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 the Role of GLP-1RA in Its Treatment
Obesity is widely recognized as an epidemic. In the U.S. alone, nearly 42% of adults are affected. It significantly impacts quality of life, both directly and by contributing to other diseases. Obesity increases the risk of cardiometabolic, cerebrovascular, oncological, and other conditions. Alongside lifestyle modifications and invasive bariatric procedures, pharmacological anti-obesity medications (AOMs) with proven clinical efficacy are used as a treatment strategy.
GLP-1RA drugs, originally developed for diabetes, also significantly reduce body weight. However, weight loss outcomes differ between patients. Researchers at the Cleveland Clinic hypothesized that the neurobeachin (NBEA) protein might play a role in response to GLP-1RA. Preclinical studies suggest that the NBEA gene affects dietary preferences. Mice with one deleted allele of this gene consumed more glucose- or fructose-rich foods than controls.
Additionally, certain NBEA variants seem to correlate with a preference for sweet foods and increased body mass index (BMI) in humans. The NBEA gene encodes a protein that guides protein kinase A (PKA) to specific targets. Since GLP-1 stimulates insulin secretion via the PKA signaling pathway, the authors of the study decided to explore the role of NBEA in GLP-1RA response.
Large and Diverse Cohorts
The researchers used large real-world cohorts linking genetic data with electronic health records (EHR). Using data from the U.S. All of Us cohort, they developed a genetic NBEA score for weight loss 12–18 months after first GLP-1RA prescription. This score was validated using the UK Biobank cohort.
Participants included individuals with overweight (BMI ≥ 27 kg/m2) or obesity (BMI ≥ 30 kg/m2) in the 6 months before GLP-1RA prescription, regardless of type 2 diabetes mellitus (T2DM) diagnosis. Of the All of Us cohort, 6556 of 255,052 members met the criteria, compared to 500 of 198,275 individuals in the UK Biobank. The All of Us cohort was more racially and ethnically diverse (21.1% Black and 14.6% Hispanic vs. 2% and 0% in the UK Biobank), inc
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