Semaglutide and PPGL Cells: New Data

A 2026 paper tested semaglutide, metformin and insulin in fresh patient-derived cultures of pheochromocytomas and paragangliomas, collectively called PPGLs. Semaglutide had significant anti-tumor effects in cluster 1 cultures, while high-dose semaglutide showed tumor-promoting effects in three cultures carrying germline RET pathogenic variants^[2]. These were laboratory findings from tumor cultures. The study did not randomize patients to semaglutide, measure clinical tumor growth after treatment, or establish a risk estimate for an individual.

What the researchers tested

PPGLs are tumors arising from chromaffin cells, which normally produce catecholamines. The paper begins from a clinical observation: glycemic dysregulation occurs in a high proportion of people with these tumors, yet evidence about how anti-diabetic medicines affect PPGL growth remains limited. The investigators addressed that question first in primary cultures prepared from patient tumors^[2]. A primary culture can preserve properties of the original tumor better than an established cell line, but it still removes cells from the full environment of a living patient.

The experiment included 54 fresh PPGL primary cultures. The abstract identifies eight cluster 1 tumors and 18 cluster 2/3 tumors. Four tumors had RET pathogenic variants, meaning disease-associated changes in the RET gene. Researchers exposed the cultures to semaglutide, metformin or insulin and assessed effects on tumor growth^[2]. The abstract does not report every concentration, exposure duration, assay method or effect size, so those details should not be reconstructed from the headline result.

Semaglutide effects differed by tumor group

The central result was not one uniform semaglutide effect. Cluster 1 PPGL cultures showed significant anti-tumor effects. In contrast, high-dose semaglutide produced tumor-promoting effects in three PPGL cultures with germline RET pathogenic variants associated with multiple endocrine neoplasia type 2, or MEN2^[2]. A fourth PPGL with a somatic RET variant did not show that same reported effect. Germline variants are inherited and present throughout the body, while somatic variants arise within tumor cells.

That contrast makes tumor biology important to the interpretation, but the numbers remain small. Three cultures with a shared genetic context can identify a signal worth testing. They cannot show how often the effect occurs among people with MEN2, whether it depends on drug exposure, or whether a cultured tumor response predicts clinical progression. The term high-dose also describes an experimental condition in the paper. It is not a clinical dosing category and should not be mapped onto an approved semaglutide regimen.

Metformin, insulin and the clinical comparison

The other therapies produced their own patterns. Metformin had overall anti-tumor effects in the primary cultures, while insulin showed tumor-promoting effects in individual cultures^[2]. These findings do not establish that one diabetes therapy treats PPGL or that another causes tumor growth. They describe responses in the tested culture system, where drug exposure and measured growth can be controlled but the whole-patient context is absent.

The authors also correlated the culture data with clinical information from 67 participants in the prospective PROSPHEO study. They reported larger median tumors among patients receiving insulin than among patients receiving metformin or a GLP-1 receptor agonist, or no anti-diabetic therapy^[2]. This was a treatment-group comparison, not a randomized drug trial. People who need insulin may differ from other patients in diabetes duration, metabolic health or other factors that could also relate to tumor size.

The clinical observation therefore supports a reason for further study, not a cause-and-effect conclusion. The abstract does not provide adjusted estimates, treatment duration or longitudinal tumor-growth rates. It also combines metformin and GLP-1 receptor agonist therapy in one comparison group. That prevents the clinical data from isolating semaglutide's contribution. For broader drug context, our semaglutide research overview separates approved clinical evidence from early laboratory work.

What this result can and cannot support

The paper supports a narrow conclusion: anti-diabetic therapies produced different growth responses across patient-derived PPGL cultures, and semaglutide's reported effects varied with tumor cluster and RET context. It does not show that semaglutide prevents PPGL growth. It also does not show that semaglutide promotes tumors in people with MEN2. The three-culture signal needs confirmation in larger experimental sets and prospective clinical research^[2].

The result should not prompt an unsupervised medication change. Stopping or switching glucose-lowering treatment can carry immediate health consequences, while this study does not provide a clinical decision rule. A person with a PPGL, MEN2 or a RET variant who uses a GLP-1 receptor agonist should discuss the new paper with the clinicians managing both conditions. US readers can also review the semaglutide regulatory overview for established product context.

What we don't yet know

The abstract does not tell us whether the culture effects persist across different exposure periods or assay conditions. It does not establish the biological mechanism behind the opposite cluster-specific responses. The sample of RET-associated tumors was too small to estimate frequency, and the report does not show whether other inherited PPGL syndromes follow the same pattern. Full clinical interpretation also requires details about patient treatment history and tumor measurements that are not present in the accessible record.

Prospective studies would need to follow defined patient groups over time, document specific therapies and exposure, and measure tumor behavior using consistent methods. Until then, the laboratory signal and the non-randomized clinical comparison should remain separate pieces of evidence. The study raises a legitimate safety and biology question. It does not answer whether semaglutide changes PPGL outcomes in patients.

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