Ozempic (semaglutide) is a prescription medication primarily used to improve blood sugar in adults with type 2 diabetes. Administered as a once-weekly subcutaneous injection, it belongs to a class of drugs called GLP-1 receptor agonists and works by mimicking a natural hormone to lower blood sugar, slow digestion, and reduce appetite. In this Cover Story, PharmaTimes Editor, MORGAN NWANGUMA, reports that while Nigerian scientists are warning against a trendy use of the drug and highlighting severe risks associated with its misuse, a recent global research finding has established that Ozempic will likely not work for a good number of individuals.
Nigerian medical experts strongly warn against the unsupervised, trendy use of Ozempic. While acknowledging its medical benefits for diabetes and obesity, they highlight severe risks associated with its misuse, including a surge in counterfeit products. For instance, since 2025 the drug has become the latest weight-loss hack in Nigeria.
Vital Safety Information
Ozempic carries a warning about potential thyroid tumours, including cancer. It should not be used by individuals with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Severe side effects can also include pancreatitis, gallbladder problems, and vision changes.
Meanwhile a team of international researchers say the drug will not work effectively for many patients, pointing to a hidden genetic trait as the reason also – for not responding to blockbuster GLP-1 drugs used to treat Type 2 diabetes.
The study team has identified genetic variants that appear to reduce the effectiveness of GLP-1 receptor agonists in certain individuals. An estimated 10% of the population carries these variants, which are linked to a little-understood phenomenon known as “GLP-1 resistance.” Clinical trial data showed that people with these genetic differences were significantly less likely to achieve healthy blood sugar levels while taking GLP-1 medications.
More than one in four people with Type 2 diabetes now use GLP-1 receptor agonists, a class of drugs that includes Ozempic. However, new research from Stanford Medicine and international collaborators suggests that genetic factors may limit the benefits of these widely prescribed treatments for some patients.
The study found that individuals with the identified variants produce higher levels of glucagon-like peptide-1 (GLP-1), a hormone that helps regulate blood sugar. Despite these elevated levels, the hormone appears to be less effective at carrying out its role, resulting in reduced responsiveness to GLP-1-based therapies.
The researchers focused primarily on blood sugar management and did not draw firm conclusions about the impact of these variants on weight loss. Medications such as Ozempic and Wegovy are typically prescribed at higher doses for obesity treatment than for diabetes care, and further studies are needed to determine whether the same genetic factors influence weight-loss outcomes.
Published in the journal Genome Medicine, the research was conducted over a decade and involved scientists from multiple countries. The study combined findings from human and mouse experiments with analyses of clinical trial data involving diabetes medications.
“In some of the trials, we saw that individuals who had those variants were unable to lower their blood glucose levels as effectively after six months of treatment,” said Anna Gloyn, DPhil, professor of paediatrics and of genetics at Stanford Medicine and one of the study’s senior authors. At that stage, physicians would often consider changing a patient’s treatment plan. Identifying likely responders in advance could help patients reach the most effective therapy sooner and move diabetes care closer to precision medicine, she said.
Markus Stoffel, MD, PhD, professor of metabolic diseases at the Institute of Molecular Health Sciences at ETH Zurich in Switzerland is the other senior author. Lead authors comprise Mahesh Umapathysivam, MBBS, DPhil, an endocrinologist and clinical researcher at Adelaide University in Australia and a former trainee with Gloyn, and Elisa Araldi, PhD, associate professor of medicine and surgery at the University of Parma in Italy who once trained with Stoffel.
“When I treat patients in the diabetes clinic, I see a huge variation in response to these GLP-1-based medications and it is difficult to predict this response clinically,” Umapathysivam said. “This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process.”
Researchers examine the Mystery of a Diabetes Drug
This research represents the first detailed examination of GLP-1 resistance, but scientists still do not know exactly what causes it.
“That is the million-dollar question,” Gloyn said. “We have ticked off this enormous list of all the ways in which we thought GLP-1 resistance might come about. No matter what we’ve done, we’ve not been able to nail precisely why they are resistant.”
Scientists concentrated on two genetic variants that lessen the actions of an enzyme called PAM (peptidyl-glycine alpha-amidating monooxygenase). This enzyme plays a unique part in the body as it activates an array of hormones, including GLP-1.
“PAM is a truly fascinating enzyme because it’s the only enzyme we have that’s capable of a chemical process called amidation, which increases the half-life or the potency of biologically active peptides,” Gloyn said.
“We thought, if you have a problem with this enzyme, there’s going to be multiple aspects of your biology that are not working properly.”
Earlier studies had shown that PAM gene variants are more common among people with diabetes. Researchers, including Gloyn, had also demonstrated that these variants impair the pancreas’s ability to release insulin. Building on these findings, the team sought to determine whether the same genetic changes also influence GLP-1, a hormone produced in the gut that helps regulate blood sugar after meals by stimulating insulin secretion, slowing stomach emptying, and suppressing appetite. GLP-1 receptor agonists are designed to mimic the effects of this hormone.
An Unexpected Finding on GLP-1 Levels
To explore the relationship between PAM variants and GLP-1 activity, researchers recruited adults with and without a PAM variant known as p.S539W. Participants consumed a glucose-rich drink, and blood samples were collected every five minutes over a four-hour period. The study focused on individuals without diabetes to minimize the influence of other factors that could affect the results.
The researchers initially hypothesized that people carrying the PAM variant would have lower GLP-1 levels, based on the assumption that the hormone might be less stable when amidation is impaired. However, the findings pointed in an unexpected direction.
“What we actually saw was they had increased levels of GLP-1,” Gloyn said. “This was the opposite of what we imagined we would find.”
“Despite people with the PAM variant having higher circulating levels of GLP-1, we saw no evidence of higher biological activity. They were not reducing their blood sugar levels more quickly. More GLP-1 was needed to have the same biological effect, meaning they were resistant to GLP-1.”
Research on rats prove GLP-1 Resistance
Because the outcomes were startling, scientists spent many years verifying their genuineness.
“We couldn’t understand this, which is why we looked as many different ways as we could to see if this was a really robust observation,” Gloyn said.
To validate their findings, the researchers collaborated with scientists in Zurich who had developed mice lacking the PAM gene. These animals exhibited many of the same features associated with GLP-1 resistance, including elevated GLP-1 levels despite reduced effectiveness of the hormone in controlling blood sugar.
One of GLP-1’s key roles is to slow gastric emptying – the process by which food moves from the stomach into the intestines. This mechanism plays an important part in regulating blood sugar levels and promoting weight loss. However, mice without the PAM gene experienced faster gastric emptying, and treatment with a GLP-1 receptor agonist failed to slow the process.
The researchers also observed diminished GLP-1 responses in the pancreas and digestive tract of these mice, even though the number of GLP-1 receptors remained unchanged.
Further investigations, conducted in collaboration with scientists in Copenhagen, revealed that PAM gene defects do not impair the ability of GLP-1 to bind to its receptor or disrupt signalling at the receptor itself. These results suggest that the underlying cause of GLP-1 resistance occurs further downstream within the biological pathway.
Genetic Variants Influence Response to Diabetes Drugs
The researchers then examined whether GLP-1 resistance affected treatment outcomes in people with Type 2 diabetes.
Analyzing data from three clinical trials involving 1,119 participants, the team found that individuals carrying PAM gene variants generally responded less effectively to GLP-1 receptor agonists. Their HbA1c levels – a key indicator of long-term blood sugar control, showed smaller improvements compared with those of non-carriers.
After six months of treatment, about 25% of participants without the variants achieved recommended HbA1c targets. In contrast, only 11.5% of individuals carrying the p.S539W variant reached those goals, while the figure was 18.5% among carriers of the p.D563G variant.
portantly, the genetic variants did not appear to influence responses to several other commonly prescribed diabetes medications, including sulfonylureas, metformin, and DPP-4 inhibitors.
“What was really striking was that we saw no effect from whether you have a variant on your response to other types of diabetes medications,” Gloyn said. “We can see very clearly that this is specific to medications that are working through GLP-1 receptor pharmacology.”
However, findings from two additional pharmaceutical company-sponsored clinical trials told a different story, showing little difference in treatment response between carriers and non-carriers of PAM variants. According to Gloyn, these studies involved longer-acting GLP-1 receptor agonists, which may be more effective at overcoming the effects of GLP-1 resistance.
Unanswered Questions about Weight Loss and Future Therapies
The research team first identified signs of GLP-1 resistance nearly a decade ago, well before GLP-1 medications gained widespread attention for their weight-loss benefits.
Only two of the clinical trials included data on weight loss, and those analyses found no significant differences between individuals with and without PAM variants. However, the available evidence was limited, making it difficult to draw definitive conclusions about the role of these genetic factors in weight management outcomes.
Gloyn noted that extensive genetic data from previous and ongoing clinical trials may already exist and could provide valuable insights into why some individuals respond less effectively to GLP-1 therapies. Future analyses of these datasets could help pave the way for more personalized approaches to diabetes treatment.
“It’s very common for pharmaceutical companies to collect genetic data on their participants,” she said. “For the newer GLP-1 medications, it would be useful to look at whether there are genetic variants, like the variants in PAM, that explain poor responders to their medications.”
Although the underlying biological mechanism remains poorly understood, Gloyn believes GLP-1 resistance is likely driven by a complex interplay of factors rather than a single cause. She compares the phenomenon to insulin resistance, which researchers have studied for decades but still do not fully understand.
Despite these uncertainties, effective therapies have been developed to help manage insulin resistance, offering hope that similar strategies could eventually be designed to overcome GLP-1 resistance as scientific understanding advances.
“There are a whole class of medications that are insulin sensitizers, so perhaps we can develop medications that will allow people to be sensitized to GLP-1s or find formulations of GLP-1, like the longer-acting versions, that avoid the GLP-1 resistance.” she said.
Scientists from the University of Oxford, University of Dundee, University of Copenhagen, University of British Columbia, Churchill Hospital, Newcastle University, University of Bath, and University of Exeter also contributed to the study.
Financial support came from Wellcome, the Medical Research Council, the European Union Horizon 2020 Programme, the National Institutes of Health (grants U01-DK105535, U01-DK085545 and UM-1DK126185), the National Institute for Health Research Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim, and Diabetes Australia.
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