David Leonardi, M.D. ABAAM, CNS

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Statin-Associated Fatigue

Nathan Daley, MD, MPH

What is fatigue?

Fatigue is a complex symptom and often used to describe a variety of slightly different experiences.   For example, fatigue may describe feelings as various as muscle weakness, unusually difficult exertion, poor exercise tolerance, sleepiness, poor concentration and cognition, and lack of motivation or interest.  In many cases, fatigue consists of several of these varieties combined.  In the end, all of these experiences promote rest, inactivity, or withdrawal and detract from quality of life and a sense of wellbeing.  Most simply, fatigue is the absence of adequate energy to live life fully.  Epidemiological and case-report studies, as well as anecdotal evidence, suggest that statins may contribute to these varieties of fatigue in some individuals1,2,3.

How can statins cause fatigue?

It is well known that statin drugs may impair cellular energy production, essentially causing “cellular fatigue”.  This research has been reviewed extensively elsewhere on this website but to summarize, statin drugs  compromise cellular energy production in two important ways.  1) statins impair the transport of creatine across the cellular membrane and, 2) they inhibit the synthesis of Coenzyme Q10 or ubiquinol.

Creatine is critical for the storage and transport of phosphate (as phosphocreatine) which, in turn, is critical for the production of ATP (adenosine tri-phosphate)4,5. ATP is the direct fuel of cellular life!  If a cell lacks sufficient ATP, then that cell dysfunctions and/or dies.  Cellular dysfunction can manifest in many ways, including the array of symptoms we call fatigue.  Statin drugs inhibit the cellular sodium-potassium transporter, which allows creatine to cross the cellular membrane6. So, essentially, statins starve a cell of creatine.  Fortunately, this starvation may be overcome by creatine supplementation7. As discussed elsewhere, buffered creatine appears to improve blood levels of creatine more efficiently than other forms of creatine.

Co-q10 is the final electron receptor in the mitochondrial electron transport chain.  This chain is where energy is transformed from electrons into ATP (often using some phosphate from creatine to do so).  Essentially, Co-q10 is centrally necessary for the production of cellular energy.  Statin drugs inhibit the enzyme that produces Co-q10 (called HMG-coA reductase) and produces a Co-q10 deficiency8,9. This is also the enzyme that synthesizes cholesterol, thus producing the desired result of statin therapy.  Just as supplementing creatine can correct the statin-induced creatine problem, Co-q10 supplementation can correct the unintended side-effect of Co-q10 deficiency.

The resulting “cellular fatigue” may manifest directly in the muscles as muscle cramps, weakness, or stiffness but may also manifest on the systemic level as the varieties of fatigue discussed above.  It is not clear why “cellular fatigue” produces muscular or physical symptoms (unusually difficult exertion, exercise intolerance, weakness) in some individuals and psychological or cognitive symptoms (sleepiness, lack of motivation,  poor cognition, low mood) in others.   This may be due to individual genetic, epigenetic, or physiological variability and symptoms may simply appear first in the most vulnerable organ.

Can statin-associated fatigue be reversed or prevented?

Based on the observations that;

1. Statins cause cellular deficiencies in both creatine and co-q10;

2. These deficiencies result in impaired ATP (energy) production; and

3. Impaired ATP production causes cellular dysfunction or fatigue that may manifest as systemic fatigue, it would seem logical that correcting these cellular deficiencies may improve the various symptoms comprising statin-associated fatigue. Yet, this approach is still very novel and research data is as yet non-existent. Therefore, a great deal of research is needed to know for sure if correcting these deficiencies will improve statin-associated fatigue, but such a positive outcome remains highly plausible.

Therefore, combined creatine and co-q10 supplementation offers a science-based approach to avoiding or correcting statin-associated fatigue while retaining the cardiovascular benefits of statin therapy.   Yet, the chances of overcoming statin-associated fatigue may be further improved by additional supplementation with vitamin D3.  Studies have shown that low levels of vitamin D3 are associated with muscle dysfunction (myopathy) and fatigue10,11,12. Most interestingly, research has also shown that vitamin D3 plays an important role in the production of phosphocreatine13. Therefore, vitamin D3 intersects with creatine and co-q10 at the mitochondria in the production of ATP!

The Safest, Most Economical and Simplest Solution

As a result of the potential benefits of buffered creatine, CoQ10, and vitamin D3 we’ve discussed, we decided to combine these ingredients into one simple nutritional supplement called Statin Sidekick™.  We believe Statin Sidekick is critically important for anyone taking a statin medication (especially those experiencing fatigue) along with anyone physically active and interested in insuring a steady supply of cellular energy. Two capsules of Statin Sidekick provides a proprietary blend of buffered creatine and CoQ10 totaling 1,500 mg along with 2,000 iu of vitamin D3. These three ingredients are included in the most optimal ratio based on published clinical trials, our original research and our patient experience at the Leonardi Institute. The recommended dose is 2 to 3 capsules twice a day (always with food) for the first week (called a “loading dose”) followed by 1 to 2 capsules twice a day thereafter. There appears to be a benefit in stopping your statin for the first week while taking the loading dose of Statin Sidekick but we don’t recommend this without first checking with your practitioner.

If you notice fatigue that you feel is related to your statin while taking Statin Sidekick™, simply increase the dose back up to 3 capsules twice a day. Of course, you should also notify your physician that your statin is causing you fatigue. You may adjust the dose of Statin Sidekick back and forth to see what dose you personally require to eliminate statin-related fatigue while optimizing cellular energy availability and performance. In unusual circumstances, a few people may even require 4 capsules twice a day. Detailed dosing instructions are included with each order. If 4 capsules of Statin Sidekick twice daily doesn’t relieve your statin side effects, the next logical step might  be to discuss with your practitioner, either an alternative statin or a lower dose of the same statin while continuing Statin Sidekick. If you’re unsuccessful with that approach you may want to discuss statin alternatives with your practitioner.

Statin Sidekick is an essential nutrient for anyone taking a statin. It provides that margin of safety and peace of mind that you’re getting the best possible performance from your brain and muscles while reducing the risk of memory loss, muscle pain and fatigue that can accompany statin use. If you would like to order Statin Sidekick, it is available on our Cycle-Breakers.com website by clicking here. Statin Sidekick is carefully tested and manufactured in full compliance of U.S. government Good Manufacturing Processes (GMP).

Statin Sidekick Supplement Facts

Serving size 2 capsules

Servings per Container 30 (60 capsules)

Active Ingredients
Amount per Serving
% DRV
Vitamin D32,000 iu500
A proprietary blend of Kre-Alkalyn® (buffered creatine) and Coenzyme Q101500 mgDRV not established

Directions: Take 2-3 capsules twice daily WITH FOOD (within 45 minutes of a meal). You may reduce the dose after the first week if you remain free of statin side effects, or increase the dose if needed.

References
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1

1Golomb B.A., Evans M.A., Dimsdale J.E., White H.L. Effects of Statins on Energy and Fatigue With Exertion: Results From a Randomized Controlled Trial ARCH INTERN MED/VOL 172 (NO. 15), AUG 13/27, 2012.

2Cham S, Evans MA, Denenberg JO, Golomb BA. Statin-associated musclerelated adverse effects: a case series of 354 patients. Pharmacotherapy. 2010; 30(6):541-553.

3Sinzinger H, O’Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol. 2004;57(4):525-528.

4The creatine-creatine phosphate shuttle for energy transport-compartmentation of creatine phosphokinase in muscle. Adv Exp Med Biol. 1982;151:115-25.

5The creatine-creatine phosphate energy shuttle. Annu Rev Biochem. 1985;54:831-62.

6Circulation. 2006;114:II_288. Lipid and Lipoprotein Metabolism: Clinical V Abstract 1495: Serum Creatine/Creatinine Ratio Elevation and Statin Myalgia

7Ann Intern Med. 16 November 2010;153(10):690-692. Creatine Supplementation Prevents Statin-Induced Muscle Toxicity

8J Clin Pharmacol. 1993 Mar;33(3):226-9. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.

9J Atheroscler Thromb. 2005;12(2):111-9. Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients.

10Boland R. Role of vitamin D in skeletal muscle function. Endocr Rev 1986; 7:434-48.Holick MF. Vitamin D Deficiency. N Engl J Med 2007; 357:266-81.

11Ceglia L. Vitamin D and skeletal muscle tissue and function. Mol Aspects Med 2008; 29:407-14.

12Sinha A, Hollingsworth KG, Ball S, Cheetham T. Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle.

13J Clin Endocrinol Metab. 2013 Mar;98(3):E509-13. doi: 10.1210/jc.2012-3592. Epub 2013 Feb 7.

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