|First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis
|Smith M, Hopkins D, Peveler RC, Holt RI, Woodward M, Ismail K
This review concluded that there was some evidence for a small increased risk of diabetes associated with second-generation antipsychotics compared with first-generation antipsychotics, for people with schizophrenia. There were limitations in both the review methods and the evidence base, but most of these were acknowledged by the authors and their cautious conclusions seem to be appropriate.
To compare the risk of diabetes associated with different classes of antipsychotic drugs taken by people with schizophrenia.
The authors searched MEDLINE, PsycINFO, EMBASE, IPA, CINAHL, and Web of Knowledge to September 2006. Search terms were reported and no language restrictions were imposed. Proceedings of conferences on diabetes (from 2000 to 2005) and reference lists of included studies and reviews were also searched. Corresponding authors of the selected studies and experts on the topic were contacted for additional information on published and unpublished studies.
Eligible studies included children or adults with schizophrenia or related disorders and compared first- versus second-generation antipsychotic drugs. Diabetes had to be measured as a primary or secondary outcome. Cross-sectional, case-control, and cohort studies and controlled trials were eligible. Second-generation antipsychotics were clozapine, olanzapine, risperidone, and quetiapine and first-generation antipsychotics were reported to be those listed in the British National Formulary.
Most of the included studies were in hospital settings and the average patient age, where reported, was 45 years. The studies used a variety of methods to diagnose diabetes, including prescription of diabetes medication. Some studies did not distinguish clearly between new and existing cases of diabetes.
Studies were selected for the review by one author based on an examination of the abstract. Where there was doubt the original article was retrieved and reviewed by all authors.
Assessment of study quality
Studies were considered to be of high quality if they met the following criteria: prospective design; appropriate diagnosis for schizophrenia; all patients did not have diabetes at baseline; consecutive or random sample; objective assessment of exposure to antipsychotic medication; use of accepted diagnostic criteria for diabetes; the time between use of an antipsychotic and development of diabetes was reported with at least one year of follow-up; and the data were controlled for six independent risk factors for diabetes. Studies not meeting each of these criteria or not reporting them were considered to be of low quality for that criterion.
The authors did not state how many reviewers assessed validity.
Approximate relative risks (odds ratios or hazard ratios) and corresponding 95% confidence intervals were extracted, where available. Where only the numbers of patients with diabetes by drug type were reported, these were used to calculate unadjusted odds ratios and 95% confidence intervals. Where the results were given after adjustments for confounding factors, the result for the largest adjusted set was used. Where a study gave separate results for different second-generation drugs, but no overall result, meta-analysis was used to derive a pooled result for all second-generation drugs for that study and this result was used in the main meta-analysis. Attempts were made to contact the study authors where data were missing.
The authors did not state how many reviewers extracted the data.
Methods of synthesis
Quantitative data from high-quality studies were pooled by meta-analysis, using a random-effects model, weighted by inverse variance. Studies in which no cases of diabetes occurred in either group were excluded from the meta-analysis. Heterogeneity between studies was assessed using the I2 statistic. Pooled relative risks were calculated for all second-generation drugs combined and (as a sensitivity analysis) for individual drugs.
Results of the review
Fourteen studies with 143,463 participants in total were included in the review; sample size ranged from 27 to 56,849. Eleven studies had sufficient data for the meta-analysis. Most of the studies were cross-sectional (four), retrospective cohort (five, four in the meta-analysis), or case-control (two); three had a prospective design. Where reported, follow-up ranged from two to 62 months (median 12 months). Most of the studies did not adjust for confounders and did not adjust for all risk factors for diabetes.
The meta-analysis found a statistically significant increased risk of diabetes in patients prescribed a second-generation antipsychotic compared with those taking first-generation drugs (RR 1.32, 95% CI 1.15 to 1.51). Significant heterogeneity was present (I2=80%). Pooled relative risks for risperidone, quetiapine, olanzapine and clozapine ranged from 1.16 to 1.39 and suggested a statistically significant increased risk of diabetes for all drugs, except risperidone.
There was some evidence for a small increased risk of diabetes associated with second-generation antipsychotics compared with first-generation antipsychotics, for people with schizophrenia.
The review question and inclusion criteria were clear. The authors searched a range of sources, without language restrictions, and attempted to locate unpublished studies. The risk of publication bias was not assessed. Study quality was assessed using appropriate criteria and the results were discussed. The authors stated that only high-quality studies were included in the meta-analysis, but it appears that most studies failed to meet several quality criteria. Some details of the included studies were presented in the paper and an online appendix. Study selection was performed by one reviewer in most cases and the processes of quality assessment and data extraction were not reported. This suggests that the review could be at risk of reviewer error and bias.
The meta-analysis pooled studies with different effect measures. From the limited information reported, it is difficult to tell whether this was appropriate, but generally relative risks and odds ratios are similar, when event rates are low, and they can therefore be combined. The presence of a high level of heterogeneity between studies also suggested that the results of the meta-analysis should be treated with caution.
This review had limitations in both its methods and the quality of the available evidence. Most of these limitations were acknowledged by the authors and their cautious conclusions seem to be appropriate.
Implications of the review for practice and research
Practice: The authors stated that people with schizophrenia should be routinely screened for diabetes (this recommendation was not derived from the review findings). They also stated that the evidence from their review should not be used as a guideline for selecting or switching antipsychotic medications.
Research: The authors stated that research was needed to increase the epidemiological evidence base for diabetes in schizophrenia and that future randomised controlled trials comparing first- versus second-generation antipsychotics should consider the trial's power to detect diabetes as an adverse event.
Smith M, Hopkins D, Peveler RC, Holt RI, Woodward M, Ismail K. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. British Journal of Psychiatry 2008; 192(6): 406-411
Subject indexing assigned by NLM
Antipsychotic Agents /classification /therapeutic use; Databases, Bibliographic; Diabetes Mellitus /chemically induced /epidemiology; Epidemiologic Methods; Humans; Middle Aged; Schizophrenia /drug therapy
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.