Metformin in Weight Loss Maintenance: A Possible Opportunity Post-GLP-RA Discontinuation?- Dr. Ashok Kumar Das

Patients who achieved weight loss with GLP-1 Receptor Agonists (RAs) can sustain their results with generic anti-obesity medications, including metformin, a study presented at the 61st Annual Meeting of the EASD 2025 in Vienna has reported.

The prospective, real-world cohort study conducted at Vanderbilt University Medical Center included 105 patients with a baseline BMI greater than 35 kg/m² who completed 12 months of GLP-1 RA therapy and achieved a BMI of ≤30 kg/m² through an 18-month Medical Weight Loss Bundle (MWLB) program. Following complete GLP-1 RA discontinuation, 40 patients transitioned to generic anti-obesity medication (AOM) combinations (mean 1.7 agents per patient). Medications prescribed included, metformin extended release 80% (n=32), topiramate 32.5% (n=13), bupropion 32.5% (n=13), phentermine 20% (n=8), and naltrexone 2.5% (n=1). It is noteworthy that metformin was most utilised agent during this period.

The study, published in Obesity, was presented at EASD 2025 by Prof. Dr. Mohamed Hassanein (United Arab Emirates). The key findings of the study are given below:

● At 12 months, there was a 23.1 kg absolute reduction (99.5 kg to 76.4 kg), BMI reduced by 8.6 kg/m² (from 36.5 to 27.9 kg/m²) and 11.6% absolute body fat reduction (from 47.1% to 35.5%), representing 18.3% ± 5.3% total weight loss (p<0.05).

● At 18 months, weight maintained at 76.1 kg versus 76.4 kg at 12 months (0.3 kg difference), BMI stable at 27.9 kg/m², representing 25.1% ± 2.6% cumulative weight loss from baseline with no significant regain after GLP-1 RA discontinuation (p>0.05 vs. 12 months).

● At 593 Days/~20 Months (N=40): Total 25.4 kg reduction from baseline (99.5 kg to 74.1 kg), BMI improved by 9.3 kg/m² (from 36.5 to 27.2 kg/m²), achieving 25.5% ± 2.4% total weight loss maintained entirely on generic AOMs without GLP-1 RA therapy.

● At 24 months, 17.8 kg reduction from baseline (99.5 kg to 81.7 kg), BMI reduced by 5.5 kg/m² (from 36.5 to 31.0 kg/m²), maintaining 20.6% ± 3.2% weight loss, though 95% attrition limits clinical interpretability.

● All comparisons from baseline to 12 and 18 months were statistically significant (p<0.05); no significant difference between 12 months, 18 months, and 593 days (p>0.05), confirming weight stability during the generic AOM maintenance phase.

The study further noted that metformin improves weight loss by enhancing insulin resistance, promoting appetite suppression through increased GLP-1 and peptide YY (tyrosine-tyrosine) secretion, increasing hypothalamic leptin sensitivity, altering gut microbiome, and inducing growth-differentiating factor 15—which collectively reduce food intake and improve metabolic function.

Following GLP-1 RA therapy, patients' reduced inflammation and improved insulin sensitivity may enhance responsiveness to these generic medications. Early responders within the first year may be suitable candidates for this cost-effective transition strategy.

This study confirms that patients transitioning from GLP-1 RA therapy to metformin-based generic maintained weight loss at 20 months. The benefit of metformin post GLP-RA seems a valid concept. However, more large, randomized controlled studies are needed in this direction.