Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials

Antipsychotic-induced dyslipidemia could increase the risk of cardiovascular diseases. This is a meta-analysis of randomized double-blind placebo-controlled trials to examine the efficacy and safety of adjunctive metformin for dyslipidemia induced by antipsychotics in schizophrenia. The standardized mean differences (SMDs) and risk ratios (RRs) with their 95% confidence intervals (CIs) were calculated using the random-effects model with the RevMan 5.3 version software. The primary outcome was the change of serum lipid level. Twelve studies with 1215 schizophrenia patients (592 in metformin group and 623 in placebo group) were included and analyzed. Adjunctive metformin was significantly superior to placebo with regards to low density lipoprotein cholesterol (LDL-C) [SMD: −0.37 (95%CI:−0.69, −0.05), P = 0.02; I2 = 78%], total cholesterol [SMD: −0.47 (95%CI:−0.66, −0.29), P < 0.00001; I2 = 49%], triglyceride [SMD: −0.33 (95%CI:−0.45, −0.20), P < 0.00001; I2 = 0%], and high density lipoprotein cholesterol [SMD: 0.29 (95%CI:0.02, 0.57), P = 0.03; I2 = 69%]. The superiority of metformin in improving LDL-C level disappeared in a sensitivity analysis and 80% (8/10) of subgroup analyses. Metformin was significantly superior to placebo with regards to decrease in body weight, body mass index, glycated hemoglobin A1c, fasting insulin, and homeostasis model assessment-insulin resistance (P = 0.002–0.01), but not regarding changes in waist circumference, waist-to-hip rate, leptin, fasting glucose, and blood pressure (P = 0.07–0.33). The rates of discontinuation due to any reason [RR: 0.97 (95%CI: 0.66, 1.43), P = 0.89; I2 = 0%] was similar between the two groups. Adjunctive metformin could be useful to improve total cholesterol and triglyceride levels, but it was not effective in improving LDL-C level in schizophrenia.


Introduction
Use of antipsychotics, particularly atypical antipsychotics, has been associated with a higher risk of metabolic and cardiovascular adverse effects 1-3 and even premature death 4,5 , which could be significantly attributed to dyslipidemia 6 , particularly elevated low density lipoprotein cholesterol (LDL-C) [7][8][9] . Dyslipidemia, such as increased level of total cholesterol, triglyceride, LDL-C and decreased level of high density lipoprotein cholesterol (HDL-C), could occur in around two-thirds of patients with schizophrenia 10 . Lifestyle and dietary interventions has been found to be safe and effective in treating dyslipidemia 11,12 . Several metaanalyses have found that topiramate 12 , metformin 13 , and rosuvastatin 14 were also effective and safe in improving dyslipidemia induced by antipsychotics in schizophrenia.
Metformin, a biguanide hypoglycemic agent, is widely prescribed for type 2 diabetes 1 . Animal studies have found metformin is effective in treating weight gain induced by olanzapine 15 and dyslipidemia induced by risperidone 16 .
Case reports and open-label studies also found that metformin could improve body weight 17 and metabolic syndrome 17 . However, the findings of randomized doubleblind placebo-controlled trials (RCTs) 6,18-28 examining the effects of adjunctive metformin for dyslipidemia induced by antipsychotics have been mixed. Some reviews and meta-analyses 11,13,[29][30][31][32][33][34][35][36][37] have examined the efficacy and safety of adjunctive metformin for antipsychotics-related weight gain and metabolic abnormalities in schizophrenia. However, the primary outcome in most meta-analyses was weight gain, rather than dyslipidemia, and some meta-analyses included open-label studies, which deviate from the standardized recommendations 38 . In addition, the findings of the previous meta-analyses 12,13,33,35,37 on adjunctive metformin for dyslipidemia, such as total cholesterol, HDL and LDL cholesterol, have been inconsistent. Thus, we conducted this meta-analysis of RCTs in English and Chinese literature to examine the efficacy and safety of adjunctive metformin for dyslipidemia induced by antipsychotics in schizophrenia.

Inclusion criteria of the meta-analysis
The inclusion criteria of this meta-analysis were made according to PICOS acronym. Participants: patients with schizophrenia diagnosed according to international or local diagnostic criteria, such as the China's mental disorder classification and diagnosis standard, 3rd edition, International Classification of Diseases, 10th edition or Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Intervention: adjunctive metformin with treatment as usual (TAU). Comparison: TAU plus placebo. Outcomes: the primary outcome was LDL-C (mg/dL); the secondary outcomes were total cholesterol (mg/dL), triglyceride (mg/dL), HDL-C (mg/dL), body weight (kg), body mass index (BMI, kg/m 2 ), waist circumference (cm), waist-to-hip rate, leptin (ug/L), glycated hemoglobin A1c (HbA1c, %), fast insulin (mIU/L) and homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose (mmol/L), blood pressure including diastolic and systolic blood pressure (mmHg), adverse drug reactions (ADRs), and discontinuation due to any reason. Study: following other meta-analyses 39,40 , only published double-blind RCTs that examined the efficacy and safety of metformin for dyslipidemia with available data were included. Studies without data of blood lipid were excluded [41][42][43] .

Data extraction
Three investigators (WLJ, DBC, and FY) independently extracted relevant data of eligible studies, including study characteristics (such as first author, publication year and sample size), basic demographic and clinical data (such as age, percentage of males, diagnostic criteria, illness duration, antipsychotic and its doses) and outcomes (efficacy, safety and tolerability of metformin). Discrepancies in literature search and data extraction were resolved through negotiation, or consultations with a senior investigator (WZ). One study 19 with 2 active treatment arms compared two different doses of metformin with placebo. The data of these three groups (2 active treatment arms + 1 placebo group) were separately extracted and analyzed in this meta-analysis. In order to avoid inflating the total number of patients in the placebo group, we assigned half of those in the placebo group to each metformin arm.

Statistical analyses
The data analyses were performed by the RevMan, version 5.3 according to the recommendations of the Cochrane Collaboration 44 . The random-effects model was used for all meta-analyzable outcomes 45 . The standardized mean differences (SMDs) and their 95% confidence intervals (CIs) were calculated for continuous outcomes. The risk ratios (RRs) and their 95% CIs were calculated for categorical outcomes. Significant heterogeneity was defined by I 2 of >50% or P value of <0.1 in Q-test.
In case of I 2 ≥ 50% for LDL-C level, a sensitivity analysis was conducted to detect the source of heterogeneity after removing 1 outlying study (SMD ≤ −0.87) 18 . Furthermore, the following six subgroup analyses were conducted to identify the sources of heterogeneity of the primary outcome: (i) Chinese vs. non-Chinese studies; (ii) studies with olanzapine vs. studies that did not use olanzapine as the primary antipsychotic medication; (iii) trial duration (weeks): ≥16 vs. <16; (iv) no sex predominance vs. male predominance (≥60%); (v) high quality (Jadad score ≥3) vs. low quality (Jadad score <3); and (vi) age (years): ≥39.3 vs. <39.3 (using the mean split of age). Sensitivity and subgroup analyses were not performed for total cholesterol and triglyceride levels, as the heterogeneity was small (I 2 = 49% and 0%, respectively). Publication bias was examined by visual funnel plots and Egger's test 46 using comprehensive meta-analysis program version 2. All meta-analytic primary and secondary outcomes were two tailed, with alpha set at 0.05.

Assessment of study quality
The quality of included RCTs was independently assessed by three investigators (WLJ, DBC, and FY) using Jadad scale 47,48 and the Cochrane Risk of bias 49 . The overall evidence levels of all meta-analytic outcomes were measured using the grading of recommendations, assessment, development, and evaluation (GRADE) system 50,51 .

Computer search
A total of 454 hits ( Fig. 1) were identified from the databases (n = 451) and manual search (n = 3). Finally, 12 studies with 13 RCTs 6,18-28 were included in this meta-analysis. Of them, one study contained two RCTs 6 .

Study characteristics
The 12 studies with 13 RCTs covered 1215 patients (592 in the metformin group (500-2550 mg/day) and 623 in the placebo group; Table 1). The mean age was 39.3 (range = 26.0-47.7) years and the mean illness duration in 11 studies with available data was 10.7 (range = 0.5-24.8) years. The mean trial duration was 15.5 (range = 8-24) weeks. Eight RCTs were conducted in China (n = 826), three in Venezuela (n = 181), and one each in Iran (n = 60) and the USA (n = 148).

Quality assessment of included study
Of the 13 RCTs, only 1 RCT 22 was rated as high risk with regards to the random sequence generation and allocation concealment (Supplemental Fig. 1). Other bias was rated as unclear in all RCTs. The Jadad total scores ranged from 2 to 5; 11 RCTs were rated as high quality (Jadad score ≥ 3). The quality of evidence for primary and secondary outcomes using the GRADE approach ranged from "low" (8.4%, 2/24), to "moderate" (45.8%, 11/24), and "high" (45.8%, 11/24) (Supplemental Table 1).

Publication bias
The funnel plots of included studies were symmetrical and Egger's test did not detect publication bias for triglyceride level (P = 0.50), body weight (P = 0.50), and fasting glucose (P = 0.97). Publication bias of other metaanalytic outcomes could not be examined due to small numbers (n < 10) of RCTs 52 .

Discussion
This meta-analysis found that adjunctive metformin was effective, safe, and generally well-tolerated in treating total cholesterol and triglyceride levels with "high" evidence level assessed by the GRADE approach within schizophrenia patients for antipsychotic-induced dyslipidemia, which is consistent with the findings in studies involving several other adjunctive medications, such as rosuvastatin (total cholesterol level vs. triglyceride level: SMD = −2.00 vs. −1.05) 14 . However, the significant superiority of metformin over placebo in the improvement of LDL-C level was driven by an outlying study 18 . Similarly, metformin was not effective in improving LDL-C level in 8 of the 10 subgroup analyses. This metaanalysis found the significant superiority of adjunctive metformin over placebo regarding LDL-C, total cholesterol, triglyceride and HDL-C level with small effect sizes 53 . Convincing evidence showed that findings with small effect size could be also reliable in clinical practice. For instance, a recent network meta-analysis that compared the efficacy and acceptability of 21 antidepressant drugs for major depressive disorder found that all antidepressants were more efficacious than placebo in improving depressive symptoms, but only small effect sizes were achieved 54 .
The mechanism of metformin underlying the treatment of antipsychotic-inducted dyslipidemia is still not clear. One possible explanation may be related to the role of metformin in improving insulin resistance 6,19,33,35 which is a risk factor of dyslipidemia 55 and could decrease lipoprotein synthesis 56 . In addition, the therapeutic effects of metformin in treating antipsychotic-inducted dyslipidemia may be associated with its role in the neuronal reduction of endogenous glucose production, increasing glucagon-like peptide-1 production, decreasing bile acid concentration in enterocytes, and modulating the gut microbiota 56 .
In this meta-analysis, adjunctive metformin showed significant benefits for reducing body weight and BMI, which is consistent with the findings of other metaanalysis 13,57 . For example, a recent meta-analysis found that a combination of metformin and lifestyle modification could significantly reduce body weight and BMI compared with placebo, lifestyle group or metformin alone 11 . Adjunctive metformin for antipsychotic-induced dyslipidemia were generally safe and well-tolerated. In this meta-analysis, seven studies reported more frequent nausea/vomiting in adjunctive metformin compared with placebo. A meta-analysis of use of adjunctive metformin for antipsychotic-induced weight gain also found that metformin could lead to more frequent reports of nausea/ vomiting than placebo 13 .
Some studies found that long-term use of metformin was associated with decreased vitamin B 12 levels, and even biochemical B 12 deficiency 2,58 . Thus, blood lactate concentration, serum B 12 levels and folate levels should be regularly screened for patients with schizophrenia when they received metformin treatment 2 . Several meta-analyses 11,13,[29][30][31][32][33][34][35][36][37] had examined antipsychotic-induced body weight and metabolic abnormalities in schizophrenia, however, only a small number of them with comparatively smaller sample size meta-analyzed dyslipidemia as a secondary outcome 33,35,37 . This meta-analysis only included double-blind RCTs examining adjunctive metformin for dyslipidemia in schizophrenia, together with a large sample size increase the robustness and reliability of meta-analytic findings.
Several limitations should be noted. First, the significant heterogeneity for primary outcome remained, even in some subgroup analyses. For this reason, we tried to compensate for study heterogeneity using the randomeffects model and conducting subgroup analyses. Second, although unpublished studies were not searched, no publication bias was found for triglyceride level, body weight, and fasting glucose in this meta-analysis. Third, the dose-response effect of metformin as an adjunctive treatment for dyslipidemia was not examined since the doses of metformin varied across included RCTs (500-2550 mg/day). Fourth, the significant superiority of metformin over placebo in improving LDL-C level was found in RCTs lasting more than 16 weeks, but not in those less than 16 weeks. Furthermore, the long-term effect (beyond 24 weeks) of adjunctive metformin for antipsychotic-induced dyslipidemia was not examined.
In conclusion, adjunctive metformin could improve total cholesterol and triglyceride levels but its therapeutic effects on LDL-C level was less certain in this meta-analysis. The prolonged effect of active agents such as metformin to treat dyslipidemia induced by antipsychotics in schizophrenia needs to be further examined.  Bold P values: P < 0.05. ADRs adverse drug reactions, BMI body mass index, CI confidence interval, HbA1c glycated hemoglobin A1c, HOMA-IR homeostasis model assessment-insulin resistance, RRs risk ratios, SMDs standardized mean differences, WHR waist-tohip ratio.