Abstract
This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu.
Background
Excessive weight gain is a known complication of long-term administration of typical and atypical antipsychotics.1,2 Weight gain is typically significant, may affect compliance, and can be associated with changes in insulin resistance. Several possible mechanisms have been suggested, including increased appetite related to neuronal receptor activity, disruption of metabolic-endocrine weight regulation, or changes in insulin resistance and glucose tolerance.1,2 Metformin improves insulin sensitivity and has been shown to reduce weight gain in patients with diabetes, polycystic ovary syndrome, and primary obesity.
Patient Population
Adult patients with significant weight gain related to antipsychotic therapy
Dosage and Duration
The oral dose is 500 to 2,550 mg daily in adults administered in 2 to 3 divided doses for up to 6 months.
Results
Metformin alone or in combination with lifestyle modification in the treatment and prevention of antipsychotic weight gain has been studied in several meta-analyses and controlled trials, enrolling more than 250 patients.1-8 Most trials lasted less than 6 months (they were most commonly 12 weeks in duration) and suggest a modest weight loss in most patients (approximately 3 to 5 kg).
Meta-analyses
A meta-analysis of available controlled trials (January 1, 1990, through June 30, 2011) evaluated the efficacy of metformin to prevent weight gain or reverse weight gain in users of antipsychotics. In a review of 7 randomized, double-blinded, placebo-controlled trials of metformin, the overall effect supported the use of metformin for this indication with a mean difference of 2.93 kg (95% CI, 0.97-4.89; I2 = 91%) in weight loss with metformin over placebo.2
A meta-analysis of randomized, double-blinded, placebo-controlled trials evaluating metformin for olanzapine-induced weight gain with a study duration of at least 12 weeks were included for review. In addition, outcome measurements must have included body weight, waist circumference, and body mass index (BMI). Twelve studies were identified and 4 were included in the meta-analysis. Weighted mean difference (WMD) for body weight was a 5.02 (95% CI, 3.93-6.10) kg decrease with metformin as compared to placebo at 12 weeks. For waist circumference, the test for heterogeneity was significant (P = .00002; I2 = 85.1%) and a random effects model was used to calculate the WMD, which was 1.42 (95% CI, 0.29-3.13) cm lower in the metformin group compared to placebo at 12 weeks. For BMI, the WMD was 1.82 (95% CI 1.44-2.19) kg/m2 lower with metformin as compared to placebo at 12 weeks.3
Controlled Trials
In a double-blinded, placebo-controlled trial, 72 adult patients (age range, 18 to 60 years) with a first psychotic episode of schizophrenia were randomized to receive 12 weeks of antipsychotics with either metformin (1,000 mg/day) or placebo. Metformin dosing was administered as 250 mg twice daily for the first 3 days, followed by 500 mg twice daily thereafter. Antipsychotics remained at a fixed dose. Oral trihexyphenidyl (for extrapyrimadal symptoms) or lorazepam (for insomnia or agitation) were allowed. The antipsychotics included risperidone sulpiride, clozapine, and olanzapine. Six patients withdrew from the trial within the first 4 weeks because of nausea (n = 3) and exacerbation of psychosis (n = 3). The primary outcome was change in body weight. Secondary outcomes included change in BMI, fasting glucose and insulin levels, and insulin resistance index (IRI). When compared to baseline, over the 12-week study period, patients in the placebo group experienced significant weight gain (mean, 3.9% or 2.5 kg) compared to a significant decrease in the metformin group (mean, 5.1% or 3.3 kg). The BMI changes were also significant in both groups (+0.9 and -1.3, respectively). More patients in the metformin group experienced a greater than 7% weight loss (40.6% vs 8.8%; P = .003). In addition, the mean IRI decreased by 0.4 and 3.5 in the placebo and metformin groups, respectively. There was no change in fasting glucose level from baseline in either group. The authors concluded that metformin is effective in promoting weight loss and improving insulin resistance induced by antipsychotics in patients with the first episode of schizophrenia.4
In a double-blinded, placebo-controlled trial, 40 adult inpatients (age range, 18 to 50 years) with first-episode schizophrenia were randomized to receive olanzapine (15 mg/day) with either metformin or placebo for 12 weeks. Metformin dosing was administered as 250 mg 3 times daily. Oral trihexyphenidyl or lorazepam were allowed as needed. Primary outcomes included change in body weight, BMI, waist circumference, waist to hip ratio, fasting glucose, fasting insulin, IRI, and the percentage of patients who gained more than 7% of their baseline body weight at 3 months. A total of 37 patients completed the trial: 18 in the metformin group and 19 in the placebo group. Body weight, BMI, waist circumference, and waist to hip ratio levels increased less in the metformin group compared to the placebo group. At week 12, mean fasting insulin and IRI levels increased significantly in the placebo group (+6.78 μIU/mL and +1.49; P < .05). No significant changes in these parameters occurred in the metformin group (0.81 μIU/mL and 0.22, respectively). There was no significant change in fasting glucose levels within the 2 groups. Significantly fewer patients in the metformin group gained more than 7% body weight (16.7% vs 63.1%; P < .001). The authors concluded that metformin was effective in reducing olanzapine induced weight gain and insulin resistance in first-episode schizophrenics.5
In a double-blinded, placebo-controlled multicenter trial, 80 adult patients with schizophrenia or bipolar disorder taking olanzapine (5 to 20 mg daily) for more than 4 months were randomized to receive either metformin (850 to 2,550 mg daily) or placebo for 12 weeks. The primary outcome was weight loss as measured by body weight, BMI, and waist circumference. A total of 72 patients completed the study. At 12 weeks, there was a significant decrease in body weight when compared to baseline values in the metformin group (1.4 kg; P = .01) but no significant change in the placebo group (-0.18 kg; P = .07). There were no significant differences in weight change between the groups. BMI was significantly decreased in the metformin group but not in the placebo group, with no differences between the groups. Waist circumference did not significantly change in either group. Glucose and insulin levels and IRI remained stable in the metformin group but significantly increased in the placebo group. Hb1C levels increased in both groups, significantly in the metformin group (P = .011) but not in the placebo group (P = .1) There were no significant differences between the 2 groups for these parameters.6
Safety
This is a limited safety profile. Refer to package labeling for complete prescribing information (eg, Warnings/Precautions, Adverse Reactions, Drug Interactions).
In data reviewed, few adverse events were observed, and there were no significant differences in the side effect profile when compared to placebo.4,7 The most frequently cited reactions related to study withdrawal were nausea or psychosis exacerbation.4,7
Therapy Considerations
Metformin alone or in combination with lifestyle modification in the treatment and prevention of antipsychotic weight gain has been studied in several meta-analyses and controlled trials, suggesting a modest weight loss in most patients (2.93 to 5 kg).
References
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