Statins and Prostate Cancer

The Wall Street Journal is reporting on a study published in the journal Cancer, and described by Reuters that links statins to reducing the risk of prostate cancer.  According to the report:

The researchers found that men who died of prostate cancer were half as likely to have taken a statin at any time, and for any duration, than men in the "control" group.  Those with fatal cancers were 63 percent less likely to have ever taken a statin, according to findings published in Cancer.

 I would love for statins to reduce the risk of prostate cancer. Readers of this blog know I am relatively pro-statin, in the right patient population. However, this study is too limited to make an actual connection, and I would not recommend taking statins solely for prostate cancer prevention.

What did the researchers do? The looked at the medical records of 380 men who died of prostate cancer and matched them with the records of another 380 men who did not have prostate cancer.  They use statistical techniques to adjust for difference such as age, weight and other medications.

What's the problem with the study? First, if the study findings are correct, such a study that uses medical  records and then looks back in time can not prove causation.  It only proves association.  This means that the study doesn't prove that taking a statin will ward off prostate cancer. Rather, the results mean that men who had died of prostate cancer were less likely to take a statin.  This is a big difference.  There are multiple examples where a confirmed association did not result into a confirmed causation (Vitamin E/C and  Folic Acid for preventing heart attacks).  In addition, there are many reasons that the association is in fact not correct.  Perhaps men who had been diagnosed with prostate cancer chose not to take statins, even if their doctors recommended it, because they were more concerned about the prostate cancer?  Perhaps men who did not have prostate cancer were extremely health conscious and were more aggressive about both doing things to prevent cancer (exercise, diet, etc.) as well as being more aggressive about  taking statin medications for high cholesterol?

Why this might be true? The only way to truly determine causation is to perform a randomized clinical trial (RCT).  Only a RCT can both eliminate some of the confounding variables (i.e. were the men without prostate cancer more aggressive about their overall health) and demonstrate the primary ingredient for causation: that exposure always precedes the outcome.  If factor "A" is believed to cause a disease,  then it is clear that factor "A" must necessarily always precede the occurrence of the disease. 

However, there are two findings from this study that support causation.  First, is dose-response relationship.  Only the newer, more potent statins showed benefit. Taking a lower potency statin was not protective.  The second is biologic plausibility. According to the Reuters report, Dr. Stephen Freedland, who studies prostate cancer at the Duke University Medical Center in Durham, but wasn't involved in the new study was quoted as stating that statins may protect against fatal prostate cancer through their known cholesterol-lowering effects, mentioning that cholesterol is a "key nutrient" for cancer cells, so lower cholesterol levels in the body could prevent more aggressive forms of cancer from developing.

Bottom Line: This study is exciting and will hopefully lead to randomized trials which can prove whether or not taking a statin will prevent prostate cancer.  For now, there is very limited evidence to suggest this would actually work, and men should not start taking a statin just to lower their risk of prostate cancer.

More Evidence that Lantus Causes Cancer

There is a new study reported in Bloomberg this morning that Sanofi’s Lantus Doubled Cancer Risk in Study of Diabetics. The study, which was presented yesterday at the San Antonio Breast Cancer Symposium retrospecitvely evaluated medical records of 23,266 patients in southern Sweden and determined that diabetics who used Lantus had a 2.9-fold greater chance of cancer, while those who took the generic drug metformin had an 8 percent lower risk.

I have previously blogged about this back in 2009 when the first reports surfaced about the link between Lantus and cancer. (See A New Problem With Insulin: Cancer ,  Lantus Causes Cancer! Why Doesn't Anyone Seem Care? and Lantus and Cancer- A Closer Look Is Not Reassuring )

Back in 2009, when the story broke, the FDA acknowledged the potential link but stated that the data was insufficient and recommended that patients not stop taking Lantus, at least without discussing this with their physicians. They stated that they were "currently reviewing many sources of safety data for Lantus, including these newly published observational studies, data from all completed controlled clinical trials, and information about ongoing controlled clinical trials, to better understand the risk, if any, for cancer associated with use of Lantus." However, we didn't hear much until January, 2011 when they released an update declaring that they had reviewed the four 2009 studies and has "determined that the evidence presented in the studies is inconclusive", and in addition had reviewed results from a 5 year study (sponsored by the makers of Lantus) which did not show an increased risk but was  "not specifically designed to evaluate cancer outcomes," concluding, "at this time, FDA has not concluded that Lantus increases the risk of cancer. Our review is ongoing, including review of information from a current clinical trial." With the new study reported today, it will be interesting to see whether the FDA chooses to give and update or reveals and additional information, such as a VA data set they are supposed to be evaluating.

According to the Bloomberg article, a Sanofi study from Sweden, Norway, Finland, Denmark and Scotland is complete and will be submitted to health authorities this month.  In addition,  U.S. study will be finished in early 2012, while a final report from Europe will come later. All of these studies combined will involve more than a million patients, which will hopefully be enough to give a more conclusive answer.

To be clear, I am not 100% convinced that Lantus causes cancer.  However, there is another long acting insulin (Levemir) which has similar efficacy to Lantus, has not been associated with cancer, and has a substantially different affinity for the insulin like growth factor (IGF) receptors that are implicated in the possible connection.  Given the mounting evidence of a cancer link with an equally effective product that appears to be safer, I can't see any reason to prescribe Lantus when Levemir is available.

Actos Causes Bladder Cancer. Maybe We Should Have Kept Avandia?

Both Germany and France have now suspended the marketing of Actos (pioglitazone) due to concerns of a link between Actos and  bladder cancer.  Though we have known about bladder cancer concerns for some time, these recent concerns about the bladder cancer link stem from a recent report analyzing the FDA's Adverse Event Reporting System (AERS), which found that 93 cases of cancer were recorded between 2004 and 2009 in patients treated with antidiabetic drugs of which 31 patients were treated with pioglitazone, representing a statistically significant increased risk of bladder cancer (ROR 4.30, 95% CI 2.82-6.52; p<0.0001). Interestingly, the FDA announced that it was going to look into the link between Actos and bladder cancer only a few days before it made it's final decision on what to do with Avandia (as if they didn't know about the Actos cancer risk before the July 2010 advisory board). 

Despite the many things you have heard about Avandia, back in July 2010, the FDA decided to severely restrict the use of Avandia for three reasons:
1. Despite limited and conflicting data, there seemed to be a signal of myocardial infarction for patients taking Avandia.
2.  The one study proving Avandia's safety, RECORD (see here for more details) was discredited by FDA scientists due to potential reporting errors.
3. The advisers on the panel felt strongly that despite limited and conflicting evidence, the signal was enough to be concerned AND because Actos (similar drug in same class) did not seem to show this signal, why would doctors ever want to prescribe Avandia?

I have blogged extensively about Nissen's meta-analysis that triggered the whole Avandia scare. Meta-analysis have major limitations.  Another group of researchers using the same data as Nissen's with different statistical  techniques concluded that Avandia did not cause heart attacks.  Large, randomized trials are the only way to determine certainty, and all available large trials (DREAM, ADOPT, ACCORD, etc.) with rosiglitazone showed no heart attack risk.  As mentioned above, the one study designed to definitively show whether or not Avandia led to cardiovascular risk (RECORD, which showed that Avandia did not cause cardiovascular risk, and in fact surpasses the FDA's standard for cardiovascular safety) was harshly criticized by those within the FDA that wanted to see Avandia pulled from the market.  Specifically, the FDA found that GSK had some errors in reporting the results of RECORD.  Though these types of errors are not uncommon in very large trials, and likely won't affect the overall results of the study, nonetheless, the deserve looking into.  However, the FDA promised to do a complete independent analysis of the RECORD results; a promise it has yet to deliver on.

The main issue here is #3: Actos appears to be safe, so let's dump Avandia. (Interestingly, independent cardiologists analyzed all the data and did not find a conclusive difference in cardiovascular risk between Actos and Avandia).  Here is the full transcript of the advisory board.  Since it is a very difficult document to read through, I have pasted some of the direct quotes below from some of the advisers who voted to either remove Avandia from the market or severely restrict its use. Based on these quotes, I feel pretty strongly that had the advisers known about Actos' bladder cancer risk, that they may have voted very, very differently.  However, the FDA did know about the association between Actos and bladder cancer.  They just chose not to mention it!   In fact, when one adviser brought up the question at the July advisory board, the FDA only briefly mentioned this and discussed it more as a class effect also seen with dual PPAR agonists.

Avandia and Actos help diabetics use their own insulin better by hitting a receptor called PPAR. There are three main PPAR receptors: Alpha, Gamma and Delta.  We don't know a whole lot about delta, but PPAR Gamma works on glucose, and PPAR alpha affects cholesterol.  Fibrates like gemfibrozil, which lower triglycerides and raise HDL or good cholesterol are PPAR alpha agonists.  Dual PPAR agonists were drugs that pharma were trying to develop that hit both alpha and gamma in order to help both with lipids and glucose.  They have not been able to make it to market due to safety concerns (raised by, guess who??? Dr. Nissen). One of the differences between Actos and Avandia, is that Actos has a higher affinity for the PPAR alpha receptor, which is why it likely does a better job on raising HDL and lowering triglycerides than Avandia.  Some have hypothesized that this might be the reason why Actos might not have the same cardiovascular issues as Avandia (though this has yet to be shown).  If in fact, as stated during the FDA meeting (I am not aware that this data is published) that the bladder cancer risk was seen in both Actos and the dual PPAR agonists.  Bladder cancer has not been seen with Avandia.  In other words, the evidence (both available and suggested by FDA quotes that are public record) suggest that Actos may have more of a bladder cancer risk than Avandia. 


Why the FDA in discussing to keep Avandia on the market would not extensively discuss the concerns of bladder cancer with Actos, paired with the weak and controversial data showing Avandia's cardiovascular risk and effort to discredit GSK's study proving Avandia's safety leads me to believe that the FDA's attack on Avandia was very much politically motivated.  Scientists look at all the available data and weigh the risks and benefits of all options before making a conclusion.  It is clear to me that the FDA's decision on severely restricting Avandia was more political then science. Based on the currently available data which now include bladder cancer risk, Avandia may actually be a better choice than Actos, but the FDA's restriction will essentially prevent any doctor from being able to prescribe Avandia after November.



Select quotes from advisers who voted to voted to either remove Avandia from the market or severely restrict its use:
DR. SCHAMBELAN: This is Morrie Schambelan. I voted E. (remove Avandia from the market) . I was one of the brain-dead kangaroos last time (meeting in 2007) who was on the fence, largely because I did see a signal for harm. I was led at that time by the comparison to active comparators, which I think is much more relevant to me than placebo. I wasn't swayed by the pioglitazone data that were presented at that time because they were pretty preliminary. I was much more persuaded this time, including Dr. Graham's analysis. I feel that pioglitazone is a perfectly acceptable alternative.

DR. SAVAGE: Peter Savage. I voted D (keep on the market with restrictions) I was also oscillating between D and E because I think that the evidence of potential harm associated with rosiglitazone is stronger now than it was in 2007. And very importantly, the evidence about pioglitazone is substantially greater than what we saw treat in 2007.

DR. FLEMING: Fleming. I voted E. My main sense about this is really explained in my answer to question number 7. There's very concerning data about safety with rosiglitazone. It's not definitive, but if TIDE is to provide that, we have many years before we're going to get that insight. We do have an alternative, pioglitazone, for which there is considerably strong safety experience. So I come down to, then, what is the continued role for rosiglitazone?

DR. THOMAS: Abraham Thomas. I voted E. The scientist in me says we should always seek the truth. But this isn't an NIH study section. This isn't the review of a journal for publication. Really, what this is is an intersection, as someone mentioned at lunch, between public policy and science. And when we look at it that way, we can't always have the absolute truth to make a decision. We have other classes that are available that we never had before for the treatment of diabetes. And if rosiglitazone was removed from the market, we still have another TZD, what has had a trial that does demonstrate no increased cardiovascular mortality, no increased cardiovascular events, in PROactive.

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.