New Delhi: When two people start the same obesity drug at the same dose, one can lose up to 20 percent of body weight while the other loses almost none. A new peer-reviewed study published in the journal Nature Wednesday sheds light on why this happens.
Conducted by American researchers, the study scanned the DNA of nearly 28,000 people taking Glucagon-like peptide-1 (GLP-1) suppressing drugs—sold as Ozempic, Wegovy, and Mounjaro—that help manage blood sugar.
They found specific genetic variants that predict how much weight a person will lose on taking these drugs, and their likelihood of experiencing nausea and vomiting.
The finding does not immediately change what a doctor does when a patient asks for prescription. But it opens the door to a future where a DNA test could guide drug choice and dosage, rather than months of expensive trial and error, medical experts told ThePrint.
“While still premature, this is a step towards precision medicine. At the moment, we can’t run genetic testing for every patient on GLP-1 drugs, but in difficult non-responders, targeted studies could help,” said Dr Ambrish Mithal, Chairman, Endocrinology and Diabetes, Max HealthCare.
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Genetic signals identified
The researchers performed a genome-wide association study, or GWAS—a large-scale scan of participants’ DNA looking for variants that correlate with specific treatment outcomes —across drugs, including semaglutide, which is sold as Ozempic and Wegovy and Tirzepatide, which is sold as Mounjaro and Zepbound.
Unlike Semaglutide, Tirzepatide targets two receptors—GLP-1 and Gastric inhibitory polypeptide (GIP)—for greater effect.
Researchers found a single genetic variant in the GLP1R gene—the gene that makes the receptor these drugs latch on to. That was linked to roughly 0.76 kg of extra weight loss.
Put simply, patients who carried this variant lost more weight on the drug than those who did not. The finding held up when tested on a separate group of over 4,800 patients whose data was drawn from hospital records.
On side effects, variants in the GLP1R gene were linked to nausea and vomiting in patients on both drugs. Tirzepatide threw up an additional finding. A variant in the GIPR gene, the second receptor that trispeptide targets, significantly raised the risk of vomiting.
Patients who carried risk variants in both genes faced nearly 15 times higher odds of vomiting on tirzepatide than those who carried neither.
The study also found that the genetic variants linked to nausea and vomiting significantly overlap with those linked to greater weight loss. Using a statistical method called co-localisation analysis, the researchers inferred that increased nausea or vomiting is associated with greater weight loss efficacy.
However, Dr Mithal said, “While people who experience more nausea may eat less and sometimes respond better, there isn’t a direct relationship between side effects and effectiveness.”
“Some patients have no side effects at all and still respond very well in terms of weight and diabetes. So this is far from an all-or-none phenomenon,” he added.
Study confirms clinical observations
According to Dr V. Mohan, an obesity researcher and chairman of the Madras Diabetes Research Foundation (MDRF), the study felt like long-overdue scientific confirmation of a clinical pattern he had been tracking for over a decade.
He explained that since the first GLP-1 drugs—Liraglutide and Exenatide—became available, followed by Semaglutide and more recently Tirzepatide, he had consistently observed four distinct types of patient responses.
These include those where both weight and blood sugar improved markedly, those where only blood sugar improved, those where only weight came down, and a small group that showed neither improvement.
The same variation held for side effects: some patients could not tolerate even the lowest starting dose, while others experienced nothing at maximum doses.
“I had always maintained that this must be due to pharmacogenomics, that genetic factors must be playing a role,” he told ThePrint. “This clinical observation of mine has now been confirmed by this paper.”
‘Ethnic differences cannot be assumed away’
The study’s most significant limitation for India is also its most candid disclosure.
Of the nearly 28,000 participants, 78 percent were of European ancestry.
The key efficacy variant is present in roughly 40 percent of Europeans, but only 20 percent of South Asians, meaning the biological signal the study identified is both less common and less well-validated in Indian populations.
India has over 101 million people with diabetes and another 136 million with prediabetes, according to the Indian Council of Medical Research, one of the highest disease burdens in the world.
Indian patients, Mohan noted, are not biologically identical to the European populations that dominate most major drug trials.
“The Dipeptidyl peptidase-4 (DPP-4) inhibitors—another class of diabetes drugs from the same incretin family, which work by preventing the breakdown of the body’s own gut hormones rather than mimicking them—are known to be significantly more effective in Indians and Koreans than in other ethnic groups,” he said.
Whether a similar ethnic variation exists for GLP-1 drugs is not yet established, but Dr Mohan said it cannot be assumed away. “Ethnic differences also have to be kept in mind when looking at the response to GLP-1 and related drugs,” he told ThePrint.
Dr Mithal reiterated, “While this is an interesting finding, it can’t be easily translated into clinical research, except in retrospect, because you can’t start doing genome analysis on everybody when you’re starting GLP-1.”
What changes about treatment
The more immediate use case is not at the start of treatment but when treatment fails, medical experts say.
Currently, when a patient does not respond after months on a GLP-1 drug, the standard clinical response is to increase the dose, extend the duration, or switch to a different drug, all of which cost time and money without any biological explanation for the failure.
A targeted genetic test, Dr Mithal said, could provide that explanation and give doctors a defensible reason to stop rather than escalate.
“This may become the first clinical implication. We can identify those unlikely to benefit, and avoid continued use of a drug that won’t work for them,” he added.
(Edited by Ajeet Tiwari)
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