Article

The Effect of Metformin on Anthropometrics and Insulin Resistance in Patients Receiving Atypical Antipsychotic Agents: A Meta-Analysis

University of Connecticut School of Pharmacy, Storrs, Connecticut, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 04/2010; 71(10):1286-92. DOI: 10.4088/JCP.09m05274yel
Source: PubMed

ABSTRACT

In the Clinical Antipsychotic Trials of Intervention Effectiveness, atypical antipsychotics (AAPs) were found to be associated with weight gain and impairment of glucose metabolism. While metformin has been shown to attenuate weight gain and insulin resistance, not all studies have shown a benefit in the reduction of antipsychotic-induced weight gain and insulin resistance.
To characterize metformin's impact on anthropometrics and insulin resistance in patients taking AAPs.
A systematic literature search of MEDLINE, EMBASE, and Cochrane CENTRAL was conducted from the earliest possible date through December 31, 2008. The search was performed using the following Medical Subject Headings and text keywords: metformin, biguanide(s), in combination with neuroleptic(s), neuroleptic drug(s), antipsychotic(s), dopamine antagonist(s), atypical antipsychotic(s), psychotropic(s), risperidone, olanzapine, quetiapine, ziprasidone, sulpiride, clozapine, iloperidone, aripiprazole, paliperidone, melperone, bifeprunox, amisulpride, zotepine, and sertindole.
Six of 62 identified studies (N = 336 participants) met our inclusion criteria: randomized, placebo-controlled trials of metformin in patients taking AAPs with data on weight, body mass index (BMI), waist circumference, insulin resistance (determined using the homeostasis model assessment of insulin resistance [HOMA-IR]), and/or a diagnosis of diabetes.
Data were independently abstracted by 2 investigators; disagreements were resolved through discussion or by a third investigator using a standardized data abstraction tool. For continuous endpoints, the weighted mean difference (WMD) of the change from baseline with 95% CI was calculated as the difference between the mean in the metformin and placebo groups. For categorical endpoints, the pooled relative risk (RR) with 95% CI was calculated. A random-effects model was used for all analyses.
Compared to placebo, the metformin group had significantly reduced weight (WMD, 3.16 kg; P = .0002), BMI (WMD, 1.21 kg/m²; P = .0001), waist circumference (WMD, 1.99 cm; P = .005), and HOMA-IR (WMD, 1.71; P = .004). The reduction in risk of diabetes was not statistically significant (RR, 0.30; P = .13).
This analysis suggests that using metformin in patients treated with AAPs may reduce metabolic risks. Additional randomized controlled trials are needed, but available data support consideration of this intervention in clinical practice.

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    • "The most efficacious of these for opposing weight gain is metformin, although results have proven to be inconsistent (Baptista et al., 2008), while both sibutramine and topiramate can facilitate weight loss (Das et al., 2012; Fiedorowicz et al., 2012). Metformin and rosiglitazone can also reduce glucose intolerance and insulin resistance in patients treated with SGAs (Baptista et al., 2009; Ehret et al., 2010). Nevertheless, both weight gain and glucose intolerance are only partially reversed by anti-diabetic drugs, and many of these medications carry additional health risks (Loke et al., 2011). "
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    ABSTRACT: Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.
    Preview · Article · Aug 2013 · The International Journal of Neuropsychopharmacology
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    • "Previous studies have indicated that activating AMPK with metformin (a classic approach to treat the metabolic syndrome) confers a disappointingly small beneficial effect against some of the metabolic effects of OLZ (Ehret et al., 2010 "
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    ABSTRACT: Olanzapine (OLZ) is an effective treatment for schizophrenia and other disorders, but causes weight gain and metabolic syndrome. Most studies to date have focused on potential effects of OLZ on CNS mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in systemic effects of OLZ. The purpose of this study was to therefore investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg/d) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for GCxGC-TOF MS metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a 'pseudo-fasted' state, which depleted hepatic glycogen reserves; OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMPK signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mTOR) pathways, and yield new insight into the metabolic side effects of this drug.
    Full-text · Article · Aug 2013 · Journal of Pharmacology and Experimental Therapeutics
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    • "For example, in 2007, Wu and colleagues[6] reported that metformin can effectively mitigate antipsychotics-induced weight gain and abnormal glucose metabolism and several other studies in China report similar findings.[7]–[11] A meta-analysis reported in 2010[12] found that metformin can reduce weight, body mass index (BMI), waist circumference and insulin resistance, but did not reduce the incidence of diabetes in patients using antipsychotics. "
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    ABSTRACT: Antipsychotic medications can cause an increase in blood glucose and the development of type II diabetes. Metformin may ameliorate these side effects.
    Full-text · Article · Jun 2013 · Shanghai Archives of Psychiatry
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