No link between semaglutide and pancreatic cancer

There is no link between semaglutide (a glucagon-like peptide-1 receptor agonist, GLP-1RA) use and pancreatic cancer using nationwide registry data from Denmark, Sweden and Norway, according to at the Annual Meeting of The European Association for the Study of Diabetes (EASD). This regulator-mandated post authorisation study, funded by Novo Nordisk, was presented by Professor Anton Pottegård, University of Southern Denmark, Odense, Denmark, and colleagues.

“This comprehensive study, using nationwide registry data from three countries, found no increased risk of pancreatic cancer with use of semaglutide as compared to use of other glucose-lowering drugs used at a similar stage as semaglutide in the treatment of T2DM,” said Pottegård.

A risk of pancreatic cancer has been hypothesised for incretin-mimetic antidiabetic drugs including GLP-1RAs. The background to this hypothesis is that initial safety signals emerged from early adverse event reporting systems and preclinical studies in rodents showing cellular changes in pancreatic tissue. And because GLP-1 medications stimulate the pancreas and were occasionally linked to acute pancreatitis in early case reports, researchers questioned whether chronic inflammation could eventually elevate cancer risk.

As part of the overall original approval process for semaglutide (Wegovy/Ozempic), a regulator-mandated post authorisation safety study was requested to estimate the risk of pancreatic cancer associated with semaglutide use as compared to use of other non-incretin drugs in the treatment of T2DM.

Using nationwide health registries from Denmark, Sweden, and Norway, the researchers conducted an active comparator, new user cohort study examining the risk of pancreatic cancer in new users of semaglutide for T2DM versus matched new users of non-incretin antidiabetic drugs (sulfonylureas, SGLT-2 inhibitors, or insulin). Eligible patients initiated semaglutide or active comparators and filled at least two prescriptions within the first year, with follow-up beginning one year after initiation.

The primary outcome was incident pancreatic cancer. Country-specific hazard ratios (HRs) and incidence rate differences (IRDs) were estimated and pooled across countries using a fixed-effects meta-analysis. Extensive sensitivity and supplementary analyses were performed to assess the robustness of findings.

In total, 97,464 semaglutide users were included, with patient characteristics well-balanced to a similar control cohort after matching. Among semaglutide users, median age ranged from 59 to 62 years, with mean follow-up after the 1-year lag period of 1.40-1.85 years. A total of 131 and 123 incident pancreatic cancer events occurred among semaglutide and active comparator users respectively (across 167,399 and 140,306 person-years of follow-up). Incidence rates were similar between groups across countries, ranging from 0.64 to 0.91 and 0.80 to 0.98 per 1,000 people per year among semaglutide and AC users respectively.

Semaglutide use was not associated with an increased risk of pancreatic cancer compared to active comparators in any country (Hazard ratio 1.00 [95% confidence interval 0.66-1.51] in Denmark, 0.82 [95% CI 0.56-1.22] in Sweden, and 0.91 [95% CI 0.55-1.51] in Norway). Pooled estimates confirmed no increased risk (pooled HR 0.91 [95% CI 0.71-1.16] and incident rate difference (IRD - or absolute risk) IRD −0.10 [95% CI −0.31 to 0.10] per 1,000 person-years). No cumulative dose-response or dose-duration effects were observed (pooled HR for high dose: 0.74 [95% CI 0.40-1.40]; pooled HR for long duration: 0.79 [95% CI 0.37-1.69]). Sensitivity and supplementary analyses consistently showed no increased risk.

 “This conclusion was supported by absence of a cumulative dose-response or dose-duration effect, consistent findings in the individual countries and in a wide range of supplementary and sensitivity analyses,” added Pottegård. ”These findings also align with current external evidence and thus further strengthen the evidence that semaglutide does not increase the risk of pancreatic cancer.”