patients. The GPRD 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.
In each jurisdiction, the investigators will assemble a study cohort that includes all
patients newly prescribed an antipsychotic medication (WHO Anatomical Therapeutic Chemical
(ATC) code N05A) from April 1, 1998 (or the earliest date of data availability at each site)
to March 31, 2010 (or the last date of data availability at each site if earlier). The date
of study cohort entry will be defined by the date of the prescription (for GPRD) or
dispensation (for all other sites) of the newly-prescribed antipsychotic. Patients in the
study cohort will be followed from the date of study cohort entry until an event (defined
below), censoring due to death or departure from the database, 365 days after cohort entry,
or the end of the study period (March 31, 2011), whichever occurs first.
The exposure categories will be separated by the type of antipsychotic medication prescribed
upon cohort entry as: 1) olanzapine users; 2) other atypical antipsychotic users; 3) typical
antipsychotic users; and 4) risperidone users. Exposure to olanzapine will be defined as a
prescription for olanzapine on the date of cohort entry. Exposure to other atypical
antipsychotics will be defined as a prescription for an atypical antipsychotic other than
olanzapine on the date of cohort entry. Exposure to typical antipsychotics will be defined
as a prescription for a typical antipsychotic on the date of cohort entry. Exposure to
risperidone will be defined as a prescription for risperidone on the date of cohort entry.
The investigators will use an analysis analogous to an intention-to-treat approach. The
primary outcome will be defined as a first hospitalization for a hyperglycemic emergency
within 365 days of the initiation of the cohort defining antipsychotic medication.
The reference group throughout all analyses will be risperidone users. The primary
comparator will be olanzapine users; other atypical antipsychotic users and typical
antipsychotic users will both serve as secondary comparators.
Inverse probability treatment weighting (IPTW) using propensity scores to estimate marginal
treatment effects will be used. These propensity scores will be estimated using logistic
regression models where treatment with the comparator antipsychotic will be regressed on a
number of pre-identified covariates that influence the risk of a hyperglycemic emergency.
The absolute difference in the probability of a hyperglycemic emergency will be estimated.
The cause-specific hazard for the comparator vs. risperidone will be estimated using
Cox-proportional hazards regression models, incorporating the IPT weights and using a robust
variance estimator. Meta-analyses of the site-specific results will then be performed using
fixed-effects models with inverse variance weighting, with the amount of between site
heterogeneity estimated using the I-squared statistic.
Secondary analyses will be performed by means of nested case-control analyses of the
cohorts. Cases will be defined as subjects having a hyperglycemic event and will be matched
to controls that did not experience a hyperglycemic event. The event date of the cases will
serve as the index date for both controls and their matched cases. Exposure will be defined
as the most recent antipsychotic medication prescribed prior to the index date. Conditional
logistic regression will be used to estimate the odds ratio of a hyperglycemic event for the
comparator vs. risperidone.
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Observational Model: Cohort, Time Perspective: Retrospective
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