Empagliflozin as an Alternative to Metformin for Antipsychotic‐Related Weight Gain: Double‐Blind Randomized Controlled Trial

ABSTRACT Background Weight gain and metabolic disturbances are common adverse effects of antipsychotic medications such as clozapine and olanzapine. Beyond their primary role in glycemic control, sodium‐glucose cotransporter 2 (SGLT2) inhibitors have been associated with weight loss and improvements in various metabolic parameters. This study compared the efficacy and safety of empagliflozin and metformin in patients with antipsychotic‐induced weight gain (AIWG). Methods In this 12‐week, double‐blind, randomized controlled trial, 84 adults with schizophrenia or bipolar disorder and established weight gain from clozapine or olanzapine were assigned to receive either empagliflozin (10 mg daily) or metformin (1000 mg daily). The primary outcome was the percentage change in body weight from baseline to week 12. Secondary outcomes included changes in absolute body weight, body mass index (BMI), waist circumference, waist‐hip ratio, and the proportion of patients achieving ≥ 5% weight loss. Exploratory outcomes assessed changes in glycemic and lipid parameters, fasting insulin, and insulin resistance (HOMA‐IR). Safety was evaluated by monitoring adverse events, treatment discontinuations, and serious adverse events. Results Of the 84 randomized participants, 38 (90.5%) in the empagliflozin group and 39 (92.9%) in the metformin group completed the 12‐week study. Both treatments produced significant within‐group reductions in anthropometric measures (all p 0.05). Both groups showed improvements in glycemic and lipid parameters, but empagliflozin resulted in significantly greater reductions in TG ( p = 0.004), fasting insulin ( p = 0.005), and HOMA‐IR ( p = 0.012), as well as a greater increase in HDL‐C ( p < 0.001) compared to metformin. The overall incidence of adverse effects was comparable (33.3% vs. 38.1%; p = 0.650), with no serious adverse events reported. Conclusions These findings suggest that empagliflozin is a promising alternative to metformin for managing metabolic complications in patients treated with clozapine or olanzapine. These findings warrant confirmation and further investigation in larger, long‐term studies. Trial registration The trial was registered prospectively at the Iranian Registry of Clinical Trials (IRCT) with the ID code IRCT20120215009014N538 on November 12, 2024