Millions of people around the world are now taking the GLP1 medication semaglutide (Ozempic/Wegovy) or the GLP1/GIP medication tirzepatide (Mounjaro/Zepbound) for weight management, diabetes, or other weight-related health issues. While both medications are highly effective on average for weight loss, there is huge variability in response from person to person – meaning that some people can experience as much as 25-30% weight loss, whereas about one in ten people experience less than 5% weight loss. Gastriointestinal tolerance (presence or absence of nausea, vomiting, diarrhea, constipation etc) to GLP1-based medications is also highly variable, across the spectrum from no GI side effects at all, to mild side effects, to severe side effects that result in complete intolerance to treatment.
A fascinating study recently published in Nature conducted a full genetic analysis of over 27,000 people using the 23andMe database, to see if they could find any genetic variants associated with weight loss response, and/or with GI side effects. Participants were people who responded to a survey and who had reported using at least one of the GLP1 semaglutide (Ozempic/Wegovy or compounded semaglutide), or the dual GLP1/GIP tirzepatide (Mounjaro/Zepbound or compounded tirzepatide). (sidebar – do not use compounded medication – more on this here)
They found a genetic missense variation allele (‘mutation’) in the GLP1 receptor that was associated with greater weight loss, though the effect size was small (only 0.76kg more weight loss per allele, so max 1.5kg for people with 2 copies of that allele). While it’s exciting to find one genetic association, this doesn’t go far to explain the huge variation in weight loss response that we see from one person to the next.
What I found much more impressive was their finding of associations linking variation in both the GLP1 receptor and the GIP receptor to medication-related nausea or vomiting. They identified two genetic variants near the GLP1 receptor gene, one linked to a57% higher likelihood of vomiting, and another to a36% higher chance of nausea. People carrying a specific GIP receptor variant were 83% more likely to vomit with tirzepatide treatment. The GIP variant is thought to partially disrupt GIP receptor function, suggesting that the higher likelihood of vomiting might reflect a reduced ability of tirzepatide’s GIP activity to buffer the nausea-inducing effect of the GLP1 component, a mechanism of GIP that has been suggested in animal studies.
These findings should be taken with a big grain of salt. This was an analysis based on self reported information, and from volunteer survey respondents. People who didn’t respond to the survey could be different. Also, some of these findings are in conflict with findings from other studies. That being said, this study suggests that we are on to something here, and these early days of wading into the genetic analyses may ultimately lead us to develop an ability to predict who may (or may not) respond to particular weight management medication(s), and who may (or may not) tolerate them well.
Disclaimer: I am/have been an investigator in clinical trials of semaglutide and tirzepatide. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide (Novo Nordisk), and tirzepatide (Eli Lilly).
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