Influence of insulin on cancer risk, possible protection from cancer with metformin examined

EASD research foundation and Sanofi-Aventis launching research programs to investigate the link between insulin and cancer.

45th Annual Meeting of the European Association for the Study of Diabetes

At a symposium today, experts acknowledged an increased risk for cancer associated with insulin therapy, but said the risk is no greater with insulin glargine (Lantus, Sanofi-Aventis) compared with other types of insulin. In addition, new data suggest that metformin may have a protective effect against cancer in patients with type 2 diabetes.

Craig J. Currie, PhD, of Cardiff University in the United Kingdom, presented the findings of an extension study that explored the relationship between insulin dose and cancer risk in patients with type 2 diabetes treated with insulin. The study analyzed 4,829 patients receiving insulin alone, 5,035 receiving insulin plus metformin and 31,421 receiving metformin alone. Insulin exposure was measured in terms of prescriptions dispensed per year: less than seven, seven to 19, 11 to 15 and more than 15.

Cancer risk was found to increase with increasing doses of insulin, with a sixfold increased cancer risk among patients taking the highest insulin dose (more than 15 prescriptions, HR=5.73) vs. metformin alone. The addition of metformin to insulin treatment cancelled out the increased cancer risk with lower doses of insulin, and halved the cancer risk at the highest insulin dose group (HR=3.20).

Currie said there was a dose-response association between insulin and cancer incidence, but data do not prove a causal relationship. This finding may be a consequence of insulin resistance rather than a direct effect of the insulin itself, according to the researchers.

Also noted, these findings “add to the rapidly accumulating evidence that metformin can play an important role in protection from cancer,” Currie said. If this observation is confirmed, metformin could potentially prevent many thousands of cancers in patients with type 2 diabetes.

Cause for concern

Concern about a possible link between insulin and increased risk for cancer was raised after the publication of four papers in Diabetologia in June. An article about the studies and the aforementioned link was previously published on the Endocrine Today website.

“What has emerged in the past few months is a whole new area of investigation with regards to diabetes and cancer,” Edwin A. M. Gale, MD, editor of Diabetologia, said during a press conference. “The message we published was a mixed one.”

Jay S. Skyler, MD, who spoke at the press conference and symposium on behalf of insulin glargine manufacturer, Sanofi-Aventis, said “careful examination of the four studies did not support the headlines” generated after the publication of these studies.

“If we discard the supposed dose effect in the German study, which several observers feel is not valid, none of the studies show a relationship between insulin glargine and cancer,” Skyler, professor of medicine at the University of Miami Leonard M. Miller School of Medicine, said in a statement.

Further, he said the link between cancer and insulin glargine based on available evidence is “unsubstantiated, unwarranted and unproven,” and a randomized, controlled trial would be “the best way to establish or refute whether there is a relationship between insulin glargine and cancer.”

During the press conference, Jeffrey A. Johnson, professor and Canada Research Chair, School of Public Health, University of Alberta, Edmonton, said that insulin, especially in high concentrations, may likely have a role in the regulation of cell growth and differentiation. Drug therapies that increase circulating insulin, such as sulfonylureas, may have a negative effect on hastening tumor growth, and drugs that improve insulin sensitivity, such as thiazolidinediones, may have a positive effect on reducing cancer outcomes, he said in a press release. However, current evidence for these other antidiabetic therapies in the diabetes/cancer relationship are limited to epidemiologic studies.

Research support

During the annual meeting, the European Foundation for the Study of Diabetes, the research foundation of EASD, announced that it will support research into diabetes and cancer with up to $4.4 million. The program will consider all approaches to further elucidate the relationship between diabetes and cancer, as well as the relationship between the different treatments of diabetes with insulin or insulin analogues and oral antidiabetic agents, either in human studies or in suitable human models, according to a press release.

In addition, Sanofi-Aventis announced the launch of a major insulin research program this week. The program will provide methodologically robust research to contribute to the debate over insulin safety. 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. The plan will encompass both preclinical and clinical programs involving human insulin and insulin glargine. – by Katie Kalvaitis

For more information:

Gale EAM. Diabetes therapy and cancer. Presented at: the 45th Annual Meeting of the European Association for the Study of Diabetes; Sept. 29-Oct. 2, 2009; Vienna.

What is striking to me is the extent to which people are seriously concerned about the relation between insulin glargine and excess cancer. On the one hand, we may have done too good a job reassuring people in the United States about this, or they may be burned out after the false concerns regarding rosiglitazone (Avandia, GlaxoSmithKline). Regardless, we need to cover this aspect of the much greater concern over here.

– Alan J. Garber, MD, PhD

Endocrine Today Chief Medical Editor