HMG-CoA REDUCTASE INHIBITORS (STATIN DRUGS) AND SERUM CoQ10 DEPLETION
 

Introduction

The following narrative describes a curious situation in the pharmaceutical industry whereby (a) liver dysfunction and myopathy contraindications specifically linked to statin-induced depletion of serum CoQ10 are clearly stated in two 1990 Merck patents, (b) the ameliorative products described in the patents were never marketed, and (c) the specific linkage between said contraindications and CoQ10 depletion is obfuscated in subsequent pharmaceutical literature.

The Merck Patents: On Combining Statin Drugs with CoQ10

Readers are advised that HMG-CoA (or 3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitors (a.k.a. statin drugs) are well known to inhibit production of CoQ10 (Coenzyme Q10 a.k.a. ubiquinone) resulting in contraindications or side effects including (but not necessarily limited to) elevated transaminase levels (i.e., liver dysfunction) and myopathy (i.e., muscle dysfunction). To address those contraindications, Merck considered combining CoQ10 with the HMG-CoA reductase inhibitors, actually obtaining separate patents as far back as 1990 in respect of addressing each said contraindication. The following summarizes the relevant text from each patent:

Elevated Transaminase Levels: United States Patent No. 4,929,437 COENZYME Q10 WITH HMG-COA REDUCTASE INHIBITORS1

The ABSTRACT of the patent reads as follows:

A pharmaceutical composition and method of counteracting HMG-CoA reductase inhibitor-associated elevated transaminase levels is disclosed. [empasis added] The method comprises the adjunct administration of an effective amount of a HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q10.2

Relevant excerpts from the BACKGROUND OF THE INVENTION are presented as follows:

Paragraph 1:

   HMG-CoA reductase inhibitors represent a new3 class of cholesterol lowering drugs. Relatively low levels of these drugs effectively reduce plasma cholesterol levels. These drugs are believed to function by inhibiting the chemical transformation HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.4

Paragraph 2:

   [...] The most serious reported adverse effects of lovastatin, a commercially available HMG-CoA reductase inhibitor, are myopathy and asymptomatic but marked and persistent increases in liver transaminases.5 [empasis added] [...]

Paragraph 3:

   A branch of the mevalonate cholesterol biosynthetic pathway ... leads to the formation of Coenzyme Q10 [...]. Coenzyme Q10 (2,3-dimethoxy-5-methyl-6-decaprenyl-1, 4-benzoquinone) is a redox component in the respiratory chain and is found in all cells having mitochondria. [...] ... the transaminase increase produced by lovastatin and other HMG-CoA reductase inhibitors is a direct consequence of inhibition of mevalonate synthesis.6 [emphasis added]

Relevant excerpts from the DETAILED DESCRIPTION OF THE INVENTION are presented as follows:

Paragraph 1:

   The present invention relates to a method of counteracting HMG-CoA reductase inhibitor-associated liver damage in a patient receiving HMG-CoA reductase therapy which comprises the adjunct administration of an effective amount of an HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q10. [emphasis added] In particular, this invention relates to a method of counteracting HMG-CoA reductase inhibitor-associated elevated transaminase levels.7

Paragraph 3:

   In its application to the counteraction of liver damage and, in particular, elevated transaminase levels, the present invention is accordingly to be understood as providing for the avoidance of liver damage and elevated transaminase levels where this may otherwise occur as well as the amelioration of said damage and elevated transaminase. [empasis added] The term counteracting is accordingly to be understood as connecting both a precautionary or prophylactic as well as curative or treatmental function.8

Paragraph 5:

   The compounds of the instant invention may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. The general amounts of HMG-CoA reductase inhibitor will be of the same or similar order to that employed in HMG-CoA reductase therapy. In general, satisfactory results are obtained by administration of 10 to 80 mg/day of the HMG-CoA reductase inhibitor in a single or divided dose. Doses of CoQ10 may vary from 25 mg to 1 g day in a single or divided dose. Tablets or capsules may also be administered which contain both compounds in the dosage ranges indicated.9

And, finally, the first of two claims states:

   1. A method of counteracting HMG-CoA reductase inhibitor-associated elevated transaminase levels in a subject in need of such treatment which comprises the adjunct administration of an effective amount of HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q10.10

Myopathy: United States Patent No. 4,933,165 COENZYME Q10 WITH HMG-COA REDUCTASE INHIBITORS11

The ABSTRACT of the patent reads as follows:

A pharmaceutical composition and method of counteracting HMG-CoA reductase inhibitor-associated myopathy is disclosed. The method comprises the adjunct administration of an effective amount of a HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q10.12

Relevant excerpts from the BACKGROUND OF THE INVENTION are presented as follows:

Paragraph 1:

   Coenzyme Q10 (2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone) is a redox component in the respiratory chain and is found in all cells having mitochondria. It is thus an essential co-factor in the generation of metabolic energy and is particularly important in muscle function. [...] Folkers et al., Proc. Natl. Acad. Sci., 82: 4513 (1985) in a double-blind study have reported improved cardiac output for some patients upon receiving an oral administration of CoQ10.13

Paragraph 4:

   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 percent 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 the added risk of high cholesterol levels.14

Relevant excerpts from the DETAILED DESCRIPTION OF THE INVENTION are presented as follows:

Paragraph 1:

   The present invention relates to a method of counteracting HMG-CoA reductase inhibitor-associated myopathy in a patient receiving HMG-CoA reductase therapy which comprises the adjunct administration of an effective amount of an HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q10.15 [...]

Paragraph 4:

   In its application to the counteraction of myopathy the present invention is accordingly to be understood as providing for the avoidance of myopathy where this may otherwise occur as well as the amelioration of myopathy. The term counteracting is accordingly to be understood as connecting both a precautionary or prophylactic as well as curvative or treatmental function.16

And, finally, the first and third of four claims state:

   1. A pharmaceutical composition comprising a pharmaceutical carrier and an effective antihypercholesterolemic amount of an HMG-CoA reductase inhibitor and an amount of Coenzyme Q10 effective to counteract HMG-CoA reductase inhibitor-associated skeletal muscle myopathy.17

   3. A method of counteracting HMG-CoA reductase inhibitor-associated skeletal muscle myopathy in a subject in need of such treatment which comprises the adjunct administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor and an effective amount of Coenzyme Q10 to counteract said myopathy.18

The above patents notwithstanding, Merck (for whatever reason) did not market a statin with adjunctive CoQ10. But the fact of the matter remains that the statin-induced depletion of CoQ10 and its relation to myopathy and liver dysfunction was known over 30 years ago. While statin-induced depletion of CoQ10 as well as the myopathy and liver dysfunction contraindications are acknowleged by the pharmaceutical industry in their product monographs, the link between CoQ10 depletion and the myopathy and liver dysfunction contraindications is not openly acknowleged as will be seen in the following section concerning the (Canadian) Compendium of Pharmaceuticals and Specialties (CPS 2011).

Compendium of Pharmaceuticals and Specialties (CPS 2011):19 Obsfuscation of CoQ10 Depletion Side Effects

Under the generic CPhA Monograph titled, HMG-CoA Reductase Inhibitors, specifically under the subtitle, SUMMARY PRODUCT INFORMATION, CPS 2011 lists six specific statin drugs: Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, and Simvastatin.20 Under the WARNINGS AND PRECAUTIONS subtitle, the monograph includes the following statements in respect of the terms Hepatic and Musculoskeletel:21

Hepatic: Statins have been associated with elevated transaminases in approximately 1% to 2% of recipients, usually occurring 3 to 12 months after initiation of treatment. It is recommended that liver function tests be performed at baseline, after 3, 6 and 12 months of therapy and then yearly, in all patients. If transaminase levels rise to 3 times the upper limit of normal and are sustained, the statin should be discontinued. Transaminase levels should slowly return to pretreatment levels after discontinuation. Statins should be used with caution in patients who regularly consume large quantities of alcohol and/or have a history of liver disease.
Musculoskeletel: Transient elevations in creatine phosphokinase (CK) are commonly seen in patients treated with statins. Usually, this is of no clinical consequence. Rarely, statin use has been associated with myopathy, characterized by muscle pain and weakness and grossly elevated CK levels (>10 times the upper limit of normal). Rhabdomyolysis defined as skeletal muscle necrosis with release of potentially toxic muscle cell components into the general circulation, has occurred rarely. Possible complication of rhabdomyolysis include myoglobinuric acute renal failure, disseminated intravascular coagulation, hyperkalemia and cardiac arrest.
   The incidence of myopathy with the use of a statin alone is reported to be 0.1 to 0.2%. The risk of myopathy or rhabdomyolysis is increased by higher statin plasma levels (e.g., higher doses, decreased hepatic clearance) and by concomitant drug therapy that inhibits statin metabolism or has its own intrinsic ability to cause myopathy (see Drug Interactions).
   Because statins can cause myopathy or rhabdomyolysis, especially in combination with certain drugs, patients should be advised to promptly report any unexplained muscle tenderness, pain or weakness to their physician and to inform their health care providers that they are taking a statin (see Drug Interactions).

Product monographs for the six specifc statin drugs listed above actually include a statement concerning decreased CoQ10 levels under the WARNINGS AND PRECAUTIONS subtitle as follows:

Atorvastatin: See Lipitor® (atorvastatin calcium)22

Effect on Ubiquinone (CoQ10) Levels: Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

Fluvastatin: See Lescol® / Lescol® XL (fluvastatin sodium)23

Cardiovascular: Effect on CoQ10 Levels (ubiquinone): A significant decrease in plasma CoQ10 levels in patients treated with fluvastatin and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

Lovastatin: See Mevacor® (lovastatin)24

Effect on CoQ10 Levels (ubiquinone): A significant decrease in plasma CoQ10 levels in patients treated with MEVACOR and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established.

Pravastatin: See Pravachol® (pravastatin sodium)25

Effect on CoQ10 Levels (Ubiquinone): A significant short-term decrease in plasma CoQ10 levels in patients treated with PRAVACHOL has been observed. Longer clinical trials have also shown reduced serum ubiquinone levels during treatment with pravastatin and other HMG-CoA reductase inhibitors. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

Rosuvastatin: See Crestor® (rosuvastatin calcium)26

Cardiovascular: Co-enzyme Q10 (ubiquinone): Ubiquinone levels were not measured in CRESTOR clinical trials. Significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

Simvastatin: See Zocor® (simvastatin)27

Endocrine and Metabolism: Effect on CoQ10 Levels (Ubiquinone): Significant decreases in circulating CoQ10 levels in patients treated with ZOCOR and other statins have been observed. The clinical significance of a potential long-term stain-induced deficiency has not been established.

It is interesting that most of the above product monographs relate potential cardiovascular issues to statin-induced depletion of CoQ10 but also state: The clinical significance of a potential long-term stain-induced deficiency has not been established. And while statin-induced hepatic and muskuloskeletal issues are pointed out in the above generic CPhA Monograph titled, HMG-CoA Reductase Inhibitors (as well as elsewhere in the above product monographs), the industry (including Merck-Frosst) fails to acknowlege a definitive link between statin-induced CoQ10 depletion and the hepatic and muskuloskeletal contraindications. Hence, either (a) the Merck statements in their 1990 patents are wrong, or (b) the pharmaceutical industry has (for whatever reason) obfuscated the issue.

Biochemical Pathway: The Direct Impact on CoQ10 Biosynthesis by Statin Drugs

Reader, the following (cholesterol) biochemical pathway28,29 (Figure 1) clearly indicates the dependence of CoQ10 (ubiquinone) production on the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase, and hence, the interference with that production by a statin drug, i.e., a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor.30

Layer 1

Figure 1. Metabolic pathway depicting the hepatic biosynthesis of cholesterol and CoQ10. (Note: Mobile device users can scroll this flowchart horizontally.)

Conclusion and Recommendations

There is clearly a direct causal link between statin treatment and CoQ10 depletion. Whereas the degree of that depletion and concomitant contraindications are undoubtedly problematic on an individual basis, readers are obviously advised to consult with their physicians and pharmacists with respect to their statin treatment protocols and also prior to any supplementation with CoQ10.


— FINIS —


  1. Jonathan A. Tobert, Inventor; Merck & Co. Inc., Assignee. Coenzyme Q10 with HMG-CoA Reductase Inhibitors. United States Patent No. 4,929,437 issued May 29, 1990.↩️

  2. Ibid.↩️

  3. As of 1990.↩️

  4. Ibid., column 1 (lines 6-12).↩️

  5. Ibid., column 1 (lines 14-18).↩️

  6. Ibid., excerpts from column 1 (lines 28-43).↩️

  7. Ibid., column 1 (lines 53-61).↩️

  8. Ibid., column 2 (lines 11-20).↩️

  9. Ibid., column 2 (lines 32-43).↩️

  10. Ibid., column 2 (lines 53-58).↩️

  11. Michael S. Brown, Inventor; Merck & Co. Inc., Assignee. Coenzyme Q10 with HMG-CoA Reductase Inhibitors. United States Patent No. 4,933,165 issued Jun. 12, 1990.↩️

  12. Ibid.↩️

  13. Ibid., excerpts from column 1 (lines 6-20).↩️

  14. Ibid., column 1 (lines 46-50).↩️

  15. Ibid., column 1 (lines 57-62).↩️

  16. Ibid., column 2 (lines 13-19).↩️

  17. Ibid., column 2 (lines 53-58).↩️

  18. Ibid., column 2 (lines 64-68) and column 3 (lines 1-2).↩️

  19. CPS 2011 — Compendium of Pharmceuticals and Specialities — The Canadian Drug Reference for Health Professionals (Ottawa: Canadian Pharmacists Association, 2011).↩️

  20. Ibid., pp. 1142–1143.↩️

  21. Ibid.↩️

  22. Ibid., Lipitor® (Pfizer), pp. 1379–1382.↩️

  23. Ibid., Lescol® / Lescol® XL (Novartis Pharmaceuticals), pp. 1347–1350.↩️

  24. Ibid., Mevacor® (Merck Frosst), pp. 1533–1535.↩️

  25. Ibid., Pravachol® (Bristol-Myers Squibb), pp. 1906–1909.↩️

  26. Ibid., Crestor® (AstraZeneca), pp.695–698.↩️

  27. Ibid., Zocor® (Merck Frosst) pp. 2912–2915↩️

  28. Cf. Gerhard Michal, Editor. Roche Biochemical Pathways, 4th Edition, Part 1 Metabolic Pathways (see https://www.roche.com/about/philanthropy/science-education/biochemical-pathways/1).↩️

  29. Cf. Kyoto Encyclopedia of Genes and Genomes (KEGG). KEGG PATHWAY Database (see https://www.genome.jp/kegg/pathway.html).↩️

  30. The cholesterol pathway depicted here is necessariy less than comprehensive as its purpose is simply to illustrate direct biochemical causality between statin treatment and CoQ10 metabolism. Readers, including health care and life sciences professionals, are therefore advised to access the previous two biochemical pathway references for additional technical details in this regard using the links provided.↩️

 
Edwin Wright