Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies

Abstract

Atypical antipsychotics increase the risk of diabetes and cardiovascular disease through their side effects of insulin resistance and weight gain. The populations for which atypical antipsychotics are used carry a baseline risk of metabolic dysregulation prior to medication which has made it difficult to fully understand whether atypical antipsychotics cause insulin resistance and weight gain directly. The purpose of this work was to conduct a systematic review and meta-analysis of atypical antipsychotic trials in healthy volunteers to better understand their effects on insulin sensitivity and weight gain. Furthermore, we aimed to evaluate the occurrence of insulin resistance with or without weight gain and with treatment length by using subgroup and meta-regression techniques. Overall, the meta-analysis provides evidence that atypical antipsychotics decrease insulin sensitivity (standardized mean difference=-0.437, p<0.001) and increase weight (standardized mean difference=0.591, p<0.001) in healthy volunteers. It was found that decreases in insulin sensitivity were potentially dependent on treatment length but not weight gain. Decreases in insulin sensitivity occurred in multi-dose studies <13days while weight gain occurred in studies 14days and longer (max 28days). These findings provide preliminary evidence that atypical antipsychotics cause insulin resistance and weight gain directly, independent of psychiatric disease and may be associated with length of treatment. Further, well-designed studies to assess the co-occurrence of insulin resistance and weight gain and to understand the mechanisms and sequence by which they occur are required.

Keywords: Antipsychotic; Insulin; Meta-analysis; Weight.

Figure 1. Forest Plot of Insulin Sensitivity Meta-Analysis

Forest plot based on pooled standardized mean differences in insulin sensitivity for each study. Square sizes are proportional to each study’s statistical weight in the meta-analysis. Diamond represents overall estimated effect of AAP on insulin sensitivity.

Figure 2. Forest Plot of Weight Meta-Analysis

Forest plot based on pooled standardized mean differences in weight for each study. Square sizes are proportional to each study’s statistical weight in the meta-analysis. Diamond represents overall estimated effect of AAP on weight.

Figure 3. Subgroup Analysis of Insulin Sensitivity by Weight Gain

Forest plot based on pooled standardized mean differences in insulin sensitivity for each study grouped by significant weight gain (determined from meta-analysis by weight). Square sizes are proportional to each study’s statistical weight in the meta-analysis. Diamond represents overall estimated effect of AAP on insulin sensitivity for studies that did not have significant weight gain (labeled as “No”), studies that did have significant weight gain (labeled as “Yes) and all studies combined (labeled as “Overall”).

Figure 4. Subgroup Analysis of Insulin Sensitivity by Treatment Length

Forest plot based on pooled standardized mean differences in insulin sensitivity for each study grouped by significant treatment length. Group 1.0 were single-dose studies, Group 2.0 were studies 13 days and less and Group 3.0 were studies 14 days and longer (max 28 days). Square sizes are proportional to each study’s statistical weight in the meta-analysis. Diamond represents overall estimated effect of AAP on insulin sensitivity for each subgroup and overall.

Figure 5. Subgroup Analysis of Weight by Treatment Length

Forest plot based on pooled standardized mean differences in weight for each study grouped by significant treatment length. Group 2.0 were studies 13 days and less and Group 3.0 were studies 14 days and longer (max 28 days). Single-dose studies were not included because studies did not record weight before and after single dose. Square sizes are proportional to each study’s statistical weight in the meta-analysis. Diamond represents overall estimated effect of AAP on weight for each subgroup and overall.