The Effect of XueZhiKang on Fatigue：Comparing With Simvastatin

Individuals at risk for cardiovascular disease (CVD) are often prescribed statins, which are medications that reduce the amount of cholesterol in the blood. By lowering cholesterol levels, these individuals have a lower incidence of coronary artery disease, ischemic stroke, and peripheral arterial disease and so on. While statins are effective at lowering cholesterol levels, their effect on fatigue is obvious and has been suggested by several studies, including one randomized, double-blind, placebo-controlled clinical trial. And XueZhiKang may be not. The purpose of this study is to compare the effect of these two medications on fatigue in persons who are at moderate to low CVD risk based on the risk estimation system in ESC(European Society of Cardiology)/ESA(European Atherosclerosis Society) guidelines (2011) for the management of dyslipidemias.

This study will enroll individuals who do not currently take cholesterol-lowering medications. Participants will be randomly assigned to receive 600mg of XueZhiKang twice a day, or 20mg of simvastatin daily for 4 weeks. Study visits will occur at baseline and Week 4. Blood will be collected for laboratory testing, and standardized psychological questionnaires will assess fatigue scores and physical activity levels at baseline and week 4. Pill count will be used to assess adherence of XueZhiKang and simvastatin treatment at week 4. At week 4, medication side effects will be monitored and tests of alanine aminotransferase (ALT), aspartate aminotransaminase (AST) and creatine phosphate kinase (CPK) will be performed. At week 4, medication efficacy will be assessed and test of low-density lipoprotein cholesterol (LDL-C) will be performed.

• XueZhiKang (Drug): Participants will receive 600mg of XueZhiKang twice a day for 4 weeks.
• simvastatin (Drug), also known as shujiangzhi: Participants will receive 20mg of simvastatin daily for 4 weeks.

Primary outcomes

• Comparison Between XueZhiKang and Simvastatin on Fatigue Scores [Measured at baseline and week 4]: At baseline and week 4, the fatigue score was assessed by a fatigue questionnaire named as Fatigue Assessment Scale (FAS) which used 10-item fatigue measure with the fatigue score ranged from 10-50. The higher score was meaning of higher level of fatigue.

Secondary outcomes

• Treatment Efficacy [Measured at baseline and week 4]: Treatment efficacy was estimated on the basis of triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), as well as LDL-C levels obtained at baseline and week 4.

Other outcomes

• Comparison of XueZhiKang With Simvastatin of Physical Activity Level [Measured at baseline and week 4]: At baseline and week 4, we estimated physical activity level by short version of international physical activity questionnaire (IPAQ) with categorical score ranged from low to high. The higher score was meaning of lower physical activity level.
• Comparison of Safety Laboratory Testings (ALT,AST,CPK) Between Simvastatin- and Xuezhikang-groups [Measured at baseline and week 4]: Fasting blood samples were collected at weeks 0 (randomization) and 4 (end of study) for clinical chemistry.
• Comparison of Safety Laboratory Testing (Cr) Between Simvastatin- and Xuezhikang-group [Measured at baseline and week 4]: Fasting blood samples were collected at weeks 0 (randomization) and 4 (end of study) for clinical chemistry.
• Treatment Adherence at Week 4 in Simvastatin- and Xuezhikang-group [Measured at baseline and week 4]: We counted the total number of pills that were dispensed to the participants at baseline and the total number of pills that were taken by participants at week 4.

Sex: All, ages: 20 Years to 65 Years

Inclusion Criteria:

1. LDL cholesterol level between 115-190 mg/dL;
2. Able to fast prior to blood draw;
3. Able to comfortably read and write in Chinese;
4. Able and willing to refrain from donating whole blood during study participation;
5. Willing to abstain from consuming large amounts of grapefruit juice.

Exclusion Criteria:

1. Current use of lipid-lowering medications;
2. Documented cardiovascular disease (CVD) by invasive or non-invasive testing (such as coronary angiography, nuclear imaging, stress echocardiography, carotid plaque on ultrasound), previous myocardial infarction (MI), acute coronary syndrome (ACS), coronary revascularization \[percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG)\] and other arterial revascularization procedures, ischaemic stroke, peripheral arterial disease(PAD);
3. Patients with type 2 diabetes, patients with type 1 diabetes with target organ damage (such as microalbuminuria);
4. Patients with moderate to severe chronic kidney disease \[glomerular filtration rate (GFR) < 60 mL/min/1.73㎡\];
5. Markedly elevated single risk factors such as familial dyslipidaemias and severe hypertension;
6. A calculated SCORE ≥5% for 10 year risk of fatal CVD;
7. Cancer;
8. HIV infected;
9. Medical or psychiatric condition that prevents full study participation or follow-up (e.g., active psychosis);
10. Active liver disease or unexplained persistent elevated transaminase levels；
11. Major surgery or hospitalization in the 3 months prior to study entry;
12. Current use of cyclosporin, erythromycin, clarithromycin, nefazodone, or any "azole" antifungals, including fluconazole, itraconazole, ketoconazole, mibefradil, or protease inhibitors;
13. Female of childbearing potential;
14. Current participation in another clinical trial.

Participant flow

Outcome results

• Treatment Efficacy (Secondary), Mean, mmol/L: Simvastatin/Baseline 1.76 +/- 1.00; Simvastatin/Week 4 1.54 +/- 1.01; XueZhiKang/Baseline 1.61 +/- 0.65; XueZhiKang/Week 4 1.36 +/- 0.69
• Comparison Between XueZhiKang and Simvastatin on Fatigue Scores (Primary), Mean, units on a scale: Simvastatin/Baseline 19.58 +/- 2.55; Simvastatin/Week 4 21.58 +/- 2.75; XueZhiKang/Baseline 19.26 +/- 1.85; XueZhiKang/Week 4 19.33 +/- 1.90
• Comparison of XueZhiKang With Simvastatin of Physical Activity Level (Other pre specified), Number, participants: Simvastatin/Baseline 14; Simvastatin/Week 4 25; XueZhiKang/Baseline 3; XueZhiKang/Week 4 3
• Comparison of Safety Laboratory Testings (ALT,AST,CPK) Between Simvastatin- and Xuezhikang-groups (Other pre specified), Mean, U/L: Simvastatin/Baseline 28.58 +/- 10.55; Simvastatin/Week 4 28.73 +/- 13.10; XueZhiKang/Baseline 30.33 +/- 13.30; XueZhiKang/Week 4 28.67 +/- 14.73
• Comparison of Safety Laboratory Testing (Cr) Between Simvastatin- and Xuezhikang-group (Other pre specified), Mean, mmol/L: Simvastatin/Baseline 72.57 +/- 14.44; Simvastatin/Week 4 71.95 +/- 14.34; XueZhiKang/Baseline 75.59 +/- 17.20; XueZhiKang/Week 4 76.51 +/- 16.39
• Treatment Adherence at Week 4 in Simvastatin- and Xuezhikang-group (Other pre specified), Number, number of pills: Simvastatin/Baseline 462; Simvastatin/Week 4 462; XueZhiKang/Baseline 3024; XueZhiKang/Week 4 3024

Adverse events

Limitations and caveats: There are some limitations to this research. First, the sample size was relative small. Second, the follow-up period was short (4 weeks).

• Results publication: Xue Y, Tao L, Wu S, Wang G, Qian L, Li J, Liao L, Tang J, Ji K. Red yeast rice induces less muscle fatigue symptom than simvastatin in dyslipidemic patients: a single center randomized pilot trial. BMC Cardiovasc Disord. 2017 May 18;17(1):127. doi: 10.1186/s12872-017-0560-z. PMID 28521773

• Jifei Tang, MD, Principal investigator, Wenzhou Medical University