Why Do People Lose Weight Differently on GLP-1RA? The NBEA Gene Was Investigated
Glucagon-like peptide-1 receptor agonists (GLP-1RA) show promising anti-obesity effects, but their efficacy varies among individuals. A newly published study examined the role of the NBEA (neurobeachin) gene in weight loss while using these drugs, analyzing two large cohorts of real-world patients.
Obesity and GLP-1RAs in Its Treatment
As is well known, obesity is among the diseases whose prevalence represents an epidemic. For example, in the United States alone, it affects nearly 42% of adults. It also significantly impacts patients’ quality of life, either directly or through its association with many other conditions. It increases the risk of cardiometabolic, cerebrovascular, oncological, and other diseases. In addition to lifestyle modifications and invasive bariatric procedures, anti-obesity pharmacotherapy (AOM) with clinically proven efficacy is used as a treatment strategy.
Medications from the GLP-1RA group, originally developed as antidiabetic drugs, also demonstrate a significant ability to reduce body weight. The degree of weight loss varies among patients. Researchers from the Cleveland Clinic hypothesized that the neurobeachin (NBEA) protein could play a role in the response to GLP-1RAs. Preclinical studies suggest that the NBEA gene influences dietary preferences. Mice in which one allele of this gene was removed consumed more food rich in glucose or fructose than control mice.
Furthermore, some variants of NBEA appear to be associated with a preference for sweet foods and with higher body mass index (BMI) in humans. The NBEA gene encodes a protein that helps target protein kinase A (PKA) to specific sites. GLP-1 stimulates insulin secretion via the PKA signaling pathway, so the authors of the presented study decided to investigate the role of NBEA in the response to GLP-1RAs.
Large and Diverse Cohorts
In the study, researchers used large real-world cohorts providing linked genetic data and electronic health record (EHR) data. Using data from the U.S. All of Us cohort, they developed an NBEA genetic score for weight loss after 12–18 months from the first prescription of a GLP-1RA. They then validated the score in the British UK Biobank database.
The analysis included individuals who were overweight (BMI ≥ 27 kg/m2) or obese (BMI ≥ 30 kg/m2) in the six months prior to GLP-1RA prescription, regardless of the presence of type 2 diabetes mellitus (T2DM). The inclusion criteria were met by 6,556 of 255,052 members of All of Us and 500 of 198,275 individuals in UK Biobank. The All of Us cohort was racially and ethnically more diverse (21.1% Black and 14.6% Hispanic vs. 2% and 0% in UK Biobank), included a larger proportion of women (64% vs. 43.6%), and had similar baseline BMI values (38.55 vs. 37.0 kg/m2, with obesity present in 89.2% vs. 91.8%).
The median ages were also similar (57.09 vs. 60.81 years), and T2DM was present in 100% of patients in UK Biobank vs. 84.3% (5,526) in All of Us. Records in UK Biobank did not include semaglutide data, as they were limited to the period before its first approval for T2DM treatment (2017). In the All of Us cohort, semaglutide was prescribed to 2,012 individuals — 30% (603) of them were randomly assigned as an independent validation cohort. Liraglutide was the most commonly prescribed (to 2,064 individuals in All of Us and 241 individuals in UK Biobank).
Individuals in the top 20th percentile of weight loss for a given GLP-1RA were considered highly responsive.
What Was Found?
Weight Loss
Liraglutide use led to an average weight loss over 12–18 months of 2.47% in the All of Us cohort and 3.44% in the UK Biobank cohort. In the case of semaglutide, the loss was 94% greater — averaging 4.87% in the All of Us cohort. The 20th percentiles, representing high responses, corresponded to reductions of 7.57% for dulaglutide, 6.38% for exenatide, 7.77% for liraglutide, and 10.9% for semaglutide. For UK Biobank participants treated with liraglutide, the top 20th percentile weight loss was 8.25%.
A significant portion of patients on GLP-1RAs did not lose weight — in the All of Us cohort, this included 36.30% of those prescribed liraglutide and 24.30% of those prescribed semaglutide; in the UK Biobank cohort, 28.63% of those prescribed liraglutide. No weight loss was more likely in younger individuals, those with lower baseline BMI, and those with shorter prescription durations. Conversely, those in the top 20th percentile tended to have been prescribed the medication for longer.
The Significance of the NBEA Score
The NBEA score incorporated 2,873 single nucleotide variants (SNVs), most of which were intronic, with only one of nine exonic variants being nonsynonymous. Cumulative genetic variation in these SNVs significantly correlated with weight loss at 12 and 18 months after starting treatment. The NBEA score improved the prediction of both nonresponse and an increased likelihood of achieving at least 20% weight loss with any GLP-1RA (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.46–1.95).
Individuals meeting the NBEA score threshold for responsiveness had an 82% higher likelihood of being highly responsive to liraglutide (OR 1.82; validated in UK Biobank OR 2.37, p = 0.008) and a 63% higher likelihood of being highly responsive to semaglutide (OR 1.63; validation OR 2.21, p < 0.05). Participants treated with liraglutide whose NBEA score indicated nonresponsiveness had a 50% greater likelihood of not losing weight, also validated in UK Biobank (OR 1.81; p = 0.041).
The NBEA score showed similar predictive estimates for GLP-1RA response after adjusting for sex, race, and T2DM status. The strongest association between the NBEA score and weight loss with GLP-1RAs was seen with semaglutide, which is generally more effective for weight reduction than liraglutide due to a modification that extends its biological half-life.
Opportunities for Individualized Therapy
One of the limiting factors of the analysis is that the vast majority of participants were diabetics taking these medications for T2DM rather than obesity. In the T2DM indication, lower GLP-1RA doses are used. EHR data also do not allow for assessment of treatment adherence.
Overall, the findings suggest that NBEA genetic variability has predictive value, and according to the study authors, the NBEA score may support future efforts to identify individuals likely to achieve significant weight loss with GLP-1RA therapy. This could enable the individualization of obesity treatment strategies. However, genes in other signaling pathways involved in satiety, insulin sensitivity, and overall weight regulation should also be evaluated first.
Editorial Team, Medscope.pro
Source: Mariam-Smith A., Breeyear J. H., Daniels N. J. et al. Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss. Diabetes Obes Metab 2025 Jul 18, doi: 10.1111/dom.16612.
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