Effect of Xuezhikang Combined with Rosuvastatin on Lipid Regulation in Patients with Atherosclerotic Cardiovascular Disease: A Real-World Study

Background Lipid control in atherosclerotic cardiovascular disease(ASCVD)patients has always been a focus, and the combination of lipid-regulating drugs has become a major trend. To evaluate the effects of Xuezhikang combined with rosuvastatin on the degree, time, rate and safety of lipid regulation in ASCVD patients. Methods ASCVD patients were randomly divided into Xuezhikang group(group A),rosuvastatin group(group B)and combination group(groupC). Plasma total cholesterol, triglyceride, high density liptein cholesterol and low density lipoprotein cholesterol were measured at various points of observation even the side effects were monitored. Compared carotid intima-media thickness (IMT),Crouse score, plaque stability before and after treatment and calculated the LDL-C success rate. Use appropriate statistical descriptions and analyses based on data characteristics. which shorten the time for plasma LDL-C to reach the standard and improve the success rate with both medication safety and the ability to stabilize plaque. It provides a new choice for the combination of lipid-regulating drugs. are better than Xuezhikang group. LDL-C comparison between


Introduction
Atherosclerotic cardiovascular disease (ASCVD) is a major global public health problem, which reduces people's quality of life and seriously endangers human health. 1 In recent years, studies have shown that hyperlipidemia, atherosclerosis and hypertension are closely related to the occurrence of cardiovascular and cerebrovascular diseases, especially the increase of serum low-density lipoprotein cholesterol (LDL-C) level is an important risk factor for coronary heart disease. 2 Active lipid-lowering intervention measures can effectively reduce the progression of atherosclerosis and the occurrence of cardiovascular events. 3 As the cornerstone of the treatment of ASCVD, statins can effectively inhibit the synthesis of cholesterol in vivo but some patients are intolerant of them. When the treatment dose is doubled, the decrease of LDL-C is only about 6%, at the same time the side effects are signi cantly increased and the bene ts are cut down. 4

,5 Xuezhikang
Capsule is a Chinese patent medicine fermented from red yeast rice and has the effect of lowering blood lipid. 6 In addition, many studies have shown that Xuezhikang has apart from lipid regulating effects, such as inhibiting in ammatory reaction, inhibiting endoplasmic reticulum oxidative stress and cell apoptosis, reducing arterial stiffness, improving cardiac and vascular endothelial function, regulating blood glucose and insulin resistance. [7][8][9][10][11] China secondary prevention of coronary heart disease (CCSPS) shows that Xuezhikang can reduce the total risk of death, coronary heart disease mortality and fewer adverse reactions in patients with ASCVD. 12 Rosuvastatin is a medium and high-intensity lipid-lowering drug which is recommended in the guideline. Compared with other statins, rosuvastatin has stronger lipid-lowering effect, and the incidence of adverse events is similar or even less than that of similar drugs. 13 Studies have shown that statins combined with Xuezhikang can better regulate lipid and improve blood pressure and blood glucose of patients. At present, the concept of cholesterol management has changed and sublimated from "strengthening statins" to "strengthening lipidlowering". According to the "LDL principle", combined lipid-lowering therapy will be the focus of blood lipid management . 14

Research Objects
Approved by the ethics Committee of the hospital (Ethics approval Number: QYFYWZLLZ5800), 80 males and 100 female patients with ASCVD were selected from the A liated Hospital of Qingdao University from May 2019 to December 2019, with an average age of (63.49±9.51) years old.

Inclusion criteria
Age 18-79 years old, without gender restriction; In line with the diagnosis of ASCVD disease in 2016 Guidelines for prevention and Treatment of Dyslipidemia in Chinese Adults; No lipid-regulating drugs were used in recent 2 weeks, total cholesterol (TC):4.40-6.47mmol/l (170-250mg/dl);triglyceride (TG)≤4.52mmol/l (400mg/dl); All kinds of chronic diseases were in stable stage without adjusted drug plan; Signed the informed consent form.

Exclusion criteria
Homozygous familial hypercholesterolemia or familial dyslipoproteinemia; Have a history of allergy or serious adverse reactions to statins; Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)≥3 times of normal upper limit (ULN); Creatinine (CREA)≥1.5 times ULN; Patients with uncontrolled severe hypertension; Hypothyroidism; History of alcohol and/or drug abuse; Use other lipid-regulating drugs; Failure to comply with lifestyle changes.

Research Methods
According to the method of random number table, the subjects were randomly divided into Xuezhikang group (group A), rosuvastatin group (group B) and combined medication group (Group C). On the basis of lifestyle change (low salt and low-fat diet, smoking cessation, walking 3-5 times a week, 30 minutes each time, etc.), Xuezhikang group: Xuezhikang 0.3g/capsule, 2 capsules a time, twice a day; Rosuvastatin group: rosuvastatin 10mg/tablet, one tablet each time, once a night; Combined medication group: rosuvastatin 10mg / tablet, half tablet each time, once a night + Xuezhikang Capsule 0.3g/tablet, 2 capsules a time, twice a day, and completed the follow-up for 6 months (Fig. 1).

Cervical vascular ultrasound examination
Before treatment (d0) and 6 months after treatment (6m), Philips IU22 color doppler ultrasound with 8-12 MHZ linear array probe frequency was used to measure the vertical distance from the inferior intima of the longitudinal long axis section of the far lateral wall to the outer surface of the middle membrane at the initial expansion of bilateral common carotid artery which 10mm from the proximal end.Each side was measured for 3 times, and the bilateral average value was taken as the intima-media thickness (IMT) of the carotid artery(IMT).Atherosclerotic plaque is formed when IMT≥1.2mm or the localized intima thickness exceeds 50% of the peripheral intima; 1.0mm≤IMT < 1.2mm indicates intima thickening; IMT < 1.0mm is considered normal. The sum of the maximum thickness of bilateral carotid plaques was crouse score to evaluate the degree of atherosclerosis. Unstable plaques and the number of stable plaques were recorded according to the echo characteristics of cervical vascular plaques. Unstable plaques included hypoechoic and mixed echogenic plaques, and stable plaques included isoechoic and strong echogenic plaques.
Plasma LDL-C target According to the 2016 Chinese Guidelines for the Prevention and Treatment of Dyslipidemia in adults, patients with ASCVD belong to the extremely high-risk population,and LDL-C < 1.8mmol/L (70mg/dl) is considered to reach the target; if the baseline LDL-C is high and cannot reach the target value, the ldL-C reduction of≥50% from the baseline is also considered to reach the target value.

Statistical methods
All the data were analyzed by SPSS 22.0 software to verify the normality of the data. The measurement data in line with the normal distribution were expressed as mean±standard deviation(x± s). For three or more groups of data, analysis of variance was used for homogeneity of variance; LSD-t test was used for comparison between groups with signi cant difference; paired t test was used for intra group comparison before and after comparison; chi square test was performed for counting data expressed by rate or constituent ratio; repeated measurement data were analyzed by ANOVA of repeated measurement data of general linear model, and univariate analysis was used when spherical test was not obeyed The correction part of the results was the criterion. The conservative Tukey test was used to reduce the type I error. P < 0.05 was considered as the difference.

General information of patients
The study included 186 ASCVD cases, according to random number table method were randomly divided into Xuezhikang group group A n=61 ,rosuvastatin group group B n=62 , and combined group(group C,n=63). During the follow-up period, 6 patients withdrew from observation,2 cases (1.08%) had drug intolerance to stop their own medication, 1 case (0.54%) had increased their creatine after taking the Chinese medicine leech powder, and 3 cases(1.61%) had been lost due to the COVID-19. Finally, 180 patients completed the follow-up, 60 cases in each group. There were no signi cant differences in gender ratio, BMI, age, hypertension, coronary heart disease, cerebrovascular disease and diabetes history among the three groups (P < 0.05). The follow-up results of each group were comparable (Table 1).

Blood lipids
Blood lipids were detected before and 1 week, 2 weeks, 1 month, 3 months and 6 months after treatment,the changes of blood lipid at each observation point of the three groups were visible,Except HDL-C, TC, TG, LDL-C showed a downward trend. Analysis of variance of repeated measurement data showed that TG, TC, LDL-C and HDL-C were not subject to mauchy's spherical test (P < 0.05), and the corrected part of Greenhouse-Geisser was the standard, TG (F = 1.888, P = 0.120), HDL-C (F=1.490 p=0.195 ,P 0.05,there was no signi cant difference in the levels of TG and HDL-C in the three groups at the same observation point, and the effects of each group on TG and HDL-C were similar; TC (F = 41.114, P < 0.001), LDL-C (F = 14.809, P < 0.001), P < 0.05, the levels of TC and LDL-C in the three groups were not equal at the same observation point, and the difference was statistically signi cant. The comparison between TC groups showed that group A: group B, P < 0.001; group A: group C, P < 0.001; group B: group C, P = 0.175. It can be seen that rosuvastatin group and combined group have the similar effect on reducing TC and are better than Xuezhikang group. LDL-C comparison between groups showed that group A: group B, P = 0.001; group A: group C, P < 0.001; group B: group C, P = 0.014. Obviously, the effect of combination group, rosuvastatin group and Xuezhikang group on reducing LDL-C in turn decreased( Table 2).
Carotid intima-media thickness and plaque total score The carotid intima-media thickness of group A, group B and group C decreased from 1.17 ± 0.17mm, 1.18 ± 0.19mm, 1.17 ± 0.16mm to 1.13 ± 0.16mm, 1.09 ± 0.18mm and 1.06 ± 0.14mm before and after treatment, and the total plaque score decreased from 3.63 ± 2.22, 3.90 ± 3.17, 4.07 ± 3.25 to 3.28 ± 2.05, 3.16 ± 2.74 and 3.29 ± 2.73, respectively, P < 0.05 , the IMT and crouse scores of the latter groups were improved. The comparison of carotid intima-media thickness of each group showed that group B: group A, P = 0.003 (P < 0.05); group C: group A, P < 0.001; group C: group B, P = 0.111 (P > 0.05). The combined group and rosuvastatin group had similar improvement effect on IMT and were superior to the Xuezhikang group. The comparison between groups on the total plaque score (crouse score) showed that group B: group A, P = 0.047 (P < 0.05); group C: group A, P=0.027 (P < 0.05); group C: group A, P = 0.810 (P > 0.05). The effect of combined group and rosuvastatin group in improving IMT was similar and better than Xuezhikang group (Table 3) . after treatment respectively. P value of each group before and after treatment were all < 0.05, the difference was statistically signi cant, that is,plaque stability could be improved in each group.Among groups, before treatment Χ 2 = 2.143, P=0.342; after treatment Χ 2 =4.163, P=0.125, P> 0.05, the difference was not statistically signi cant, it can be considered that the ability of plaque stability in each group is equal (Table 3).

Blood lipid success rate and time
The LDL-C level of group A began to reach the standard at 2W after administration, while that of group B and group C the success rate of each group was compared,among the groups, Χ 2 = 52.012, P < 0.001,the rate is not all the same. Further comparison shown that group A: group B, group A: Group C, P < 0.001, group B: group C, P=0.002 (P < 0.017),indicting that the LDL-C success rate of group C, group B and group A decreased in turn after 6 months' medication (Table 3). In group A, group B and group C, the time to reach the standard of blood lipid was (96.21 ± 58.75) days, (92.61 ± 65.61) days, (62.07 ± 53.25) days,F= 4.363, P=0.015 (P < 0.05). Further comparison shown that group A: group B, P = 0.824 (P > 0.05); group A: Group C, P = 0.030 (P < 0.001), group B: Group C, P = 0.011 (P < 0.05). The time for reaching the standard of LDL-C in the treatment groups was earlier than that in the rosuvastatin group and Xuezhikang group. It was not considered that there was difference in the target time between rosuvastatin group and Xuezhikang group in the LDL-C reaching patients in this observation (Table 3).
There was no statistically signi cant difference, and the treatment scheme is safe and reliable, no difference among groups (Table 4).

Summary
In this study,low-dose rosuvastatin combined with Xuezhikang can signi cantly reduce the level of blood lipid (except HDL) in patients with ASCVD, shorten the time to reach the standard of LDL-C, increase the success rate, improve arteriosclerosis, stabilize plaque and have safety at the same time.

Strengths and limitations
The main risk factor for atherosclerotic cardiovascular disease is the sustained damage of hypercholesterolemia to the vascular endothelium, and the control of Low-density lipoprotein level is a therapeutic target for ASCVD risk reduction. At present, lipid-regulating methods mainly include diet and exercise control and drug therapy. As a typical representative of lipid-lowering drugs, statins have become the cornerstone of prevention and treatment of cardiovascular diseases. Studies have shown that there is a causal relationship between myalgia, temporary elevation of alanine aminotransferase and new onset diabetes mellitus and the use of statins. The side effects limit the use of statins, especially the use of high-dose statins in special populations. [15][16][17] Even with good statin treatment compliance, 30-70% of patients still fail to meet the standard LDL-C level according to different risk levels. 18 Short term supplementation of monaclin-K can improve blood lipid and lipid metabolism in patients with low cardiovascular risk and hypercholesterolemia. 19 Therefore, western countries take monascus fermentation extract (such as red yest rice) and other nutritional preparations as a bene cial supplement of lipid-lowering therapy for people with statin intolerance or high-dose statins, but do not think that nutritional agents can be used as lipid-lowering drugs alone. 15,20 Xuezhikang is a biological preparation re ned from red koji, which is rich in monacolins, especially cholesterol synthase inhibitor (HMC-CoA). Different from western countries, Chinese guidelines for the prevention and treatment of dyslipidemia in adults (2016 revision) include Xuezhikang (1.2 g/d) as a moderate-intensity lipid-regulating drug.
A real-world study is the main advantage of this study, which reduces the in uence of some miscellaneous factors in retrospective analysis. Another advantage is re ected in the chose of combined drugs, Xuezhikang is a compound component, ergosterol, unsaturated fatty acids and other components assist in lipid regulation and they also has an impact on improving cardiovascular outcomes,further more, in combination therapy ,the dose of rosuvastatin was small with few side effects,which provides a new idea for combined lipid-lowering.The limitations of this study include the following:(1)The small sample size of this study has a certain in uence on the extrapolation of the results.(2)The followup time of this study is short, and it has some limitations to observe the changes of carotid artery plaque.(3)In the use of drugs, compliance with combination drugs needs to be considered.

Comparison with existing literature
In this study, ASCVD patients after the treatment of Xuezhikang, rosuvastatin, small dose rosuvastatin combined with Xuezhikang for 6 months, TC, TG, LDL-C in each group decreased signi cantly. The effect of combined group on TC reduction was similar to rosuvastatin group and better than that of Xuezhikang group. There was no signi cant difference in the effect of TG between the combined group, rosuvastatin group and Xuezhikang group, while the effect of LDL-C was decreased in turn. Different from most previous studies, HDL of ASCVD patients in this study did not increase signi cantly, and there was no signi cant difference among the groups.This is similar to Wang TJ, Lien AS, Chen JL, et al. in the randomized clinical study on the treatment of hyperlipidemia patients with red yeast rice (RyR), the HDL did not rise, which may be related to the increase of plasma levels of mir-33a and mir-33b, and the inhibition of cell cholesterol output. 21,22 In terms of time e ciency, reaching the target time of the combined group was earlier than the other two groups, and there was no signi cant difference between rosuvastatin group and Xuezhikang group in reaching the standard of LDL-C. The difference in standard reaching time of LDL-C in each group is out of sync with the difference in plasma LDL-C level, which may be related to the fact that the calculation of the standard reaching time is based on the time node, lack of data continuity, and there may have a bias.In terms of plaque bene t, the effect of combination group and rosuvastatin group in improving IMT and crouse score were similar and better than Xuezhikang group. Each group could improve the stability of carotid artery plaque, but there was no statistical difference among the three groups.It can be seen that the time of LDL-C reaching the standard was not synchronized with the improvement of IMT, Crouse score and plaque stability,which could not deny the existence of bias and needed to be further veri ed.Studies have shown that the red yeast rice extract can lower cholesterol levels and increase cardiovascular bene ts, but the bene t is not dependent on the initial cholesterol level, and high-dose rosuvastatin can increase the level of ATP binding cassette A1 protein (ATP binding cassette A1 transporter) in macrophages in atherosclerotic plaque, and inhibit the out ow of ATP binding cassette A1 mediated cholesterol from apolipoprotein carrying macrophages. 23 IBIS−4 study,Reversal study,ASTEROID study and SATURN study have showed that the plaque can be reversed when LDL-C decreased to 1.8-2.1 mmol/L (70-80 mg/dl) and HDL increased signi cantly at the same time during intensive statin treatment.The observation time of these studies ranges from 13 months to 24 months. [24][25][26][27] The time of ARTMAP study and COSMOS study were relatively short (6-19 months) and the plaque reversion was also achieved under the conventional dose of statins. 28,29 In addition to LDL-C control and HDL maintenance, plaque improvement may also be related to race.During the treatment, there were adverse reactions in all three groups, mainly liver function damage, followed by CK/CKMB increase, dizziness, headache, fatigue. There was no signi cant difference in adverse reactions among the three groups. Many studies have shown that Xuezhikang alone or Xuezhikang combined with low-dose rosuvastatin has good tolerance and safety. 30,31 Combined with this study, it can be further seen that Xuezhikang combined with low dose rosuvastatin does not signi cantly increase the adverse reactions in patients, which is relatively safe.

Conclusion
In clinical practice, patients who have been treated with statins but still have poor lipid control or other conditions that require combination therapy, Xuezhikang combined with low-dose rosuvastatin is a good option, but the compliance and economic cost of combination therapy need to be further considered.     Figure 1 Flowchart of the participants through the trial   Cumulative LDL-C standard-reaching rate of each observation point in each treatment group