Miriam E Tucker

September 15, 2015

STOCKHOLM — The risk of pancreatic cancer was not elevated with incretin-based drugs compared with other glucose-lowering therapies, new research shows.

The results, from a 7-year nationwide Danish case-control study, suggest that diabetes itself is a risk factor for pancreatic cancer independent of a specific drug effect, Reimar W Thomsen, MD, PhD, of the department of clinical epidemiology, Aarhus University Hospital, Denmark, said here today at the European Association for the Study of Diabetes (EASD) 2015 Meeting.

Concern has arisen from some observational studies suggesting that incretins could cause pancreatitis and/or pancreatic cancer through stimulation of glucagonlike peptide-1 (GLP-1) receptors in the pancreas, Dr Thomsen said.

But large trials, including SAVOR-TIMI (of saxagliptin) and EXAMINE (of alogliptin), involving 16,492 and 5380 patients over medians of 2.1 and 1.5 years, respectively, found no difference between dipeptidyl peptidase 4 (DPP-4) inhibitor treatment and placebo with regard to pancreatitis or pancreatic cancer.

In the current study, which examined both GLP-1 mimetics and DPP-4 inhibitors, "pancreatic-cancer risk is increased to comparable levels for all glucose-lowering agents — incretins or nonincretins — despite different drug actions. This fact suggests that diabetes is a strong risk factor in itself for pancreatic cancer, independent of the specific drug effects."

Dr Thomsen continued, "When comparing glucose-lowering agents internally, incretin therapy is not associated with increased cancer risk vs other therapies, while insulin-based therapies may relate to higher risk. Whether this is due to insulin therapy or due to more metabolically severe diabetes isn't clear from this design."

Asked to comment, Andrew G Renehan, PhD, professor of cancer studies and surgery, the Christie NHS Foundation Trust, Institute of Cancer Sciences, University of Manchester, United Kingdom, told Medscape Medical News, "I think it's reassuring. A lot of the early [reports] overinflated the risk. Now things are looking a little more even."

However, Dr Renehan, who also chairs the EASD's Diabetes and Cancer Study Group, pointed out, "It's not definitive yet….The use of incretins is still relatively young."

Dr Thomsen and his team have already published an analysis showing no increased risk of pancreatitis with incretins, in Diabetes Care earlier this year, as reported by Medscape Medical News.

Risk Due to Drug or Diabetes?

Dr Thomsen and colleagues identified 6036 incident pancreatic-cancer cases from databases for all hospitalizations and all prescriptions in Denmark from 2005 to 2012. They matched those individuals for age, gender, and residence to 60,360 population controls who had never taken glucose-lowering medication.

The pancreatic-cancer rates for those who had ever used DPP4 inhibitors was 1.66%, compared with just 0.50% for controls, giving an adjusted odds ratio of 3.9. The risk was also significantly elevated for GLP-1 analogs, 0.55% vs 0.23%; the adjusted odds ratio was 2.7.

However, the same effect was seen with nonincretin glucose-lowering drugs. Ever-use of metformin was associated with a 14.68% incidence of pancreatic cancer, compared with 6.09% for never-use of diabetes drugs, with an adjusted odds ratio of 2.7.

The risk was actually elevated for insulin: There, the pancreatic cancer rate was 9.39% vs. 2.61% for population controls, with adjusted odds ratio 3.6.

"We see that these drugs are also strongly associated with pancreatic cancer," Dr Thomsen noted.

In a subsequent internal comparison using metformin monotherapy as the reference, the pancreatic-cancer risk was not elevated with sulfonylurea monotherapy. The risk was elevated for dual and polytherapy, but not more so with combinations containing incretin-based medications. However, the risk was elevated with combinations that included insulin.

Still in question, Dr Thomsen said, is whether this "is severity of diabetes, or the drugs, or both." But either way, "we found no evidence for a causal association between incretin-based drugs and pancreatic cancer."

Dr Renehan told Medscape Medical News that the ideal study to answer the question definitively would involve large databases from multiple countries, providing enough data on new users as well as prevalent users in order to eliminate bias from duration of use. Ideally, such studies would also last longer than any of them have thus far. "Most cancer epidemiologists would like to see a drug exposure of at least 8 to 10 years before they consider it closable."

Dr Thomsen has no relevant financial relationships, and the study had no industry involvement. Aarhus University Hospital is involved in other studies with funding from various companies, including those on diabetes therapy. Dr Renehan has no relevant financial relationships.

European Association for the Study of Diabetes 2015 Meeting. Stockholm, Sweden. Abstract 17, presented September 15, 2015.


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