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Original Investigation | Meta-analysis

Type 2 Diabetes Mellitus in Youth Exposed to Antipsychotics A Systematic Review and Meta-analysis

Britta Galling, MD1; Alexandra Roldán, MD2; René E. Nielsen, MD, PhD3; Jimmi Nielsen, MD, PhD4,5; Tobias Gerhard, PhD6,7; Maren Carbon, MD1; Brendon Stubbs, PhD8,9; Davy Vancampfort, PhD10; Marc De Hert, MD, PhD10; Mark Olfson, MD, MPH11; Kai G. Kahl, MD12; Andres Martin, MD13; Jeff J. Guo, MD14; Hsien-Yuan Lane, MD, PhD15,16; Fung-Chang Sung, PhD, MPH17; Chun-Hui Liao, MD16,17; Celso Arango, MD18; Christoph U. Correll, MD1,19,20
[+] Author Affiliations
1Psychiatry Research, Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, Glen Oaks, New York
2Department of Psychiatry, Institut d’Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
3Unit for Psychiatric Research, Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
4Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
5Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
6Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey
7Institute for Health, Health Care Policy, and Aging Research, Rutgers University, New Brunswick, New Jersey
8Physiotherapy Department, South London and Maudsley National Health Service Foundation Trust, Denmark Hill, London, England
9Institute of Psychiatry, King’s College London, De Crespigny Park, London, England
10Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Belgium
11New York State Psychiatric Institute, Department of Psychiatry, The College of Physicians and Surgeons, Columbia University, New York
12Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
13Child Study Center, Yale School of Medicine, New Haven, Connecticut
14College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, Ohio
15Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
16Department of Psychiatry, China Medical University, Taichung, Taiwan
17Department of Public Health, China Medical University, Taichung, Taiwan
18Child and Adolescent Psychiatry Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, CIBERSAM, Madrid, Spain
19Hofstra North Shore–Long Island Jewish School of Medicine, Hempstead, New York
20The Feinstein Institute for Medical Research, Manhasset, New York
JAMA Psychiatry. 2016;73(3):247-259. doi:10.1001/jamapsychiatry.2015.2923.
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Importance  Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern.

Objective  To assess T2DM risk associated with antipsychotic treatment in youth.

Data Sources  Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015.

Study Selection  Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months.

Data Extraction and Synthesis  Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk.

Main Outcomes and Measures  The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls

Results  Thirteen studies were included in the meta-analysis, including 185 105 youth exposed to antipsychotics and 310 438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1 342  121 patients and 2 071 135 patient-years), and 8 studies included healthy controls (298 803 patients and 463 084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P < .001) per 1000 patients. The incidence rate was 3.09 (95% CI, 2.35-3.82; P < .001) cases per 1000 patient-years. Compared with healthy controls, cumulative T2DM risk (odds ratio [OR], 2.58; 95% CI, 1.56-4.24; P < .0001) and incidence rate ratio (IRR) (IRR, 3.02; 95% CI, 1.71-5.35; P < .0001) were significantly greater in antipsychotic-exposed youth. Similarly, compared with psychiatric controls, antipsychotic-exposed youth had significantly higher cumulative T2DM risk (OR, 2.09; 95% CI, 1.50-52.90; P < .0001) and IRR (IRR, 1.79; 95% CI, 1.31-2.44; P < .0001). In multivariable meta-regression analyses of 10 studies, greater cumulative T2DM risk was associated with longer follow-up (P < .001), olanzapine prescription (P < .001), and male sex (P = .002) (r2 = 1.00, P < .001). Greater T2DM incidence was associated with second-generation antipsychotic prescription (P ≤ .050) and less autism spectrum disorder diagnosis (P = .048) (r2 = 0.21, P = .044).

Conclusions and Relevance  Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously and for the shortest necessary duration, and their efficacy and safety should be monitored proactively.

Figures in this Article


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Figure 1.
Forest Plot of Incidence Rate Ratio for T2DM per Patient-Years in Antipsychotic-Exposed Youth vs Psychiatric Controls

T2DM indicates type 2 diabetes mellitus.

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Figure 2.
Forest Plot of Incidence Rate Ratio for T2DM per Patient-Years in Antipsychotic-Exposed Youth vs Healthy Controls

FGA indicates first-generation antipsychotic; SGA, second-generation antipsychotic; and T2DM, type 2 diabetes mellitus.

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Figure 3.
Subgroup Analyses: Unadjusted, Cumulative Risk, and Incidence

The T2DM cases in parentheses indicate the number of cases per patient-years if different from T2DM cases per number of patients (data missing of one study53). IRR indicates incidence rate ratio; OR, odds ratio; T1DM, type 1 diabetes mellitus; and T2DM, type 2 diabetes mellitus.

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