Regulator-mandated study finds no link between semaglutide use and pancreatic cancer

New research presented at the Annual Meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy, Sept. 28–Oct. 2, found no link between semaglutide use and pancreatic cancer in nationwide registry data from Denmark, Sweden and Norway. The regulator-mandated post-authorization study was presented by Anton Pottegård, a professor at the University of Southern Denmark in Odense, and colleagues.

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) indicated for the treatment of type 2 diabetes mellitus (T2DM) and weight management. A risk of pancreatic cancer has been hypothesized for incretin-mimetic antidiabetic drugs, including GLP-1RAs.

The hypothesis arose from early safety signals in adverse event reporting systems and preclinical studies in rodents showing cellular changes in pancreatic tissue. Because GLP-1 medications stimulate the pancreas and were occasionally linked to acute pancreatitis in early case reports, researchers also questioned whether chronic inflammation could eventually elevate cancer risk.

As part of the original approval process for semaglutide (Wegovy/Ozempic), regulators requested a post-authorization safety study to estimate the risk of pancreatic cancer associated with semaglutide use compared with other non-incretin drugs used to treat 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 started semaglutide or an active comparator and filled at least two prescriptions within the first year. Follow-up began one year after treatment started.

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

In total, 97,464 semaglutide users were included, with patient characteristics well balanced against those of a matched control cohort. 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 pancreatic cancer cases occurred among semaglutide users and 123 among active comparator users (across 167,399 and 140,306 person-years of follow-up, respectively). Incidence rates were similar between groups across countries, ranging from 0.64 to 0.91 per 1,000 people per year among semaglutide users and 0.80 to 0.98 among active comparator users.

Semaglutide use was not associated with an increased risk of pancreatic cancer compared with 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 also showed no increased risk (pooled HR 0.91 [95% CI 0.71–1.16] and incidence rate difference [IRD, or absolute risk] −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.

Pottegård concludes, “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.

“This conclusion was supported by the 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. These findings also align with current external evidence and thus further strengthen the evidence that semaglutide does not increase the risk of pancreatic cancer.”

Provided by
European Association for the Study of Diabetes

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