Full text of DOI:10.1592/phco.22.11.841.33629

_
R EVIEW S F T H ERA PEUTIC S
Olanzapine-Associated Diabetes Mellitus
Elizabeth A. Koller, M.D., and P. Murali Doraiswamy, M.D.
Study Objective. To explore the clinical characteristics of hyperglycemia in
patients treated with olanzapine.
Design. Retrospective, epidemiologic survey of spontaneously reported
adverse events related to olanzapine therapy.
Setting. Government-affiliated drug evaluation center.
Patients. Two hundred thirty-seven patients with olanzapine-associated
diabetes or hyperglycemia.
Intervention. One hundred ninety-six cases from January 1994–May 15,
2001, were identified with the United States Food and Drug
Administration’s MedWatch Drug Surveillance System, and 41 cases
published through May 15, 2001, were identified with MEDLINE or
through meeting abstracts.
Measurements and Main Results. Of the 237 cases, 188 were new-onset
diabetes, 44 were exacerbations of preexistent disease, and 5 could not be
classified. Mean patient age for newly diagnosed cases was 40.7 ± 12.9
years and male:female ratio was 1.8. Seventy-three percent of all cases of
hyperglycemia appeared within 6 months of start of olanzapine therapy.
Eighty patients had metabolic acidosis or ketosis, 41 had glucose levels of
1000 mg/dl or greater, and 15 patients died. When olanzapine was
discontinued or the dosage decreased, 78% of patients had improved
glycemic control. Hyperglycemia recurred in 8 of 10 cases with
rechallenge.
Conclusions. Number of reports, temporal relationship to start of olanzapine
therapy, relatively young age, and improvement on drug withdrawal suggest
that olanzapine may precipitate or unmask diabetes in susceptible patients.
(Pharmacotherapy 2002;22(7):841–852)
OUTLINE
Demographic Features
Time to Onset
Methods
Results
Nature of Hyperglycemia Reports
Olanzapine Dosages
Serious Outcomes
Metabolic Acidosis
Mental Status Changes
Setting
Pancreatitis or Hyperamylasemia
Deaths
Additional Risk Factors
Concomitant Drugs
Olanzapine Withdrawal and Rechallenge
Discussion
From the Division of Metabolic and Endocrine Drug
Products, Center for Drug Evaluation and Review, Food and
Drug Administration, Rockville, Maryland (Dr. Koller); and
the Departments of Psychiatry and Medicine, Duke University
Medical Center, Durham, North Carolina (Dr. Doraiswamy).
The contents of this publication represent the views of
the authors and do not necessarily constitute an official
position of the U.S. Food and Drug Administration or the
U.S. Government.
Address reprint requests to Elizabeth Koller, M.D., 5600
Fishers Lane, Room 14B04, Rockville, MD 20857.
Conclusion

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PHARMACOTHERAPY Volume 22, Number 7, 2002
Olanzapine (Zyprexa; Eli Lilly and Company,
and published cases vary in the completeness of
the demographic and clinical information
provided, we have specified where such data
were missing. Hence, this is a descriptive report
based primarily on summary statistics.
Indianapolis, IN), marketed in the United States
since 1996, is a psychotropic agent indicated for
the management of schizophrenia1, 2 and short-
term treatment of acute manic episodes in bipolar
disorder in adults.1 In addition to approved
indications, it has been administered for the
treatment of a variety of other conditions
including psychosis in dementia and Parkinson’s
disease, delusional or resistant depression,
conduct disorders, aggression, agitation, resistant
anxiety disorders, and delirium.3–6 Known
adverse reactions to olanzapine include
orthostatic hypotension, weight gain, akathisia,
increased salivation, and somnolence.1 Published
reports of hyperglycemia occurring in association
with olanzapine began occurring in 1998.7–28
The spectrum of reported illness ranged from
mild glucose intolerance to diabetic ketoacidosis
and nonketotic hyperosmolar coma. To gain
further insight into the clinical characteristics of
diabetes reported in association with olanzapine,
we attempted to identify all such cases that had
been submitted to the Food and Drug
Administration’s (FDA) MedWatch surveillance
program.
2
We used correlation coefficients, ␹ tests, and
unpaired t tests (all two-tailed) to assess the
relationship between certain variables or groups;
p values of 0.05 or less were viewed as
significant.
Results
We identified 237 distinct cases of olanzapine-
associated diabetes or hyperglycemia, including
41 cases in 22 publications.7–28 Of these reports,
215 originated in the United States and 22 were
from international sources.
Nature of Hyperglycemia Reports
Among the 237 reports, there were 188 (79%)
cases of newly diagnosed hyperglycemia, 44
(19%) cases of exacerbation of established
preexistent diabetes, and 5 (2%) cases that could
not be classified. Of the 188 cases of newly
diagnosed hyperglycemia, 153 cases fit the serum
glucose or glycohemoglobin criteria for the
diagnosis of diabetes. Of the patients whose
diabetes was determined by fasting blood glucose
level, all but two had fasting glucose levels of 140
mg/dl or greater. Of the 35 patients with new-
onset hyperglycemia whose reports did not
include sufficient glucose data for the diagnosis
of diabetes, 19 received antidiabetic drug therapy.
Five of the 19 patients were also reported to be
acidotic or ketotic. Another three patients were
acidotic or ketotic at the time of hyperglycemia,
but lacked additional diagnostic data. In
addition to these 188 newly diagnosed cases,
there were 44 reports of patients with established
diabetes in whom metabolic status worsened
after starting olanzapine. As stated previously,
there were five additional cases in which it was
unclear whether the diabetes was newly
diagnosed or preexistent.
Methods
We identified cases by querying the FDA
MedWatch Drug Surveillance System (January
1994–May 15, 2001). Published cases were
identified by means of MEDLINE (through May
15, 2001). Selected abstracts from national
psychiatry meetings also were reviewed. We
combined reports occurring in multiple
identification systems. Drug utilization data
were obtained from the National Prescription
Audit Plus (IMS Health, Inc., Plymouth Meeting,
PA) and the National Disease and Therapeutic
Index (IMS Health, Inc.) databases.
We assessed documentation of diabetes,
severity of hyperglycemia, whether the hyper-
glycemia was newly diagnosed, demographic
features, time to onset of hyperglycemia, and
effect of drug discontinuation. We defined
“documentation” of newly diagnosed diabetes on
the basis of a fasting glucose level of 126 mg/dl
(7 mmol/L) or greater, a random glucose level of
200 mg/dl (11 mmol/L) or greater, or elevated
glycohemoglobin values; and/or presence of
metabolic acidosis or ketosis; and/or physician
institution of an antidiabetic drug. Patients
without definitive documentation were classified
separately. Because individual MedWatch reports
Demographic Features
At the time of the adverse event, those with
newly diagnosed hyperglycemia were younger
than those with an exacerbation of preexistent
diabetes (Table 1). Among the 153 cases (151
with age data) of newly diagnosed diabetes that
were diagnosed by serum glucose or
glycohemoglobin levels, the mean ± SD age was

OLANZAPINE-ASSOCIATED DIABETES MELLITUS Koller and Doraiswamy
843
Table 1. Age Distribution of 226 Patients with Olanzapine-Associated Hyperglycemia
Distribution by Age Cohort (yrs), no.
11–20 21–30 31–40 41–50 51–60 61–70
Nature of Hyperglycemia Report
Age (yrs)a
≥ 70
Newly diagnosed hyperglycemia (n=184)
Glucose or glycohemoglobin level (n=151)
Drug therapy ± acidosis or ketosis (n=20)
Less well documented (n=13)
40.7 ± 12.9
39.8 ± 12.4
47.4 ± 12.4
41.3 ± 17.0
12
9
0
23
20
2
60
55
3
55
45
8
20
11
5
10
8
1
4
3
1
0
3
1
2
2
4
1
Exacerbation of preexistent diabetes (n=38)
Unknown if new onset or exacerbation (n=4)
51.7 ± 15.4
38.8 ± 5.4
42.6 ± 13.8
2
0
0
0
7
3
11
1
8
0
4
0
6
0
Totals
aData are mean ± SD.
14
23
70
67
28
14
10
Age was unknown for 11 patients. Age range of the 226 patients was 13–79 years. Hyperglycemic events were categorized by type of
documentation available and patient’s age in years at the time of the event.
39.8 ± 12.4 years (range 13–75 yrs), and 68% of
these cases occurred before the age of 45 years.
Fifty percent of these cases occurred in the third
and fourth decades of life. There were twice as
many men as women in this subgroup. Twelve
cases of newly diagnosed hyperglycemia occurred
in the 11–20-year age group, and six of these
cases were pediatric patients younger than 18
years. Of the 44 patients (38 with age data) with
exacerbation of preexistent diabetes, mean age
was 51.7 ± 15.4 years (range 17–79 years), with a
male:female ratio of 1.5.
Time to Onset
The time to diagnosis of hyperglycemia for all
subjects for whom these data were available (209
patients) ranged from 2 days to 45 months, but
for 73% (153 patients), it was 6 months or less
from the time olanzapine therapy was started
(Figure 1). Among those with newly diagnosed
diabetes documented by glucose or
glycohemoglobin levels and for whom adequate
time-to-onset information was available (142
patients), the onset of diabetes occurred within
the first month of olanzapine therapy in 18
patients (13%). Forty-seven percent of such
cases occurred within the first 3 months, and
70% of such cases occurred within 6 months of
drug exposure. Time-to-onset information was
available for 38 of 44 patients with exacerbation
of preexistent diabetes. In these patients, the
glycemic exacerbation was observed within the
first month of olanzapine therapy in 55% of
cases, within the first 3 months in 84%, and
within the first 6 months in 97%.
Information on race was available for 150
patients, and of these, 84 (56%) were Caucasian,
58 (39%) were of African descent, 5 (3%) were
Hispanic, and 3 (2%) were Asian.
Unknown whether newly diagnosed or exacerbation
Exacerbation of preexisting diabetes
80
Newly diagnosed hyperglycemia (less well documented)
Newly diagnosed diabetes (pharmacologic treatment or acidosis-ketosis)
Newly diagnosed diabetes (glucose or glycohemoglobin level)
70
60
50
40
30
20
10
0
Olanzapine Dosages
Dosage information was available for 202
(85%) of the 237 cases. In these patients, the
mean ± SD olanzapine dosage was 15.6 ± 7.0
mg/day (range 2.5–40 mg/day). Mean daily
doses did not differ by sex (male patients 15.3 ±
6.8 mg, female patients 15.6 ± 7.2 mg). Mean
daily doses were lower for patients with
preexistent diabetes (13.2 ± 6.2 mg) versus those
with new-onset hyperglycemia (16.1 ± 7.0 mg)
(p=0.02) and tended to be higher in those with
ketosis or acidosis (16.6 ± 6.8 mg) than in those
without (15.0 ± 7.0 mg) (p=0.12). There was no
significant correlation between dose and the
reported glucose level or between dose and time
≤ 1
> 1–3
> 3–6
> 6–9
> 9–12
> 12–24
> 24–36
> 36
Time (months)
Figure 1. Time to hyperglycemic event. Hyperglycemic
events were categorized by the time to occurrence after start
of olanzapine therapy. Data were available for 209 (88%) of
the 237 patients. Among these, hyperglycemia was
identified within the first 6 months of olanzapine therapy in
153 patients (73%). A notable number of cases had delayed
onset up to 45 months.

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PHARMACOTHERAPY Volume 22, Number 7, 2002
Table 2. Characteristics of the 15 Patients Who Died
to onset. Drug levels, which may be more predic-
tive of clinical effects, typically were not available.
Characteristic
Age, mean ± SD (yrs)
M/F (no.)
Data
43.1 ± 16.3
8/7
Serious Outcomes
Ethnic background (no.)
Caucasian
African-American
Asian
Metabolic abnormalities ranged from mild
glucose intolerance to diabetic ketoacidosis and
hyperosmolar coma. In 69 cases, the blood
glucose level was 700 mg/dl or greater. Of these,
at least 65 (94%) had newly diagnosed diabetes
and 2 (3%) had exacerbation of preexistent
diabetes. Two other cases could not be classified
because of incomplete information. (In two
additional cases, the patients progressed to
hyperosmolar coma with glucose values of 1676
mg/dl and 800 mg/dl, respectively. Eight months
earlier, the first patient had a fasting glucose of
131 mg/dl and a hemoglobin A1c of 6.4%. The
second patient developed hyperglycemia again
with rechallenge.) Of these 69 patients, 41
(59%) had blood glucose levels of 1000 mg/dl or
greater. Thirty-eight (93%) of the 41 cases were
newly diagnosed diabetes. At least 43 (62%) of
the cases with high glucose levels occurred
within 6 months of the start of olanzapine
therapy. (Hyperglycemia [800 mg/dl] occurred
within 3.5 months of rechallenge in an additional
patient.) The mean age of these patients was
42.4 ± 12.7 years (if glucose ≥ 700 mg/dl but
< 1000 mg/dl) or 41.4 ± 9.4 years (if glucose
≥ 1000 mg/dl). Information on ethnic back-
ground was available for 50 of those with high
glucose levels (≥ 700 mg/dl). Forty-two percent
(21 patients) were African-American, whereas
54% (27 patients) were Caucasian.
6
1
1
7
Unknown
Hyperglycemia presentation (no.)
Newly diagnosed
Exacerbation
14
1
Time to onset < 3 mo. (no.)
Olanzapine dose, mean ± SD (mg)
Glucose level ≥ 700 mg/dl (no.)
Acidotic (no.)
8
17.9 ± 10.3
3
9
Setting
Most cases occurred in the community setting.
In four patients, hyperglycemia was identified
during incarceration in a prison. In two of these
patients, glucose levels were 1622 and 1299
mg/dl, respectively. In a third patient, the
glycohemoglobin was 13%, and the patient
subsequently died. The fourth patient, with a
history of diabetes, had a glucose level of 800
mg/dl and was reported to be “unresponsive to
high insulin doses.” Whether the mental status
changes that can occur with hyperglycemia were
the reason for incarceration was not known.
Pancreatitis or Hyperamylasemia
Pancreatitis or hyperamylasemia in association
with hyperglycemia was reported in 17 patients.
Of the 10 patients with concomitant acidosis or
ketosis, 7 had elevated lipase levels, diagnostic
computed tomographic findings, and/or
treatment with pancreatic enzymes. Six patients
with reported pancreatitis or hyperamylasemia
had glucose values of 700 mg/dl or greater, and
four of these patients had elevated lipase levels or
confirmatory imaging studies. One case occurred
in a 15-year-old boy who died of necrotizing
pancreatitis 1 month after diabetes mellitus was
diagnosed.
Metabolic Acidosis
There were 80 cases of ketosis or metabolic
acidosis; 92% (74 patients) of these cases were
newly diagnosed diabetes. In three patients,
whether the diabetes was newly diagnosed or
preexistent was unclear. Although the degree of
acidosis was generally mild, the presenting
glucose value was 500 mg/dl or greater in 57
patients. In 41 patients, the acidosis or ketosis
was accompanied by glucose values of 700 mg/dl
or greater.
Mental Status Changes
Deaths
In 43 patients, mental status changes (obtun-
dation or confusion) occurred in conjunction
with the hyperglycemia. Of these, 42 patients
had newly diagnosed diabetes and 1 had
exacerbation of preexistent diabetes.
Fifteen patients (8 male and 7 female patients,
6 Caucasian) died, including the 15-year-old boy
(Table 2). Fourteen of these deaths occurred in
patients with newly diagnosed diabetes. For
eight of these patients, the time to onset was less

OLANZAPINE-ASSOCIATED DIABETES MELLITUS Koller and Doraiswamy
845
than 3 months. The mean daily dose of
olanzapine was 17.9 ± 10.3 mg. Of the 15
deaths, 13 occurred during or shortly after a
hyperglycemic episode, with acidosis or ketosis
reported in 9 of the 13 cases. In the other two
cases, the patients died a month after the
hyperglycemia was identified, one with
necrotizing pancreatitis and the other of
unknown causes. Often, these patients had many
medical problems at the time of death, making it
difficult to assign a primary role for the
hyperglycemia in their deterioration. One of the
patients, a 39-year-old woman with symptoms of
polydipsia and blurred vision, died after 8
months of olanzapine therapy. At autopsy, the
vitreal glucose level was 867 mg/dl, and the
patient was acidotic.
with glucose levels of 700 mg/dl or greater
(35%), however, did not differ from that in
patients with glucose levels less than 700 mg/dl
(33%) (␹2=0.1, degrees of freedom [df]=1,
p=0.75). Valproate therapy was reported in seven
cases (41%) of pancreatitis or hyperamylasemia.
The other most frequently reported concurrent
drugs were lithium, benztropine, conventional
antipsychotics, thyroid hormone, antidepressants
(fluoxetine, paroxetine, sertraline, venlafaxine),
and clonazepam. A trend for a higher frequency
of lithium therapy in those with glucose levels of
700 mg/dl or greater (20%) than that in patients
with lower glucose levels (9%) failed to reach
significance (␹2=3.4, df=1, p=0.06).
Olanzapine Withdrawal and Rechallenge
Complete data on the course of diabetes were
lacking in many cases. Olanzapine was discon-
tinued for various reasons in 105 cases, but
follow-up data were available only for 76 of these
cases. Of the 76 cases, 60 patients (79%) were
reported to have improved, and 16 (21%) did not
improve. Complete follow-up information was
not available to determine how many of the
patients who improved had glucose levels that
returned to normal or how many of these patients
required continuing therapy. Nonetheless, some
of the cases with more complete information
were compelling. A thin, otherwise healthy, 72-
year-old man with a negative family history of
diabetes was hospitalized for psychiatric
decompensation after self-discontinuation of
drug therapy. His glucose levels were normal,
and he was started on olanzapine 10 mg/day.
Approximately 2 months later, for behavioral
changes, his dosage was decreased to 5 mg/day.
Shortly thereafter, the patient became polydipsic
and somnolent. He was hospitalized with a
glucose level of 1600 mg/dl. Olanzapine was
discontinued. The patient was treated initially
with insulin and later with oral antidiabetic
agents. Subsequently, these also were discon-
tinued. The patient remained normoglycemic
without antidiabetic agents for 8 months after the
hyperglycemic episode—although subsequently a
low dosage of an oral antidiabetic was required.
Of the nine patients switched from olanzapine
to another identified atypical antipsychotic,
glucose control improved in five of seven patients
switched to risperidone and in one of two
patients switched to quetiapine. Two patients
who developed diabetes while taking olanzapine
also had a history of hyperglycemia with
Additional Risk Factors
The reports did not uniformly provide
systematic information on risk factors for
diabetes. Limited body weight data were
available for 169 patients. Approximately 24% of
these patients did not appear either to be
overweight or to have had sustained weight gain.
Of the 80 patients with newly diagnosed
hyperglycemia for whom family history
information was provided, 43 (54%) had a
positive family history (in 2 cases, it was remote),
and 37 (46%) had a negative family history for
diabetes. Hepatitis, a putative risk factor,29, 30 was
reported in six patients (five with hepatitis C and
one with hepatitis B). There was also no
systematic pattern of concomitant drug therapy,
as reported below.
Concomitant Drugs
There was no consistent pattern of
concomitant drug therapy that emerged from the
data reported for these patients. Only a limited
number of patients were receiving drugs known
to induce hyperglycemia. One patient received
systemic steroids for sinusitis, two others
received nonsystemic steroids as a cream or
inhaler, one had been taking niacin, and nine had
been taking thiazide diuretics. Of note, eight
patients had been taking another atypical
antipsychotic (risperidone [three patients],
clozapine [four], or quetiapine [one]).
Treatment with valproate, a controversial putative
risk factor for hyperglycemia,31–34 was reported
for 59 of the 190 patients with some information
on serial or concomitant drug therapy. The
frequency of known valproate therapy in those

846
PHARMACOTHERAPY Volume 22, Number 7, 2002
diagnosed cases in our sample (40.7 yrs) is
clozapine.
considerably less than the typical mean age of
patients with newly diagnosed type 2 diabetes.
Data from the National Health Interview Surveys
(NHIS) indicate that the overwhelming majority
of newly diagnosed cases of type 2 diabetes
occurs in older individuals, with the highest
incidence in the 65–74-year age cohort
(8.6/1000/yr).37 In the U.S. population,
prevalence also increases with age: 81% of
diabetes cases are in people older than 44 years.
Indeed, in the 65–74-year and the 75-year and
older age groups, 11% and 10%, respectively,
have diabetes. In contrast, the incidence of
diabetes in people aged 25–45 years is
1.79/1000/year, and only 1% in that age group
have the disease.37 Figure 2 illustrates an indirect
comparison of the cumulative relative frequency
of new-onset diabetes cases by age in our study
with that of the U.S. population. The frequency
of newly diagnosed cases in the 0–44-year age
group appears to be twice as high among
olanzapine-treated patients (66%) than in the
U.S. population (33%). When we compared the
distribution of olanzapine-associated new-onset
cases with that of the NHIS using the same age
groups, we determined that the difference was
statistically significant (␹2=113.6, df=5,
p<0.0001). These data suggest that the onset of
diabetes mellitus occurs earlier in life among
The olanzapine dosage was reduced in at least
six patients. Follow-up data were available only
for five patients because one patient died of
complications before a response to the lower
dosage could be assessed. Of the five patients,
three improved and two had no change. For
patients in whom olanzapine was not discon-
tinued, insufficient data were available to
determine the course of their diabetes.
Ten patients were rechallenged with
olanzapine. Of these, eight (80%) experienced
deterioration in glycemic control. This occurred
within 3 days of rechallenge for two patients. In
two others patients, deterioration in glycemic
control occurred 7 and 8 days after rechallenge.
Approximately 5–6 months after reinstitution of
olanzapine, another patient developed diabetic
ketoacidosis and hyperamylasemia complicated
by diffuse clotting and death. Among the 10
patients, outcome was unknown for one patient.
The one other patient who did not have a
recurrence of hyperglycemia had an interval
weight loss of at least 24 pounds. Glycemic
control again improved after olanzapine
discontinuation in three patients.
Discussion
We identified 237 cases of newly diagnosed
hyperglycemia or diabetes mellitus, or diabetic
exacerbation, associated with olanzapine. These
reports are most notable for the number of
patient in whom glucose levels equaled or
exceeded 700 mg/dl and for the relatively young
age of these patients. In contrast to our findings,
the hyperosmolar diabetic state typically is found
in elderly patients, often living alone, who
decompensate because of a stroke, infection, or
drug therapy and who are unable to ingest
sufficient fluid.35, 36 We also identified other
significant outcomes, including metabolic
acidosis or ketosis in 80 patients, obtundation or
confusion in 43, pancreatitis or hyperamylasemia
in 17, and death in close temporal proximity to
the hyperglycemic episode in 13. The gravity of
these outcomes highlights the need to further
examine this potential association.
100
90
80
70
60
50
40
Newly diagnosed hyperglycemia with olanzapine
30
Olanzapine use
20
New-onset diabetes in U.S. population
10
0
0–24
25–44
45–54
55–64
Age (years)
65–74
≥ 75
Figure 2. Distribution by age. Age distribution of
olanzapine-associated new-onset diabetes was compared
with the distribution of new-onset diabetes cases in the U.S.
population.37 The National Disease and Therapeutic Index
drug appearance data from office visits for 1996–2000 were
used to assess olanzapine treatment by age.38 Drug
appearances include new and refill prescriptions, as well as
samples provided to patients by physicians. Patient age was
unspecified for 2.8% of drug appearances. There were twice
as many cases of diabetes associated with olanzapine in the
0–44-year age range as there were in the U.S. population
survey, demonstrating the relatively young age of these
cases. The two distributions were different (p<0.0001).
Several of our findings suggest a relationship
between olanzapine therapy and diabetes. These
include the number of cases reported, the
temporal relationship to the start of olanzapine
therapy, and the prompt reversibility of
hyperglycemia with drug withdrawal in some
cases. Furthermore, the mean age in the newly

OLANZAPINE-ASSOCIATED DIABETES MELLITUS Koller and Doraiswamy
847
observed with clozapine-associated hyperglycemia.39
No other clear risk factors for olanzapine-
associated hyperglycemia emerged from this
study other than possibly race and lithium
therapy. African-Americans compose about 10%
of patients receiving olanzapine (Figure 4) but
compose nearly 39% (58 of 150) of cases of
diabetes with ethnic heritage information in this
report. Although the prevalence of diabetes was
higher among African-Americans than among
Caucasians for all age groups, the disparity in
prevalence increases with age. The prevalence of
diabetes is approximately 1.3 times higher in the
25–44-year age group and is only 2-fold higher in
older age groups.37 We did not find a clear dose
effect, although there was a trend for newly
diagnosed cases and cases with ketosis or
acidosis to have higher mean olanzapine daily
doses. There was a weak association between
concomitant lithium therapy and very high
glucose levels. Lithium can cause diabetes
insipidus and weight gain43 and, as such, increase
the risk for hyperosmolar states.
those receiving olanzapine than it does in the
general population, with the sharpest rise in
those younger than 44 years. The age
distribution of patients with olanzapine-
associated newly diagnosed hyperglycemia is also
to the left of the age distribution for all
olanzapine prescription recipients (based on
utilization data from IMS Health, Inc.38). This
suggests that the distribution of cases is unlikely
to simply reflect the age distribution of the
population that receives the drug. This relatively
young age at the time of onset of hyperglycemia
also was observed with another atypical
antipsychotic, clozapine.39
In addition to the relative youth of the
olanzapine-associated cases, the observed
imbalance between the sexes is atypical of
diabetes. The male:female ratio for all cases of
newly diagnosed hyperglycemia in our series was
1.8. Data from NHIS indicate a male:female
prevalence ratio of 0.8 and a male:female
incidence ratio of 0.7.37 There is no known sex
disparity for the prevalence of schizophrenia or
bipolar disease.40–42 The National Disease and
Therapeutic Index data indicate that the
male:female ratio of olanzapine therapy is 0.8
(Figure 3).38 This same sex disparity was
There is no obvious mechanism by which
olanzapine might impair carbohydrate metabo-
lism. Although weight gain can occur during
therapy,1 the prompt onset of diabetes in many
A
B
3.8
2.8
35.4
42.2
60.8
55.0
Drug Appearances by Sex (%)
Hyperglycemia Cases by Sex (%)
Female
Unspecified
Male
Female
Unspecified
Male
Figure 3. Sex of patients with olanzapine-associated hyperglycemia (A) and sex of patients treated with olanzapine (B).
National Disease and Therapeutic Index drug appearance data from office visits for 1996–2000 were used.38 Drug appearances
include new and refill prescriptions, as well as samples provided to patients by physicians. The patterns do not explain the sex
differences observed in the adverse event reports. Curiously, these data indicate that 58% of the men versus 44% of the women
receiving olanzapine were younger than 45 years. Diabetes in this age group is more common in women.37

848
PHARMACOTHERAPY Volume 22, Number 7, 2002
patients (six cases within the first week of
treatment) argues against a primary role for
weight gain in the development of olanzapine-
associated diabetes. Weight gain may contribute
to the late-onset hyperglycemia that was
observed. The variations in the time to onset of
hyperglycemia may reflect several mechanisms of
action (e.g., direct islet cell toxic reaction vs
interference with non–insulin-mediated glucose
utilization vs insulin resistance). There is no
overt chemical similarity between olanzapine and
become aware of a particular adverse event from
experience, literature, and/or changes to product
labels. Also, clinicians possibly were more
attuned to hyperglycemia because weight gain is
a known adverse effect1 and glucose monitoring
may have been more common in such patients.
Although we know the total number of
prescriptions, approximately 15 million between
1996 and 2000 inclusive, we cannot determine
patient-year-exposure (i.e., we have no precise
estimates on patient carryover from year to year
or the numbers of patients who received
olanzapine in the populations who contributed to
other compounds known to be islet cell toxins
45
(Figure 5).44,
Olanzapine also may be
unmasking diabetes in genetically vulnerable
patients. The metabolism of olanzapine in
sensitive individuals may differ from that in
unaffected individuals as well.
There are limitations to this report. The
MedWatch database relies on spontaneous
adverse event reporting. Substantial under-
reporting is characteristic of systems such as
MedWatch.46–53 Indeed, olanzapine does not
require specific routine laboratory monitoring,
and the symptoms of diabetes may be missed in
low-functioning patients. Distortions in
reporting may occur over time as prescribers
these reports).54
Furthermore, control
populations were absent, and case descriptions
may be incomplete. Even indirect comparisons
of age distribution of our cases with population
patterns derived from another study can be
biased by several factors. Hence, we cannot
determine causality or incidence. The possibility
that other factors (e.g., detection bias, preexistent
risk factors, prior drug therapy, or concomitant
drugs) contributed to the hyperglycemia cannot
be excluded. Nonetheless, the MedWatch
surveillance system can provide signals for
adverse events, including those that might not be
A
B
2.0
3.0
2.3
3.3
2.5
10.2
38.7
56.0
82.0
Hyperglycemia Cases by Ethnic Group (%)
Drug Appearances by Ethnic Group (%)
Asian
Hispanic
Caucasian
Black
Others or Unknown
Asian
Hispanic
Black
Caucasian
Figure 4. Ethnic background of patients with olanzapine-associated hyperglycemia for whom such information was available
(A) and ethnic background of patients treated with olanzapine (B). National Disease and Therapeutic Index drug appearance
data from office visits for 1996–2000 were used.38 Drug appearances include new and refill prescriptions, as well as samples
provided to patients by physicians. The patterns do not explain the racial differences observed in the adverse event reports.

OLANZAPINE-ASSOCIATED DIABETES MELLITUS Koller and Doraiswamy
849
identified during relatively short efficacy trials.
Indeed, preliminary findings from
evaluation of patients with weight loss or
polydipsia could be delayed. Mental status
changes associated with hyperglycemia or
hypoglycemia may be mistaken for psychotic or
antisocial behavior and result in improper
management or incarceration. The availability of
insulin can magnify the lethality of suicide
attempts.25 Further, switching to another
antipsychotic agent or noncompliance with the
offending agent while a patient is taking
antidiabetic pharmacotherapy may result in
hypoglycemia.58
In patients with olanzapine-associated
diabetes, the decision to switch to another
antipsychotic versus continuing olanzapine is a
difficult one. In the absence of prospective,
direct-comparison studies, whether substantive
differences exist in the hyperglycemic risk for the
various atypical antipsychotic agents is not
known. Moreover, changing to another drug
carries the risk of a psychotic flare.
a
retrospective analysis of a large prescription
claims database suggest that the risk for incident
diabetes (defined as starting antidiabetic
pharmacotherapy) was comparably higher (about
3-fold) in patients receiving a number of
antipsychotic agents, including olanzapine, than
in those who did not.55 These findings, in turn,
are supported by results of smaller studies
suggesting that antipsychotic agents, including
some conventional neuroleptics, are associated
with altered glucose tolerance and insulin
response, especially in the setting of tardive
dyskinesia,56, 57 and that glucose tolerance
improves with the discontinuation of
antipsychotic agents.56 Finally, hyperglycemia
associated with many of the newer antipsychotics
has been reported,58–61 although the majority of
published cases implicate clozapine or
olanzapine.
A drug that potentially precipitates diabetes in
patients with chronic mental illness has
implications for the patients and their families
and clinicians.25, 58 Low-functioning patients may
lack sufficient insight to recognize the symptoms
of diabetes or may lack access to medical care.
Because olanzapine is known to cause weight
gain, dry mouth, and sedation,1 laboratory
Conclusion
These results suggest a causal relationship
between olanzapine and development or
worsening of diabetes. The onset of hyper-
glycemia may be rapid and severe, the association
is not dose dependent, and the risk does not
CH3
N
Cl
CH3
N
CH3
N
F
CH3
N
N
N
N
CH3
Cl
N
S
Cl
N
CH3
N
O
N
S
O
H
H
Haloperidol
Olanzapine
Clozapine
Chlorpromazine
HO
H
N
O
N
O
O
O
H
OH
OH
NH
NH
HO
N
O
H2N
NH2
H
N
O
H3C
N O
O
O
Alloxan
Streptozocin
Pentamidine
Figure 5. Chemical structures. The physical chemical properties of olanzapine that could contribute to B cell toxic reaction are
unknown. Alloxan, streptozocin, and pentamidine are chemical compounds known to induce glucose intolerance through islet
cell damage. Chlorpromazine, a classic antipsychotic agent, also has been associated with diabetes,44 and haloperidol alters the
insulin response to a carbohydrate load.45 Although these compounds all have ring structures, the rings are not uniformly
planar nor are any of the side chains common to all.

850
PHARMACOTHERAPY Volume 22, Number 7, 2002
vanish with extended therapy. Awareness of the
potential safety issues will help guide drug
selection and direct adverse event monitoring so
that patients may more fully benefit from the
substantial therapeutic efficacy offered by the
atypical antipsychotic agents. Because spon-
taneous adverse event surveillance can neither
establish causality nor determine true incidence
and prevalence, further research is indicated.
pancreatitis documented by lipase levels and/or
computed tomography. Five patients with
glucose levels of 700 mg/dl or greater died. One
patient had an abnormal fasting glucose level in
his record (137 mg/dl) prior to starting
olanzapine, but the physicians were unaware of
its existence or its significance before the patient
progressed to a hyperosmolar state and died.
Mean olanzapine dosage in 43 cases was 14.1 ±
7.3 mg/day (using the maximum known
therapeutic dose and excluding an overdose of
1500 mg). No correlation was noted between
time to onset and dosage (r=0.37, 36 patients).
Some information for concomitant drug therapy
was available for 41 cases (79%). Four patients
received no concomitant drugs, three were taking
a thiazide diuretic, four received nonsystemic
corticosteroids (nasal or inhaled), and two were
taking systemic corticosteroids (cloprednol 5 mg
or prednisone 10 mg). One patient was taking
quetiapine; another may have been taking
risperidone concurrently. Seven patients received
valproate, and six were taking lithium.
Olanzapine was discontinued in 27 patients.
Although follow-up was incomplete, insulin
dosages were decreased successfully in two
patients, and antidiabetic drug therapy was
discontinued in another two patients. For the
latter two patients, oral antidiabetic agents
needed to be instituted 8 and 13 months later,
respectively.
Addendum
Subsequent to acceptance of our manuscript
for publication, we extended our FDA MedWatch
inquiry through February 2002, and the findings
support our original observations.62–64 We
identified an additional 52 cases of hyper-
glycemia (42 domestic, 10 foreign). Of these, 37
were newly diagnosed hyperglycemia, 13 were
exacerbation of preexistent diabetes, and 2 could
not be categorized. Among the cases with age
information, the mean ± SD age at the time of
diagnosis was 45.1 ± 14.4 years overall (48
patients), 43.4 ± 13.2 years for those with newly
diagnosed hyperglycemia (35 patients), and 50.0
± 17.6 years for those with exacerbation of
preexistent disease (12 patients). Two cases
occurred in children aged 14 and 16 years,
respectively. The male:female ratio was 1.8:1 (51
patients).
Of the 34 patients with ethnic background
information, 19 (56%) were Caucasian, 10 (29%)
were African-American, 3 (9%) were Asian, and 2
(6%) were Hispanic. Among 38 cases with time-
to-onset data, hyperglycemia occurred within 6
months of starting olanzapine in 23 patients
(60%). Ketosis and/or acidosis in the setting of
hyperglycemia was reported in 20 cases. Of five
reports of pancreatitis, four cases were documented
by lipase levels or computed tomographic
findings; two cases were complicated by death.
Eight additional deaths occurred; one of these
deaths occurred in a 35-year-old man within 1
month of diagnosis and after olanzapine had
been discontinued.
Acknowledgments
The authors are indebted to the pharmacists,
nurses, physicians, and patients who submitted
MedWatch reports and particularly to those who
provided follow-up information.
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