This study constituted a systematic review and meta-analysis to determine the efficacy and safety of RYR extract for cardiovascular outcomes and lipid lowering effects in MI participants. Our meta-analysis indicated that administration of RYR extract at a dose of 1,200 mg/day could significantly improve clinical efficacy with few adverse effects, compared to placebo. The results of subgroup analyses strongly indicated clinical efficacy, an outcome which did not vary following both primary and secondary analyses.

Our findings demonstrated that RYR extract has the potential to reduce the incidence of nonfatal MI, revascularization, and sudden death, while improving lipid profiles. This finding is in agreement with the report from Shang, et al. that demonstrated RYR to be effective for reducing cardiovascular events in CHD patients with dyslipidemia11.

The mechanism whereby the incidence of nonfatal MI, revascularization, and sudden death were decreased by RYR extract remains unclear. Studies conducted in animals demonstrated that RYR increased endothelial nitric oxide synthase (eNOS) expression in vascular endothelial cells and erythrocytes, and the expression of caveolin-1 level decreasing in aorta wall. These changes are predicted to induce nitric oxide production, which was confirmed by an increase in nitrate and nitrite (NOx) levels in plasma and cGMP in the aorta wall. Histopathological study of aorta wall in rats with high cholesterol diet revealed that the development of typical plagues with macrophage infiltration was observed, while the abnormality in rats with high cholesterol diet treated with RYR were not found. In addition, the morphology of aorta wall in RYR group was also comparable to the normal control group25.

Moreover, RYR ameliorated oxidative stress and abnormal hemorheology, improved the pathology of atherosclerosis, and increased eNOS expression in aortic endothelium, in association with a decrease in plasma lipid levels25,26. A 2017 study showed that RYR extract significantly decreased oxidative stress27. An oxidative stress increasing expedites the progression of atherosclerosis and increases the risk of cardiovascular events by raising inflammatory reactions, endothelial dysfunction, thrombogenic tendency, plaque instability, and the migration, proliferation, and transformation of smooth muscle cells28. Shen et al. showed that RYR reduced the macrophage content in atherosclerotic lesions, consistent with plaque regression29. One possible mechanism proposed for the action of RYR is that RYR inhibits progression of vulnerable plaque and rupture by mitigating macrophage endoplasmic reticulum (ER) stress, consequently inhibiting apoptosis and the NF-κB pro-inflammatory pathway.

Our meta-analysis demonstrated that RYR extract significantly decreased LDL, TC, and TG. This is not surprising given that an established mechanism of RYR action is the inhibition of HMG CoA reductase30. Additionally, a recent study conducted in animal model found that RYR also increased the hepatic bile acids excreted, thereby increasing the need for availability of intrahepatic cholesterol used for the synthesis of additional bile31. Silverman found that a 1 mmol/L reduction in LDL level was associated with a 23% reduction in the risk of cardiovascular events3. Moreover, LDL reduction was correlated with a significant decline in the rates of myocardial infarction (MI), stroke, or coronary revascularization32.

The CTT analyses demonstrated the relationship between LDL reduction and cardiovascular mortality. The LDL reduction 1 mmol/L decreased 20% coronary deaths and 8% in other cardiac death33. However, the CTT meta-analysis found statin therapy reduced ASCVD risk but there were no associated between LDL reduction and reduction risk34.

In a previous meta-analysis, Li et al. found that RYR extract significantly decreased LDL, TC, and TG but had no effect on HDL levels35. Moreover, a previous report suggested that RYR reduced LDL levels significantly when compared with placebo; the effect of RYR did not differ significantly from that achieved with other lipid lowering agents36.

We confirmed the results of our meta-analysis by conducting a sensitivity analysis. By utilizing the one-removal approach method and changing the model to analysis of all outcomes, we found that the results remained unchanged. Therefore, our sensitivity analysis for all outcomes confirmed the robustness of our results pertaining to all outcomes.

In this meta-analysis, we synthesized all available RCT studies performing RYR treated on cardiovascular outcomes and lipid profile. The results suggest that RYR supplementation in an effective adjunct to diet therapy in borderline hypercholesterolemia patients. The current lipid management guideline37 recommended all patients with cardiovascular risk should be promoted a healthy life style change including exercise and diet therapy. Their reinforcement of life style change in these participants are sufficient38. Therefore, RYR supplementation could be a potentially alternative diet therapy.

According to the treatment duration, six weeks of RYR intervention (n = 3) has showed a significant reduction of LDL-C. As the case of statins, a reduction of LDL-C has been firstly observed within 2–4 weeks. Then, a stable LDL-C level could be found after 6 weeks of treatment39,40. In subgroup analysis, the result revealed that treatment at 6-week showed a better improvement than the trials with more than 4 years. Similar findings were also observed in case of HDL-C, TC, and TG. It could be explained that long term use of statin may result to drug resistance. The resistance has been related to several factors such as polymorphism of HMG-CoA reductase, P-glycoprotein, Apolipoprotein E, PCSK9, low density lipoprotein receptor (LDLR), and tumor necrosis factor α (TNF-α) genes. The resistance is probably from nonadherence to the treatment which exhibits insufficient LDL-C response to the treatment41.

The strength of our study is that it comprehensively summarizes the effects of RYR extract, the study being undertaken in a manner that is in accordance with a high standard of systematic review and meta-analysis, and reported in alignment with PRISMA13. The meta-analysis of RCT sits at the top of the hierarchy of clinical evidence. Indeed, this is the first systematic review and meta-analysis of RCT investigating efficacy and safety of RYR extract on cardiovascular outcomes and lipid profile. All of the studies included in our analysis administered RYR extract products using protocols that utilized similar laboratory analyses as well as a comparable time to follow-up (4 weeks − 4.5 years). Since there were no restrictions regarding the date or language used in the studies included in this meta-analysis, we are confident that the efficacy and safety of RYR products is quite consistent across studies. This strongly suggests that our results can be generalized to a large number of clinical practices.