Facing the Shadow Side of Statins: Petition Urges FDA to Mandate CoQ10 Recommendation on Statin Labels

Nutrition and anti-aging pioneer Julian Whitaker, MD, has petitioned the Food and Drug Administration to force manufacturers of statin drugs to include a recommendation for Co-enzyme Q10 supplementation on the labels of these widely used cholesterol-lowering agents.

The petition, filed on behalf of Dr. Whitaker by the Virginia-based law firm of Emord and Associates, cites the potential long-term risks of liver dysfunction, cardiomyopathy, and congestive heart failure (CHF) secondary to use of statin drugs. In addition to blocking cholesterol synthesis in the liver, statins also inhibit endogenous production of CoQ10, a vital coenzyme for mitochondrial energy production.

Dr. Whitaker is requesting that the FDA commissioner require pharmaceutical companies to include the following "black box" warning on all statin labels and package inserts: HMG CoA reductase inhibitors block the endogenous biosynthesis of an essential co-factor, coenzyme Q10 required for energy production. A deficiency of coenzyme Q10 is associated with impairment of myocardial function, with liver dysfunction and with myopathies (including cardiomyopathy and congestive heart failure). All patients taking HMG CoA reductase inhibitors should therefore be advised to take 100 to 200 mg per day of supplemental coenzyme Q10. The petition was filed with FDA last May.

Dr. Whitaker, director of the Whitaker Wellness Institute, Newport Beach, CA, and editor of the popular Health and Healing newsletter, is one of a number of increasingly outspoken physicians who believe widespread statin use, as promoted by the National Cholesterol Education Program's clinical guidelines, will likely have downstream adverse effects largely preventable with a simple and relatively inexpensive nutrient.

He stressed he is not challenging the therapeutic benefits of statins. But he believes physicians and federal regulators must reckon with the fact that these drugs block synthesis of an essential cofactor for proper function of tissues like the myocardium which are under high, constant metabolic stress.

He urged the FDA commissioner to "act without delay" to compel inclusion of the warning statement. "Failure to do so unnecessarily leaves long-term statin drug users—up to 575,000 Americans—at risk for statin-induced liver dysfunction and myopathies including cardiomyopathy and CHF," he stated in the petition.

In an interview with Holistic Primary Care, Dr. Whitaker said inclusion of the warning statement would be a huge public health victory, with the potential to prevent thousands of statin-related myopathies. A warning label would put responsibility for prevention squarely on the shoulders of the medical community. "If a doctor fails to heed a warning label, liability falls to the doctor. But without a warning label, there can be no liability, no accountability."

So far, the FDA has done nothing, and has given no indication as to when they might consider Dr. Whitaker's petition. "You'd think, given a matter with extraordinary public health implications that they would act on it. But so far, that's not the case," said Jonathan W. Emord, the attorney who drafted the petition. "We may ultimately be compelled to file suit against the agency in federal court." Dr. Whitaker added he will take legal action "sooner rather than later."

CoQ10, also known as ubiquinone for its seeming omnipresence in metabolically active tissues, is produced in the liver and transported to other tissues by the blood. It operates within the mitochondria as an electron shuttle, moving electrons from one carrier complex to the next during oxidative phosphorylation.

Given its incessant activity, it is not surprising that the myocardium holds the largest concentration of endogenous CoQ10 in the body. Exercise is known to increase CoQ10 concentration in heart and skeletal muscle, and it is these tissues that will first show the effects of CoQ10 deficiency.

The precursor to this key coenzyme is hydroxymethylglutarate (HMG), also the precursor to cholesterol. Inhibition of HMG-CoA reductase, an enzyme that transforms HMG into mevalonate, simultaneously inhibits synthesis of both cholesterol and CoQ10, resulting in an increase in unprocessed HMG, which is measurable in urine.

The incidence of side effects associated with statin-induced CoQ10 depletion is dose-dependent. For patients taking 10–20 mg per day, it is low at an estimated 0.2%. At an 80 mg dose, the incidence of liver dysfunction, general myopathy, skeletal muscle myopathy and serum transaminase elevations increases to 6%, according to the Physician's Desk Reference.

In human studies, CoQ10 is usually deficient in patients suffering from CHF. Introduction of statins in this vulnerable population further decreases CoQ10 and reduces myocardial function. By the early 1990s, there were double-blind studies showing that individuals treated with statins had CoQ10 decreases in the range of 40%–50% or more (Ghirlanda G, et al. J Clin Pharmacol 1993; 33(3): 226–229; Watts GF, et al. J Clin Pathol 1993; 46(11): 1055–1057).

Researchers at the department of medicine, University of Bologna showed that therapy with simvastatin, 20 mg, reduced plasma CoQ10 levels from a mean of 1.08 mg/dl to 0.80 mg/dl, and platelet CoQ10 levels from 104 to 90 ng/mg. Addition of 100 mg CoQ10 as a dietary supplement not only reversed these processes, but actually produced net CoQ10 increases from the baseline without altering the lipid lowering effect of the drug (Bargossi AM, et al. Mol Aspects Med 1994; 15 Suppl: s187–s193).

A Tale of Two Patents

As early as 1989, the potential for adverse events seemed strong enough for Merck, manufacturer of Simvastatin (Zocor®), to obtain two patents on statin-CoQ10 combination formulas, which were granted in 1990 (to review the patent documents, go to the US Patent and Trademark Office site at www.uspto.gov, search for patent numbers 4,933,165 and 4,929,437).

Patent no. 4,933,165 notes that, "high levels of lovastatin can reduce CoQ10 in the liver," and later states that, "Although cholesterol-lowering therapy through the use of HMG-CoA reductase inhibitors is generally free of side reactions, it would be of considerable benefit to counteract the myopathy observed in a small percentage of patients. Since CoQ10 is of benefit in congestive heart failure patients the combination with HMG-CoA reductase inhibitors should be of value in such patients who also have added risk of high cholesterol levels."

The patented combination was invented by Michael S. Brown, MD, a Nobel Prize-winning molecular geneticist at University of Texas Health Science Center. The document indicates that Merck intended the combination to have "both a precautionary or prophylactic as well as curative or treatmental function." In principle, the drug-nutrient combo would ameliorate existing myopathy as well as prevent it.

The second patent (No. 4,929,437) identifies the statin-CoQ10 combination as a method of preventing or reversing the persistent liver transaminase levels—an indicator of potential hepatic damage—seen in up to 2% of individuals taking statins.

In the 12 years since the patents were granted—a period characterized by exponential increases in statin use—Merck opted against developing these combination formulas for reasons the company chooses not to disclose.

Janet Skidmore, director of Merck's media relations group, declined to comment other than to say, the company has "to look at which compounds have the greatest opportunity, which ones are safest and most effective, and that fill an unfulfilled need." Ms. Skidmore added that Merck does not routinely make public the reasons behind a decision not to develop a particular product.

She did add that Merck and Schering Plough are currently engaged in a joint venture to develop a formula marrying simvastatin with ezetimibe (Zedia), a novel agent that reduces cholesterol by a different chemical mechanism. Dr. Brown, inventor of Merck's patented statin-Q10 formula, was not available for comment.

Peter Langsjoen, MD, of the Institute for Biomedical Research, University of Texas, Austin, one of the nation's leading CoQ10 researchers, believes the country is in the opening chapter of a statin-induced epidemic of cardiomyopathy and CHF. "In my practice of 17 years in Tyler, Tex., I have seen a frightening increase in heart failure secondary to statin usage," he said in a recent posting to Red Flags Weekly (www.redflagsweekly.com), a website that addresses controversies in science and medicine. "I see two to three new statin cardiomyopathies per week."

Dr. Langsjoen strongly supports Dr. Whitaker's petition to the FDA. Referring to Merck's 1990 patents, he said, "never before in history has the medical establishment knowingly created a life-threatening nutrient deficiency in millions of otherwise healthy people, only to then sit back with arrogance and horrific irresponsibility and watch to see what happens."

Q10 in the Clinic

Beyond reversing statin-induced CoQ10 depletions, Dr. Langsjoen contends that CoQ10 should be a mainstay in the management of cardiovascular disease. He has published a number of clinical trials showing marked improvements in both laboratory markers and functional outcomes.

In a cohort of 143 patients with chronic, stable, non-hypertrophic cardiomyopathy (nearly all of whom were in NYHA Classes III and IV), 100 mg CoQ10 increased serum coenzyme levels from a baseline of 0.85 mcg/ml to 2.0 mcg/ml within 3 months. Mean ejection fractions rose from a mean of 44% to 60% within 6 months. Eighty-five percent of the patients had global improvements resulting in reductions of one or two NYHA assessment classes (Langsjoen PH, et al. Int J Tissue React 1990; 12(3): 169–171). There was no evidence of toxicity or adverse events associated with CoQ10 therapy.

In a separate 8-year study, he and his colleagues treated 424 patients with various forms of cardiovascular disease, using adjunctive CoQ10 at a dose of 75 mg to 600 mg per day (average of 242 mg). The aim was to increase whole blood coenzyme levels above 2.10 mcg/ ml. The subjects included those with hypertension, ischemic cardiomyopathy, dilated cardiomyopathy, primary diastolic dysfunction, mitral valve prolapse, and valvular heart disease.

Overall, 58% of patients had improvements by one NYHA functional class, 28% improved by 2 classes, and 1.2% by 3 classes. Supplementation allowed many patients to reduce the number of other medications they needed: 43% were able to drop between 1 and 3 drugs, while only 6% required addition of drugs (Langsjoen H, et al. Mol Aspects Med 1994; 15 Suppl: s165–s175).

CoQ10 appears to have direct effects on myocardium. Dr. Langsjoen treated 7 patients with hypertrophic cardiomyopathy using an average of 200 mg CoQ10 per day, to achieve blood levels of 2.9 mcg/ml. Echocardiographic assessment at 3 months showed a 24% reduction in mean interventricular septal thickness (from 1.51 ± 0.17 cm to 1.14 ± 0.13 cm) and a 26% reduction in mean posterior wall thickness (from 1.37 ± 0.13 cm to 1.01 ± 0.15 cm). All patients had improvements in self-rated symptoms of fatigue and dyspnea (Langsjoen PH, et al. Mol Aspects Med 1997; 18 Suppl: s145–s151).

CoQ10 is obtainable from certain foods, with pork, beef, chicken and herring being particularly rich sources. However, it is nearly impossible to obtain therapeutic levels in the range of 200 mg per day from dietary sources alone. For people deficient in the coenzyme, supplementation is the only practical means of obtaining needed levels. The vast majority of the CoQ10 in supplements sold in the US is supplied by Kanegafuchi Chemical Industry, a Japanese company.

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