WHAT’S NEW: Convincing evidence
This is the first randomized controlled trial to show convincingly that metformin alone or in combination with lifestyle changes is superior to lifestyle changes alone or placebo for reducing weight gain and other adverse metabolic outcomes induced by second-generation antipsychotics.
Intensive lifestyle interventions
Prior studies found that intensive lifestyle interventions can help reduce antipsychotic-related weight gain. A 3-month randomized controlled trial compared an early behavioral intervention (dietary counseling, an exercise program, and behavior therapy) with routine care in 61 patients with first-episode psychosis who were taking risperidone, olanzapine, or haloperidol;6 significantly fewer patients assigned to behavioral intervention had an increased initial body weight of more than 7%: 39% in the behavioral intervention group vs 79% in the routine care group (P<.002).
Small samples, small effect sizes
Past studies of metformin for antipsychotic-associated weight gain have generally shown a small benefit, though small sample sizes and small effect sizes prohibited definitive conclusions. Unlike the study by Wu and colleagues,1 none of these past studies were designed to compare the combination of metformin and lifestyle intervention with metformin alone, lifestyle intervention alone, or placebo alone.
Klein et al conducted a randomized placebo-controlled trial of metformin in 39 children ages 10 to 17 whose weight had increased more than 10% on atypical antipsychotic therapy.7 The children treated with placebo gained a mean of 4 kg and increased their mean BMI by 1.12 kg/m2 during 16 weeks of treatment, while those in the metformin group did not gain weight and decreased their mean BMI by 0.43 kg/m2.
Baptista et al randomized 40 in-patients with schizophrenia, who were being switched from conventional antipsychotics to olanzapine, to either metformin (850-1750 mg/d) or placebo. Both groups gained a similar amount of weight after the 14-week study (5.5 vs 6.3 kg, metformin vs placebo). Three patients who started with high fasting glucose had decreases while taking metformin, and 3 patients given placebo developed elevated fasting glucose during the study.8
In another randomized controlled trial of metformin vs placebo in 80 patients who had been taking olanzapine for at least 4 months, Baptista et al found only a small, insignificant difference in weight loss after 12 weeks of treatment (metformin group lost 1.4 kg, placebo group lost 0.18 kg, P=.09). They reported that both groups were highly motivated to lose weight and were compliant with the healthy lifestyle recommendations.9
An adequately powered study
The trial1 highlighted in this PURL had an adequate sample size to compare metformin plus a lifestyle intervention with either treatment alone or placebo. It showed a clinically important effect of metformin both by itself and in conjunction with the lifestyle intervention.
CAVEATS: Consider switching drugs
Before adding metformin to help with weight loss, primary care clinicians should contact the patient’s psychiatrist to discuss the option of switching antipsychotic medications. Switching from a medication with a higher risk for weight gain, such as olanzapine, to one with a lower risk, such as aripiprazole or ziprasidone, can lead to significant weight loss.10
Not an option for some
However, some patients, especially those taking clozapine, may have already tried multiple antipsychotic agents without success, and switching is not an option for them.
Prescribing metformin
CHALLENGES TO IMPLEMENTATION: Adherence
These study participants were under the care of an adult caregiver who monitored and recorded food and medication intake and exercise level. The lifestyle intervention was thorough and structured and this kind of program is often not available to us for our patients. As a consequence, we may not obtain the same results as in this study. However, even the metformin-alone group showed improvements, and if our patients can reliably take their second-generation antipsychotic, they should also be able to take metformin reliably.
Patient resistance
Some patients may resist taking an additional medication to treat the side effects of their antipsychotic medication. Taking the time to educate them about the increased risk of diabetes and cardiovascular disease related to weight gain may help convince them to do so. Warn them about possible gastrointestinal adverse effects of metformin, which tend to lessen or disappear with time.
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.
