Muscle Characteristics Associated With Statin Therapy

Myopathy Clinical Trial

Official title:

Muscle Characteristics Associated With Statin Therapy

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00990834
• Other study ID #: MCAST
• Status: Withdrawn
• Phase: N/A
• First received: October 5, 2009
• Last updated: May 21, 2015
• Start date: November 2009
• Est. completion date: June 2011

Study information

• Verified date: May 2015
• Source: Scripps Health
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate the mechanism of statin-related myopathy by evaluating muscle samples before and after statin exposure.

Description:

Statins have been proven to reduce cardiovascular events and mortality in large clinical trials but remain underutilized partly due to the associated myopathy. Severe reactions manifested as rhabdomyolysis are rare but myalgia is commonly noted in clinical practice. The pathophysiology of these events remains obscure. Previous studies suggest that statins block the downstream products (such as cellular signaling molecules) of the mevalonate pathway needed for normal muscle function. Other studies show that statins are associated with gene expressions involved in muscle damage such as atrogin-1. We will quantify these entities pre and post statin therapy to better understand these reactions.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 21 Years to 90 Years

Eligibility

Inclusion Criteria:

• Primary surgeon's permission.

• Patient is > 21 years of age.

• Patient will go through a two phase surgery with the two procedures one to eight months apart.

• Patient or representative understands the nature of the study.

• Normal thyroid stimulating hormone (TSH).

• LDL-cholesterol > 100 mg/dL or highly sensitive C-reactive protein (hsCRP) > 2.0.

• One of the following risk factors: male > 45 year old or female > 55 year old, smoker, hypertension, first degree family history of coronary artery disease < 55 year old, HDL <40 mg/dL, chronic kidney disease, diabetes mellitus, previous TIA or stroke, previous coronary artery disease.

Exclusion Criteria:

• Has been on a lipid-lowering medication previously.

• Severe illness (e.g. trauma or sepsis) more than 24 hours before obtaining the first biopsy.

• Less than a 10% reduction of LDL after 3 months of therapy (indicative of non-adherence).

• Contraindications to statins such as liver failure.

• History of underlying muscle disorder.

• Taking amiodarone.

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Myopathy

Intervention

Drug:
• simvastatin
simvastatin 80 mg PO daily for one to eight months.

Locations

Country	Name	City	State
United States	Scripps-Mercy Hospital	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Scripps Health

Country where clinical trial is conducted

United States, 

References & Publications (14)

Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther. 2005 Dec;19(6):403-14. — View Citation

Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006 Mar 23;354(12):1264-72. — View Citation

Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, Babiychuk EB. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol. 2006 Sep;210(1):94-102. — View Citation

Flint OP, Masters BA, Gregg RE, Durham SK. Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro. Toxicol Appl Pharmacol. 1997 Jul;145(1):91-8. — View Citation

Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39. Review. Erratum in: Circulation. 2004 Aug 10;110(6):763. — View Citation

Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. 2007 Dec;117(12):3940-51. — View Citation

Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006 Dec 19;114(25):2788-97. Epub 2006 Dec 11. Review. — View Citation

Matzno S, Yasuda S, Juman S, Yamamoto Y, Nagareya-Ishida N, Tazuya-Murayama K, Nakabayashi T, Matsuyama K. Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein. J Pharm Pharmacol. 2005 Nov;57(11):1475-84. — View Citation

Nishimoto T, Ishikawa E, Anayama H, Hamajyo H, Nagai H, Hirakata M, Tozawa R. Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs. Toxicol Appl Pharmacol. 2007 Aug 15;223(1):39-45. Epub 2007 May 24. — View Citation

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998 Nov 5;339(19):1349-57. — View Citation

Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003 Apr 5;361(9364):1149-58. — View Citation

Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16;333(20):1301-7. — View Citation

Shishehbor MH, Patel T, Bhatt DL. Using statins to treat inflammation in acute coronary syndromes: Are we there yet? Cleve Clin J Med. 2006 Aug;73(8):760-6. Review. — View Citation

Young JM, Florkowski CM, Molyneux SL, McEwan RG, Frampton CM, George PM, Scott RS. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol. 2007 Nov 1;100(9):1400-3. Epub 2007 Aug 16. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Atrogin-1 expression.		One to eight months.	Yes
Primary	Intramuscular Ras level.		One to eight months.	Yes
Secondary	Intramuscular Coenzyme Q10 level.		One to eight months.	Yes
Secondary	Intramuscular mitochondrial to nuclear DNA ratio.		One to eight months.	Yes
Secondary	Intramuscular geranylgeranylpyrophosphate.		One to eight months.	Yes
Secondary	PPAR-gamma coactivator-1-alpha expression.		One to eight months.	Yes