Why Do Some People Respond Less Strongly to Ozempic-Like Drugs? Study Points to PAM Gene Variants

Ozempic, Wegovy, and similar GLP-1 drugs have rapidly moved to the center of diabetes and obesity treatment in recent years, but the same drug does not produce the same results in everyone. For people with type 2 diabetes, this difference is especially important: if blood sugar remains slow to reach target levels, the issue may not simply be medication timing, lifestyle, or adherence, but may also involve the body’s sensitivity to GLP-1 signaling itself.

A study published in *Genome Medicine* combined human genetic data, mouse experiments, and reanalysis of three clinical trials of diabetes drugs, focusing on the PAM gene. The research team noted that about 10% of the general population carries certain PAM variants, and that these variants are associated with type 2 diabetes risk, GLP-1 levels in the body, and the degree of blood sugar improvement after receiving GLP-1 receptor agonists.

The enzyme encoded by the PAM gene participates in the maturation process of multiple peptide hormones. In the study, two PAM variants, p.S539W and p.D563G, reduced serum PAM amidation activity by about 52% and 20%, respectively. Interestingly, people carrying the variants and mice lacking the Pam gene had higher circulating GLP-1 levels instead; however, the researchers speculated that chronically elevated GLP-1 signaling may be accompanied by lower sensitivity, creating a state similar to “GLP-1 resistance.”

Clinical data gave this mechanistic hypothesis more weight. After conducting a pooled analysis of three trials involving a total of 1,119 participants, the research team found that people carrying the p.S539W variant had a smaller reduction in HbA1c after treatment with GLP-1 receptor agonists: an average decrease of about 0.69%, compared with about 1.24% among non-carriers. After six months, 11.5% of carriers achieved HbA1c below 7%, compared with 25.3% of non-carriers.

This difference did not appear in the same way with other diabetes drugs. The research report stated that for sulfonylureas, metformin, or DPP-4 inhibitors, people carrying related PAM variants did not show the same response gap. This led the researchers to lean more toward the view that PAM variants affect treatment response related to the GLP-1 pathway, rather than suggesting that all glucose-lowering drugs are less effective in general.

However, the study’s conclusions currently point mainly to blood sugar control and should not be directly extrapolated to weight-loss effects. Stanford Medicine’s explanation of this decade-long international study also specifically noted that whether these variants affect the weight-loss effects of drugs such as Ozempic or Wegovy remains unclear. GLP-1 drugs act simultaneously on insulin secretion, gastric emptying, appetite, and central nervous system signaling, and blood sugar and body weight may not necessarily be governed by the same set of limiting factors.

Background Context

This finding also fills in a less visible part of the discussion around GLP-1 treatment. Many recent studies have focused on how stopping medication, restarting it, side effects, and insurance coverage affect whether patients can use these drugs long term; the PAM study pushes the question to another level: even if patients continue taking the medication, genetic differences may make it harder for some people to reach the same blood sugar targets. It is not yet a testing guideline that can be used immediately in clinical practice to determine prescriptions, but it offers a more concrete biological entry point for precision diabetes treatment.