CoQ10

Coenzyme Q10 supplementation decreased statin-related muscle symptoms in 75% of patients.

Aida Skarlovnik, et all. Coenzyme Q10 Supplementation Decreases Statin-Related Mild-to-Moderate Muscle Symptoms: A Randomized Clinical Study. Med Sci Monit. 2014; 20: 2183–2188.

“Coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs”

A successful trial with CoQ10 supplementation was reported by Caso et al who assessed in a double-blinded protocol the effect of CoQ10 (100 mg/d, n = 18) or vitamin E (400 IU/d, n = 14) for 30 days in patients with myopathic symptoms. Pain severity decreased by 40% (P < 0.001) and pain interference with daily activities decreased by 38% (P < 0.02) in the group treated with CoQ10. In contrast, no changes in pain severity (9%, P = not significant) or pain interference with daily activities (11%, P = not significant) were observed with vitamin E. These results suggest that CoQ10 supplementation may decrease muscle pain associated with statin treatment.

Am J Cardiol. 2007 May 15;99(10):1409-12. Epub 2007 Apr 3.Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007 May 15;99(10):1409-12. Epub 2007 Apr 3.

Statin use is associated with an increased likelihood of diagnoses of musculoskeletal conditions, arthropathies, and injuries … Several factors may explain the musculoskeletal adverse events of statin therapy, including the inhibitory effect on coenzyme Q10 synthesis, selenoprotein synthesis, and the mitochondrial respiratory chain.

Ishak Mansi, MD et al. Statins and Musculoskeletal Conditions, Arthropathies, and Injuries. JAMA Intern Med. 2013;173(14):1318-1326

The clinical use of lovastatin is to reduce a risk of cardiac disease, and if lovastatin were to reduce levels of CoQ10, this reduction would constitute a new risk of cardiac disease, since it is established that CoQ10 is indispensable for cardiac function.

We have conducted three related protocols to determine whether lovastatin does indeed inhibit the biosynthesis of CoQ10.

1. Protocol was done on rats
2. Protocol involved patients in a hospital, and the other involved a
3. A volunteer who permitted extraordinary monitoring of CoQ10 and cholesterol levels and cardiac function

All data from the three protocols revealed that lovastatin does indeed lower levels of CoQ10.

Although a successful drug, lovastatin does have side effects, particularly including liver dysfunction, which presumably can be caused by the lovastatin-induced deficiency of CoQ10.

K. Folkers et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A. 1990 Nov; 87(22): 8931–8934.

Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.

Mortensen SA1, Leth A, Agner E, Rohde M.Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997;18 Suppl:S137-44.

Statin treatment decreased circulating CoQ10…The findings of this study provide a potential mechanism for statin-associated muscle symptoms (SAMS) and suggest that CoQ10 supplementation may be a promising complementary approach for SAMS.

Qu H et al. The effect of statin treatment on circulating coenzyme Q10 concentrations: an updated meta-analysis of randomized controlled trials.Eur J Med Res. 2018 Nov 10;23(1):57. doi: 10.1186/s40001-018-0353-6.

The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins.

Banach M1Statin therapy and plasma coenzyme Q10 concentrations–A systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res. 2015 Sep;99:329-36. doi: 10.1016/j.phrs.2015.07.008. Epub 2015 Jul 17.

These side effects raise concerns in patients as well as in doctors and are likely to reduce patients’ adherence and, as a consequence, the cardiovascular benefit. Therefore, it is mandatory that clinicians improve their knowledge on the clinical aspects of muscular and hepatic side effects of statin therapy as well as their ability to manage patients with statin intolerance

Marcello Arca and Giovanni PignaTreating statin-intolerant patients. Diabetes MetabSyndrObes. 2011; 4: 155–166.

Selenium

Statin medications lower selenium levels in users

Arnaud J1, Akbaraly TN, Hininger-Favier I, Berr C, Roussel AM. Fibrates but not statins increase plasma selenium in dyslipidemic aged patients–the EVA study. J Trace Elem Med Biol. 2009;23(1):21-8. doi: 10.1016/j.jtemb.2008.08.001. Epub 2008 Oct 10.

Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency.

Okuyama H1 et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99. doi: 10.1586/17512433.2015.1011125. Epub 2015 Feb 6.

We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway–the isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy.

Moosmann B1, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet. 2004 Mar 13;363(9412):892-4.

The resultant inhibition of Sec-tRNA isopentenylation profoundly decreases selenoprotein expression. This effect might seamlessly explain the immunosuppressive, redox, endothelial, sympatholytic, and thyroidal effects of statins and fibrates as well as their common side effects and drug interactions.

The objective of this study was to evaluate the possible benefits of coenzyme Q and selenium supplementation administered to patients with statin-associated myopathy (SAM)

Symptoms of SAM significantly improved in the active group (p < 0.001):
the intensity of muscle pain decreased from 6.7 to 3.2
muscle weakness decreased from 7.0 to 2.8
muscle cramps decreased from 5.33 to 1.86
tiredness decreased from the initial 6.7 to 1.2

compared to no significant changes in placebo group.

Coenzyme Q10 and selenium in statin-associated myopathy treatment. Canadian Journal of Physiology and Pharmacology 91(2):165-70 • February 2013

Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway.
Moosmann B1, Behl C.Trends Cardiovasc Med. 2004 Oct;14(7):273-81.

The primarily affected selenoprotein was glutathione peroxidase (GPx), whose biosynthesis, steady-state expression level, and catalytic activity were significantly reduced with 10 to 100 nM concentrations of the different compounds.

We conclude that statins inhibit the expression of inducible selenoproteins by preventing the mevalonate-dependent maturation of the single human selenocysteine-tRNA and may thereby evoke an increased vulnerability of the liver to secondary toxins. Selenoprotein modulation might constitute an important mechanism of statins to bring forth their clinical effects.

Kromer A1, Moosmann B. Statin-induced liver injury involves cross-talk between cholesterol and selenoprotein biosynthetic pathways. Mol Pharmacol. 2009 Jun;75(6):1421-9. doi: 10.1124/mol.108.053678. Epub 2009 Mar 30.

Increased amounts of selenoproteins observed in response to selenium supplementation were shown in several studies to correlate with increases in the corresponding mRNA levels.

Christinan B. Allan, et al. Responsiveness of selenoproteins to dietary selenium. Annual Review of Nutrition. Vol, 19:1-16 1996.

Vitamin K2

Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification.

Okuyama H1 et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99. doi: 10.1586/17512433.2015.1011125. Epub 2015 Feb 6.

“Vitamin K dependent proteins have been demonstrated to inhibit vascular calcification.A high intake of menoquinones, especially MK-7, MK-8 and MK-9, could protect against CHD”

Gast GCet al. A high menaquinone intake reduces the incidence of coronary heart disease. NutrMetab Cardiovasc Dis. 2009 Sep;19(7):504-10. doi: 10.1016/j.numecd.2008.10.004. Epub 2009 Jan 28.

Past research has also shown that vitamin K slowed the development of insulin resistance in elderly men,11 adding to the growing evidence that vitamin K has a potentially beneficial role in insulin metabolism. The fact that statins interfere with your body’s synthesis of this vitamin is likely one reason why they, in turn, may increase your diabetes risk. Insulin resistance is not only a precursor to type 2 diabetes but is also a risk factor in many other chronic diseases.

Vitamin K supplementation for 36 months at doses attainable in the diet may reduce progression of insulin resistance in older men.

Yoshida Met al. Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes Care. 2008 Nov;31(11):2092-6. doi: 10.2337/dc08-1204. Epub 2008 Aug 12.

“Although our study could not provide the underlying mechanism, we speculate that [carboxylated osteocalcin] or vitamin K could modulate adipokines or inflammatory pathways other than the IL-6 pathways. Alternatively, [carboxylated osteocalcin] can directly regulate glucose disposal at skeletal muscle or adipose tissues.”

Hyung, J. et al. Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial. Diabetes Care 2011 Sep; 34(9): e147-e147.

Zinc

Patients previously not treated with a lipid-lowering agent (n = 20; mean age 49.15 +/- 3.28 years) were treated with either 10 mg/day of Simvastatin (n = 11), or Atorvastatin (n = 9) for 4 months.

Statin treatment was associated with a significant reduction in mean serum zinc. These changes may be related to the known anti-inflammatory properties of the statin class of drugs.

Ghayour-Mobarhan M et al. Effect of statin therapy on serum trace element status in dyslipidaemic subjects. J Trace Elem Med Biol. 2005;19(1):61-7.

Ananda S Prasad, the most noted authority in the world on zinc, has shown through is research that zinc deficiency increases inflammation and induces endothelial dysfunction. Zinc deficiency correlated with higher lipid peroxidation and molecules adhering to endothelial lining.

Ananda. P. Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 2013 Mar 1;4(2):176-90. doi: 10.3945/an.112.003210.

Broccoli sprouts – sulforaphane

A 2011 meta-analysis confirmed that the higher the dosage of statin drugs being taken, the greater the diabetes risk.

Preiss Det al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22;305(24):2556-64. doi: 10.1001/jama.2011.860.

A 2010 meta-analysis of 13 statin trials, consisting of 91,140 participants, found that statin therapy was associated with a 9 percent increased risk for incident diabetes
Sattar, N et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. The Lancet. Volume 375. Issue 9716. P 735-742. Feb 27 2010.

In a 2009 study, statin use was associated with a rise of fasting plasma glucose in patients with and without diabetes, independently of other factors such as age, and use of aspirin, β-blockers, or angiotensin-converting enzyme inhibitors.
The study included data from more than 345,400 patients over a period of two years. On average, statins increased fasting plasma glucose in non-diabetic statin users by 7 mg/dL, and in diabetics, statins increased glucose levels by 39 mg/dL.
Rishi Sukhija, MD et al. Effect of Statins on Fasting Plasma Glucose in Diabetic and Nondiabetic Patients. Journal of Investigative Medicine. Volume 57. Issue 3. 2105.

Sulforaphane from broccoli sprouts reduced glucose production, improved blood sugar levels and HbAIc in type 2 diabetics.
Annika S. Axelsson et al. Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Science Translational Medicine 14 Jun 2017:

For our primary analysis, we matched 6972 pairs of statin users and nonusers. The risk for cataract was higher among statin users in comparison with nonusers in the propensity score–matched cohort

Jessica Leuschen, MD et al. Association of Statin Use With Cataracts. A Propensity Score–Matched Analysis. JAMA Ophthalmol. 2013;131(11):1427-1434

The dietary component sulforaphanedemonstrates an ability to protect human lens cells against oxidative stress and thus could potentially delay the onset of cataract.

Liu H et al. Sulforaphane can protect lens cells against oxidative stress: implications for cataract prevention. Invest Ophthalmol Vis Sci. 2013 Aug 5;54(8):5236-48. doi: 10.1167/iovs.13-11664.

Black Pepper Extract

Black pepper extract (bioperine) has been shown to make nutrients more bioavailable in the body along with increasing antioxidant capacities of the body including reducing lipid peroxidation, an important aspect of heart health.

CoQ10 Bioavailability
Bioavailability of coenzyme Q10 (CoQ10) was evaluated with and without BioPerine® supplementation in a double-blind, single dose clinical study. After 21 days of supplementation, co-administration of BioPerine®resulted in an absolute increase in CoQ10 serum levels by 1.12 μg/ml as compared to the absolute increase of 0.85 μg/ml in the control group. A 30% increase was observed in the area under the curve of CoQ10 supplemented with BioPerine® compared to control.

VladimirBadmaev et al. Piperine derived from black pepper increases the plasma levels of coenzyme q10 following oral supplementation. Journal of Nutritional Biochemistry. 2000 Feb 11:2:109-113

https://www.sciencedirect.com/science/article/pii/S0955286399000741?via%3Dihub

Selenium Bioavailability
In a double-blind study, bioavailability of selenium was evaluated alone and in combination with BioPerine®. The serum selenium levels were approximately 30% higher in the group receiving selenium with BioPerine® after 2 weeks of treatment with a plateau in the subsequent time-points tested. The serum selenium levels were within normal limits in both groups at all time-points tested.

Selenium absorption is enhanced in the presence of black pepper extract
Dudhatra, G., Mody, S., Awale, M., Patel, H., Modi, C., Kumar, A., et. Al (2012). “A Comprehensive Review on Pharmacotherapeutics of Herbal Bioenhancers”. The Scientific World Journal
Volume 2012, Article ID 637953, 33 pages

Zinc Bioavailability
Zinc absorption is enhanced in the presence of black pepper extract
Dudhatra, G., Mody, S., Awale, M., Patel, H., Modi, C., Kumar, A., et. Al (2012). “A Comprehensive Review on Pharmacotherapeutics of Herbal Bioenhancers”. The Scientific World Journal
Volume 2012, Article ID 637953, 33 pages

Rats fed piperine from black pepper for 8 weeks showed an increased absorption of zinc in their intestinal tract
Enhanced intestinal uptake of iron, zinc and calcium in rats fed pungent spice principles – Piperine, capsaicin and ginger (Zingiberofficinale). Journal of Trace Elements in Medicine and Biology 27(3) • January 2013

K2 bioavailability
Vitamin K2 absorption is enhanced in the presence of black pepper extract
Dudhatra, G., Mody, S., Awale, M., Patel, H., Modi, C., Kumar, A., et. Al (2012). “A Comprehensive Review on Pharmacotherapeutics of Herbal Bioenhancers”. The Scientific World Journal
Volume 2012, Article ID 637953, 33 pages