Statins and diabetes: What’s going on?

April 5, 2012 § Leave a comment

Statins: Are they connected to diabetes?

Statins: Are they connected to diabetes? Image by http://www.flickr.com/photos/8011986@N02/2681415971/sizes/z/in/photostream/

In late February, the U.S. Food and Drug Administration announced new labeling recommendations for some statins, a class of drugs that lower levels of low-density lipoprotein cholesterol in blood. One of the recommendations was to warn health-care professionals of a possible risk of the drugs inducing diabetes. The recommendation has cardiologists in an uproar, with some accusing the FDA of fear-mongering and scaring patients off statins and others calling statins “a moral hazard.”  (If the link doesn’t work, try sticking “Cardiologists respond to FDA’s glucose, cognition warnings” into Google.)

But in all the fuss, a critical fact is getting lost: Researchers don’t have a solid understanding how a statin could interfere with glucose homeostasis at the molecular level. As Eric Topol of The Scripps Research Institute, who wrote an op-ed piece in The New York Times warning about the statin-diabetes link, says, “Nothing has been done to probe this and get the root cause established.”

“The aspirin of the 21st century”

Statins have been hailed in the media as “the aspirin of the 21st century.” Introduced in the 1980s, statins inhibit HMG-CoA reductase, the enzyme that plays an important role in cholesterol production in the liver. The earlier statins, such as Pravachol, are lower in potency, and their use over time hasn’t shown a possible side effect of diabetes, explains Topol. More recent statins to appear on the market, such as Lipitor and Crestor, are more potent. Pfizer, the company that sells Lipitor, pulled in $12.4 billion in 2008, making Lipitor the top-selling branded pharmaceutical in the world. These potent statins have been linked to the development of diabetes.

Statins are effective in decreasing mortality in people who already suffer from cardiovascular disease. Clinicians recommend patients with high blood cholesterol levels and at risk of developing heart disease to take statins.

As more potent statins are prescribed at increasingly higher doses, “it isn’t too surprising that we’re only now seeing some adverse effects that we didn’t initially see back in 1985,” says Daniel Ory at the University of Washington in St Louis. Statins have also been linked to other side effects, such as memory loss.

Since 2008, data from several large-scale clinical trials indicate that some statins may induce diabetes in some patient groups. The FDA says it used the data from the recent clinical trials to make its new labeling recommendation to highlight the possible risk of diabetes. In an interview with Medscape, Amy Egan, the FDA’s deputy director for safety in the division of metabolism and endocrinology products, said, “We continue to believe that the benefits of statins far outweigh their risks, but we do want clinicians and patients to be aware of their side effects so that they can be used in the most safe and effective manner possible.”

Indeed, P. Roy Vagelos of Regeneron Pharmaceuticals, a policy adviser to ASBMB’s Public Affairs Advisory Committee, echoed the same sentiment at a congressional hearing in mid-March (PDF of Vagelos’ written testimony here). During the Q&A session, when asked by a committee member about the potential risks of statins, he said they “have been studied probably more than any class of drugs that I’m aware of.” He added the benefits of taking the drugs outweighed the risks.

HMG-CoA reductase is the target for stations. Image from http://en.wikipedia.org/wiki/File:Protein_HMGCR_PDB_1dq8.png

HMG-CoA reductase is the target for stations. Image from http://en.wikipedia.org/wiki/File:Protein_HMGCR_PDB_1dq8.png

But because millions of patients worldwide take statins — the U.S. alone is estimated to have 20 million users — and a subset of them may be at the risk of developing diabetes, these observations need to be understood on a molecular level. There are several ideas around that hypothesize how statins may affect glucose metabolism, but the details haven’t yet been fully established.

Molecular puzzle

One idea involves GLUT4, a glucose transporter in cardiac and striated muscle cells, explains Carolyn Ecelbarger of Georgetown University. Statins can have toxic effects on skeletal muscle, leading to a condition known as rhabdomyolosis. The condition was the reason for the 2001 recall of Baycol, a statin made by Bayer. Ecelbarger suggests that modest insulin resistance may exist in cells of muscles suffering from rhabdomyolosis. The insulin resistance would interfere with the trafficking of GLUT4-containing vesicles. If GLUT4 is inefficiently trafficked, Ecelbarger speculates that the skeletal muscle, for instance, wouldn’t be able to effectively pull glucose out of the bloodstream.  “This is just one possibility of what might occur at the level of the cell,” she says.

Beatrice Golomb’s group at the University of California, San Diego, has been working on understanding what statins are doing at the cellular level. Golomb presented some data at an American Heart Association meeting in March in San Diego from work done with two statins, Zocor and Pravachol. She says that statins upset the prooxidant-antioxidant balance in cells in older patients with preexisting metabolic syndromes. In these patients, statins push cells into a prooxidant state, which throws off the function of mitochondrial electron-transport chain and causes glucose to rise as an attempt to counter the malfunctions in respiration.

In addition, cholesterol has several functions, one of which is in helping the transport of key antioxidant molecules, says Golomb. When a statin shuts down in vivo cholesterol production, a cell can lose its ability to transport antioxidants. People tend to think of cholesterol as a substance “that accumulates in arteries to cause plaque,” says Golomb. “But a huge amount of energy in every cell in the body is involved in cholesterol production, and that’s because cholesterol has a lot of vital functions. One of those vital functions is cell energy and the other one of those vital functions is antioxidant transport.”

As both Golomb and Ory point out, the target of statins, HMG-CoA reductase, is vital for more than just the production of cholesterol. There is the whole other class of molecules produced from the HMG-CoA reductase pathway.  “Statins inhibit the conversion of HMG-CoA to mevalonate,” says Ory. “That will prevent the production of the sterols, including cholesterol, downstream, but it will also disrupt the isoprenoid pathway.”

Need to figure out if there is a cause-and-effect between statin use and diabetes. Image by http://www.flickr.com/photos/jill_a_brown/2629206224/sizes/z/in/photostream/

Need to figure out if there is a cause-and-effect between statin use and diabetes. Image by http://www.flickr.com/photos/jill_a_brown/2629206224/sizes/z/in/photostream/

Isoprenoids are important molecules, such as myristoyl and farnesyl, which help a diverse number of proteins function, including the Rab GTPases. “To make a lot of cholesterol, you have to have a very robust production at the level of HMG-CoA reductase. If you inhibit it enough, you can really have a marked reduction at the end of the pathway but still provide enough function of HMG-CoA reductase to support isoprenoid synthesis,” explains Ory. But a potent statin could even inhibit isoprenoid synthesis and have an impact on all the proteins that depend on isoprenoid modifications.

On the genomic level, both Ory and Topol say, the research on statin-induced diabetes should not be hard to kick off. The pharmaceutical companies producing statins “have tens of thousands of samples sitting in freezers,” says Topol. “If any of those were consented for a genomewide study, it could be done very inexpensively today. We could get single loci in the genome that account for the statin-induced diabetes.” He adds that these loci wouldn’t necessarily reflect a cause and effect “but at least we would start to understand what loci in the genome are tracking with this untoward, unexpected and undesirable outcome.”

Need more elbow grease

Most of the possibilities are speculations, so researchers need to start biochemically delving into the phenomenon of statin-induced diabetes, say the experts. It’s not even clear if there is a cause-and-effect relationship between statins and diabetes at the molecular level, and that needs to be established first.

But the time to do this kind of research is right. “The climate was extremely hostile to any discussion of any possible problems with statins,” says Golomb. But now that some statins are coming off-patent, “I think there is a little bit more openness to discuss problems with statins.”

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