Statins for influenza. Why don't we know if it works yet?

Statins for influenza are in the news again, this time because of a paper given at the Annual Meeting of the Infectious Disease Society of America (IDSA). We'll get to it in a moment, but first a little background.

Statins are cholesterol lowering drugs that are taken by tens of millions of people (including me; I take 20 mg of generic simvastatin a day). The statins are a group of drugs that competitively inhibit an enzyme, 3 hydroxy 3 methylglutaryl coenzyme A reductase (HMG-CoA reductase). They are quite effective in lowering cholesterol and have an excellent safety profile (not perfect, but no drug is perfect except the ones that don't do anything, and even then a placebo effect can give an adverse reaction). But these drugs also seem to do a lot of other things beside lower cholesterol, some of which seem to modify the way your immune system works. That's why they are also referred to as immunomodulators. One immune system effect seems to prevent activation of a transcription factor (a signal to your DNA to make specific proteins) called NF-kappaB. Somehow this produces an anti-inflammatory effect.

Some severe cases of influenza are complicated by an immune dysregulation (sometimes called a cytokine storm) characterized by runaway production of inflammation-associated chemicals in the lung and other organs. Hence the thought that an immunomodulator might be of use. We first posted on the suggestion that statins might be helpful in this way as far back as 2005 when we were still on our old site at Blogger.com (remember, you heard it here first):

In an extremely interesting article in the Clinicians Biosecurity Network Weekly Bulletin (issue of 9/27/05) Borio and Bartlett review a suggestion of David Fedson, an expert on vaccines (and former Director of Medical Affairs at Aventis Pasteur), that statins (tradenames Zocor or Lipitor) might be helpful in preventing serious complications of influenza, perhaps by dampening the cytokine response.

[snip]

The idea that statins might be helpful for sepsis or influenza is based on more than speculation about mechanism. In 2004 Almog et al. (Circulation, Aug 17 2004;110(7):880-885) reported that patients admitted to the hospital with acute bacterial infections and who were on statins for more than a month for other reasons had a dramatically reduced incidence of severe sepsis (19% versus 2.2%) and reduced admission to the Intensive Care Unit (12.2% vs. 3.7%). [NB: sepsis is a similar immune dysregulation to the one caused by influenza.] An interesting point is that patients on statins might be expected to be at greater risk because they are taking a medication for a pre-existing medical condition.

Another study (.pdf available free on line here) looked back at the experience of over 700 patients that were admitted to a hospital for pneumonia. About 100 of them were also taking statins. Using 30-day mortality as a measure of outcome, the statin group had about two thirds fewer deaths than the non-statin group (odds ratio .36, 95% confidence interval .14 - .92). (Effect Measure, September 29, 2005)

At the time it was too early to say anything with confidence, but we were puzzled why Dave Fedson's (prescient) suggestion wasn't being followed up. He continued to urge deeper study and published a review of the relevant literature (abstract here). When a study was published in Nature showing that the 1918 pandemic virus caused a sepsis-like immune dysregulation in mouse studies (our post here), Fedson wrote a frustrated letter to the The Times of London, begging for urgent action. We quoted some of the letter in a 2007 post, "Statins for H5N1. The road not taken. Why?":

The report in Nature describing the increased host immune response caused by the 1918 pandemic influenza virus is the latest in a series of studies suggesting it is the host response (the "cytokine storm") that is probably responsible for most deaths now being seen with H5N1 [bird flu] infections. If the H5N1 virus leads to the next human pandemic, and if the situation is similar to that in 1918, there could be 350 million deaths worldwide.

Conventional vaccines will be too little too late, and limited supplies of antiviral medications will be available in only a few countries. However, we have recently learnt that statins (the drugs used to treat high cholesterol) decrease mortality due to pneumonia by 40-60 per cent, suggesting that, by modifying the influenza "cytokine storm", statins could be life-saving.

The scientific rationale for considering statins for pandemic use is persuasive, but the public health rationale is hugely compelling. Unlike vaccines and antivirals, generic statins are available in almost all countries, and treating an individual patient would probably cost less than £1. The pandemic might be imminent, yet nothing is being done by scientists and health officials to explore this idea. Why? (Letter from David Fedson to The Times [of London], October 4, 2006)

At the time (2006) we thought Dave Fedson asked a good question. Why was there no apparent action?

In 2007 we again raised the statin issue in connection with another study showing statin's protective effect in chronic obstructive pulmonary disease (COPD), pneumonia and influenza in 76,000 patients from a health maintenance organization who took statins for at least 90 days. Deaths from COPD were cut dramatically and cut significantly for pneumonia and influenza. Later that year we wondered again (in a post about new antivirals) why statins weren't on the research agenda?

While we are talking about new drugs, however, it is somewhat disappointing not to see more information on the utility of a class of old drugs, the statins. Statins are cheap, plentiful and have a fairly good safety profile.

The statins are used for their cholesterol lowering feature but seem to have other effects as well. Now a paper on another cholesterol lowering drug, gemfibrozil, is also showing an ability to protect against the lethal effects of influenza infection (Budd et al., Antimicrob Agents Chemother. 2007 Jun 11). Survival against H2N2 in mice increased from 26% to 52% after an intraperitoneal injection of gemfibrozil 4 to 10 days after intranasal inoculation with the virus. Maybe we should be looking at the cholesterol connection a little closer?

The new drugs under development will have to go through an intense process of safety and efficacy testing. Meanwhile we also have drugs like the statins and gemfibrozil that are available and approved and could be brought into service immediately in the event of a pandemic. No big bucks here. These are drugs off patent and not hugely profitable.

But wouldn't it be useful to be investigating their utility a little more avidly? Or am I missing something? (Effect Measure, June 21, 2007)

Then earlier this year we revisited the science in a long post, "More on the science of the influenza 'cytokine storm'." There we tried to explain the science behind an important paper in the Proceedings of the National Academy of Sciences with the unintriguing title, "TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection" (Aldridge et al., PNAS). It was Dave Fedson that tipped me off to the paper over a long lunch. The paper suggested a role for a class of drugs called peroxisome proliferator activated receptor (PPAR) agonists, one of which is the diabetes drug, Avandia. Our take:

Before you run out and buy Avandia, you should know that there are some significant questions about risk of heart attack for those taking it long term for diabetes. On the other hand, balancing that risk against death from a pandemic flu virus suggests it is worthwhile to consider as part of our arsenal should a pandemic develop. Unfortunately, I fear it will be put on the shelf with other possibly effective and low cost approaches, like statins. Antivirals and vaccines seem to be the only weapons that the infectious disease folks can imagine. (Effect Measure, April 3, 2009)

These are not the only places where the statin-influenza connection came up at Effect Measure (here's another). We mention them because this has been on the scientific radar screen for at least 5 years. This week we did get some more information from the IDSA meetings. There is no paper, only press accounts (here, here, here, here) and Mike Coston at Avian Flu Diary also has a good account where he also reviews his previous posts (Mike is one of the best in flublogia; if you are interested in flu and don't read his blog, you should). I looked at the abstract for the paper and it reports different numbers than the press accounts, so I'm not sure which numbers are correct, although the bottom line is the same: people who were using statins for their cholesterol when they were admitted to the hospital for swine flu had lesser odds of dying than those who didn't:

[Lead author Meredith] Vandermeer and colleagues scrutinised medical records of 2,800 people who were hospitalised with seasonal flu in 10 states during the 2007-2008 influenza season.

In that group of patients, 17 of 801 who were on statins in the hospital (~2.1%) died of influenza or its complications. Of the 1,999 who were not on statins in the hospital, 64 died (~3.2%). Vandermeer said that represented a 54% decreased risk, taking into account other risk factors such as age and use of antiviral drugs.

She said that the database did not allow the researchers to determine the dose of statin that patients were on nor how long the patients had been taking the cholesterol-lowering drugs. She said that the researchers are analysing the data to determine if one brand of statin is associated with better odds of surviving the flu than another.

"We believe that statins may be able to mediate an immune response in addition to being able to lower cholesterol," she said. However, Vandermeer said the results of the study would not be sufficient to makes recommendations for prescribing statins for treatment of infectious diseases. (Ed Sussman, Doctor's Guide)

The two groups (statin users and non-statin users) were not exactly alike with respect to other risk factors that might affect survival, so it wasn't sufficient to compare 2.1% with 3.2%. The statin users were more likely to be older, male and White or Asian. As the use of statins would suggest, they were also more likely to have an underlying health condition like heart disease and to have been vaccinated against flu last season. Some of these differences would tend to increase the mortality of statin users, others to decrease it. To account for the differences the researchers employed a standard statistical technique called multiple logistic regression, which produced the 54% decreased risk number in the press reports (the decrease in odds in the abstract is 66%).

So have we finally taken the statin road? The study was done by scientists from a number of state health departments, universities and CDC. That sounds like some kind of buy-in. How much, we don't know yet. But a post on the IDSA paper at Nature's blog, The Great Beyond, suggests that it isn't exactly pedal to the metal:

While researchers are calling for studies to evaluate the effectiveness of the cholesterol lowering drugs known as statins for reducing influenza-associated deaths, one such study is just getting underway, largely on volunteerism and shoestring funding.

[snip]

At a press teleconference, VanderMeer suggested that double-blind, placebo-controlled studies be carried out in a hospital setting. I haven't seen anyone report that one such study has already begun. Gordon Bernard at Vanderbilt University is studying the effects of rosuvastatin (Crestor) in patients hospitalized with the flu. It’s a randomized, double-blind, placebo-controlled study and the researchers recruited their first patient this week, Bernard told Nature.

Finding the funding for such a study has been difficult. But, Bernard realized that the current H1N1 pandemic presents an unprecedented opportunity to study this intervention. “We’ve never seen this kind of thing happen with so many patients with severe symptom,.” he says.

In August, he and his collaborators decided to begin working on a volunteer basis to get the study underway, including getting all the necessary approvals. Astra Zeneca, which manufactures Crestor, agreed to provide medication and placebo, but would not fund that the study. “We’re still working as a volunteer group and continuing to put feelers out in every way we can,” Bernard says.

As for the positive press for statins, Bernard calls it something of a double-edged sword. “It lends credence to the idea that we should have a randomized trial,” he says, but “It also makes it difficult at the bedside.” As patients hear more about statins possibly being effective, it can complicate recruitment into placebo-controlled studies, he says. (Brendan Maher with contributions by Declan Butler, The Great Beyond)

Hmmm. On the statin road, perhaps, but not full speed ahead. Why not?