Statin medications and selenium

Statin medications: good news and bad news?  On the one hand, statin medications are effective at reducing cholesterol levels, and, are good, apparently, at reducing the number of deaths from heart attacks.   On the other hand, we have seen a very considerable rise in the number of cases of chronic heart failure … in the same period that statin medications have been prescribed.  Drs. Okuyama and Langsjoen and their colleagues have explained the pharmacological mechanisms by which this medical paradox may be occurring [Okuyama].

Statins inhibit the body’s production of Coenzyme Q10
Okay, I was aware of the evidence from well-designed studies linking the taking of statin medications to decreased plasma levels of Coenzyme Q10.   Coenzyme Q10 is an important factor in cellular energy production and is an important lipid-soluble antioxidant [Folkers, Littarru, McMurray].  And I knew that the energy-deprived heart is a failing heart [Folkers, Molyneux, Mortensen].  So, I knew that anyone taking a statin medication needs to talk to his or her cardiologist about taking a good Coenzyme Q10 supplement.

Statins also inhibit the body’s production of selenoproteins
But Drs. Okuyama and Langsjoen go further in their explanation of the unintended consequences of taking a statin medication.  Further than the inhibiting effect of the statins on the body’s bio-synthesis of Coenzyme Q10.

They explain how the statin medications inhibit the body’s production of the selenium containing proteins called selenoproteins.  Among these selenoproteins are the glutathione peroxidases and the thioredoxin reductases.  These selenoproteins function as antioxidant enzymes to help suppress the oxidative damage caused to lipids and proteins and DNA by harmful free radicals.

Drs. Okuyama and Langsjoen argue that the statin medications’ impairing of the body’s production of selenoproteins might well be a factor in the marked increase in cases of congestive heart failure in recent years.   After all, it is known that selenium deficiency is associated with the development of dilated cardiomyopathy (= decreased ability of the weakened heart to pump blood).

Keshan disease and selenium deficiency
Right.  I had read about the often fatal heart disease called Keshan disease in a selenium-poor region of China and about the successful treatment of Keshan disease with selenium supplementation [Chen].   I was immediately interested in what Drs. Okuyama and Langsjoen have to say.  I had to do a Medline search to see what other evidence there is for a link between the taking of statin medications and decreased production of selenoproteins.

Side-effects of statin medications and selenoprotein production
Rather quickly, I found the published articles by the researchers Moosmann and Behl and Kromer and Moosmann at the Johannes Gutenberg University in Mainz, Germany.

They show how the statin medications reduce the body’s production of cholesterol by inhibiting the biological pathway in which mevalonic acid and its derivative mevalonate are produced.  Mevalonate is necessary for the production of cholesterol.  Less mevalonate equals less cholesterol.

However, mevalonate is also needed for the body’s production of isopentenyl pyrophosphate (IPP), and IPP is necessary for the body’s production of the amino acid selenocysteine [Moosmann].

Less selenocysteine = fewer selenoproteins
We know that the selenium that we ingest from food and supplements does not float around in the blood and in the cells in its elemental form.  The selenium is incorporated either into the amino acid selenomethionine or into the amino acid selenocysteine.  Similarly, selenocysteine does not exist freely in the cells.

Selenocysteine is incorporated into the 25 known selenoproteins.  There are some 22,000 proteins in the human body.  Only 25 of these proteins are selenoproteins containing selenocysteine.  Despite their relative rarity, the selenoproteins are important for many and various functions:

• antioxidant function
• heart muscle function
• skeletal muscle function
• immune function
• thyroid function
• reproductive function
• cancer preventive function [Bellinger]

Unintended consequence of statin medications
In severely abbreviated form, the statins have the following adverse side-effects related to the production of selenoproteins:

• statins block the formation of mevalonate
• less mevalonate means less production of selenocysteine
• less selenocysteine means fewer selenoproteins formed

Inhibition of selenoprotein synthesis even more serious than inhibition of Coenzyme Q10 bio-synthesis?
If the body’s production of Coenzyme Q10 is blocked by the use of statin medications, then it is possible to compensate for this adverse effect of the statin medications by taking a good Coenzyme Q10 supplement with meals [Folkers, Littarru].

In the case of the statin medications’ (unintended) inhibition of the synthesis of selenoproteins, however, the answer is not so easy.  Increasing the dosages and frequency of selenium supplementation will not be helpful if the problem is that the body cannot use the selenium to produce the amino acid selenocysteine.

The blocking of the metabolizing of mevalonate by the statin medications effectively deprives the body of the IPP substance that it needs for the development and maturation of selenocysteine.  And the selenoproteins need selenocysteine to become selenoproteins [Moosmann].  This is a serious side-effect of the statin medications.

The connection to heart failure?
Remember: we are defining heart failure as a disease in which the heart muscle is deprived of energy.  Heart failure is characterized by the following adverse events:

• low levels of cellular ATP production
• increased mitochondrial dysfunction
• increased oxidative damage from harmful free radicals
• increased endothelial dysfunction
• poor calcium handling [Sharma]

Heart failure is a disease with a poor prognosis despite the many medical and device therapies available to cardiologists [Mortensen, Sharma].  Adjuvant treatment with Coenzyme Q10 supplements — in addition to conventional heart failure medication — has been shown to help significantly.

Drs. Okuyama and Langsjoen and their fellow researchers have described the adverse effects of statin medications on Coenzyme Q10 and selenium function in the heart muscle.

They have raised the question whether the epidemic proportions of heart failure in our times might be aggravated by the extensive use of statin medications.  They have urged that the guidelines for the use of statins be critically reevaluated.

In the meantime, a randomized controlled trial in which healthy elderly study participants, aged 70 – 88 years, were given 200 micrograms of a high selenium yeast preparation and 200 milligrams of Coenzyme Q10 daily for four years has shown significant benefits for the active treatment group as compared with the placebo group:

• reduced heart disease mortality
• better heart function shown on echocardiograms
• reduced levels of a bio-marker for heart disease

Bottom line for us as patients
Anyone taking a statin medication should surely talk with his or her cardiologist about the potentially harmful effects of the statin medications on the body’s Coenzyme Q10 status and the body’s glutathione peroxidase status.

Moreover, we should be aware that there seems to be a special inter-relationship between selenium and Coenzyme Q10 such that the two supplements taken in combination enhance the effect, each of the other.

Sources

Bellinger, F. P., Raman, A. V., Reeves, M. A., & Berry, M. J. (2009). Regulation and function of selenoproteins in human disease. The Biochemical Journal, 422(1), 11-22.

Chen, J. (2012). An original discovery: selenium deficiency and Keshan disease (an endemic heart disease). Asia Pacific Journal of Clinical Nutrition, 21(3), 320-326.

Folkers, K., Vadhanavikit, S., & Mortensen, S. A. (1985). Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proceedings of The National Academy of Sciences of The United States of America, 82(3), 901-904.

Folkers, K, Langsjoen, P., Willis, R., Richardson, P., Xia, L.J.,  Ye, C.Q., & Tamagawa, H.  (1990”.  Lovastatin decreases coenzyme Q levels in humans. Proceedings of The National Academy of Sciences of The United States of America 87, no. 22: 8931-8934.

Kromer, A., & Moosmann, B. (2009). Statin-induced liver injury involves cross-talk between cholesterol and selenoprotein biosynthetic pathways. Molecular Pharmacology, 75(6), 1421-1429.

Littarru, G. P., & Langsjoen, P. (2007). Coenzyme Q10 and statins: biochemical and clinical implications. Mitochondrion, 7 SupplS168-S174.

McMurray, J. V., Dunselman, P., Wedel, H., Cleland, J. F., Lindberg, M., Hjalmarson, A., & Wikstrand, J. (2010). Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure). Journal of The American College of Cardiology, 56(15), 1196-1204.

Molyneux, S. L., Florkowski, C. M., George, P. M., Pilbrow, A. P., Frampton, C. M., Lever, M., & Richards, A. M. (2008). Coenzyme Q10: an independent predictor of mortality in chronic heart failure. Journal of The American College of Cardiology, 52(18), 1435-1441.

Moosmann, B., & Behl, C. (2004). Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway. Trends in Cardiovascular Medicine, 14(7), 273-281.

Moosmann, B., & Behl, C. (2004). Selenoprotein synthesis and side-effects of statins. Lancet (London, England), 363(9412), 892-894.

Mortensen, S. A., Rosenfeldt, F., Kumar, A., Dolliner, P., Filipiak, K. J., Pella, D., & … Littarru, G. P. (2014). The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC. Heart Failure, 2(6), 641-649.

Sharma, A., Fonarow, G. C., Butler, J., Ezekowitz, J. A., & Felker, G. M. (2016). Coenzyme Q10 and Heart Failure: A State-of-the-Art Review. Circulation. Heart Failure, 9(4), e002639.