NIHR Signal Metformin shows early promise for controlling clozapine-related weight gain

Published on 30 August 2016

People with schizophrenia who were taking clozapine had greater weight loss, reductions in waist circumference, and lower glucose and triglycerides, when given metformin compared to placebo. There was no significant difference in “good” cholesterol (HDL cholesterol) or blood pressure measures.

Clozapine is used to treat schizophrenia that has not responded to treatment with at least two other antipsychotics. However, it has the most negative impact on metabolic function and is strongly associated with weight gain.

Current UK practice is to treat clozapine-related weight gain with lifestyle, behaviour, physical activity and diet interventions. The drug orlistat can be used if these treatments are unsuccessful.

SIGN guidelines recommend considering the use of metformin, and this review suggests it is likely to be beneficial, though this is early stage research.

Share your views on the research.

Why was this study needed?

Schizophrenia is a serious and chronic mental health condition. It affects around 1 in 100 people in their lifetime.

Many respond to initial drug treatment but around 20% of people do not respond sufficiently well. After two attempts with different antipsychotic medicines, the recommended treatment is the antipsychotic, clozapine.

Although clozapine is effective in treating schizophrenia it can have adverse effects on, glucose levels, cholesterol, triglycerides and blood pressure. Evidence suggests that people receiving clozapine have almost double the risk of developing a metabolic disorder such as diabetes compared to people on other antipsychotics.

These side effects can be difficult to manage solely by increased physical activity, therefore focus has shifted to medications. One option is metformin, which is used to treat diabetes and may help to control these metabolic effects.

This study compared trials using metformin or placebo to control metabolic side effects in people receiving clozapine.

What did this study do?

This systematic review and meta-analysis included eight randomised controlled trials of 478 adults comparing metformin or placebo for clozapine-related metabolic effects. Trials were excluded if they included people with diabetes.

Six of eight trials were carried out in China or Taiwan; the others were performed in Venezuela and Iran, which may affect the applicability of their findings to the UK.

Five studies used the DSM-IV or DSM-IV-TR to classify mental health conditions and three trials used a Chinese classification system, these classification systems may be different to those used in the UK.

The included trials were described as of “fair quality”, with generally low levels of risk of bias. Only three studies used an intention-to-treat analysis. This analysis may be misleading as the non-random drop out of participants or cross over or people from control to treatment groups are not taken into account. Well-designed European trials would help to resolve and uncertainty in the research so far.

What did it find?

After a follow-up period of 12 weeks to six months:

  • There was greater weight loss for people on metformin compared to placebo (mean difference ‑3.12kg, 95% confidence interval [CI] ‑4.88kg to ‑1.37kg).
  • BMI was lower for people on metformin than placebo (mean differences ‑1.18kg/m2, 95% CI ‑1.76kg/m2 to ‑0.61kg/m2).
  • Waist circumference was smaller in people receiving metformin compared to placebo (mean difference ‑1.69cm, 95% CI ‑3.06cm to ‑0.32cm).
  • Glucose and triglycerides were significantly lower for metformin compared to placebo.
  • There was no significant difference in HDL cholesterol or blood pressure between metformin and placebo.

What does current guidance say on this issue?

NICE recommends that clozapine is given to adults (2014 guidance), and children and young (2013) whose schizophrenia has not responded to treatment with at least two antipsychotic drugs. NICE recommends that clozapine-associated weight gain is treated following its guidelines on obesity. This involves first treatment using interventions targeting lifestyle, behaviour, physical activity and diet. If these are unsuccessful, NICE recommends the obesity medication orlistat.

SIGN 2013 guidelines recommend considering the use of metformin for any antipsychotic related obesity.

What are the implications?

Metformin shows promise in controlling weight gain and some of the other metabolic side effects of using clozapine to treat schizophrenia.

The clinical significance some of these results is not clear. For example, weight was measured at the start and end of the trials. This was not contextualised by information about people’s weight gain whilst on clozapine, so it was not clear what impact metformin had on this weight gain.

The quality and applicability to the UK of the included trials mean that this review does not provide strong enough evidence to change practice. Better quality, UK-relevant randomised controlled trials are required.

Citation and Funding

Siskind DJ, Leung J, Russell AW, et al. Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(6):e0156208.

The authors received an Intra-Faculty Collaborative Workshop grant from the University of Queensland School of Medicine, which covered the open access publication costs. The main author of the review is part-funded by an Early Career Fellowship from the Australian National Health and Medical Research Council.

Bibliography

NICE. Obesity: identification, assessment and management. CG189. London: National Institute for Health and Care Excellence; 2014.

NICE. Psychosis and schizophrenia in children and young people: recognition and management. CG155. London: National Institute for Health and Care Excellence; 2013.

NICE. Psychosis and schizophrenia in adults: prevention and management. CG178. London: National Institute for Health and Care Excellence; 2014.

SIGN. Management of schizophrenia. SIGN 131. Edinburgh: Scottish Intercollegiate Guidelines Network; 2013.

Why was this study needed?

Schizophrenia is a serious and chronic mental health condition. It affects around 1 in 100 people in their lifetime.

Many respond to initial drug treatment but around 20% of people do not respond sufficiently well. After two attempts with different antipsychotic medicines, the recommended treatment is the antipsychotic, clozapine.

Although clozapine is effective in treating schizophrenia it can have adverse effects on, glucose levels, cholesterol, triglycerides and blood pressure. Evidence suggests that people receiving clozapine have almost double the risk of developing a metabolic disorder such as diabetes compared to people on other antipsychotics.

These side effects can be difficult to manage solely by increased physical activity, therefore focus has shifted to medications. One option is metformin, which is used to treat diabetes and may help to control these metabolic effects.

This study compared trials using metformin or placebo to control metabolic side effects in people receiving clozapine.

What did this study do?

This systematic review and meta-analysis included eight randomised controlled trials of 478 adults comparing metformin or placebo for clozapine-related metabolic effects. Trials were excluded if they included people with diabetes.

Six of eight trials were carried out in China or Taiwan; the others were performed in Venezuela and Iran, which may affect the applicability of their findings to the UK.

Five studies used the DSM-IV or DSM-IV-TR to classify mental health conditions and three trials used a Chinese classification system, these classification systems may be different to those used in the UK.

The included trials were described as of “fair quality”, with generally low levels of risk of bias. Only three studies used an intention-to-treat analysis. This analysis may be misleading as the non-random drop out of participants or cross over or people from control to treatment groups are not taken into account. Well-designed European trials would help to resolve and uncertainty in the research so far.

What did it find?

After a follow-up period of 12 weeks to six months:

  • There was greater weight loss for people on metformin compared to placebo (mean difference ‑3.12kg, 95% confidence interval [CI] ‑4.88kg to ‑1.37kg).
  • BMI was lower for people on metformin than placebo (mean differences ‑1.18kg/m2, 95% CI ‑1.76kg/m2 to ‑0.61kg/m2).
  • Waist circumference was smaller in people receiving metformin compared to placebo (mean difference ‑1.69cm, 95% CI ‑3.06cm to ‑0.32cm).
  • Glucose and triglycerides were significantly lower for metformin compared to placebo.
  • There was no significant difference in HDL cholesterol or blood pressure between metformin and placebo.

What does current guidance say on this issue?

NICE recommends that clozapine is given to adults (2014 guidance), and children and young (2013) whose schizophrenia has not responded to treatment with at least two antipsychotic drugs. NICE recommends that clozapine-associated weight gain is treated following its guidelines on obesity. This involves first treatment using interventions targeting lifestyle, behaviour, physical activity and diet. If these are unsuccessful, NICE recommends the obesity medication orlistat.

SIGN 2013 guidelines recommend considering the use of metformin for any antipsychotic related obesity.

What are the implications?

Metformin shows promise in controlling weight gain and some of the other metabolic side effects of using clozapine to treat schizophrenia.

The clinical significance some of these results is not clear. For example, weight was measured at the start and end of the trials. This was not contextualised by information about people’s weight gain whilst on clozapine, so it was not clear what impact metformin had on this weight gain.

The quality and applicability to the UK of the included trials mean that this review does not provide strong enough evidence to change practice. Better quality, UK-relevant randomised controlled trials are required.

Citation and Funding

Siskind DJ, Leung J, Russell AW, et al. Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(6):e0156208.

The authors received an Intra-Faculty Collaborative Workshop grant from the University of Queensland School of Medicine, which covered the open access publication costs. The main author of the review is part-funded by an Early Career Fellowship from the Australian National Health and Medical Research Council.

Bibliography

NICE. Obesity: identification, assessment and management. CG189. London: National Institute for Health and Care Excellence; 2014.

NICE. Psychosis and schizophrenia in children and young people: recognition and management. CG155. London: National Institute for Health and Care Excellence; 2013.

NICE. Psychosis and schizophrenia in adults: prevention and management. CG178. London: National Institute for Health and Care Excellence; 2014.

SIGN. Management of schizophrenia. SIGN 131. Edinburgh: Scottish Intercollegiate Guidelines Network; 2013.

Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis

Published on 16 June 2016

Siskind, D. J.,Leung, J.,Russell, A. W.,Wysoczanski, D.,Kisely, S.

PLoS One Volume 11 , 2016

BACKGROUND: Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine's impact on glucagon-like peptide (GLP-1). There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine. METHODS: We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group's trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers. RESULTS: Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg) and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2). Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results. CONCLUSIONS: Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered. TRIAL REGISTRATION: PROSPERO registration number: CRD42015029723.

Expert commentary

The place of metformin in antipsychotic-related weight gain in schizophrenia remains unclear. Evidence of modest weight loss (circa 3kg) and BMI reduction is largely based on low-quality trials from China. Uncertainties remain about whether the benefits of metformin vary with prior antipsychotic use, duration of illness and/or pre-treatment weight gain.

This study further complicates matters by suggesting that the mechanism of weight gain differs for clozapine compared with other antipsychotics. On balance we’re none the wiser: metformin may support weight loss in people with schizophrenia who are taking antipsychotics but the effects are modest, heterogeneous and likely to have been over-estimated. Large, pragmatic, high-quality randomised controlled trials are needed.

Scott Weich, Professor of Psychiatry, Warwick Medical School, University of Warwick