Thursday, July 2, 2009

Lantus and Cancer- A Closer Look Is Not Reassuring

Kevin MD brought up the issue of Lantus and cancer on his blog, linking to both my original post which stated that patients should be concerned, as well as a post from Amy Tenerich at Diabets Mine who takes a more conservative approach, like the ADA and AACE. ( I do question the motivations of these groups in my recent post on this matter: Lantus Causes Cancer! Why Doesn't Anyone Seem Care? ). Some responders to my inital post felt that I had not read the studies correctly. Therefore, below is my detailed interpretation of the four studies recently presented which caused the controversy.

The first study was a German study of 127,000 patients, which 20,000 were treated with Lantus. Most of these patients had Type 2 diabetes. Overall, this study found a correlation with all insulins and cancer, but no difference between the analogue insulins. However, because patients on combination analogue and human insulin were excluded in the study, the dose of lantus was much lower than the other analogues. The researchers then adjusted for insulin dose, and they found a dose dependent relationship of cancer and Lantus. The magnitude of this effect was such that 1 cancer might be caused for every 100 patients taking Lantus for a year. One of the limitations of the study was that it was not possible to break the analysis down by types of cancers caused. Given this and other possible limitations, the editors of the journal decided not to publish this study until these results could be replicated in other studies/countries, especially considering the importance of the findings if corroborated.

Since then 3 other studies were performed, and subsequently all four were published together.

The second study was a Swedish study matched a national cancer database and a national diabetes database looking for a connection. This study included over 120,000 patients of which about 6000 were on Lantus. They found no increase in risk for cancer with Lantus when taken with other kinds of insulin. These patients were younger, and more likely to have type 1 diabetes. However, analysis of patients who took Lantus alone, most of whom had type 2 diabetes, showed a doubling of breast cancer, which was highly statistically significant (though no increase in other types of cancers).

A third Scottish study used national database registeries similar to the Swedish study and they found exactly the same thing. The patients who took Lantus with other insulins, who were generally younger type 1 diabetics had no increased risk of cancer with Lantus compared to human insulin (actually had lower rates) but the patients on Lantus without other insulins, mostly older type 2 diabetics had a higher risk of cancer. There was also similarly an increased risk of breast cancer in women taking Lantus alone, which was about the same magnitude as the Swedish study.

The fourth study looked at cancer risks associated with a range of insulins. This retrospective UK study looked at over 62,000 adults that were started on oral agents and/or insulin. Diabetes developed in adulthood, so these were mostly type 2 diabetics. In general, the study found no difference between human insulin and analogue insulins like glargine (Lantus). However, the study did find that metformin use is associated with a lower risk of cancer, and seemed to abolish cancer risk. Also, only 10,000 patients in the study were on insulin, and only 2000 on Lantus. Plus, it was not clear who was taking meformin plus Lantus. Thus, given the very small number of patients on Lantus, some of who may have been taking metformin, this negative finding is not all that reassuring.

Taken together, in my opinion, these 4 studies strongly suggest a link between new cancers in adult type 2 diabetics who are taking Lantus alone. Now, we can't say that Lantus actually causes cancer. In fact, it is unlikely that Lantus actually causes cancer alone, because it takes years to develop most cancers. However, it is more likely that Lantus causes existing cells to grow and divide more rapidly. Usually, the body's own natural cancer fighting abilities take care of these cells. In other words, though Lantus may not cause cancer, adult type 2 diabetics taking Lantus seem to develop clinically apparent cancers at much higher rates (double for breast cancer) then those not on Lantus. Though whether or not Lantus is causative of cancer is an interesting academic discussion. However, from the patient's standpoint if taking Lantus increases the likelihood they will develop cancer, that's all they need to know.

Large observational studies are far from perfect. The can detect differences (i.e. adult type 2 diabetics taking Lantus were more likely to get cancer), but can detect the reasons for these differences. The only way to show actually causation would be a very large, randomized control trial conducted over years. However, this will take years to complete. The Europeans are suggesting meta-analysis of even larger databases to find out sooner.

Until we know for sure, given a possible risk for Lantus increasing the rate of cancer development, I would suggest it would be prudent to stop taking Lantus if you are a type 2 diabetic, especially if you are not taking other kinds of insulin. Detemir insulin (Levemir) is a reasonable alternative. Though it has not been studies as extensively, its effect on the IGF-1 receptor (the purported mechanism of the cancer association) if much, much less than Lantus.


JohnARNP said...

Dr Mintz
I have a dog in this hunt since I am on Lantus myself. Your analysis seems to be quite different than medpage today, especially that of the Swedish and the Scottish study.
The authors of the Scottish study themselves wrote in their conclusions: "Overall, insulin glargine use was not associated with an increased risk of all cancers or site-specific cancers in Scotland over a 4 year time frame. Given the overall data, we consider the excess of cases of all cancers and breast cancer in the subgroup of insulin glargine only users to more likely reflect allocation bias rather than an effect of insulin glargine itself. In the Discussion section they also say "our primary hypotheses that exposure to insulin glargine was associated with an adverse effect on total cancer rates or site-specific cancer was refuted, and these data are reassuring in this regard."
As far as the Swedish study is concerned it is fraught with limitations. The authors also comment,... "We have no evidence of whether the difference in incidence rate for breast cancer among users of insulin glargine monotherapy, compared to users of insulin glargine together with other types of insulin, is caused by random fluctuations...Any suggestion of an explanation would be pure speculation." Because of the severe limitations and confounding variables, the Swedish study authors also state" No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies can be drawn from the results of this study. For one, I would have liked to see the ability to control for genetic factors when looking at breast cancer, considering we are talking about a county with a population roughly the size of New Jersey.
I believe this is why the ADA came out with such a strong statement. This is not because of money, but it is because these studies are severely limited and definitely conflicting. Should there be more studies? Sure. But as you point out with Avandia, lets not pull data out of poorly designed studies and scare people for no reason.

Joshua Levy said...

You might want to check out this paper:

They hold that the basic analysis of the German paper was flawed from the start. (And the paper completely worthless.) They point out that the raw data shows Lantus was safer than other insulins, but it was only through the author's analysis that it became unsafe, and they don't agree with this analysis.

Personally, I think your first blog on lantus was one sided, but that was your opinion. What bothered me about it was that it mostly discussed politics, money, and conspiracy theory, rather than science. In this entry you are at least talking about science.

The link above discuss the science in depth. I'm also curious as to why you did not talk about the fifth study. The one that used better experimental methodology and found no link between Lantus and cancer.

Joshua Levy

Anonymous said...

Jan 12th, 2011
Sanofi’s Lantus Isn’t Linked to Cancer in FDA Review.

(this is why you dont jump the Gun Dr. Mintz and scare many people away from a good drug that was keeping their diabetes in control)

Dr. Matthew Mintz said...

Actually, the FDA didn't say Lantus wasn't linked to cancer. It said it wasn't sure. Specifically, "that the evidence presented in the studies is inconclusive, due to limitations in how the studies were designed and carried out and in the data available for analysis." Furthermore, the FDA will continue to look into this. "Our review is ongoing, including review of information from a current clinical trial, and the Agency will update the public when it has additional information."
The fact is that it isn't clear whether or not Lantus causes cancer. I am just concerned about some of the signals. Since there is a very similar (some would argue better) alternative to Lantus called Levemir, which in the test tube seems safer, my recommendation to patients is until we know for sure, not to use Lantus and switch to Levemir.