Sunday, July 26, 2009

Sick About Singulair

The New York Times' business section recently reported that despite a second-quarter earnings fall, hurt by lower sales of its cholesterol drugs (specifically Vytorin, see my posts on why you should no longer use this product), Merck actually beat profit forecasts due to good sales of its asthma drug Singulair. Singulair's quarterly sales jumped 16 percent to $1.3 billion. That's a lot of money! Indeed, based on pharmacy data (via, thanks again Mr. Medsaver for this great resource), Singualir was the 4th most commonly prescribed drug in 2008 at a close to 26 million prescriptions! Moreover, a recent report from the WSJ Health Blog states that Merk is looking to put Singualir over the counter.

I have no ill will towards Merk. It is an American company that has come up with some products that I find beneficial for patients including Fosamax (which is now generic) and Januvia, and they are the makers of two important vaccines: Gardisil and Zostavax. However, I am concerned about high sales of the asthma drug Singulair, because national guidelines state it should not be used as a first line therapy for asthma.

Facts about asthma

According to the American Lung association, in 2007, it was estimated that 22.9 million Americans currently have asthma. Of these, 12.3 million Americans (3.8 million children under 18) had an asthma attack. In 2005, there were 3,884 deaths attributed to asthma. During 2006, 444,000 hospitalizations and close to 1.7 million emergency room visits were attributed to asthma.

In 2007, the NIH released updated guidelines about asthma. Regarding treatment, the guidelines suggest that all asthmatics with persistent asthma (symptoms or rescue medication use more than twice a week) be initiated on inhaled corticosteroids (ICS). ICS's are considered first line treatment for all asthmatics, from babies to children to adults and to the elderly. The reason is based on solid evidence that these agents work the best in improving lung function and decreasing symptoms. Singulair is listed as an alternative agent. Singulair is an anti-leukotriene. Leukotrienes, like histamines, are substances released in an allergic response that cause the airways to tighten up. Thus, Singulair works in the same way that antihistamines work: by treating the symptoms. ICS's work by blocking inflammation which is what causes the release of leukotrienes in the first place. Singulair is not anti-inflammatory, ICS's are. Singulair treats the symptoms, whereas ICS's treat the problem. This is why study after study proves that ICS's are superior to Singulair, and why guidelines place ICS's as first line treatment and Singulair as alternative.

Does Singulair work?
Of course Singulair works. In order for a drug to be approved by the FDA, the drug company has to show that its product is efficacious. The problem is that it has to show that it is efficacious compared to placebo. Thus, Singulair works better than a sugar pill. However, compared to any other asthma medication, it is not as good. Even when added on to an ICS, it is not as good as other add ons, such as long acting beta agonists (LABA's).

Why do physicians prescribe so much Singulair when is not what the guidelines recommend?

This is an extremely important question. Some may chalk it up to drug company marketing. However, all the ICS and ICS/LABA making companies due their job marketing their product as well. I think the main reason has to do with fear of ICS's. Corticosteroids are different than the kind of steroids athletes take. However, they are not without side effects. Earlier studies on older medications showed some growth delay in children, which is why pediatricians may be so reluctant to use ICS's. However, more recent studies showed that for the newer agents, long term use with mild to moderate doses did NOT cause growth delay. In 2002, the NIH reviewed all the literature and determined that at low to medium doses of ICS's, there are NO SIGNIFICANT SIDE EFFECTS. This is when ICS's became considered first line therapy for ALL asthmatics.

The other issue is the convenience factor of a pill vs. an inhaler. Inhaler use is clearly not as easy as taking a pill (Singulair comes chewable for children).

The thought is probably, "it's a once a day pill that might help my patient, and probably won't hurt them, so why not give it try?" The problem with this approach, is the failure to consider the risks of uncontrolled asthma. Uncontrolled asthma leads to ER visits, hospitalizations, and possible even death. Asthma is a serious disease. For patients who have persistent asthma, following the guideline recommendations of ICS's as first line agents is the right thing to do.

What about allergies?

Singulair is also indicated for allergic rhinitis or allergies. As above, like histamine, leukotrienes play a role in allergic rhinitis, and this is why Singulair is used. I have posted about Singulair and allergic rhinitis previously. Basically, there are several treatments for nasal allergies:Non-sedating antihistamines (Claritin, Zyrtec, Allegra), Leukotriene modifiers (Singulair), inhlaed nasal steroids (Flonase or fluticasone, Rhinocort, Nasacort, Veramyst) and inhaled nasal antihistamines (Astepro). Muliple studies that show that fluticasone (Flonase) is better than Singulair, better than Claritin, and several studies that show that the combination of Singulair and Claritin is not better than either agent alone. However, in one study, though the combination of Singulair and Claritin was better than either agent alone, the individual agents were no better than placebo. An excellent review by Dr. Robert Nathan showed that "leukotriene receptor antagonists (Singulair) are sometimes more effective than placebo, are no more effective than nonsedating antihistamines (Claritin) , and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis." Finally, a recent guideline from World Health Organization suggests that for patients with mild, intermittent allergic rhinitis; treatment with non-sedating antihistamines and leukotriene modifiers were both acceptable forms of treatment, but patients with more chronic or bothersome symptoms, inhaled nasal steroids should be used.

Some would argue that having both allergies and asthma together would be a reason to take Singulair. There is no question that treating allergic rhinitis may help with asthma symptoms. However, the killing two birds in one stone approach simply hasn't been proven to be the case. If you have allergic rhinitis that makes your asthma worse, you should take the most effective agent, which is inhaled nasal steroids.

What if I am taking Singulair for asthma?

Singulair has been proven more effective than placebo, and in some individuals controls their asthma and allergies. However, a recent internet survey revealed that about 55% of asthmatics have uncontrolled asthma, and many of them are on regular medications. Asthma control is the key, according to the new NIH guidelines. If your asthma is well controlled on Singulair, then it is probably OK to take. However, there is a theoretical risk that by taking Singulair (treating the symptoms without treating the underlying inflammation), that though you feel well now, your lung function will be worsening over time. More importantly, if you are taking Singulair and your asthma is not well controlled, then you should definitely switch to at least an inhaled corticosteroid, or possibly an agent combining an ICS with a long acting brochodilator (LABA) such as Advair or Symbicort. There are many ways to determine asthma control, including how much rescue medications you are taking and how asthma affects your daily life. The easiest way to determine your asthma control is by taking the Asthma Control Test

Wednesday, July 22, 2009

Finally! FDA Questions Safety, Quality of Electronic Cigarettes

As reported first in the WSJ Health Blog, the FDA is finally looking into electronic cigarettes, and they don't like what they see. Here is the FDA press release and here is the full report.

I have previously posted on my concerns about the safety of e-cigarettes. These posts are some of my more popular ones, with so many readers not understanding my concern. Their points are that e-cigarettes are at least better than tobacco cigarettes, and nicotine itself is safe, since it is sold over the counter. However, the FDA seems to validate my concerns. Here's what they found.

  • In testing 19 products from two manufacturers, investigators found that the majority tested positive for tobacco impurities thought to be harmful to humans.

  • In one sample, the FDA’s analyses detected diethylene glycol, a chemical used in antifreeze that is toxic to humans

  • Half of the samples appeared to contain known carcinogens

  • Some products testing positive for nicotine even though the label said no nicotine was present.

The FDA is also concerned about the appeal of e-cigarettes and the easy availability to children:

These products are marketed and sold to young people and are readily available online and in shopping malls. In addition, these products do not contain any health warnings comparable to FDA-approved nicotine replacement products or
conventional cigarettes. They are also available in different flavors, such as chocolate and mint, which may appeal to young people

Thus, I stand by the statements in my previous posts. Electronic cigarettes are not safe and should not be used to replace tobacco products, nor as a substitute for smoking cessation agents.

Wednesday, July 8, 2009

Let Google Solve Our EMR problems

The Wall Street Journal reported today that Google was going to launch their own operating systems for PC's competing with Microsoft's dominant Windows platform. Google seems to continuously creating new, innovative and useful products. This very blog is hosted on blogger, which is now a Google product. Since they seem to be doing such a good job, why not let them solve the electronic medical records problem?
EMR's are a big part of President Obama's health care plan. I certainly value the use of EMR's. They provide me the data I need when I need it. They allow me to communicate more effectively with my staff. Using e-Prescribing in our EMR I am able to fill prescriptions faster and more accurately for my patients. Finally, through our EMR, patients can communicate directly with their physicians. (We use Touchworks by Allscripts. I have no vested interest in the product or company)
However, I do not believe that EMR will really save a lot of money. Time is money, and EMR's do not save time. EMR's do improve quality of care. They allow you to do more in a given amount of time, but do not save time., and in fact may add time because you can do more. The best example I can give for non-EMR users is that just in the way that your email and Blackberry have not saved you any time from the days when you relied on phone calls and the US postal service (have they not instead created more work?), EMR's do not save time. Politicians point to cost savings in preventing duplicate work. There might be a few duplicate tests or procedures prevented, but likely not that many and not nearly enough to call investment in EMR's a cost-reducer.
In my post $19 Billion For Health IT-Money Well Spent? I also call into questoin how the stimulus package is funding health IT. Looks like that money went to hospitals to improve exsiting systems, and not to help the primary care physician offset the HUGE cost of implementing an EMR in his or her practice. The software, hardware and support needed for most EMR's cost far more than the average physician practice can afford.
The real issue with EMR's is interoperability. The are many companies that make many products and not too many systems talk to each other. In our hospital alone, we now use up to eight different computer systems to store and retrieve patient information. Your primary care doctors EMR should be able to talk to the Pharmacy's computers, the lab's computers, the hospital's computers, the radiologist's computers, the specialists consulant's computers, etc.
Regardless of whether you support a single payer system or a tax rebate for patients to purchse their own health care; wouldn't it make sense to have one really good EMR that every doctor could use? Wouldn't it be great if this was on a web based platform, meaning that all you would need is a computer (or netbook, or web based mobile phone) and a high speed internet connection and you could have access? Most docs already have that. Wouldn't it be great if interfaces could be created so that all parties "spoke" to each other? Wouldn't it be great if this system could include functionality so that patients could communicate with their physicians, request appointments, and see their lab results?
Who better to create this EMR than Google? The interoperability/interface issue stems from the fact that there are so many proprietary systems. Each company that makes an EMR wants its EMR to be used by everyone. Just throwing money at all of these companies is not going to solve the problem or make EMR's more affordable or usable. The goverment already has a pretty good EMR used in the VA. It works well inside the VA, but doesn't talk to others. Even in a single payer, government run health care system, would you have the goverment re-vamp the VA EMR? Why not go to the pros at Google? They have already started the process with Google Health, though this is a personal health record and not an EMR. They good create a Google Medical record (GMR) that interfaces with their existing Google Health platform. Sure, they would have a monopoly, but in this case the benefits to the public, patients and doctors far outweight the risks. If the Google EMR was supported by the goverment, then you could create restrictions to limit any of their profit.

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.

Wednesday, July 1, 2009

Lantus Causes Cancer! Why Doesn't Anyone Seem Care?

The answer is probably money, but more on that later.

I recently posted on the Lantus/cancer connection in my post A New Problem With Insulin: Cancer. The concern was triggered in a press release about a recent European report based on one earlier and three new studies which show a link between Lantus, a long acting insulin, and cancer. As I mentioned, I though it was interesting that more alarm has not been raised, particularly here in the US. Nissen's poorly done Avandia study got major press, and people stopped taking the drug (He was recently proven wrong- see here fore more info). Yet, for Lantus, the report is not about one study, but four studies that show similar findings that Lantus increases rates of cancer. In addition there are some biologically plausible reasons (more later) and a clear dose response. If you look at the criteria for causation, the Lantus/cancer connection seems to ring true. Yet, there seems to be not that much in the press and little public outcry to pull the medication from the market. This may be in part to the fact that the news cycle is now 24/7 Michael Jackson, but other medical stories, like the FDA and Tylenol, seem to be getting some attention, so this can't be the entire reason.

What do the experts say? The Europeans are making "an urgent call for more research". Yet, the US response is much more subdued. The official response from the American Diabetes Association (ADA) stated that findings from these research papers are conflicting and inconclusive, and cautioned against over-reaction until more information is available. A similar response can be found from The American Association Of Clinical Endocrinologists (AACE), the smaller but more academic group of diabetes specialists.

Where is the media attention on this? Where is the warning to patients? Why doesn't anyone seem to care?
MJ aside, here are some reasons:

1. The US experts don't want to say too much because of their ties to the drug companies. Both the ADA and AACE receive huge amounts of money from corporate sponsors, specifically the drug companies. In fact, back in 5/07 the experts issued a joint statement that had similar comments on the Avandia scare (which turned out to be correct). Sanofi-Aventis, the maker of Lantus, gives money to both of the ADA and AACE, and their members are unlikely to bite the hand that feeds them.

2. Though not all endocrinologists think alike, based on national and international diabetes recommendations, the expert guidelines recommend the use of insulin in type 2 diabetes much sooner than I would recommend. I have blogged in the past that I believe the endocrinologist making these recommendations may have a conflict of interest in that they have an incentive to make recommendations that will lead more patients toward insulin is because insulin use in type 2 diabetics is how they make their living. It is possible that the endocrinology experts are cautious about scaring the public about Lantus, because this may cause concern about all insulins, which they believe is the best treatment for diabetes.

3. The reason why Avandia drew more attention is because Dr. Nissen and some Congressmen were the ones making the noise, not the specialty societies. The Nissen meta-analysis on Avandia, from the data analyzed, to the publication, to the media frenzy had political motivations, whereas the Lantus studies do not. (See a timeline of the politics of the Avandia study in my post Diabetes Conspiracy )

What now?
Thanks to a comment on my previous post, I looked into the matter a little more. One of the problems with insulin is that is that it is related to insulin like growth factor (IGF-1) which has been shown to stimulate tumor growth. Regular human insulin has some affinity for the IGF-1 receptor, but Lantus has a much greater affinity, which is the likely reason more cancers were seen. There happens to be another long acting insulin on the market called Levemir that has very little affinity for the IGF-1 receptor (less than even human insulin) and is as effective as Lantus. In 2008, Lantus just missed the top 25 most commonly prescribed branded drugs at #26 with over 10.25 million prescriptions that year. Levemir came in at #170 with only 1.3 million prescriptions. Though I doubt this is public knowledge, I would guess that Novo Nordisk (the company that makes Levemir) is not giving nearly as much to these organizations as Sanofi Aventis (makers of Lantus), but I could be wrong. Since Levemir is a newer drug, is was not included in these studies and one can not rule out potential harm. That said, its low affinity for IGF-1 is reassuring. Thus, upon further reflection, I think that all diabetic patients who are on Lantus should talk to their doctor about insulin use, and if they need it, ask their doctor to consider switching them to Levemir.

Update: Via Med Page today, FDA just announced they were going to look into this. Not sure how much press this will garner. Certainly more valuable use of their time then trying to take down Tylenol.