A Letter from the Institute of Biochemistry

Institute of Biochemistry - University of Ancona
Via Ranieri - 60131 Ancona-Italy

Phone: +39-071-2204674
Fax: +39-071-2801932
e- mail: littarru@popcsi.unian.it

Prof. Gian Paolo Littarru

Ancona, September 5th, 2001

HFD-511
United States Food and Drug Administration
5600 Fishers Lane.
Rockville MD 20857, USA

Object: Biochemical and Potential Clinical Consequences of Inhibiting Coenzyme Q10 Biosynthesis by HMG-CoA Reductase Inhibitors: A Critical Opinion by the International Coenzyme Q10 Association.

Dear Sirs,

Please accept this letter as a position statement on the growing problem of adverse side effects related to the use of HMG-CoA reductase inhibitors. The International Coenzyme Q10 Association is a group of scientists and medical professionals with a research focus on coenzyme Q10, which plays a crucial role in cellular ATP production. It has been demonstrated that HMG-CoA reductase inhibitors, also known as statins, block the biosynthesis of coenzyme Q10 and of dolichol, besides the well known effect on cholesterol synthesis. Several studies have shown that administration of different kinds of statins can lead to a parallel decrease of coenzyme Q10 and cholesterol in plasma (1- 9). Animal studies have also demonstrated a tissue depletion in the course of statin treatment (10 - 12) which was particularly evident in aged animals (13) . We can reasonably hypothesize that in some conditions where other CoQ10 impoverishing situations exist, treatment with statins may seriously impair plasma and possibly tissue levels of coenzyme Q10. A physiological decline in tissue CoQ10 has for instance been implicated in ageing (17,18) which would make the elderly more susceptible to statin-induced CoQ10 depletion.

A decrease in tissue coenzyme Q10 may have adverse effects on cellular ATP production, as has been proven in dogs and guinea pigs (12, 13), and may manifest clinically as diastolic left ventricular dysfunction with symptoms of fatigue and exertional dyspnea. In patients with pre-existing congestive heart failure the addition of statin therapy causes a decrease in blood CoQ10 levels and a decline in myocardial function (1). Although statin therapy has been shown to have benefits, the long-term response in ischemic heart disease may have been blunted due to the CoQ10 depleting effect. Some evidence of this has already appeared in that oral CoQ10 supplementation in diabetic patients receiving HMG-CoA reductase inhibitors reduced cardiothoracic ratio (9).

It is reasonable to suggest that skeletal muscle pathology such as myalgia and rhabdomyolysis is also related to decreases in tissue coenzyme Q10 concentrations. There are some indications of rapid improvement in statin-induced myalgia and fatigue with supplemental CoQ10. In different kinds of muscle disease the beneficial effects of coenzyme Q10 supplementation have been shown to correlate with improvement in oxidative phosphorylation as monitored by NMR techniques (14 - 16). A few cases have already been reported where CoQ10 reverses the condition of cardiac failure in the course of treatment with statins (1).

These observations may relate to two Merck & Co., Inc. patents for combining CoQ10 with statin in the same capsule: US Patent 4929437, issued May 29, 1990 and US Patent 4933165, issued June 12, 1990, both titled "Coenzyme Q10 with HMG-CoA Reductase Inhibitors". It is possible that the recently reported statin-related deaths are the tip of a side effect iceberg and the magnitude of the potential problem cannot be overstated. It is urgently incumbent upon the scientific community, the pharmaceutical industry and the regulatory bodies, such as the United States Food and Drug Administration to be certain that we are not inadvertently creating a life-threatening deficiency of an essential co-factor in many millions of patients.

Attached are pertinent supporting publications and abstracts along with copies of the Merck & Co., Inc. statin/CoQ10 combination patents.

This letter has been reviewed by all of the undersigned members of the Scientific Committee of the International Coenzyme Q10 Association who feel that studies are warranted to examine whether the clinical use of statins can be made safer and possibly more effective by the addition of coenzyme Q10.

We should make every effort to investigate the reasons for, and to prevent further developments of, what have already been serious medical consequences.

We would very much appreciate your input and response.

With all due respect,

Gian Paolo Littarru, M.D., Professor Biochemistry
University of Ancona, Italy
Chairman of the International CoQ10 Association

On behalf of:

M. Flint Beal, M.D., Prof. - Cornell Medical Center, NY, USA

Frederick L. Crane, Ph.D., Prof. - Purdue University, IL USA

Gustav Dallner, Ph.D., Prof.. - Stockholm University, Sweden

Udo Hoppe, M.D., Prof. - Paul Gerson Unna-Skin Research Centre, Germany

Takeo Kishi, Ph. D. Prof. - Kobe Gakui University, Japan

Peter Langsjoen M.D. - Diplomate American Board of Cardiology, TX, USA

Giorgio Lenaz M.D. Ph.D. Prof. - Bologna University, Italy

Svend Aage Mortensen M.D. Prof. - Heart Centre Rigshospital, Copenhagen, Denmark

Tetsuya Nakamura Ph.D. Prof. - Shibaura Institute of Technology, Japan

Etsuo Niki Ph.D. Prof. - Human Stress Signal Research Centre, Japan

Roland Stocker Ph.D. Prof. - Heart Research Institute, Sydney, Australia

Yoshitomo Oka M.D. Ph.D. Prof. - Yamaguchi University School of Medicine, Japan

Yorihiro Yamamoto Ph.D. Prof. - School of Engineering, University of Tokyo, Japan

(Enclosures)

References

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2. Ghirlanda G., Oradei A., Manto A., Lippa S., Uccioli L. et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double blind, placebo-controlled study. J. Clin. Pharmacol. 3: 226-229, 1993

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19. Walravens PA, Greene C, Frerman FE Lovastatin, isoprenes, and myopathy. Lancet 4; 2: 1097-8 1989