Genetic Variants Explain Why GLP-1 Drugs Like Ozempic Don't Work for 10% of Patients

New research published March 29 in Genome Medicine reveals that approximately 10% of people carry genetic variants in the PAM enzyme that make GLP-1 drugs like Ozempic and Wegovy significantly less effective for diabetes treatment. The decade-long study found that individuals with PAM variants like p.S539W have elevated GLP-1 hormone levels but reduced biological activity, with only 11.5% reaching target HbA1c levels after six months compared to 25% without the variants. Experiments in humans and mice confirmed the resistance occurs after receptor binding, though the precise biological mechanism remains unknown. However, two pharmaceutical-funded trials suggest longer-acting GLP-1 formulations may overcome this genetic resistance, and the variants don't affect response to other diabetes medications like metformin.

Genetic Variants in PAM Gene Linked to GLP-1 Resistance

• ▪About 10% of the population carries certain genetic variants linked to GLP-1 resistance.
• ▪Individuals with GLP-1 resistance have higher than normal levels of the hormone GLP-1 but the hormone appears to be less effective at regulating blood sugar.
• ▪The research on GLP-1 resistance focused on two specific genetic variants that affect an enzyme called PAM (peptidyl-glycine alpha-amidating monooxygenase).

Research Findings from Human and Animal Studies

• ▪In mice without the PAM gene, food moved through the stomach more quickly and treatment with GLP-1 drugs did not slow this process.
• ▪The study on GLP-1 resistance was published March 29 in Genome Medicine and represents a decade of work involving experiments in both humans and mice.
• ▪Individuals with the PAM variant had increased levels of GLP-1, which was the opposite of what researchers expected to find.
• ▪Experiments with collaborators in Copenhagen showed that the PAM defect does not affect how GLP-1 binds to its receptor or how signals are transmitted.
• ▪Despite having higher circulating levels of GLP-1, people with the PAM variant showed no evidence of higher biological activity and were not reducing their blood sugar levels more quickly.
• ▪The number of GLP-1 receptors in the pancreas and gut of mice without the PAM gene remained unchanged despite reduced responsiveness to GLP-1.
• ▪Mice lacking the PAM gene showed similar signs of GLP-1 resistance, with elevated hormone levels that failed to improve blood sugar control.
• ▪Researchers studied adults with and without a PAM variant known as p.S539W by having participants drink a sugary solution and testing their blood every five minutes over a four-hour period.

Impact on Clinical Treatment Outcomes and Drug Response

• ▪Two additional clinical trials funded by pharmaceutical companies showed no difference in response between PAM variant carriers and non-carriers when using longer-acting GLP-1 drugs.
• ▪After six months of GLP-1 drug treatment, about 25% of participants without PAM variants met the recommended HbA1c target, compared with 11.5% of those with the p.S539W variant.
• ▪In a combined analysis of three clinical trials with 1,119 participants, individuals with PAM variants responded less effectively to GLP-1 drugs and were less likely to reach target HbA1c levels.
• ▪PAM genetic variants did not affect how patients responded to other common diabetes medications, including sulfonylureas, metformin and DPP-4i.
• ▪Anna Gloyn stated that longer-lasting GLP-1 drug formulations may help overcome GLP-1 resistance.
• ▪More than one in four people with Type 2 diabetes use GLP-1 receptor agonists.

Unanswered Questions About Biological Mechanisms

• ▪The underlying biological mechanism of GLP-1 resistance remains unknown despite this being the most detailed investigation so far.
• ▪Anna Gloyn stated that researchers have not been able to determine precisely why individuals with PAM variants are resistant to GLP-1 despite testing numerous hypotheses.
• ▪The biological cause of GLP-1 resistance is likely influenced by multiple factors, similar to insulin resistance which scientists still do not fully understand despite decades of research.

Perspective of Anna Gloyn

• ▪Anna Gloyn stated that longer-lasting GLP-1 drug formulations may help overcome GLP-1 resistance.
• ▪Anna Gloyn stated that researchers have not been able to determine precisely why individuals with PAM variants are resistant to GLP-1 despite testing numerous hypotheses.

Perspective of Patients with PAM genetic variants

• ▪PAM genetic variants did not affect how patients responded to other common diabetes medications, including sulfonylureas, metformin and DPP-4i.

Perspective of Pharmaceutical companies funding GLP-1 research

• ▪Two additional clinical trials funded by pharmaceutical companies showed no difference in response between PAM variant carriers and non-carriers when using longer-acting GLP-1 drugs.

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