What You Should Know:
– A new study from Mayo Clinic, released this past weekend, signals a significant advancement in understanding and potentially mitigating the challenging side effects associated with popular GLP-1 agonist medications like Wegovy and Zepbound.
– Led by Mayo Clinic physician and obesity expert Andres Acosta, MD, PhD, the research reveals that it is now possible to predict which patients are most likely to experience gastrointestinal (GI) side effects, particularly nausea – the most common reason people discontinue these widely used weight-loss drugs, affecting up to 70% of users.
– The findings have immediate and potentially transformative implications for how these blockbuster drugs are prescribed and for the development of new, more effective treatments with better tolerability.
Tackling Treatment Hurdles: The Challenge of GLP-1 Side Effects
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven effective for treating obesity and type 2 diabetes mellitus. However, their use is often hampered by gastrointestinal adverse effects, with nausea being a primary concern that limits tolerability and leads many patients to abandon treatment. The Mayo Clinic study sought to address this critical issue by identifying predictors for these adverse events.
A Novel Approach: Genetic Risk Score and Machine Learning
The research, detailed in a paper titled “A GENETIC RISK SCORE ASSOCIATED WITH NAUSEA RESULTING FROM GLP-1 AGONIST TREATMENT: A POST-HOC ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL OF LIRAGLUTIDE“, involved a post-hoc analysis of a randomized, placebo-controlled trial that investigated the effects of liraglutide in patients with obesity.
Researchers utilized a machine-learning (ML) assisted genetic risk score (GRS), previously reported and termed CTSGRS (calories to satiation GRS). This score incorporates single nucleotide polymorphisms (SNPs) in 10 genes related to genetic predisposition to obesity, satiation, the GLP-1 receptor, or endogenous GLP-1 synthesis. The study analyzed genetic data from 110 participants to assess the association between this CTSGRS and observed adverse effects. The aim was to determine if this genetic score could identify patients at higher risk of experiencing side effects while on GLP-1RA treatment.
Genetic Profile Strongly Linked to Nausea and Headache Risk
The study yielded compelling results. Using machine learning and the genetic data, researchers found that patients with a high-CTSGRS (indicating a certain genetic profile) who were receiving liraglutide were significantly more likely to develop nausea (68%) compared to patients with a low-CTSGRS (30%). This represents an odds ratio of 5.0, underscoring a strong association. This difference was not observed in patients receiving a placebo (19% in the high-CTSGRS group vs. 13% in the low-CTSGRS group experienced nausea).
The user-provided summary highlighted that this means patients with certain genetic markers were more than twice as likely to experience nausea, a finding consistent with these specific results.
Furthermore, high-CTSGRS patients receiving liraglutide were also significantly more likely to report headaches, with an odds ratio of 5.4. There was also a trend indicating that individuals with a high-CTSGRS were more prone to experiencing GI-related side effects in general (73% vs. 53% in the low-CTSGRS group).
Interestingly, the development of nausea was not found to be associated with changes in total body weight loss at either 5 or 16 weeks of treatment. The study also noted that two individuals in each CTSGRS group withdrew from the trial due to nausea, and one individual with a high-CTSGRS decreased their medication dose because of this side effect.
Genetic Score Also Predicts Weight Loss Efficacy
The CTSGRS score has previously been linked to the effectiveness of GLP-1RA treatment. Prior research cited in the paper indicated that a low CTSGRS score is associated with a two-fold greater weight loss with liraglutide treatment. This suggests that the genetic risk score could offer a dual benefit: predicting both potential for side effects and likelihood of successful weight loss.
Personalized Prescribing and Future Drug Development
The study concludes that an elevated CTSGRS was associated with an increased risk of nausea and headaches in adults receiving liraglutide. The authors suggest that these findings, when viewed alongside previously published data on weight loss efficacy, implicate that unique genetic profiles in pathways regulating satiation can be key to optimizing both the effectiveness and tolerability of GLP-1RAs for chronic weight management.
These results pave the way for a more personalized approach to prescribing GLP-1 medications. By identifying patients with genetic markers that predispose them to nausea or other side effects before treatment begins, clinicians could potentially match patients to the most suitable medications or implement proactive management strategies. This could significantly reduce the number of patients who abandon treatment due to adverse effects.
