Metformin reduces 12-month change in body weight among people newly commenced on clozapine: a retrospective naturalistic cohort study

Abstract

Background: People with schizophrenia have a 15–20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap. Methods: We retrospectively analysed digital health records of patients with TRS aged 18–65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio. Results: Among 90 patients initiated on clozapine, metformin use ( n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight. Conclusion: In this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.

Metformin for the prevention of clozapine‐induced weight gain: A retrospective naturalistic cohort study

“…Potential moderators of CLZ‐induced weight gain and metformin response have been reported in the literature. For example, a previous retrospective cohort study found that younger individuals (i.e., those below the median sample age of 32 years) gained significantly more weight than older individuals above the median age 24 . This is consistent with our finding in which there was an inverse association between age and body weight 12 months after CLZ initiation, implying that younger patients gain more weight than their older counterparts.…”

“…Our findings replicate and extend another recently published retrospective chart review that evaluated the effect of metformin in patients with TRS initiated on CLZ 24 . The metformin group ( n = 48) demonstrated a smaller increase in percentage body weight (1.32% vs. 5.95%, p = 0.031) compared with the non‐metformin treated group ( n = 42).…”

CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine

“…We previously found that in the year after commencement of clozapine, people who were commenced on metformin by their treating team had significantly less weight gain than those who were not commenced on metformin. 21 Two previous RCTs examined metformin co-commencement with olanzapine, an antipsychotic with a similar, albeit slightly less-adverse, metabolic profile to clozapine. One RCT demonstrated amelioration of weight gain, 37 while the other RCT had equivocal results.…”

“… 20 In a retrospective naturalistic cohort study of patients routinely commenced on clozapine, patients who were taking metformin in the subsequent 12 months had a significantly lower increase in percentage body weight gain than patients who were not taking metformin (1.32% versus 5.95%, p = 0.031). 21 …”

“…20 In a retrospective naturalistic cohort study of patients routinely commenced on clozapine, patients who were taking metformin in the subsequent 12 months had a significantly lower increase in percentage body weight gain than patients who were not taking metformin (1.32% versus 5.95%, p = 0.031). 21 Preventing rather than ameliorating weight gain is important. Weight gain compromises treatment adherence which can lead to relapse in psychosis among people with TRS.…”