Findings of meta-analysis suggest concurrent metformin administration may reduce the metabolic risk of those taking atypical antipsychotic agents

A systematic review and meta-analysis conducted by researchers at the University of Connecticut (UCONN) School of Pharmacy, Storrs, Conn., and Hartford Hospital, Hartford, Conn., suggest that using metformin along with atypical antipsychotic agents (such as olanzapine, risperidone, quetiapine, and clozapine) may result in better anthropometric measurements and decreased insulin resistance.

The meta-analysis, which systematically pooled available literature through December 31, 2008, has recently been made available on-line ahead-of-print in the Journal of Clinical Psychiatry.

Atypical antipsychotic agents are efficacious agents for the treatment of psychiatric illness, but studies such as CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) have shown that their use is associated with adverse metabolic effects including cardiovascular disease, obesity, reductions in insulin sensitivity, and more type 2 diabetes mellitus. Furthermore, data suggests that atypical antipsychotic agent effectiveness may be limited by the impact of these side effects on adherence.

According to Craig I. Coleman ,PharmD, senior investigator on the project and associate professor of Pharmacy Practice at the UCONN School of Pharmacy, “Our meta-analysis provides further evidence that some types of metabolic disturbances can be attenuated with metformin.” Dr Coleman continued on to explain that those at high-risk of developing new-onset diabetes because of insulin resistance and/or obesity have also been found to benefit from drug therapy with metformin and some other oral anti-diabetic agents including glitazones and alpha-glucosidase inhibitors.

In order to conduct their meta-analysis, researchers conducted a systematic literature search of MEDLINE, EMBASE, and Cochrane CENTRAL in order to identify randomized, placebo-controlled trials of metformin in patients taking atypical antipsychotic agents and reporting data on at least 1 of the following end points: body weight, body mass index, waist circumference, insulin resistance (determined using the homeostasis model assessment of insulin resistance [HOMA-IR]), or a new diagnosis of diabetes mellitus.

Their search ultimately identified 6 trials randomly assigning a total of 336 participants to either metformin (dose ranging from 750 mg to 2,250 mg/d) or placebo for 12 to 16 weeks. All trials required patients to be receiving an atypical antipsychotic agent associated with a high- (clozapine and olanzapine) or moderate-risk (quetiapine and risperidone) of metabolic disturbances. Compared with placebo, those receiving metformin had a significantly reduced body weight (weighted mean difference, 3.16 kg, 95% CI, -4.80 to -1.53; P=.0002), body mass index (weighted mean difference, 1.21 kg/m2, 96% CI, -1.84 to -0.59; P=.0001), waist circumference (weighted mean difference, 1.99 cm, 95% CI, -3.39 to -0.59; P=.005), and HOMA-IR (insulin resistance) measurements (weighted mean difference, 1.71, 95% CI, -2,88 to -0.53; P=.004) compared with placebo.

A trend toward a reduction in risk of new-onset diabetes was also seen, albeit not statistically significant (relative risk reduction, 70%; P=.13).

“I would not rule out the possibility that metformin could slow or prevent the development of diabetes in those taking atypical antipsychotic agents,” emphasized Dr. Coleman. “Our analysis was likely underpowered to evaluate this particular end point due to the small number of cases observed in clinical trials.”

The researchers also evaluated whether metformin would likely have differing efficacy in adults compared to children or whether it was started at the time of atypical antipsychotic therapy or added to existing therapy. “It did not appear that any of these variables greatly altered the efficacy of metformin,” said Dr. Coleman.

The paper concluded by suggesting that additional randomized controlled trials be conducted to confirm this meta-analysis’ findings. In particular, the researchers point out the paucity of data with metformin in patients taking multiple antipsychotic agents at one time. The authors also stressed that while the available data support consideration of this intervention in clinical practice, either dechallenge from the offending atypical antipsychotic agent or re-emphasizing lifestyle modification, may be preferable initial strategies to adding on an additional medication.