Blood lipids are the general term for cholesterol, triglycerides, and lipids in serum. Hyperlipidemia refers to plasma lipoprotein disorders. It is a metabolic disease, and its direct damage to the body is not obvious, and it generally does not have specific clinical discomfort symptoms. Cholesterol is the total amount of cholesterol contained in various lipoproteins in the blood. It exists in the human body mainly in the form of free cholesterol and cholesteryl esters, and its level is related to the patient's age, gender, dietary habits and genetic factors, but its metabolic changes are relatively slow and is less valuable than LDL for risk assessment and prediction of atherosclerotic cardiovascular disease. Triglycerides are formed when the three hydroxyl groups in the glycerol molecule are esterified by fatty acids and, similar to cholesterol, their levels are influenced by both genetics and the environment. However, unlike cholesterol, the metabolism of triglycerides is more influenced by diet and time, and triglyceride measurements may vary considerably within a short period of time in the same individual with dietary changes. There was a study suggested that elevated triglycerides are likely to have atherogenic effects by affecting the structure of lipoproteins, and that mild to moderate elevations in serum triglyceride levels may increase the risk of coronary heart disease in patients. LDL is the lipid core that makes up the atherosclerotic plaque and is also the initial and maintaining element of the chronic inflammatory response that is the pathological manifestation of atherosclerosis, so an increase in LDL is a major risk factor for the occurrence and development of atherosclerosis. HDL is responsible for reverse cholesterol transport - transporting cholesterol from peripheral tissues to the liver for circulation or excretion in the form of bile acids, reducing cholesterol deposition in the vascular wall and acting as an anti-atherosclerotic agent.
Dyslipidemia, characterized by elevated LDL and cholesterol, is a noteworthy risk factor for atherosclerotic cardiovascular diseases(ASCVD). Other types of dyslipidemia, such as increased TG and decreased HDLC, are also associated with the development of ASCVD. The ultimate treatment goal for dyslipidemia is to effectively reduce the risk of developing ASCVD. In the 2016-edition of the Chinese Guidelines for the Prevention and Treatment of Dyslipidemia, it is recommended that patients with dyslipidemia need to be assessed for residual risk of ASCVD. LDL and cholesterol levels can be independent predictors of the risk of ASCVD in individuals or groups of patients. Cholesterol accounts for 50% of LDL, and although the two levels are generally parallel, cholesterol is susceptible to HDL, and LDL plays a central role in the development of ASCVD. So lowering LDL levels is the main target of intervention in the treatment of dyslipidemia in clinical practice.
Although there is no clear evidence to support that lower lipid levels are associated with a lower risk of ASCVD, nor is there evidence of a specific lipid threshold for ASCVD risk reduction, current medication guidelines in most countries, mainly in China, support the setting of lipid-lowering targets rather than minimizing lipid levels. Apart from considerations of improving patient compliance and facilitating physician assessment of lipid-lowering efficacy, the main reasons are that lipid modulation is a long-term treatment and intensive use has a borderline effect - a significant increase in adverse drug reactions, a doubling of the patient's financial burden, a small but modest increase in lipid-lowering benefit, and no reduction in all-cause mortality.
Statins are clinically preferred and are Class I Recommendations and Class A Evidence in a variety of cardiovascular guidelines, including lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, resuprastatin and pitavastatin. As inhibitors of HMG-COA reductase, statins inhibit cholesterol synthesis of the rate-limiting enzyme HMG-CoA reductase, reduce cholesterol synthesis and subsequently cells are upregulated to indicate LDL receptors, and accelerate serum LDL catabolism, while inhibiting very low-density lipoprotein synthesis, thereby regulating blood lipids to reduce coronary heart disease mortality. A number of studies[46–49] have demonstrated that while regular doses of statins have a significant benefit in primary prevention in patients at high cardiovascular risk, further studies are needed to investigate the benefit in patients at low and intermediate risk. Similarly, there is no evidence to support that the benefits of intensive treatment with statins outweigh the risks, including (1) the benefits of short-term intensive intervention in the perioperative period in cardiovascular patients; (2) the benefits of long-term intensive intervention in patients with dyslipidemia-the proportional reduction in TC and LDLC, and the incidence of cardiovascular events and all-cause mortality; (3) the cost of medication to patients doubling may lead to reduced compliance; and (4) a significant increase in adverse reactions, predominantly abnormal liver function, but also including myalgia, headache, insomnia and various gastrointestinal symptoms. How are statin adverse reactions alleviated? Guidelines suggest switching to another statin, reducing dosage, decreasing the frequency of dosing or discontinuing the statin, but the latter three management options not only reduce the benefits of lipid modulation but may increase the risk of cardiovascular events.
Xuezhikang, the only natural lipid regulator recognized by several authoritative guidelines in the cardiovascular field [including: ACC, AHA 2013 Guidelines for the Treatment of Blood Cholesterol to Reduce the Risk of Atherosclerosis in Adults, ESC, EAS 2011, 2016 Guidelines for the Management of Dyslipidemia, China 2007 Guidelines for the Diagnosis and Prevention of Chronic Stable Angina, 2016 Guidelines for the Prevention and Treatment of Dyslipidemia in Adults, 2018 Guidelines for the Rational Use of Drugs in Coronary Heart Disease. Guidelines, 2018 Guidelines for the Diagnosis and Treatment of Stable Coronary Heart Disease, 2018 Guidelines for the Diagnosis and Treatment of Acute Myocardial Infarction with Chinese and Western Medicine] is recognized as a natural lipid-regulating drug. Its main ingredient is monascus - which has been used for centuries in China as a food colouring and flavour enhancer. It is refined through a modern GMP-standard process by adding special monascus to rice fermentation. It has a mechanism similar to that of statins, with 13 natural statin complexes as the main ingredients. It is unique in reducing the risk of adverse reactions associated with the use of a single statin. A number of RCTs[53–60] have demonstrated that Xuezhikang can lower cholesterol and LDL levels, reduce the incidence of adverse events, reduce the risk of cardiovascular events and recurrence, and significantly reduce coronary heart disease mortality and all-cause mortality. It is also inexpensive compared to synthetic statins. Based on the original lipid-lowering treatment with synthetic statins, the addition of Xuezhikang can be equivalent to intensify the effective of statin treatment and mitigate the risk of adverse reactions.
To investigate the benefits and risks of intensifying statin therapy with Xuezhikang, this study included 2042 patients in 14 RCTs, with 1022 patients in the trial group (statin plus Xuezhikang) and 1020 patients in the control group (statin alone), and conducted a meta-analysis of the combined effect sizes of efficiency, TC, TG, LDLC, HDLC and adverse events. The results showed that compared with statins used alone, the addition of Xuezhikang intensive treatment could (i) significantly increase the effective rate, (ii) more effectively reduce TC, TG and LDLC levels and increase HDLC levels, (iii) significantly reduce the incidence of adverse events, and (iv) the lipid-regulating effect of simvastatin combined with Xuezhikang on LDLC was not significant.
The 14 RCTs included in this study were low to moderate quality studies with obvious limitations, including: 1. All studies did not specify sample size estimates, which may affect test validity; 2. Although all included studies indicated that cases were randomly assigned to two groups, only eight studies clearly indicated the randomization method they used, while the remaining studies did not mention the specific randomization method and allocation concealment method, which is subject to unknowable selectivity bias. The remaining studies did not mention the specific randomization method and allocation concealment method, resulting in unknowable selectivity bias; 3. All cases did not mention whether they were blinded, either blinding of investigators and subjects or blinded evaluation of study outcomes, resulting in unknowable implementation bias and measurement bias; 4. Funnel plots of efficiency rates were found to be consistent with an inverted funnel shape with a narrow top and a wide bottom, but the lower part of the graph was lax and there are all hollow dots in the graphs, suggesting that there are insufficient large sample studies, low sample quality and publication bias; 5. Only 8 studies fully reported adverse events during the study period and follow-up, resulting in follow-up bias, Moreover, none of the three major systemic adverse reactions of statins - liver, muscle and digestive system - have been tracked and reported, which is not highly targeted; 6. In the study design, the effective rate of all studies took the proportion of cholesterol reduction as the threshold. TC and LDLC were equally important in lipid-regulating therapy, but only 11 RCTS reported LDLC levels; TG was reported in each RCTS. Since TG is easily affected by diet, only 10 RCTS mentioned whether to add therapeutic dietary intervention, which would cause unknown bias in this study.
In summary, for the RCT study with statins combined with Xuezhikang as the intervention in the trial group, this analysis recommends: 1. The RCT should be designed more precisely before starting the study, for example, sample size estimation, clear randomization method, clear allocation method, application of blinding, and the number of adverse reactions and case shedding in the trial should be recorded based on facts; 2. Large sample clinical trials can be conducted to provide more comprehensive and objective clinical treatment; 3. The design of outcome indicators of the study should (1) if lipid-regulating efficacy is the study objective, the magnitude of lipid regulation of TC and LDLC should be the primary outcome indicator, and TG, HLDL and other lipoproteins should be secondary outcome indicators; (2) if safety is the study objective, the reporting of adverse effects should include liver, muscle and digestive system; (3) if TG is reported, whether to include dietary control should be considered.
In Conclusion, the information extracted from the 14 RCTs included in this study was systematically evaluated and the results showed that Xuezhikang combined with statins had better and more stable modulation of cholesterol, triglyceride and LDL levels than statins used alone in terms of regulation of lipids in patients with hyperlipidemia, and there is a lower incidence rate of adverse events. The RCTs included in this study were of low to moderate quality and more high quality RCTs with large samples are needed to provide more reliable evidence.