Article

Prediabetes in Patients Treated With Antipsychotic Drugs

Zucker Hillside Hospital, Glen Oaks, NY 11004, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 12/2011; 73(4):460-6. DOI: 10.4088/JCP.10m06822
Source: PubMed

ABSTRACT

In 2010, the American Diabetes Association (ADA) proposed that individuals with fasting glucose level of 100-125 mg/dL (5.6-6.9 mmol/L) or glucose level of 140-199 mg/dL (7.8-11.0 mmol/L) 2 hours after a 75-g oral glucose tolerance test or hemoglobin A(1c) 5.7%-6.4% be classified as prediabetic, indicating increased risk for the emergence of diabetes mellitus. At the same time, the ADA formulated guidelines for the use of metformin for the treatment of prediabetes.
To determine the prevalence of prediabetes in a cohort of psychiatrically ill adults receiving antipsychotics and to compare the clinical and metabolic features of prediabetic patients with those of patients with normal glucose tolerance and those with diabetes mellitus.
The 2010 ADA criteria were applied to a large, consecutive, single-site European cohort of 783 adult psychiatric inpatients (mean age: 37.6 years) without a history of diabetes who were receiving antipsychotics. All patients in this cross-sectional study underwent measurement of body mass index (BMI), waist circumference, oral glucose tolerance test, and fasting insulin and lipids from November 2003 through July 2007.
413 patients (52.8%) had normal glucose tolerance, 290 (37.0%) had prediabetes, and 80 (10.2%) had diabetes mellitus. The fasting glucose and/or hemoglobin A(1c) criteria were met by 89.7% of prediabetic patients. A statistically significant intergroup gradient from normal glucose tolerance to prediabetes and from prediabetes to diabetes mellitus was observed for waist circumference, triglycerides, fasting insulin levels, and frequency of metabolic syndrome (P = .02 to P < .0001). Only 19/290 prediabetic patients (6.6%) met the 2010 ADA criteria for treatment with metformin.
Prediabetes is highly prevalent in adults treated with antipsychotic drugs and correlates with markers of increased intraabdominal adiposity, enhanced lipolysis, and insulin resistance. Criteria for using metformin to prevent the emergence of diabetes mellitus may need to be revised for this population.

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Available from: Marc De Hert, Feb 01, 2016
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Prediabetes in Patients Taking Antipsychotics
e1
J Clin Psychiatry
Prediabetes in Patients Treated With Antipsychotic Drugs
Peter Manu, MD; Christoph Correll, MD; Ruud van Winkel, MD, PhD;
Martien Wampers, PhD; and Marc De Hert, MD, PhD
ABSTRACT
Background:
In 2010, the American Diabetes
Association (ADA) proposed that individuals
with fasting glucose level of 100–125 mg/dL
(5.6–6.9 mmol/L) or glucose level of 140–199
mg/dL (7.8–11.0 mmol/L) 2 hours after a 75-g
oral glucose tolerance test or hemoglobin A
1c
5.7%–6.4% be classified as prediabetic, indicating
increased risk for the emergence of diabetes
mellitus. At the same time, the ADA formulated
guidelines for the use of metformin for the
treatment of prediabetes.
Objective:
To determine the prevalence of
prediabetes in a cohort of psychiatrically ill
adults receiving antipsychotics and to compare
the clinical and metabolic features of prediabetic
patients with those of patients with normal
glucose tolerance and those with diabetes
mellitus.
Method:
The 2010 ADA criteria were applied to a
large, consecutive, single-site European cohort of
783 adult psychiatric inpatients (mean age: 37.6
years) without a history of diabetes who were
receiving antipsychotics. All patients in this cross-
sectional study underwent measurement of
body mass index (BMI), waist circumference, oral
glucose tolerance test, and fasting insulin and
lipids from November 2003 through July 2007.
Results:
413 patients (52.8%) had normal
glucose tolerance, 290 (37.0%) had prediabetes,
and 80 (10.2%) had diabetes mellitus. The
fasting glucose and/or hemoglobin A
1c
criteria
were met by 89.7% of prediabetic patients.
A statistically significant intergroup gradient
from normal glucose tolerance to prediabetes
and from prediabetes to diabetes mellitus was
observed for waist circumference, triglycerides,
fasting insulin levels, and frequency of metabolic
syndrome (P = .02 to P < .0001). Only 19/290
prediabetic patients (6.6%) met the 2010
ADA criteria for treatment with metformin.
Conclusions:
Prediabetes is highly prevalent
in adults treated with antipsychotic drugs and
correlates with markers of increased intra-
abdominal adiposity, enhanced lipolysis, and
insulin resistance. Criteria for using metformin
to prevent the emergence of diabetes mellitus
may need to be revised for this population.
J Clin Psychiatry
© Copyright 2011 Physicians Postgraduate Press, Inc.
Submitted: December 27, 2010; accepted April 18, 2011.
Online ahead of print: December 27, 2011
(doi:10.4088/JCP.10m06822).
Corresponding author: Peter Manu, MD, Zucker Hillside
Hospital, Medical Services, 75-59 263rd St, Glen Oaks, NY
11004 (pmanu@lij.edu).
I
n January 2010, the American Diabetes Association (ADA) published
criteria for the identification of prediabetes, a term that indicates a high
risk for the future development of diabetes mellitus.
1
The risk is defined by
the results of widely available and highly reliable biochemical assessments,
including impaired fasting glucose (fasting plasma glucose level in the range
of 100–125 mg/dL) or impaired glucose tolerance (plasma glucose level in
the range of 140–199 mg/dL 2 hours after the ingestion of 75 g of glucose)
or a glycosylated hemoglobin (A
1c
) level in the range of 5.7%–6.4%. Predia-
betes is associated with abdominal obesity, hypertension, and dyslipidemia,
with decreased levels of high-density lipoprotein (HDL) cholesterol and/or
increased triglycerides.
1–3
The management of prediabetes aims to prevent or delay the emergence
of type 2 diabetes through weight loss of 5%–10% of body weight and at least
150 min/wk of physical activity of moderate intensity. In addition to these
lifestyle changes, pharmacologic intervention with metformin has been rec-
ommended for patients who have both an elevated fasting glucose level and
abnormal glucose tolerance plus at least 1 other significant risk factor, such as
hemoglobin A
1c
level > 6%, family history of diabetes in a first-degree relative,
obesity, elevated triglycerides, low levels of HDL cholesterol, hypertension,
and age younger than 60 years.
1,4
The prevalence of prediabetes, as reflected in studies published after the
ADAs 2010 statement, is difficult to pinpoint, because the proposed glyco-
sylated hemoglobin (A
1c
) criterion was not uniformly applied and the oral
glucose tolerance test not always performed. The most complete data indi-
cate a prevalence of 29.5% among 2,332 individuals aged 35–74 years from
Qingdao, China,
5
and 44.9% in a multiethnic cohort comprising 8,696 in-
dividuals aged 40–75 years from Leicestershire, United Kingdom.
6
In the
United States, data collected for the National Health and Nutrition Exami-
nation Survey from 2005 to 2006 indicated a prevalence of prediabetes of
34.6% among 1,547 nondiabetic adults (age > 18 years) without a history of
myocardial infarction,
7
but the hemoglobin A
1c
criterion was not used. This
omission may have significance, because prediabetes diagnosed by hemoglo-
bin A
1c
level > 5.6% appears to be more prevalent in the United States than
prediabetes diagnosed by fasting glucose, at least among older adults.
8
A vast body of literature has identified patients treated with second-
generation antipsychotics as a group at high risk for the emergence of type 2
diabetes mellitus.
9–12
This assessment is based on data demonstrating consid-
erable weight accrual during treatment with these drugs, which is the main
reason for the increased prevalence of glucose intolerance,
13–15
atherogenic
dyslipidemia,
16–19
and metabolic syndrome
20–23
in this population. From this
vantage point, the presence of prediabetes has enormous significance because
its identification and proper management could mitigate the adverse meta-
bolic effects of medications used to treat the vast number of patients with
schizophrenia, bipolar disorder, major depression, and other severe mental
illnesses. Simply put, the antipsychotic-related diabetes mellitus generally is
an irreversible condition, while the medical treatment of a prediabetic state
offers the chance of avoiding a disease that leads to multiorgan dysfunction,
shortens life, and contributes greatly to the cost of medical care worldwide.
To our knowledge, this study is the first application of the 2010 ADA
criteria for the definition of prediabetes
1
to a psychiatric population treated
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Prediabetes in Patients Taking Antipsychotics
e2
J Clin Psychiatry
with antipsychotic drugs. Our primary goal was to establish
the prevalence of prediabetes and to compare the psychiat-
ric and metabolic characteristics of patients with this entity
with antipsychotic-treated patients who have normal glucose
tolerance. We further aimed to compare patients who have
prediabetes with those who have diabetes. We hypothesized
the presence of a biological gradient for markers of intraab-
dominal adiposity and insulin resistance from normal glucose
tolerance to prediabetes and then to diabetes and thought that
prediabetes would be more common in patients treated with
second-generation antipsychotics with high metabolic liabil-
ity, such as clozapine and olanzapine, as compared with those
treated with antipsychotics with low to medium metabolic
liability, such as aripiprazole, amisulpride, and risperidone.
METHOD
Setting
From November 2003 through July 2007, consecutively
admitted patients without a history of diabetes, hospitalized
at the University Psychiatric Center, Catholic University
Leuven in Kortenberg, Belgium, were asked by their treat-
ing psychiatrist to agree to a routine metabolic screening.
Psychiatric diagnoses were established according to DSM-IV
by experienced psychiatrists affiliated with the University
Psychiatric Center and responsible for the patients treatment.
Symptom severity was assessed by the treating psychiatrist
using the Global Assessment of Functioning (GAF)
24
from
0 (worst) to 100 (best) and the Clinical Global Impressions
Severity of Illness scale (CGI-S) from 1 (normal) to 7 (ex-
tremely ill).
25
Selection of Subjects
The study cohort comprised 820 nondiabetic patients.
Fifteen patients (1.8%) declined to consent to metabolic
screening, and 22 (2.7%) were not treated with antipsychotic
drugs. Therefore, the data used in this cross-sectional study
were obtained from 783 patients (95.5%) who met the
following inclusion criteria: current treatment with anti-
psychotic drugs; not known prior to admission, including the
period during which they had received outpatient treatment
at our institution, to have diabetes mellitus; and not currently
receiving oral hypoglycemic drugs or insulin. All subjects
gave written informed consent, and the study was approved
by the University Psychiatric Centers Ethics committee.
Metabolic Screening
The metabolic screening included measurements of
height, weight, body mass index (BMI), waist circumference,
arterial blood pressure, glycosylated hemoglobin (A
1c
), and
fasting blood glucose, insulin, and lipids and a 2-hour oral
glucose tolerance test performed after the ingestion of 75 g
of glucose. All laboratory tests were performed in the same
laboratory using the same methods throughout the study
period as described previously.
13
The fasting glucose level, 2-hour postprandial glucose
level during an oral glucose tolerance test, and hemoglobin
A
1c
data were used to define normal glucose tolerance (fast-
ing glucose level less than 100 mg/dL, 2-hour postprandial
glucose level less than 140 mg/dL, and hemoglobin A
1c
level
less than 5.7%), prediabetes (fasting glucose level 100–125
mg/dL, 2-hour postprandial glucose level 140–199 mg/dL,
or hemoglobin A
1c
level 5.7%–6.4%), and diabetes melli-
tus (fasting glucose level greater than 125 mg/dL, 2-hour
postprandial glucose level greater than 199 mg/dL, or hemo-
globin A
1c
level greater than 6.4%).
1
The fasting glucose and
insulin data were used for the homeostatic model assess-
ment of insulin resistance (HOMA-IR).
24
The weight and
height were used to calculate the BMI and classify patients
as underweight (BMI less than 18.5), normal weight (BMI,
18.5–24.9), overweight (BMI, 25.0–29.9), and obese (BMI, 30
or greater). The waist circumference, arterial blood pressure,
and fasting glucose, triglycerides, and HDL cholesterol levels
were used to determine whether the patient met criteria for
metabolic syndrome, which was defined by the presence of
at least 3 of the following 5 items: waist circumference > 88
cm in women and > 102 cm in men, fasting blood glucose
level 100 mg/dL, serum triglycerides 150 mg/dL, HDL
cholesterol < 40 mg/dL in men and < 50 mg/dL in women,
and arterial blood pressure 130/85 mm Hg or current treat-
ment with antihypertensive agents.
26
Statistical Analyses
Analyses of variance and χ
2
tests were used to compare
continuous and categorical variables, respectively, in patients
with normal glucose tolerance, prediabetes, and diabetes
mellitus. The Bonferroni correction was applied to clusters of
dependent variables. Analyses were 2-sided, with α of P < .05,
using JMP 5.0.1, 1989–2003 (SAS Institute Inc, Cary, North
Carolina).
RESULTS
The 783 patients participating in this study had a mean ± SD
age of 37.6 ± 11.7 years, and the gender distribution within the
Clinical Points
In 2010 the American Diabetes Association (ADA)
published criteria for the identification of prediabetes,
a term that indicates a high risk for the future
development of diabetes mellitus: fasting plasma
glucose level in the range of 100–125 mg/dL or a
glycosylated hemoglobin (A
1c
) level in the range of
5.7%–6.4% or plasma glucose level in the range of
140–199 mg/dL 2 hours after the ingestion of 75 g
of glucose.
Prediabetes was identified in 37% of psychiatric
inpatients who were receiving antipsychotics.
Weight reduction through decreased caloric intake
and increased physical activity is the keystone of the
management of prediabetic state in this population.
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Prediabetes in Patients Taking Antipsychotics
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J Clin Psychiatry
sample indicated a moderate male predominance (61.1%). A
substantial majority of the patients had been admitted for the
treatment of schizophrenia (66.9%) or schizoaffective disor-
der (12.6%). Overall, the severity of functional impairment
was moderate, as reflected by a mean CGI-S score of 4.3 and
GAF score of 55.8. Most patients (94.5%) were treated with
second-generation antipsychotics (Table 1).
The proportions of patients treated with the same anti-
psychotic drug for more than 3 months were 81.4% for those
receiving first-generation antipsychotics, 76.0% for cloza-
pine, 56.6% for amisulpride, 46.2% for risperidone, 46.2%
for olanzapine, 38.7% for quetiapine, and 12.2% for ari-
piprazole. In addition to antipsychotics, 337 patients (43%)
were receiving benzodiazepines, 255 (32.6%) were treated
with antidepressants, and 210 (26.8%) were receiving mood
stabilizers. Anticholinergic drugs had been prescribed
to 102 patients (13.0%) for prevention of extrapyramidal
symptoms.
More than half of the patients were overweight (37.2%) or
obese (20.7%), and close to one-third (30.8%) had metabolic
syndrome.
Prevalence of Prediabetes
The 2010 ADA criteria
1
identified normal glucose tol-
erance in 413 subjects (52.8%), prediabetes in 290 subjects
(37.0%), and newly diagnosed diabetes mellitus in 80 sub-
jects (10.2%).
The diagnosis of prediabetes was established by the pres-
ence of 1 criterion in 209 patients (72.1%). Seventy-one
patients (24.5%) had 2 positive criteria, and 10 patients
(3.4%) fulfilled all 3 criteria. An abnormal hemoglobin A
1c
level was the sole defining abnormality in 120 of the 290
prediabetic patients (41.4%). The fasting glucose and/or
hemo globin A
1c
criteria were present in 89.7% of predia-
betic patients.
Demographic and Psychiatric Features
of Prediabetic Patients
Compared with patients with normal glucose tolerance,
the prediabetic group was older (mean age, 40.6 vs 33.7 years,
P < .0001) and had fewer male patients (56.6% vs 66.5%,
P = .007). The distribution of psychiatric diagnoses was es-
sentially similar, the exception being a greater frequency of
schizoaffective disorder in prediabetic patients compared
with subjects with normal glucose tolerance (15.2% vs 9.7%,
P = .03). The groups did not differ significantly in terms of
smoking status, functional impairment, or clinical assess-
ment of the severity of psychiatric illness (Table 1).
Antipsychotic Drug Treatment and Prediabetes
Patients with prediabetes were almost twice as likely to
be treated with clozapine than patients with normal glucose
tolerance (13.3% vs 9.7%, P = .001). The groups were similar
with regard to the utilization of all other second-generation
Table 1. Demographic and Clinical Features of Patients With Normal Glucose Tolerance, Prediabetes, and Newly Discovered
Diabetes
Feature
Total
(N = 783)
Normal Glucose
Tolerance (n = 413)
Normal Glucose Tolerance
vs Prediabetes, P Value
a
Prediabetes
(n = 290)
Prediabetes vs Diabetes
Mellitus, P Value
a
Diabetes
Mellitus (n = 80)
Age, mean ± SD, y 37.6 ± 11.7 33.7 ± 10.7 < .0001 40.6 ± 13.0 .0001 46.9 ± 11.7
Male gender, n (%) 478 (61.1) 275 (66.5) .007 164 (56.6) .22 39 (48.8)
Smoking, n (%) 485 (61.9) 256 (62.0) .73 176 (60.7) .36 53 (66.2)
Psychiatric diagnosis, n (%)
Schizophrenia 524 (66.9) 287 (70.0) .25 191 (65.9) .08 36 (45.0)
Schizoaffective disorder 99 (12.6) 40 (9.7) .03 44 (15.2) .45 15 (18.8)
Bipolar disorder 114 (14.6) 63 (15.3) .35 37 (12.8) .29 14 (7.5)
Major depression 19 (2.4) 5 (1.2) .14 8 (2.7) .07 6 (7.5)
Personality disorder 27 (3.5) 16 (3.9) .77 10 (3.5) .26 1 (1.3)
GAF score, mean ± SD 55.8 ± 12.5 55.3 ± 12.9 .30 56.3 ± 12.4 .67 56.9 ± 10.5
CGI-S score, mean ± SD 4.3 ± 0.9 4.4 ± 0.9 .19 4.3 ± 0.9 .60 4.2 ± 0.9
Antipsychotic drug, n (%)
Olanzapine 236 (30.1) 130 (31.5) .27 80 (27.6) .39 26 (32.5)
Risperidone 195 (24.9) 108 (26.2) .48 69 (23.8) .81 18 (22.5)
Quetiapine 111 (14.2) 58 (14.0) .72 38 (13.1) .21 15 (18.8)
Clozapine 104 (13.3) 40 (9.7) .001 53 (13.3) .33 11 (13.8)
Amisulpride 53 (6.8) 33 (8.0) .37 18 (6.2) .16 2 (2.5)
Aripiprazole 41 (5.2) 25 (6.1) .48 14 (4.8) .34 2 (2.5)
First-generation 43 (5.5) 19 (4.6) .35 18 (6.2) .68 6 (7.5)
a
Boldface values reflect differences statistically significant after Bonferroni correction.
Abbreviations: CGI-S = Clinical Global Impressions-Severity of Illness, GAF = Global Assessment of Functioning.
Table 2. Frequency of Normal Glucose Tolerance, Prediabetes, and Newly Discovered Diabetes by Antipsychotic Used
Variable, n (%)
Olanzapine
(n = 236)
Risperidone
(n = 195)
Quetiapine
(n = 111)
Clozapine
(n = 104)
Amisulpride
(n = 53)
Aripiprazole
(n = 41)
First-Generation
Antipsychotic (n = 43)
Normal glucose tolerance 130 (55.1) 108 (55.4) 58 (52.8) 40 (38.4) 33 (62.2) 25 (60.9) 19 (44.1)
Prediabetes
a
80 (33.9) 69 (35.4) 38 (34.2) 53 (51.0) 18 (34.0) 14 (34.2) 18 (41.9)
Diabetes mellitus
b
26 (11.0) 18 (9.2) 15 (13.5) 11 (10.6) 2 (3.8) 2 (4.9) 6 (14.0)
a
P = .097 across the row.
b
P = .340 across the row.
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Prediabetes in Patients Taking Antipsychotics
e4
J Clin Psychiatry
antipsychotics and of first-generation antipsychotics. The
prevalence of prediabetes was highest in patients treated
with clozapine (51.0%) and lowest among those receiving
olanzapine (33.9%), but across all antipsychotics used, the
P value was not significant (Table 2). The proportion of pa-
tients comedicated with mood-stabilizing drugs was similar
in the groups with normal glucose tolerance and prediabetes
(25.9% vs 25.5%, P = .91), and there were no differences in
the frequency of utilization of lithium (5.3% vs 3.8%, P = .34)
and valproic acid (18.4% vs 17.6%, P = .78).
Markers of Metabolic Abnormalities in Prediabetes
The 2010 ADA criteria separated well patients with pre-
diabetes from those with normal glucose tolerance and those
with diabetes, as demonstrated by the strong statistical sig-
nificance (P < .0001) of the comparisons of fasting glucose,
2-hour postprandial glucose, and hemoglobin A
1c
levels.
Fasting insulin levels and HOMA-IR were also clearly dif-
ferent in the 3 groups (Table 3).
Insulin resistance, as assessed by HOMA-IR values, had
a crescendo gradient from normal glucose tolerance to
prediabetes to diabetes in patients treated with clozapine
(P < .0001), olanzapine (P < .0001), quetiapine (P < .0001),
risperidone (P < .0001), and amisulpride (P = .0014) but not
in patients treated with aripiprazole (P = .246) and first-
generation antipsychotics (P = .154).
The proportion of obese individuals (BMI 30) was
almost double in the prediabetes group compared with par-
ticipants with normal glucose tolerance (25.2% vs 13.6%,
P = .0001). The waist circumference was significantly larger
in prediabetic patients than in subjects with normal glucose
tolerance, particularly for female patients (Table 3).
Compared with the normal glucose tolerance group, pre-
diabetic patients had higher mean plasma triglyceride levels
(138.5 vs 159.2 mg/dL, P = .002) and low-density lipoprotein
(LDL) cholesterol levels (114.2 vs 122.8 mg/dL, P = .003). The
groups were essentially similar with regard to fasting total
cholesterol and HDL cholesterol (Table 3).
The prevalence of metabolic syndrome among patients
with prediabetes was substantially higher than in patients
with normal glucose tolerance (41.0% vs 16.2%, P < .0001).
Progression of Anthropometric and Metabolic
Abnormalities From Prediabetes to Diabetes
Compared with prediabetic patients, those with newly dis-
covered diabetes mellitus in our cohort were older (P = .0001),
had a higher BMI (P = .0001), a greater prevalence of obe-
sity (P = .006), a larger waist circumference (P = .0003 for
males and P = .0045 for females), higher triglycerides levels
(P = .0017), and a greater prevalence of metabolic syndrome
(P < .0001).
Prediabetic Patients Eligible
for Treatment With Metformin
Twenty-one of the 290 prediabetic patients (7.2%) had
a fasting glucose level in the range of 100–125 mg/dL and
a 2-hour response to the 75-g glucose tolerance test in the
range of 140–199 mg/dL. Nineteen of these 21 patients
(90.5%) also had at least 1 other notable risk factor, such as
hemoglobin A
1c
level > 6%, family history of diabetes in a
Table 3. Anthropometric and Metabolic Features of Patients With Normal Glucose Tolerance, Prediabetes, and Newly
Discovered Diabetes
Feature
Tot al
(N = 783)
Normal Glucose
Tolerance
(n = 413)
Normal Glucose
Tolerance vs Prediabetes,
P Value
a
Prediabetes
(n = 290)
Prediabetes
vs Diabetes
Mellitus, P Value
a
Diabetes
Mellitus
(n = 80)
BMI, mean ± SD 26.4 ± 4.9 25.7 ± 4.3 .005 26.7 ± 5.4 .0001 29.4 ± 5.8
BMI, n (%)
< 18.5 19 (2.4) 8 (1.9) .14 11 (3.8) .02 0 (0)
18.5–24.9 311 (39.7) 181 (43.8) .12 110 (37.9) .03 20 (25.0)
25.0–29.9 291 (37.2) 168 (40.7) < .05 96 (33.1) .91 27 (33.8)
> 29.9 162 (20.7) 56 (13.6) .0001 73 (25.2) .006 33 (41.3)
Waist circumference, mean ± SD, cm
Male 96.3 ± 12.3 94.4 ± 11.0 .02 97.2 ± 13.1 .0003 105.7 ± 12.9
Female 92.4 ± 15.5 88.5 ± 13.8 .004 93.7 ± 15.1 .005 101.8 ± 17.7
Fasting glucose level, mean ± SD, mg/dL 91.7 ± 12.2 85.4 ± 6.4 < .0001 93.4 ± 10.9 < .0001 117.9 ± 28.6
2-h Postprandial glucose level, mean ± SD
b
104.4 ± 26.2 84.4 ± 21.5 < .0001 108.5 ± 37.6 < .0001 192.7 ± 73.5
Hemoglobin A
1c
, % 5.5 ± 0.4 5.2 ± 0.3 < .0001 5.7 ± 0.4 < .0001 6.3 ± 0.7
Fasting insulin, mean ± SD, μU/mL 11.7 ± 9.2 9.9 ± 7.2 .0007 11.9 ± 8.2 < .0001 20.2 ± 17.9
HOMA-IR, mean ± SD 2.8 ± 2.9 2.1 ± 1.6 < .0001 2.8 ± 2.1 < .0001 6.3 ± 7.1
Total cholesterol, mean ± SD, mg/dL 202 ± 78.3 197.7 ± 97.8 .21 205.4 ± 43.2 .19 213.4 ± 62.2
Triglycerides, mean ± SD, mg/dL 153.7 ± 108.5 138.5 ± 81.2 .002 159.2 ± 95.5 .002 212.0 ± 220.2
Cholesterol, mean ± SD, mg/dL
LDL 118.5 ± 38.5 114.2 ± 35.9 .003 122.8 ± 40.6 .75 124.5 ± 43.3
HDL
Males 46.7 ± 13.0 47.2 ± 13.3 .77 46.8 ± 12.4 .16 43.6 ± 13.5
Females 60.0 ± 17.7 63.1 ± 18.1 < .05 58.8 ± 16.0 .06 53.4 ± 15.2
Metabolic syndrome, n (%) 241 (30.8) 67 (16.2) < .0001 119 (41.0) < .0001 55 (68.8)
No. of metabolic syndrome criteria,
mean ± SD
1.8 ± 1.2 1.3 ± 1.1 < .0001 2.1 ± 1.3 < .0001 3.3 ± 1.4
a
Boldface values reflect differences statistically significant after Bonferroni correction.
b
Glucose level taken during an oral glucose tolerance test.
Abbreviations: BMI = body mass index, HDL = high-density lipoprotein, HOMA-IR = homeostatic model assessment of insulin resistance,
LDL = low-density lipoprotein, OGTT = oral glucose tolerance test.
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Prediabetes in Patients Taking Antipsychotics
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first-degree relative, obesity, elevated triglycerides, low levels
of HDL cholesterol, hypertension, and age younger than 60
years, and were, therefore, eligible for treatment with met-
formin according to the 2010 guidelines published by the
ADA.
4
The metformin-eligible prediabetic patients were similar
with regard to age, gender, psychiatric diagnosis, severity
of illness, global assessment of function, and fasting insulin
levels compared with the 271 prediabetic patients who did
not fulfill the criteria for treatment with metformin, but the
metformin-eligible patients had a higher mean ± SD BMI
(30.0 ± 7.3 vs 26.5 ± 5.1, P = .0049) and larger mean ± SD waist
circumference (102.7 ± 14.8 cm vs 95.1 ± 13.9 cm, P = .0230)
and were more likely to receive clozapine (36.8% vs 17.0%,
P = .03).
DISCUSSION
In the first application of the 2010 ADA diagnostic
guidelines
1
to a European patient population treated with
antipsychotic drugs, 37% fulfilled criteria for prediabetes
and 10.2% had previously undiagnosed diabetes. Compared
with patients with normal glucose tolerance, the prediabetic
patients were older and had higher body mass index and
prevalence of overweight and obesity, increased abdominal
adiposity, higher insulin levels and resistance to insulin,
higher levels of atherogenic lipids (ie, LDL cholesterol and
triglycerides), and an increased prevalence of metabolic
syndrome. The excess in body mass index and abdominal
distribution of adiposity found by us confirms the primary
role of central obesity in the pathogenesis of insulin resis-
tance in this population.
9–11
The largest contributor to the identification of predia-
betes in this sample of psychiatric patients was the test for
hemoglobin A
1c
, which was the sole defining abnormality in
120 of the 290 prediabetic patients (41.4%). The fasting glu-
cose and/or hemoglobin A
1c
criteria were present in 89.7%
of prediabetic patients. These findings highlight 3 important
contributions of our study to clinical practice and research.
First is the fact that the addition of hemoglobin A
1c
to the def-
inition of prediabetes produces a remarkable increase in its
prevalence. Second is that reliance on fasting glucose, advo-
cated by the American Psychiatric Association in the widely
used guidelines for detection of metabolic abnormalities in
patients treated with second-generation antipsychotics,
26,27
is likely to miss a majority of patients with prediabetes. Third
is that the more cumbersome test of oral glucose tolerance
has only a limited value for the discovery of prediabetes in
this population.
The point prevalence of prediabetes was similarly high in
patients treated with first- and second-generation antipsy-
chotics. This finding might seem surprising, given the widely
spread belief in a difference in “metabolic liability” between
these 2 classes of drugs, which was considered a reflection
of their lower appetite-stimulating effect through central H
1
receptor blockade. In fact, first-generation antipsychotics are
part of a heterogeneous group of compounds, and treatment
with the so-called low-potency drugs from this class has
been recently shown to be associated with an increased risk
for diabetes that was similar to those of olanzapine and clo-
zapine.
9,14
Within the second-generation antipsychotic class,
clozapine was noted to have the strongest association with
prediabetes (point prevalence, 51%), a predictable finding,
given its established potential for significant weight gain and
alteration in insulin sensitivity and production.
9,14
In con-
trast stands the fact that the prevalence of prediabetes among
patients treated with olanzapine (33.9%) is much lower than
in patients receiving clozapine, despite similar central H
1
affinity of these 2 drugs and comparable treatment-emergent
weight gain.
9,28
Our data suggest a potential metabolic advantage of
aripiprazole, but the findings must be interpreted very cau-
tiously, given the fact that only a minority of patients had
been receiving this drug for more than 3 months. If con-
firmed in longitudinal research, a possible explanation
might be a more frequent progression to diabetes in patients
treated with olanzapine, clozapine, and low- and mid-
potency first-generation antipsychotics than in those receiv-
ing aripiprazole,
14
which is also suggested by the substantial
difference in the rate of diabetes among patients treated with
these drugs and aripiprazole in our cohort. The findings also
indicate that aripiprazole is unique among second-generation
antipsychotics used in this clinical sample with regard to the
crescendo gradient of insulin resistance from normal glu-
cose tolerance to prediabetes and diabetes, as HOMA-IR was
statistically similar in prediabetic and diabetic patients
treated with aripiprazole. Of interest is also the fact that
prediabetes was not associated with a greater utilization
of valproic acid, despite reports indicating that this mood
stabilizer contributes to weight gain in pediatric and adult
patients.
29
Finally, nonpharmacologic factors, such as un-
healthy lifestyle behaviors and genetic/familial risk,
30
might
also increase the risk for the emergence of prediabetes.
Of great importance for the management of prediabetes
is the identification of patients eligible for treatment with
metformin.
4,21
In our cohort, only 21 prediabetic patients
(7.2%) had concomitant impaired fasting glucose and glu-
cose tolerance, a frequency that is slightly lower than those
observed in surveys of the general population, ranging
from 8.2%–9.4%.
4,21
Nineteen of the 21 patients (6.6% of
prediabetic patients) had at least 1 additional risk factor for
diabetes and were, thus, eligible for a therapeutic trial with
metformin. Compared with the other prediabetic patients,
those eligible for treatment with metformin were more likely
to be treated with clozapine and had larger waist circum-
ferences. The use of metformin for prevention of diabetes
is not approved by the US Food and Drug Administration
but has been proposed by expert panels convened by the
American Diabetes Association
31
and the American College
of Endocrinology.
4,32,33
Metformin might be particularly
beneficial in psychiatric patients whose prediabetes has been
produced by antipsychotic-related weight gain, a population
in which the use of this drug has led to significant weight loss
and reduced intraabdominal adiposity.
34
Page 5
©
COPYRIGHT 2011 PHYSICIANS POSTGRADUATE PRESS, INC.
©
COPYRIGHT 2011 PHYSICIANS POSTGRADUATE PRESS, INC.
Prediabetes in Patients Taking Antipsychotics
e6
J Clin Psychiatry
The results of this study need to be interpreted within its
limitations. Although relatively large, the study cohort was
predominantly white and drawn from a European country
with a relatively high standard of living and easy access to
high-quality medical care. In addition, the cross-sectional
design of the study prevented the assessment of the relation-
ships between the development of glucose intolerance, the
duration of the psychiatric illness, and psychotropic drug
regimen. Furthermore, the number of measured noncardio-
metabolic variables was limited and missing regarding lifestyle
behaviors. The cohort included patients with a primary
diagnosis of schizophrenia, mood disorders, and personal-
ity disorder, who may have different lifestyle behaviors and
genetic factors that influence cardiometabolic risk prior to
the administration of antipsychotic drugs.
35
Nonetheless,
while awaiting confirmation in additional, multiethnic sam-
ples and from other continents, the finding that more than
1 of 3 antipsychotic-treated mentally ill adults in this study
had prediabetes is clearly alarming. These results should
further stimulate concerted efforts toward widespread car-
diometabolic monitoring, which has remained inadequate,
36
as well as toward more aggressively preserving or restoring
glucose tolerance, insulin sensitivity, and overall metabolic
health.
30,37
Drug names: aripiprazole (Abilify), clozapine (Clozaril, FazaClo, and
others), lithium (Lithobid and others), metformin (Fortamet, Glucophage,
and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone
(Risperdal and others), valproic acid (Stavzor, Depakene, and others).
Author affiliations: Zucker Hillside Hospital, Glen Oaks, and Albert
Einstein College of Medicine, Bronx (Drs Manu and Correll); Feinstein
Institute for Medical Research, Manhasset (Dr Correll), New York;
University Psychiatric Center, Catholic University Leuven, Kortenberg,
Belgium (Drs van Winkel, Wampers, and De Hert); and South Limburg
Mental Health Research and Teaching Network, Maastricht University,
Maastricht, The Netherlands (Dr van Winkel).
Author contributions: Drs Manu and Correll contributed equally to
this work.
Potential conflicts of interest: Dr Manu has served on speakers or
advisory boards of Eli Lilly, Bristol-Myers Squibb, and Forest. Dr Correll
has been a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly,
Intra-Cellular Threrapies, Pfizer, and Otsuka; has received grant/
research support from NARSAD, National Institute of Mental Health,
and Ortho-McNeil-Janssen; has received honoraria from Abbott and
Ortho-McNeil-Janssen; has served on speakers or advisory boards of
Actelion, AstraZeneca, Bristol-Myers Squibb, Intra-Cellular Therapies,
Merck, Otsuka, Pfizer, and Sepracor/Sunovion; and has been a Data
Safety Monitoring Board Member of Bristol-Myers Squibb, Cephalon,
and Otsuka. Dr De Hert has been a consultant to, received grant/research
support and honoraria from, and has served on speakers or advisory
boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag,
and Sanofi-Aventis. Drs van Winkel and Wampers report no financial
or other potential conflicts of interest.
Funding/support: None reported.
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Page 7
  • Source
    • "Medication-induced carbohydrate craving and/or reduced activity levels because of sedation cause weight gain (Elmslie et al., 2001). Especially the use of second generation antipsychotics (SGAs) is associated with glucose dysregulation (Guo et al., 2006; Manu et al., 2012 Manu et al., , 2014). Additionally, life-style factors and specific psychopathological features could increase the prevalence of T2DM in patients with bipolar disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Abnormalities in the glucose metabolism cause nervous and organic damage and are a cardiovascular risk factor. They could be a main cause for the increased morbidity and mortality rates found in patients with bipolar disorders. The exact prevalence of diabetes and pre-diabetic abnormalities, however, is not clear. Methods: 85 euthymic outpatients with bipolar disorders from two university hospitals in Germany underwent an oral glucose tolerance test, laboratory screening and clinical measurements. Socio-demographic data, medication, severity of illness, global functioning and life quality were assessed. Results: Diabetes mellitus was found in 7% of the patients, pre-diabetic abnormalities in 27%. The group of patients with abnormalities in the glucose metabolism had significantly lower quality of life and global functioning. Higher BMI, leptin, triglycerides and CRP levels significantly increased the likelihood for pre-diabetes/diabetes. Limitations: The low sample size did only allow limited assessment of impact of medication on the results. No healthy controls were assessed. Conclusions: One-third of the patients with bipolar disorders showed abnormalities in the glucose metabolism and this was associated with impaired global functioning and lower quality of life. Early detection and intervention strategies fitting the needs of patient with bipolar disorder are needed to improve both physical and mental health.
    Full-text · Article · Sep 2015 · Journal of Affective Disorders
  • Source
    • "Neuropharmacology atypical antipsychotics have a reduced liability to trigger extrapyramidal side effects, they induce intolerable metabolic side effects (Manu et al., 2012). Therefore, it remains critical to identify additional therapeutic mechanisms for treatment of psychotic symptoms associated with schizophrenia and other psychiatric disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Studies described here tested the hypothesis that phosphodiesterase 10A inhibition by a selective antagonist, MP-10, activates the dopamine D2 receptor expressing medium spiny neurons to a greater extent than the D1 receptor expressing neurons. We used regional pattern of c-Fos induction in the neostriatal subregions of rodents and direct assessment of D1-positive and-negative neurons in the DRd1a-tdTomato mice for the purpose. MP-10 (1, 3, 10 or 30 mg/kg, PO) dose-dependently increased c-Fos immunopositive nuclei in all regions of neostriatum. However, the effect was statistically greater in the dorsolateral striatum, a region known to be activated preferentially by the D2 antagonism, than the D1-activated dorsomedial striatum. The D2 antagonist, haloperidol (0.3, 1, or 3 mg/kg, PO) produced an identical, regional pattern of c-Fos induction favoring the dorsolateral striatum of the rat. In contrast, the D1 agonist, SKF82958 (0.5, 1, or 2 mg/kg, PO), induced greater expression of c-Fos in the dorsomedial striatum. The C57Bl/6 mouse also showed regionally preferential c-Fos activation by haloperidol (2 mg/ kg, IP) and SKF82858 (3 mg/kg, IP). In the Drd1a-tdTomato mice, MP-10 (3 or 10 mg/kg, IP) increased c-Fos immunoreactivity in both types of neurons, the induction was greater in the D1-negative neurons. Taken together, both the regional pattern of c-Fos induction in the striatal sub-regions and the greater induction of c-Fos in the D1-negative neurons indicate that PDE10A inhibition produces a small but significantly greater activation of the D2-containing striatopallidal pathway.
    Full-text · Article · Jul 2015 · Neuropharmacology
  • Source
    • "Obesity and insulin resistance are recognised side effects of some antipsychotic drugs, and 37 % of a large cohort of 783 adult psychiatric inpatients receiving this treatment were recently found to have prediabetic dysglycaemia Significant improvement with metformin in HOMA- IR and fasting insulin BMI body mass index, IGT impaired glucose tolerance, IFG impaired fasting glucose, FPG fasting plasma glucose, HOMA-IR homeostatic model assessment–insulin resistance [142]. A number of randomised, controlled trials have demonstrated benefits in terms of improved glycaemic regulation and weight loss associated with coadministration of metformin with antipsychotic gents143144145146147148149150. "
    [Show abstract] [Hide abstract] ABSTRACT: People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed 'prediabetic'. The term prediabetes usually refers to high-normal fasting plasma glucose (impaired fasting glucose) and/or plasma glucose 2 h following a 75 g oral glucose tolerance test (impaired glucose tolerance). Current US guidelines consider high-normal HbA1c to also represent a prediabetic state. Individuals with prediabetic levels of dysglycaemia are already at elevated risk of damage to the microvasculature and macrovasculature, resembling the long-term complications of diabetes. Halting or reversing the progressive decline in insulin sensitivity and β-cell function holds the key to achieving prevention of type 2 diabetes in at-risk subjects. Lifestyle interventions aimed at inducing weight loss, pharmacologic treatments (metformin, thiazolidinediones, acarbose, basal insulin and drugs for weight loss) and bariatric surgery have all been shown to reduce the risk of progression to type 2 diabetes in prediabetic subjects. However, lifestyle interventions are difficult for patients to maintain and the weight loss achieved tends to be regained over time. Metformin enhances the action of insulin in liver and skeletal muscle, and its efficacy for delaying or preventing the onset of diabetes has been proven in large, well-designed, randomised trials, such as the Diabetes Prevention Program and other studies. Decades of clinical use have demonstrated that metformin is generally well-tolerated and safe. We have reviewed in detail the evidence base supporting the therapeutic use of metformin for diabetes prevention.
    Full-text · Article · Jun 2015 · Drugs
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