ORIGIN: No Increase in Cancer With Insulin in Dysglycemia

June 26, 2013

CHICAGO — A new analysis of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial in patients with prediabetes or type 2 diabetes using basal insulin for a median of 6 years has shown no increased risk for any cancers.

The findings were presented here at the American Diabetes Association (ADA) 2013 Scientific Sessions by Louise Bordeleau, MD, from McMaster University, Hamilton, Ontario. "We haven't shown an association in this trial. We haven't seen any increased signal for cancer events," she observed.

Session cochair Bessie A. Young, MD, MPH, VA Puget Sound Healthcare, Seattle, Washington, said: "This is a large randomized controlled study in patients on insulin glargine [Lantus, Sanofi], so it is reassuring that they have over 5 years of follow-up and there was no increased incidence of cancer. Physicians have been worried about it because insulin is a potential growth factor, so there was concern that it may cause cancer."

But Craig Currie, PhD, an epidemiologist from Cardiff University, United Kingdom, told Medscape Medical News: "I'm still concerned that this trial doesn’t adequately answer the question of whether insulin promotes cancer in people with type 2 diabetes. Nobody's arguing that insulin causes cancer, we're saying it increases the rate at which these cancers present. I'm personally convinced it does…and there are a plethora of data now that say there is a problem with [insulin] and all outcomes, including all-cause mortality, cardiovascular disease, cancer, and all the microvascular outcomes [in type 2 diabetes], and that it is worse than the other alternatives."

Others were more guarded. Robert Fredericks, MD, an endocrinologist in private practice in Reno, Nevada, said he believes insulin should be an option for some type 2 diabetes patients. "But I think we don't know how to use it as well as we should.We need to learn how to appropriately personalize our understanding of [type 2] diabetes so that we can recognize when insulin is appropriate and how aggressively to use it."

Neutral Effect of Insulin Glargine on Cancer Events

The ORIGIN study was an international double-blind trial in 12,537 patients with cardiovascular disease or at high risk for cardiovascular events who had an impaired fasting glucose/impaired glucose tolerance (around 12%) or type 2 diabetes; they were randomly assigned to receive insulin glargine or standard care. The study was a 2 x 2 factorial design, with another group assessing n-3 fatty acids vs placebo.

As previously reported, the trial was negative, showing no impact of either omega-3 fatty acids or insulin glargine in reducing a composite end point of MI, stroke, or cardiovascular death. However, the results were also portrayed as reassuring, illustrating that this type of insulin at least does not accelerate cardiovascular events, something that has been a concern.

The trial was also set up to look for other possible safety issues, such as cancer, and it was this outcome that Dr. Bordeleau reported in-depth in Chicago.

All cancer deaths and cancer-related hospitalizations were collected from the date of randomization and at every visit, she noted. And cancers not requiring hospitalization and any other cancer events were also ascertained starting in January 2010.

There were 953 patients with a cancer event (7.6% of total study population), for a cancer incidence of 1.32/1000 person-years (1.32%/year). The median insulin dose in those randomized to insulin glargine was 0.31 U/kg at 1 year and 0.40 U/kg at 6 years.

After adjustment for confounders, there was no increased risk for cancer among those taking insulin glargine vs those receiving standard care (hazard ratio [HR], 0.94; P = .52).

Nor was there any increased risk for any individual cancer, including lung, colorectal, breast, prostate, any skin, or other cancer, said Dr. Bordeleau. Numbers of pancreatic cancer cases were too small to look at individually, she noted.

She and her colleagues also looked at whether there were interactions between other parameters in the trial and cancer outcome, but found nothing.

"Daily exposure to glargine for a median of 6.2 years had a neutral effect on cancer events, and this was not modulated by metformin or sulfonylurea [treatment], HbA1c levels on trial, or weight," she observed.

EASD Symposium on Issue of Insulin in Type 2 Diabetes

But during the question-and-answer session, Dr. Currie observed that "the rates of cancer you are reporting are 3 to 4 times less than we'd expect in this age group. I think they've just been screened out at baseline."

He then asked asked Dr. Bordeleau if the ORIGIN investigators had analyzed cancer results by dose of insulin glargine. She replied that they had not, because the insulin dose was "fairly low" and this analysis wasn't preplanned. However, "it could be done down the road," she observed.

To Medscape Medical News, Dr. Currie commented: "It's such a low dose [of insulin] that they were giving these people because they were so early on in the natural history of the disease, and some were prediabetic, and you've got all sorts of stuff contaminating both arms. They are saying there is too low a dose [of insulin], but they still could still split it into 'high' and 'low' dose; they could have tried to separate them out. They did it with metformin; they looked a dose of metformin so they could have looked at [the] dose of insulin. They don't want to find an association, trust me.

"Nobody is arguing that insulin causes cancer, we're saying it increases the rate at which these cancers present," he said, stressing that this is not an issue unique to insulin glargine but applies to all insulins.

Such is the concern, says Dr. Currie, that at its Barcelona meeting in September, the European Association for the Study of Diabetes (EASD) will be holding a special symposium on the subject of insulin in type 2 diabetes.

"They've switched the promotion of the ORIGIN trial since it didn't show anything and it essentially said there is no point in giving people insulin at an early stage of diabetes. Now they are trying to get some benefit, by trying to come up with a defense against a potential association between insulin and cancer and other things, all-cause mortality and cardiovascular events."

"I can't disclose too much but there will be contemporary data coming out that I think will potentially scare people a bit. The tide is turning. I think within 2 or 3 years, certainly 5 years, insulin is going to be a highly restricted drug in type 2 diabetes. The elephant in the room is insulin," he concluded.

Dr. Bordeleau reported that the ORIGIN trial was sponsored by Sanofi, which markets insulin glargine. Dr. Young, Dr. Currie, and Dr. Fredericks have reported no relevant financial disclosures.

American Diabetes Association 2013 Scientific Sessions. Abstract 281-OR , presented June 24, 2013.

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