Coenzyme Q10:Coenzyme Q10: Who needs it?Who needs it?

Geneva Clark Briggs, Geneva Clark Briggs, PharmDPharmD, , BCPSBCPS

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Coenzyme Q10Coenzyme Q10

Available in more than 100 singleAvailable in more than 100 single--ingredient and combinationingredient and combination--ingredient ingredient productsproductsGreater than $200 million in sales/yearGreater than $200 million in sales/year

Coenzyme Q10Coenzyme Q10

Other names: Other names: ubiquinoneubiquinone, , ubidecarenoneubidecarenone, , coenzyme Qcoenzyme QA fat soluble A fat soluble benzoquinonebenzoquinoneproduced in produced in mitochondria (mitochondria (heart, liver, kidney and pancreas) Mol Biotechnol 2007;37:31-7.

Coenzyme Q10Coenzyme Q10

Component of the mitochondrial Component of the mitochondrial electron transport chain electron transport chain

NADH, nicotinamide adenine dinucleotide; Q, CoQ10; C,cytochrome C; Fe- S, iron-sulfur clusters; ADP, adenosine diphosphate; ATP, adenosine triphosphate.

Mol Biotechnol 2007;37:31-7.

Coenzyme Q10Coenzyme Q10

Two forms Two forms -- ubiquinoneubiquinone and and ubiquinolubiquinolReduced form, Reduced form, ubiquinolubiquinol, inhibits , inhibits protein and DNA oxidation and lipid protein and DNA oxidation and lipid peroxidationperoxidationOnly lipid soluble antioxidant Only lipid soluble antioxidant synthesized endogenouslysynthesized endogenously

Some Purported Indications Some Purported Indications for CoQ10for CoQ10

Familial CoQ10 deficiencies Familial CoQ10 deficiencies StatinStatin induced induced myopathymyopathyHeart failureHeart failureHypertensionHypertensionParkinsonParkinsons diseases disease

Clinical Syndromes of CoQ10 Clinical Syndromes of CoQ10 Deficiency Deficiency

Inherited metabolic muscle and Inherited metabolic muscle and mitochondrial diseasesmitochondrial diseases MyopathyMyopathy with recurrent with recurrent myoglobinuriamyoglobinuria

and CNS involvementand CNS involvement CerebellarCerebellar ataxia with variable CNS ataxia with variable CNS

involvementinvolvement Isolated Isolated myopathymyopathy Mitochondrial Mitochondrial encephalomyopathyencephalomyopathy

Clinical Syndromes of CoQ10 Clinical Syndromes of CoQ10 DeficiencyDeficiency

Supplementation may reduce symptomsSupplementation may reduce symptomsMay require high doses and 6 months or May require high doses and 6 months or more of therapy to improve symptomsmore of therapy to improve symptomsUbiQGelUbiQGel -- FDA orphan drug status for FDA orphan drug status for treating mitochondrial treating mitochondrial encephalomyopathiesencephalomyopathies

Prevention/Treatment of Prevention/Treatment of StatinStatin Induced Induced MyalgiaMyalgia

Biosynthetic PathwayBiosynthetic Pathway

Tyrosine or Phenylalanine

4OH-Benzoate

Ubiquinone

Decaprenyl-PP

Acetyl-CoA

HMG-CoA

Mevalonate

Farnesyl-PP

Squalene

Cholesterol

HMG CoAreductase

Am J Cardiol 2006; 97:8994.

AHA/ACC/NHLBI DefinitionsAHA/ACC/NHLBI Definitions

myopathymyopathy -- any disease of muscle any disease of muscle myalgiamyalgia -- focal or diffuse muscle aches or weakness focal or diffuse muscle aches or weakness with no elevation of with no elevation of creatinecreatine kinasekinasemyositismyositis -- muscle pain with a systemic muscle pain with a systemic inflammatory response and elevated inflammatory response and elevated creatinecreatinekinasekinase more than 3more than 3 ULNULNrhabdomyolysisrhabdomyolysis -- severe muscle damage with severe muscle damage with damage to another organ, notably the kidneys, damage to another organ, notably the kidneys, myoglobinuriamyoglobinuria and and creatinecreatine kinasekinase more than 10more than 10ULNULN

Indirect Support for CoQ10 Indirect Support for CoQ10 TheoryTheory

Familial CoQ10 deficiency Familial CoQ10 deficiency severe causes mitochondrial severe causes mitochondrial myopathicmyopathic

changes with exercise intolerance and changes with exercise intolerance and recurrent recurrent myoglobinuriamyoglobinuria..

Less severe is associated Less severe is associated cerebellarcerebellar ataxia, ataxia, muscle weakness.muscle weakness.

Proc Natl Acad Sci U S A 1989;86:2379-2382.Neurology 1997;48:1238-1243.

Neurology 2001;57:515-518.

Do statins decrease CoQ10?Do statins decrease CoQ10?

Some small studies do show Some small studies do show plasma plasma levels with treatment levels with treatment Other studies show no change in CoQ10 Other studies show no change in CoQ10 levelslevels

Clin Pharmacol Ther 2008;8:731-9.Atherosclerosis 2007;195:e182-9.

Nutr Metab Cardiovasc Dis 2008;18:105-11.Int J Cardiol 2007;118:173-7.

Lipid Corrected CoQ10 LevelsLipid Corrected CoQ10 Levels

CoQ10 is carried in blood by CoQ10 is carried in blood by lipoproteinslipoproteinsWhen plasma levels are corrected for When plasma levels are corrected for lipid values on statins lipid values on statins -- no change in no change in CoQ10 levelsCoQ10 levels

Int J Cardiol 2007;118:173-7.Eur J Clin Invest 2005;35:251-8.

Studies of CoQ10 in Studies of CoQ10 in MyalgiaMyalgiaStudy population Study Design Results 18 patients with statin induced myopathy, elevated CK levels

Prospective, 25 control muscle biopsy samples

Muscle structure was normal in 14, showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients. Muscle CoQ10 concentration not statistically different between patients and control subjects. Muscle CoQ10 was normal in 4, < normal in 10, > normal in 4.

Arch Neurol 2005;62:1709-12.

Studies of CoQ10 in Studies of CoQ10 in MyalgiaMyalgiaStudy population Study Design Results 44 patients with myalgia on statins, CoQ10 200 mg/day or placebo, 12 weeks, simvastatin titrated to 40 mg/day, reduced dose or stopped therapy if myalgia developed

Randomized, placebo-controlled

16 of 22 [73%] CoQ10 tolerated 40 mg/day vs 13 of 22 [59%] with placebo, p = 0.34 16 of 22 [73%] CoQ10 stayed on therapy vs 18 of 22 [82%] with placebo, p = 0.47

Am J Cardiol 2007;100:1400-3.

Studies of CoQ10 in Studies of CoQ10 in MyopathyMyopathy

Study population Study Design Results Patients with myopathic symptoms secondary to statin, CoQ10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days

Randomized, double-blind

Pain severity 40% (p

What we donWhat we dont know for sure ...t know for sure ...

Do plasma levels of CoQ10 need to be Do plasma levels of CoQ10 need to be corrected for lipid levels?corrected for lipid levels?Do lower circulating CoQ10 levels Do lower circulating CoQ10 levels reflect low mitochondrial levels?reflect low mitochondrial levels?Do lower plasma levels have long term Do lower plasma levels have long term impact?impact?

Genetic Risk Factors Associated Genetic Risk Factors Associated with with StatinStatin Induced Induced MyalgiaMyalgia

Curr Opin Rheumatol 2008;20:648-55.

Reviews of the IssueReviews of the Issue

American College of Cardiology American College of Cardiology -- The value of The value of coenzyme Q10 with coenzyme Q10 with statinstatin use has not been clearly use has not been clearly established.established. J Am J Am CollColl CardiolCardiol 2005;46:1842005;46:184--221.221.The present evidence does not support coenzyme The present evidence does not support coenzyme Q10 supplementation in Q10 supplementation in statinstatin--induced induced myopathymyopathyCurrCurr OpinOpin LipidolLipidol 2008;19:5532008;19:553--7.7.There is insufficient evidence to prove the etiologic There is insufficient evidence to prove the etiologic role of CoQ10 deficiency in role of CoQ10 deficiency in statinstatin--associated associated myopathymyopathy.. J Am J Am CollColl CardiolCardiol 2007;49:22312007;49:2231--7.7.

Other Medications That May Other Medications That May Lower CoQ10Lower CoQ10

GlyburideGlyburide, , phenforminphenformin, and , and tolazamidetolazamidePropranololPropranolol, , metoprololmetoprolol, and , and alprenololalprenololPhenothiaxinePhenothiaxine antipsychotic antipsychotic TricyclicTricyclic antidepressantsantidepressantsMethyldopaMethyldopaHydrochlorothiazideHydrochlorothiazideClonidineClonidineHyrdralazineHyrdralazine

BUT no evidence of AE from lowering or benefit of supplementation

CoQ10 and Heart CoQ10 and Heart FailureFailure

COQ10 Mechanism of Action COQ10 Mechanism of Action in Heart Failurein Heart Failure

Enhance cardiac contractilityEnhance cardiac contractility essential cofactor for mitochondrial essential cofactor for mitochondrial

electron transport and myocardial energy electron transport and myocardial energy supplysupply

Reduce endothelial dysfunctionReduce endothelial dysfunction

Studies of CoQ10 in Heart Studies of CoQ10 in Heart FailureFailure

Approved for this use in Japan since Approved for this use in Japan since 197419745 double blind studies (~900 subjects) 5 double blind studies (~900 subjects) found found symptomssymptoms 1 found 1 found

hospitalizationshospitalizations

2 found no benefits (~85 subjects)2 found no benefits (~85 subjects)Clin Investig. 1993;71(suppl 8):S134-6.

J Am Coll Cardiol. 1992;19:216A. Biofactors. 1999;9:285-9.

Clin Cardiol. 2004;27:295-9.Eur Heart J. 2006 ;27:2675-81.

J Am Coll Cardiol. 1999;33:1549-52.Ann Intern Med. 2000;132:636-40.

Studies of CoQ10 in Heart Studies of CoQ10 in Heart FailureFailure

Low plasma levels have been shown to Low plasma levels have been shown to be an independent predictor of HF be an independent predictor of HF mortalitymortality3.7% (95%CI 1.593.7% (95%CI 1.59--5.77) net 5.77) net improvement in the ejection fractionimprovement in the ejection fraction0.28 L/minute (95%CI 0.030.28 L/minute (95%CI 0.03--0.53) 0.53) average increase in cardiac outputaverage increase in cardiac output

J Am Coll Cardiol 2008;52:1435-41.J Card Fail 2006;12:464-72.

Reviews of the IssueReviews of the Issue

ACC ACC -- The value of coenzyme Q10 in The value of coenzyme Q10 in cardiovascular disease treatment has cardiovascular disease treatment has not been clearly established.not been clearly established.

J Am Coll Cardiol 2005;46:184-221.

Severe Heart FailureSevere Heart Failure

Case where Case where ubiquinolubiquinol should be used should be used instead of instead of ubiquinoneubiquinone ubiquinoneubiquinone has very low bioavailability in has very low bioavailability in

severe heart failure (? gut edema)severe heart failure (? gut edema) small study found improved serum levelssmall study found improved serum levels

Biofactors 2008;32(1-4):119-28.

CoQ10 and HypertensionCoQ10 and Hypertension

COQ10 Mechanism of Action COQ10 Mechanism of Action in Hypertensionin Hypertension

CoQ10 decreases CoQ10 decreases cytoplasmiccytoplasmic NADH NADH levels and thereby diminishes the levels and thereby diminishes the reductive power that drives superoxide reductive power that drives superoxide synthesis in endothelium and vascular synthesis in endothelium and vascular smooth musclesmooth muscle

HypertensionHypertension

MetaMeta--analysis of 12 clinical trials (362 analysis of 12 clinical trials (362 patients) concluded CoQ10 has the patients) concluded CoQ10 has the potential to lower systolic and diastolic potential to lower systolic and diastolic blood pressure, without significant side blood pressure, without significant side effectseffects

J Hum Hypertens 2007;21:297-306.

HypertensionHypertension

Systolic decrease Systolic decrease -- ~16 mm Hg ~16 mm Hg Diastolic Diastolic -- ~10 mm Hg~10 mm HgReduction occurs gradually over monthsReduction occurs gradually over monthsEffective dose varies widelyEffective dose varies widely 100100--200 mg/day200 mg/day

Mol Aspects Med 1994;15 (Suppl):S265-72.

CoQ10 and ParkinsonCoQ10 and Parkinsons s DiseaseDisease

Possible Mechanism of Action Possible Mechanism of Action in Parkinsonin Parkinsons Diseases Disease

Patients with PD have reduced activity Patients with PD have reduced activity of complex I and II/III in the of complex I and II/III in the mitochondrial electron transport chain mitochondrial electron transport chain in mitochondria isolated from platelets in mitochondria isolated from platelets and and substantiasubstantia nigranigraCoenzyme Q10 is the electron acceptor Coenzyme Q10 is the electron acceptor for complexes I and II for complexes I and II

ParkinsonParkinsons Diseases Disease

2 positive/3 negative trials (n=140)2 positive/3 negative trials (n=140)1,200 mg/day of CoQ10 slowed 1,200 mg/day of CoQ10 slowed progressive deterioration of function progressive deterioration of function [total Unified Parkinson Disease Rating [total Unified Parkinson Disease Rating Scale]Scale] did not postpone the onset of symptomatic did not postpone the onset of symptomatic

therapy or affect UPDRS motor score therapy or affect UPDRS motor score Arch Neurol. 2002;59:1541-1550. Neurosci Lett. 2003;341:201-204.

Arch Neurol. 2007;64:938-44.Arch Neurol 2003;60:1170-2.Exp Neurol 2004;188:491-4.

Possible Indications Lacking Possible Indications Lacking Data or Still Under StudyData or Still Under Study

DuchenneDuchennessmuscular dystrophymuscular dystrophyAIDSAIDSPeriodontal diseasePeriodontal diseaseAlzheimerAlzheimers diseases disease

DownDowns syndromes syndromeMale infertilityMale infertilityMigraineMigraineDiabetesDiabetesAmyotrophic lateral Amyotrophic lateral sclerosissclerosis

General Issues with CoQ10General Issues with CoQ10

No absolute contraindicationsNo absolute contraindications Little info on use during pregnancy and in Little info on use during pregnancy and in

kidskids

DI: DI: Case reports of Case reports of INR in combo with INR in combo with

warfarinwarfarin, study found no interaction, study found no interaction Possible mild decrease in BP and glucosePossible mild decrease in BP and glucose

AEAE GI upset, diarrhea GI upset, diarrhea

General Issues with CoQ10General Issues with CoQ10

BioavailabilityBioavailability Varies significantly between individuals and Varies significantly between individuals and

productsproducts SoftgelSoftgel capsule in oil and capsule in oil and nanoparticularnanoparticular

appear to be bestappear to be best Measure plasma levels to ensure Measure plasma levels to ensure

absorptionabsorption Divided doses also appear better than one Divided doses also appear better than one

large doselarge dose

DosageDosage

Condition Most Common Dose

Mitochondrial cytopathies

150 mg/day or 2 mg per kg/day with titration, up to 3,000 mg/day in some patients

Parkinsons disease 1,200 mg/day in four divided doses

Heart failure 50-300 mg/day

Hypertension 100-200 mg/day

With statins ? 60-300 mg/day

Consumer Lab TestingConsumer Lab Testing

Example Example passedpassed productsproducts Nature MadeNature Made CoQ10 200 mg (200 mg per CoQ10 200 mg (200 mg per softgelsoftgel, in , in

oil)oil)

Nature's BountyNature's Bounty Extra Strength QExtra Strength Q--SorbSorb Co QCo Q--10 (200 10 (200 mg per mg per softgelsoftgel, in oil), in oil)

BioSolvBioSolv Advanced Formula Advanced Formula QuinogelQuinogel 100 mg (100 100 mg (100 mg per mg per softsulesoftsule, , solubilizedsolubilized and in oil)and in oil)

Vitamin WorldVitamin World UbiquinolUbiquinol 100 mg (100 mg per rapid 100 mg (100 mg per rapid release release softgelsoftgel, in oil), in oil)

Failed productFailed product Healthy America CoQ10 (150 mg per Healthy America CoQ10 (150 mg per softgelsoftgel))

www.consumerlab.com

Dietary Sources of CoQ10Dietary Sources of CoQ10

Internat J Vit Nutr Res 1986;56:57-63. J Food Comp Analysis 2001;14:409-417.

Food Source mcg/g Food Source mcg/g

Pork heart Reindeer Beef heart Soybean oil Canola oil Sardine Mackerel Pork Beef liver Beef

126.8-203 157.9 113.3 92.3 63.5 - 73.4 64.3 43.3 24.3-41.1 39.2 31.0 - 36.5

Sesame oil Soybeans Peanuts, roasted Sesame seeds Pork liver Chicken Pistachios, roasted Ham Walnuts, raw

32.0 19 - 30.1 26.7 23.0 22.7 14.0 - 21.020.1 20.0 19.0

Also Found in Many Other Also Found in Many Other ProductsProducts

CoQ10 Bottom LineCoQ10 Bottom Line

Although touted for many indications, Although touted for many indications, little consistent evidence for little consistent evidence for effectiveness effectiveness May be of benefit inMay be of benefit in Familial CoQ10 deficienciesFamilial CoQ10 deficiencies HypertensionHypertension ParkinsonParkinsons diseases disease Heart failureHeart failure

Appears to be safeAppears to be safe

Coenzyme Q10:Who needs it?Coenzyme Q10Coenzyme Q10Coenzyme Q10Coenzyme Q10Some Purported Indications for CoQ10Clinical Syndromes of CoQ10 Deficiency Clinical Syndromes of CoQ10 DeficiencyPrevention/Treatment of Statin Induced MyalgiaBiosynthetic PathwayAHA/ACC/NHLBI DefinitionsIndirect Support for CoQ10 TheoryDo statins decrease CoQ10?Lipid Corrected CoQ10 LevelsStudies of CoQ10 in MyalgiaStudies of CoQ10 in MyalgiaStudies of CoQ10 in MyopathyWhat we dont know for sure ...Genetic Risk Factors Associated with Statin Induced MyalgiaReviews of the IssueOther Medications That May Lower CoQ10CoQ10 and Heart FailureCOQ10 Mechanism of Action in Heart FailureStudies of CoQ10 in Heart FailureStudies of CoQ10 in Heart FailureReviews of the IssueSevere Heart FailureCoQ10 and HypertensionCOQ10 Mechanism of Action in HypertensionHypertensionHypertensionCoQ10 and Parkinsons DiseasePossible Mechanism of Action in Parkinsons DiseaseParkinsons DiseasePossible Indications Lacking Data or Still Under StudyGeneral Issues with CoQ10General Issues with CoQ10DosageConsumer Lab TestingDietary Sources of CoQ10Also Found in Many Other ProductsCoQ10 Bottom Line