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Clozapine Use in Patients With Schizophrenia and the Risk of Diabetes, Hyperlipidemia, and Hypertension
A Claims-Based Approach
Brian C. Lund, PharmD;
Paul J. Perry, PhD;
John M. Brooks, PhD;
Stephan Arndt, PhD
Arch Gen Psychiatry. 2001;58:1172-1176.
ABSTRACT
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Background Numerous case reports have linked clozapine to the development of diabetes
mellitus and hyperlipidemia in patients with schizophrenia. However, investigators
have been unable to clearly demonstrate this association when compared with
a control group receiving conventional antipsychotics.
Methods Medical and pharmacy claims from the Iowa Medicaid program were used
to compare incidence rates for diabetes, hyperlipidemia, and hypertension
in 552 patients receiving clozapine and 2461 patients receiving conventional
antipsychotics (eg, haloperidol, chlorpromazine hydrochloride), with the use
of a retrospective cohort design. Logistic regression was used to compare
incidence rates adjusting for age, sex, and duration of available follow-up.
Results No significant differences in overall incidence rates for diabetes,
hyperlipidemia, or hypertension were observed in patients receiving clozapine
vs conventional antipsychotics. However, among younger patients (aged 20-34
years), clozapine administration was associated with a significantly increased
relative risk of diabetes (2.5 [95% confidence interval, 1.2-5.4]) and hyperlipidemia
(2.4 [95% confidence interval, 1.1-5.2]), but not hypertension (0.9 [95% confidence
interval, 0.4-2.0]).
Conclusions These data suggest that clozapine may not be an independent cause of
diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible
populations by increasing weight or affecting insulin secretion and resistance.
This finding requires confirmation in other settings and patient populations
and with the other atypical antipsychotics (risperidone, olanzapine, and quetiapine
fumarate). The potential long-term medical and economic implications of the
early induction of diabetes and hyperlipidemia in patients with schizophrenia
warrant further study.
INTRODUCTION
SINCE 1994, several case reports and uncontrolled studies have linked
the atypical antipsychotic clozapine with the development of diabetes mellitus.1, 2, 3, 4, 5
Similar reports have been published with the atypical agents olanzapine6, 7 and quetiapine fumarate.8
One hypothesis proposes that diabetes may occur secondary to weight gain associated
with the atypical antipsychotics.9 Some investigators
propose more direct physiological mechanisms, including effects on glucose
regulation and insulin secretion and resistance.3, 10
Further complicating this relationship is the observation that patients with
schizophrenia have a higher rate of diabetes than does the general population.11, 12
While evidence continues to mount, investigators have been unable to
clearly demonstrate that clozapine leads to a significantly increased rate
of diabetes in patients with schizophrenia when compared with conventional
antipsychotics.13 Therefore, the primary objective
of this study was to compare the incidence rates of diabetes in patients with
schizophrenia receiving clozapine vs conventional antipsychotics, with the
use of Medicaid claims data. As clozapine has also been associated with hyperlipidemia,14, 15 incidence rates for the additional
weight-related outcomes of hyperlipidemia and hypertension were compared as
secondary objectives.
SUBJECTS AND METHODS
DATA SOURCE AND CASE SELECTION
The study was approved by the University of Iowa, Iowa City, institutional
review board. Claims data for the Iowa Medicaid program were obtained through
the Iowa Department of Human Services. Data from both medical and pharmacy
claims were used, and patient identifiers were encrypted to protect patient
confidentiality. Each Medicaid medical claim identifies a service provided,
gives the date the service was provided, and includes up to 4 International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Pharmacy claims were used to identify the drug
products dispensed and the date of fill. An associated data set containing
Medicaid eligibility information was used to obtain demographic information
such as sex and date of birth.
Medical claims from the years 1990 to 1994 were used to identify all
patients with a diagnosis of schizophrenia (identified by ICD-9 code 295.xx, excluding 295.7x). For these patients, the additional
codes for schizoaffective disorder (ICD-9 code 295.7x)
and bipolar affective disorder (ICD-9 code 296.xx,
excluding 296.2x and 296.3x) were identified. From these diagnostic codes,
the number of months the patient was diagnosed as having schizophrenia, schizoaffective
disorder, or bipolar affective disorder were summed. Entry into the analysis
required at least two thirds of these months to be coded for schizophrenia.
The goal of this restriction was to isolate patients with schizophrenia by
eliminating patients who were longitudinally considered schizoaffective or
bipolar, because these populations might have a different intrinsic risk for
diabetes than do patients with schizophrenia. Medical claims for psychiatric
diagnoses were limited to the years 1990 to 1994, because the processing of
psychiatric claims was changed in 1995 and the claims were unavailable after
this point. Pharmacy claims and nonpsychiatric medical claims were unaffected
by this change and were available for the years 1990 to 1998. Pharmacy claims
were used to create a longitudinal drug history for each patient, beginning
with the first observed medical claim for schizophrenia. Individual antipsychotic
agents were identified from the pharmacy claims by means of both the National
Drug Code field and the drug name text field. Antipsychotic agents classified
as conventional agents were chlorpromazine hydrochloride, fluphenazine hydrochloride,
haloperidol, loxapine, mesoridazine besylate, molindone hydrochloride, perphenazine,
pimozide, prochlorperazine edisylate, thioridazine hydrochloride, thiothixene,
trifluoperazine hydrochloride, and triflupromazine hydrochloride. Risperidone,
olanzapine, and quetiapine were considered atypical antipsychotics.
RATES OF DIABETES, HYPERLIPIDEMIA, AND HYPERTENSION
The outcomes of interest were the development of diabetes, hyperlipidemia,
or hypertension. A diabetes outcome was defined as either a medical claim
with an ICD-9 code for diabetes (ICD-9 code 250.xx) or a pharmacy claim for a glucose-reducing agent
(ie, insulin, sulfonylurea, etc). Similarly, the occurrence of hyperlipidemia
was identified by either an appropriate ICD-9–coded
medical claim (ICD-9 code 272.xx) or a pharmacy claim
for a lipid-lowering medication. For both diabetes and hyperlipidemia, the
occurrence of drug therapy was considered sufficient to identify an outcome
because these drugs are almost exclusively used for the primary indication.
In contrast, the occurrence of hypertension was identified only through medical
claims coded for hypertension (ICD-9 codes 401.xx,
402.xx, 403.xx, 404.xx, and 405.xx). A pharmacy claim for a primary antihypertensive
drug was not considered a reliable indicator for hypertension because of the
large number of secondary indications for these agents, particularly in psychiatry
(eg, ß-blockers for antipsychotic-induced akathisia).
Patients who met entry criteria for a diagnosis of schizophrenia were
separated into either the clozapine or conventional antipsychotic group, on
the basis of observed treatments. The clozapine treatment group consisted
of patients who had at least 1 pharmacy claim for clozapine during the observation
period (1990-1998). The first month of clozapine treatment was defined as
the index month. Beginning with this index month, treatment was followed up
until an end point occurred. End points for the clozapine group were the end
of available follow-up data, clozapine discontinuation, the addition of an
atypical antipsychotic, or the occurrence of an outcome (ie, diabetes, etc).
Patients in whom an outcome was observed before the index month were considered
to have a preexisting condition and excluded from the determination of the
incidence rate for that outcome. For example, a patient with a pharmacy claim
for insulin before starting clozapine treatment was excluded from the outcome
analysis for diabetes, but not for hyperlipidemia or hypertension.
The conventional antipsychotic group consisted of all patients who received
conventional antipsychotics, with 2 exclusions. First, all patients who qualified
for the clozapine group were excluded from the conventional group. Second,
patients who received an atypical antipsychotic before the first observed
month of treatment with conventional antipsychotics were excluded. The first
month of conventional antipsychotic treatment was defined as the index month.
As in the clozapine group, patients were followed up from the index month
until an end point occurred. The end points for the conventional antipsychotic
group were identical to those for the clozapine group except that patients
were allowed to change antipsychotic regimens, provided only conventional
antipsychotics were involved.
STATISTICAL ANALYSES
The sex distribution between treatment groups was compared by a  2 test. Inspection of the distribution of duration of follow-up and
age indicated distinctly skewed data, violating the assumptions for standard
parametric tests. Consequently, we used nonparametric tests, as necessary.16, 17 Unadjusted comparisons of cumulative
incidence rates for diabetes, hyperlipidemia, and hypertension between groups
were performed with Fisher exact test. Logistic regression was used for the
multivariate comparison of incidence rates adjusting for index age, sex, and
duration of follow-up. All statistical analyses and database manipulations
were performed with the SAS system version 6.12.18
All P values are 2-tailed at the significance level
of .05.
RESULTS
POPULATION CHARACTERISTICS
A total of 4770 patients with at least 1 medical claim for schizophrenia
were identified. Of these, 3013 (63.2%) satisfied entry criteria for the analysis.
The conventional antipsychotic group included 2461 patients and the clozapine
group included 552 patients. Among patients receiving conventional antipsychotics,
77.5% received monotherapy with an oral agent during the index month. These
included haloperidol (19.8%), thiothixene (14.8%), thioridazine (14.7%), trifluoperazine
(7.2%), fluphenazine (6.8%), chlorpromazine (5.3%), and other oral monotherapy
(8.9%). The remaining 22.5% of the conventional antipsychotic group received
monotherapy with a long-acting injectable antipsychotic (11.5%) or some combination
regimen of conventional antipsychotics (11.0%) during the index month.
The mean (±SD) age during the index month was 42.9 ± 17.1
years in the conventional antipsychotic group compared with 37.4 ±
12.1 years in the clozapine group (Mann-Whitney, z
= -6.18, n = 3013, P<.001). The clozapine
group had a significantly larger proportion of men than the conventional antipsychotic
group (61.4% vs 49.5%; 21 = 25.48, P<.001).
INCIDENCE RATES OF DIABETES, HYPERLIPIDEMIA, AND HYPERTENSION
The mean (±SD) duration of available follow-up was 24.5 ±
26.9 months for the conventional antipsychotic group and 25.5 ± 24.4
months for the clozapine group (Mann-Whitney, z =
2.45, n = 3013, P = .01). The overall cumulative
incidence rates of diabetes, hyperlipidemia, and hypertension are presented
in Table 1. There were no significant
differences in the overall incidence rates for diabetes, hyperlipidemia, or
hypertension between patients receiving clozapine vs conventional antipsychotics.
These differences remained nonsignificant after adjusting for index age, sex,
and duration of follow-up by logistic regression.
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Table 1. Cumulative Incidence Rates for Patients Receiving Conventional
Antipsychotics vs Clozapine*
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While the overall incidence rate of diabetes was similar between groups,
the effect of clozapine was significant in younger patients (Table 2). In patients 20 to 34 years of age, the incidence rate
for diabetes was 5.0% in the clozapine group and 2.0% in the conventional
antipsychotic group, representing a relative risk of 2.5 (95% confidence interval,
1.2-5.4). Diabetes incidence rates were not significantly different between
antipsychotic groups among other age strata. A similar age effect was observed
with hyperlipidemia (Table 2).
Among patients 20 to 34 years old, the hyperlipidemia incidence rate was 4.6%
in the clozapine group and 2.0% in the conventional antipsychotic group, representing
a relative risk of 2.4 (95% confidence interval, 1.1-5.2). In contrast, no
age effect was observed for hypertension (Table 2).
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Table 2. Cumulative Incidence Rates Among Patients Aged 20 to 34 Years*
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COMMENT
In recent years, clozapine has been linked to the development of diabetes
in a number of individual cases, but the general scope of the effect has not
been characterized. A recent naturalistic follow-up study of 82 patients starting
clozapine treatment reported an alarming diabetes rate of 36.6% (30/82) within
5 years.4 While this rate appears elevated,
there was no comparison group available to directly test for the effect of
clozapine. The only study that has incorporated a control group contrasted
rates of diabetes and glucose intolerance in a series of 63 clozapine-treated
patients and 67 patients receiving depot injections of high-potency conventional
antipsychotics.13 The authors reported an increased
rate of diabetes or impaired glucose tolerance among clozapine-treated patients,
but the difference did not reach statistical significance (P = .06). As the sample size was somewhat limited, the study may have
lacked sufficient power to detect an effect of clozapine on the occurrence
of diabetes.
The present study, however, involved data from more than 3000 patients
with schizophrenia and more than 550 patients taking clozapine. While this
sample size provided a greater than 99% power to detect a small effect size
(Cohen W = 0.1),19 we were unable to demonstrate
a significantly increased risk for diabetes, hyperlipidemia, or hypertension
among clozapine users when compared with a control group treated with conventional
antipsychotics. However, the age-stratified results suggested that age was
a significant factor in the relationship between clozapine and diabetes.
There are numerous potential hypotheses for the influence of age on
clozapine-induced diabetes and hyperlipidemia. The fact that the overall incidence
rates were not increased suggests that clozapine may not be an independent
risk factor for diabetes and hyperlipidemia but may modify other risk factors
in younger patients. In the case of diabetes, family history, advancing age,
obesity, and lack of physical activity are the strongest known risk factors.20 As clozapine can produce substantial weight gain,
increased diabetes risk may occur through the modification of this risk factor,
particularly in younger, genetically susceptible patients. Alternatively,
clozapine may promote hyperglycemia through inhibition of insulin secretion
or promoting peripheral insulin resistance, as can be observed with other
drugs.10, 21 This hypothesis is
supported by the observation that not all cases of clozapine-related diabetes
have involved weight gain.5 Thus, for younger
patients with schizophrenia who have not developed diabetes or hyperlipidemia,
but are predisposed, clozapine may provide a sufficient insult through weight
gain or some direct physiological mechanism to produce a clinically evident
syndrome. Of course, this hypothesis requires confirmation in other settings
and patient populations. If confirmed, the medical and economic implications
of the early induction of diabetes and hyperlipidemia demand further study.
It is unknown whether this effect is unique to clozapine or can be generalized
to other atypical antipsychotics.
As this study has important clinical implications, the estimated incidence
rates for diabetes, hyperlipidemia, and hypertension must be carefully scrutinized.
A common criticism of claims-based research is that disease states are inadequately
coded in medical claims and, therefore, important outcomes may go unreported.
While this may cause the outcome rates to be artificially low, the bias is
likely to be similar between the clozapine and conventional groups and therefore
not affect comparisons between treatment groups. Also, the age-stratified
prevalence of diabetes in this population (data not presented) was slightly
higher than rates previously reported from clinical data,12
suggesting a reasonable sensitivity in detecting the occurrence of diabetes
from Medicaid data. An exception may be the hypertension rates, which are
likely underestimated because pharmacy claims could not be used to maximize
detection. It should also be noted that the incidence rates reported in this
study were not strictly defined temporally, such as a 1-year incidence rate.
Therefore, it is difficult to directly compare the incidence rates with those
reported in other studies. However, among the nonschizophrenic Iowa Medicaid
recipients aged 20 to 34 years, the incidence rate of diabetes by similar
methods and time periods was 1.7% (95% confidence interval, 1.6%-1.9%).
Another potential difficulty is the lack of important patient characteristics
that can be controlled for as independent risk factors for developing an outcome,
such as family history, weight gain, etc. One such factor that was available
was age during the index month of antipsychotic treatment. The patients in
the conventional group were significantly older, which could have artificially
inflated the overall outcome rates for this group. However, the differences
in incidence rates remained nonsignificant after controlling for index age
and duration of follow-up with logistic regression.
Another issue is related to the potential for monitoring bias in patients
treated with clozapine. As a result of the frequent hematologic monitoring
required for clozapine, clinicians may have more interaction with these patients
and be more likely to order other tests, including glucose and lipids. This
bias could elevate the observed incidence rates of diabetes and hyperlipidemia
among patients treated with clozapine. While this is a potential limitation
of our study design, the lack of increased risk for hypertension argues against
a strong monitoring bias. Also related to monitoring bias, as reports of clozapine-induced
diabetes increased over time, clinicians may have been more likely to screen
for this condition. However, there was not an increase in the rate of diabetes
diagnoses over time in our study.
An additional criticism is the validity of considering all conventional
antipsychotics together. Of particular concern is the reported difference
in weight gain reported with low-potency vs high-potency conventional antipsychotics.9 However, a within-class analysis in this study population
actually suggested a trend toward lower incidence rates with low-potency conventional
antipsychotics, particularly with hypertension.
It is apparent from the available literature that screening for diabetes
and hyperlipidemia should be considered in the routine monitoring of patients
receiving clozapine. This study specifically observed that younger patients
treated with clozapine were at greater risk than were their counterparts receiving
conventional antipsychotics. We concur with other investigators in recommending
a fasting glucose and lipid panel every 6 months.4
In addition to laboratory monitoring, weight and blood pressure should be
recorded at each visit. A tendency to ignore hyperglycemia in patients receiving
clozapine has been reported, and it should be emphasized that appropriate
action must be taken in response to abnormal screening results.4
Unfortunately, it is unknown whether diabetes and hyperlipidemia may be prevented
or delayed in this population through lifestyle interventions to control weight.
With vigilant monitoring and the institution of appropriate interventions,
we may be able to reduce the medical morbidity and mortality in patients treated
with clozapine.
AUTHOR INFORMATION
Accepted for publication March 23, 2001.
We thank the University of Iowa Public Policy Center (Iowa City) for
providing access to the Medicaid data and the Iowa Medicaid Drug Utilization
Review Commission (Des Moines) for their support of this research.
From the Division of Clinical and Administrative Pharmacy, College
of Pharmacy (Drs Lund, Perry, and Brooks), Department of Psychiatry, College
of Medicine (Drs Perry and Arndt), and Department of Biostatistics, College
of Public Health (Dr Arndt), University of Iowa, Iowa City.
Corresponding author and reprints: Brian C. Lund, PharmD, University
of Iowa, College of Pharmacy, 443 S Pharmacy Bldg, Iowa City, IA 52242-1112
(e-mail: brian-lund{at}uiowa.edu).
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