Cancer-Glargine Data Inconclusive, Groups Agree: Patients urged not to change insulins.

ATLANTA — Reaction by medical societies and the Food and Drug Administration to articles published last month suggesting a link between insulin glargine and cancer has been swift and unified: Patients with diabetes who are using glargine should not change their insulin regimen, because there is no clear evidence of such a relation.

The American Association of Clinical Endocrinologists said it “does not recommend that the use of any insulin be changed.”

AACE is among several other professional societies—and the U.S. Food and Drug Administration—cautioning patients and physicians not to over-interpret the inconclusive findings from four studies published online by the journal Diabetologia examining a possible association between glargine and cancer (www.diabetologiajournal.org/cancer.html).

In an editorial, Dr. Edwin A.M. Gale, editor of Diabetologia, and Dr. Ulf Smith, president of the European Association for the Study of Diabetes, state that “the studies reported are far from conclusive, but they do indicate the need for further investigation of the issue.”

Because the cancer risk was seen within a short period of time from exposure to glargine, the data do not suggest that glargine (Sanofi-Aventis' Lantus) causes cancer, they said. Rather, glargine might accelerate the progress of preexisting malignancies.

But Dr. Paul Jellinger said the studies show no definitive evidence of such a mechanism. “The data are inconclusive, the studies contradict themselves, and it's premature to make any recommendations to change insulin regimens. Each patient's concerns should be addressed individually,” said Dr. Jellinger, a clinical endocrinologist in Hollywood, Fla., and a past president of AACE. He participated in the AACE position statement, which was chaired by Dr. Yehuda Handelsman, a clinical endocrinologist in Tarzana, Calif.

He added, however, that “there's also a higher incidence of certain cancers in type 2 diabetes to begin with. The subject of diabetes and cancer merits further investigation.”

Like the other groups, the American Diabetes Association also advised patients not to stop taking their insulin without consulting their physicians: “The [ADA] cautions against over-reaction until more information is available.”

The data comprise four studies published online simultaneously by EASD. They are summarized at right (see sidebar).

The Food and Drug Administration noted that the duration of follow-up was shorter for all the studies than what is generally considered necessary to evaluate cancer risk from a drug exposure. Further, “inconsistencies in findings within and across the individual studies raise concerns as to whether an association between the use of insulin glargine and cancer truly exists. Additionally, differences in patient characteristics across the treatment groups may have contributed to a finding of increased cancer risk.”

The agency said it is reviewing several sources of safety data for glargine, including completed and ongoing controlled clinical trials, to better assess whether there is a risk of cancer associated with the insulin analogue. Discussions are taking place between the FDA and Sanofi-Aventis to determine if additional safety and efficacy studies will need to be performed. The FDA said it will communicate its findings with the public as soon as its review of insulin glargine is complete.

Sanofi-Aventis also issued a statement saying that the company “stands behind the safety of Lantus. … The results of these data clearly show that no definitive conclusions can be drawn regarding a possible causal relationship between Lantus use and the occurrence of malignancies.”

The editorialists pointed to other noteworthy findings from the studies. For example, the results of the Welch study showing that hazard ratios for cancer increased for all insulin-based regimens is consistent with other data suggesting that insulin use overall increases the risk for malignancy.

Also in the Welch study, the most striking finding was the protective effect of metformin, including the suggestion that adding metformin to monotherapy with sulfonylureas or insulin slowed the rate of cancer development.

“These observations suggest that metformin may come to play a major role in cancer prevention in diabetes. For present purposes, however, the points to note are that concomitant metformin use is potentially a major confounder when it comes to estimating the risks of insulin therapy. … Furthermore, the lack of effect of metformin on breast cancer, if confirmed, might help to explain why this particular cancer has tended to emerge from the analysis conducted in the previous two studies,” they commented.

In an EASD statement, Dr. Smith summarized the findings as follows: “We have no conclusive proof that Lantus is associated with a higher rate of cancer. The German study is suggestive, but relies on a statistical correction for insulin dose. The Swedish and Scottish studies are essentially negative in all respects except that of breast cancer. Individually, as we have emphasised, neither study is in any way conclusive. Taken together, however, they make it clear that there is indeed a case to answer.” He added that new data will be presented at the EASD meeting in Vienna in September.

Dr. Smith and Dr. Gale reporting having no duality of interest. Dr. Jellinger is on the speakers' bureau for several pharmaceutical companies, including Novo Nordisk, Amylin Lilly, and Takeda.