EASD: Insulin Analogues, Cancer Linked, but No Causality Shown

On the other hand, metformin and possibly thiazolidinedione drugs may protect against cancer in diabetic patients, according to several prominent researchers.

The concerns were first raised by German researchers in a database analysis submitted in 2008 to the EASD's official journal, Diabetologia. The research linked insulin glargine to increased cancer risk.

The journal's editor, Edwin Gale, MD, of the University of Bristol in the U.K., said the results were potentially so momentous that he requested three other research groups to perform confirmation studies using other databases in Sweden, Scotland, and the U.K. as a whole.

Gale said he expected the results to be negative, and some were. But the Swedish study produced data to support the link, reported German scientists.

The four papers appeared in Diabetologia, along with an editorial, this past June, sparking headlines around the world.

Shortly afterward, the FDA announced a safety review of insulin glargine. Ulf Smith, MD, PhD, president of EASD and a diabetologist at the University of Gothenburg in Sweden, said here that the associations between insulin products and cancer risk fell far short of demonstrating causality.

They deserve more research, but do not warrant any change in treatment protocols at this time, he said.

"I'm not changing my clinical practice because we are not at that stage yet," Smith said, but added that he will closely monitor the results of studies now in the planning stage.

Sanofi-aventis, makers of insulin glargine, said it would sponsor its own research program, including "several rigorous epidemiological studies" in the U.S. and Europe.

"The research program is designed to generate more information on whether there is any association between cancer and insulin use and to assess if there is any difference in risk between insulin glargine and other insulins," according to a company statement.

What has emerged most clearly, the researchers agreed, is that patients receiving insulin-based agents -- and, to a lesser extent, sulfonylurea drugs -- appear more likely to be diagnosed with cancer.

Jeffrey Johnson, PhD, of the University of Alberta in Edmonton, Alberta, reviewed data he and other scientists had reported earlier this year, covering patients in Canada's Saskatchewan province from 1995 to 2006. Compared with patients receiving metformin monotherapy, those taking sulfonylurea drugs were at 30% greater risk of being diagnosed with cancer (P<0.05), Johnson said.

The data also showed that patients receiving insulin with fewer than 12 prescriptions per year had a significant 67% increase in the likelihood of cancer diagnosis, relative to those on sulfonylurea monotherapy. Those receiving more insulin prescriptions had a whopping sevenfold increase in risk, he said.

The researchers generally agreed on several other points:

• The retrospective data now available do not permit conclusions about causality.
• The current evidence suggesting insulin glargine-treated patients are at more risk for cancer than patients receiving other insulin-based agents is weak.
• No association has been seen between metformin or thiazolidinediones and increased cancer risk.
• Some studies have suggested that metformin can reduce cancer risk, both alone and in combination with insulin agents.
• It's possible that insulins may promote cancer through their action as growth factors.
• It's also possible, however, that patients treated with insulins are at increased risk for cancer because of the underlying disease, not because of the drugs.

Jay Skyler, MD, of the University of Miami, reviewed the four papers appearing in the June Diabetologia. His conclusion was that none of the studies supports a special risk for insulin glargine above that of other insulin drugs.

Skyler also said that cancer incidences among patients treated with insulin glargine in uncontrolled analyses did not differ from those reported in the CDC's Surveillance, Epidemiology, and End Results database after adjusting for patient age.

At the press conference, he said cancer incidence among those receiving detemir was significantly lower than among patients treated with NPH insulin. There was no significant difference in cancer rates between the detemir and glargine analogues, he said.

European Association for the Study of Diabetes (EASD) 45th Annual Meeting: Symposium S09. Presented October 1, 2009.