Natural Polypill Xuezhikang : Its Clinical Benefit and Potential Multicomponent Synergistic Mechanisms of Action in Cardiovascular Disease and Other Chronic Conditions

Abstract

Polypill has been a hot issue since it was first advanced in 2003. This new concept immediately spurred a worldwide discussion. Xuezhikang is a partially purified extract of fermented red yeast rice (Monascus purpureus). It is composed of 13 kinds of natural statins, unsaturated fatty acids, ergosterol, amino acids, flavonoids, alkaloid, trace element, and other substances, and thus could be regarded as a natural lipid-lowering polypill. Interestingly, Xuezhikang in the China Coronary Secondary Prevention Study trial lowered lipid levels less as compared with provastatin in the Cholesterol and Recurrent Events trial, but seemed to gain more benefit in reducing the cardiovascular events and the risk of death from cancer. In recent years, Xuezhikang has been further demonstrated to have additional health benefits and thus raised great interest. This article reviews the clinical benefits of Xuezhikang and the potential multicomponent synergetic mechanism. The authors hold that polypill is anticipated to be a more effective and feasible way to treat complicated diseases.

Introduction

I n the beginning of the 21st century, the population is facing the serious challenge of cardiovascular diseases (CVD). Although it is becoming less lethal, the prevalence of CVD continues to increase and it is still the number one killer.¹ In fact, ground may be being lost on the advancements in developed countries because of increasing risk factors in the population. The major risk factors such as blood pressure, cholesterol, blood glucose, body–mass index, smoking, and others are significantly correlated with the morbidity of CVD. Multiple interventions resulted in dramatic reductions in CVD, which was more effective than interventions targeting a single risk factor.² Furthermore, the combination of several drugs in low dose could not only improve efficacy and reduce adverse reactions of drugs, but also increase the compliance of patients and reduce the cost of treatment.³ Then, is it a possible treatment regimen to put multiple drugs into one pill? Furthermore, is it a feasible way in real-world clinical practice?

The Conception of Polypill

In 2003, Wald and Law quantified the efficacy and adverse effects of the proposed formulation: One statin drug (atorvastatin 10 mg/d or simvastatin 40 mg/d); three antihypertensive drugs (thiazide, β-blocker, angiotensin-converting enzyme inhibitor, each at half standard dose); folic acid (0.8 mg/d); aspirin (75 mg/d) from published meta-analysis and cohort studies (including over 750 trials with 400,000 participants), and first introduced a polypill concept in the British Medical Journal. If taken by people above age 55 years, this polypill regimen could reduce CVD by 80% with acceptable safety.⁴ The accompanying editorial called it “one of the boldest claims for a new intervention.”⁵ This new concept immediately stirred up a worldwide discussion and raised a variety of debates and concerns.^6,7 Although the composition and reasonableness of this polypill and its clinical benefits still need further verification, the focus on intervention of multiple risk factors in modern medicine has no doubt been the trend of combination therapies for complicated diseases. Recent trials supported the recommendation that such multidrug regimens would be quite cost-effective in reducing the burden of CVD.^8,9

Xuezhikang, a Natural Polypill with Multicomponents

Xuezhikang is a partially purified extract of fermented red yeast rice (Monascus purpureus). The health-enhancing qualities of this yeast have been known and used in China for over 2000 years. Xuezhikang is composed of 13 kinds of natural statins, unsaturated fatty acids, ergosterol, amino acids, flavonoids, alkaloid, trace element, and others¹⁰ (Fig. 1), and thus could be regarded as a natural polypill. Evidence showed that fermented red yeast rice lowered cholesterol levels moderately compared to other statin drugs, but with the added advantage of causing fewer adverse effects.^11,12 To demonstrate the long-term therapeutic effect and safety of Xuezhikang in prevention of a second coronary heart disease (CHD) event, a multicenter, randomized, placebo-controlled study (CCSPS, China Coronary Secondary Prevention Study) was conducted in China. The results showed that Xuezhikang significantly decreased the recurrence of coronary events and the occurrence of new cardiovascular events and deaths, improved lipoprotein regulation, and was safe and well tolerated.¹³ The study was the first large-scale clinical trial in an Eastern population who suffered from a mild or moderate degree of hyperlipidemia and previous myocardial infarction. CCSPS was thus included in the Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults. ¹⁴ The CCSPS study is quite comparable with CARE (the Cholesterol and Recurrent Events) study¹⁵ in terms of the target population, sample size, baseline lipid level, and follow-up time. However, Xuezhikang in CCSPS lowered lipid levels less as compared with provastatin in CARE, but seemed to gain more benefit in reducing the cardiovascular events. Since the effect of Xuezhikang is partially attributed to the presence of statins, it has been hypothesized that relatively high concentrations of unsaturated fatty acids and other natural compounds found in Xuezhikang may work in concert with the statins to provide additional health benefits.¹⁶

FIG. 1.

Active ingredients in Xuezhikang.

Xuezhikang is composed of 13 kinds of natural statins, unsaturated fatty acids, ergosterol, amino acids, flavonoids, alkaloid, trace elements, and so on.

Clinical Benefits of Xuezhikang and Its Potential Synergetic Mechanism Modulation of Overall Lipid Profiles

A meta-analysis of randomized controlled trials on Chinese red yeast rice for primary hyperlipidemia showed a significant reduction in serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), and an increase in high- density lipoprotein-cholesterol (HDL-C) levels compared with placebo. The lipid modification effects appeared to be similar to those of pravastatin, simvastatin, atorvastatin, lovastatin, or fluvastatin.¹²

Incontrovertibly, the main lipid-lowering mechanism of Xuezhikang is the component of statins, especially lovastatin as a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, which can reduce endogenous cholesterol synthesis, and increase the activity of LDL receptor on the surface of liver cells to promote the clearance of LDL through feedback mechanisms.

As another major component in Xuezhikang, polyunsaturated fatty acids (PUFAs) can decrease TG,¹⁷ reduce the rate of lipid shuttle driven by cholesteryl ester transfer protein, increase HDL, reduce small LDL production, and get the cholesterol out of the vessel wall. As for α-linolenic acid and γ-linolenic acid, their effects on serum levels of TC, TG, and HDL-C were significant.¹⁸ The OPTILIP study found that an increased intake of n-3 long-chain PUFAs caused a reduction in plasma triacylglycerol and favorable changes in LDL size.¹⁹ Furthermore, a diet enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce blood levels of neutral lipids, TC, LDL, very-low- density lipoprotein, and increase HDL.¹⁸ The intake of omega-3-acid ethyl esters can significantly decrease serum TG, along with plasma concentrations of certain lipoproteins up to 45%.²⁰ The COMBOS study confirmed significant improvements across a range of lipid indicators by taking PUFAs in combination with statins.²¹ In addition, ergosterol in Xuezhikang can compete with the cholesterol absorption site to interfere with the absorption of cholesterol, reducing exogenous cholesterol. Moreover, most flavonoids can reduce levels of TG, TC, and LDL.²² All of the abovementioned components might be involved in the mechanism of Xuezhikang to modulate overall lipid profiles.

Antiatherosclerosis Effects

Xuezhikang can not only reduce the proportion of atherosclerotic substance in the plaque, but also effectively improve endothelial function through its potent anti-inflammatory and lipid-lowering effects.^23,24 to set more mature collagen and more stable fibrous cap. Anti-inflammatory action of Xuezhikang plays an important role in early-stage treatment of atherosclerosis. Xuezhikang can inhibit the serum levels of inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6),²⁵ serum oxidized LDL, C-reactive protein (CRP)²⁶ and fibrinogen,²⁷ high-sensitivity C-reactive protein (Hs-CRP), matrix metalloproteinase-9 (MMP-9),²⁸ and regulate the balance between thromboxane and prostacyclin²⁹ in patients.

Lovastatin in Xuezhikang is an inhibitor of endothelial HMG-CoA reductase. It was reported that it could upregulate endothelial constitutive nitric oxide synthase (ecNOS) expression predominantly by post-transcriptional mechanisms, suggesting that the HMG-CoA reductase inhibitor may have beneficial effects in atherosclerosis beyond that attributed to the lowering of serum cholesterol by increasing ecNOS activity.³⁰ Furthermore, upregulation and activation of ecNOS in endothelial cells will increase the secretion of plasma NO, which may play an important role in vasodilation, antivascular smooth-muscle cell proliferation, and inhibition of platelet aggregation.

The metabolites of N-3 PUFA, another main component of Xuezhikang, can directly or indirectly play a role in the immune system, and contribute to slowing the progression³¹ of atherosclerosis by modulating inflammation, platelet activation, endothelial functions, and so on.³² The dietary intake of long-chain n-3 PUFAs was inversely associated with concentrations of IL-6, matrix metalloproteinase-3 (MMP-3),³³ and reduced the release of interleukin-1β (IL-1β), granulocyte colony-stimulating factor,³⁴ reflecting lower levels of inflammation and endothelial activation for a lower prevalence of subclinical atherosclerosis.³⁵ The study by Hilpert et al. suggested that unsaturated fatty acids differentially affected concentrations of apolipoprotein B–containing lipoprotein subclasses to attenuate the impairment of endothelial function,³⁶ whereas increased intakes of α-linolenic acid exerted anti-inflammatory effects by inhibiting IL-6, IL-1β, and TNF-α production in cultured peripheral blood mononuclear cells.³⁷ Higher consumption of total linolenic acid was associated with lower prevalence odds of carotid plaques and with lesser thickness of segment-specific carotid intima-media thickness,³⁸ and the intake of EPA and DHA for 26 weeks could alter the gene expression profiles of peripheral blood mononuclear cells to a more anti-inflammatory and anti-atherogenic status.³⁹

As for flavonoids, they protect blood vessels through inhibiting platelet aggregation, and by anti-inflammatory and antioxidant effects.⁴⁰ Some scholars found that dietary flavonoids, such as quercetin and (-)-epicatechin, can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function.⁴¹ Many other studies showed that a flavonoids-enriched diet could reduce the levels of soluble vascular cell adhesion molecule-1 and increase the anti-inflammatory response in blood mononuclear cells,⁴² which suggested an improvement in endothelial function that may reflect an overall improvement in the inflammatory process underlying atherosclerosis.⁴³

Furthermore, many animal experiments show that magnesium has an anti-atherosclerosis effect, the mechanisms of which may be reducing lipemia, protecting blood vessels, decreasing free radicals and lipid-peroxide, and affecting the level of hormone.⁴⁴ Selenium supplementation increases the activity of antioxidative glutathione peroxidase 1 in endothelial cells of patients,⁴⁵ which may also prevent the progress of arteriosclerosis. In addition, antioxidative effects of sterins in Xuezhikang may also have some value in atherosclerosis prevention.⁴⁶

Liver Protection Effects

It was reported that combining other therapies with Xuezhikang in the treatment of fatty liver could have the effects of relieving clinical syndromes and improving liver function.⁴⁷ Another study also showed that Xuezhikang may have potential clinical application in the treatment of nonalcoholic fatty liver disease for its function of reversing aminotransferase abnormalities, and the common therapeutic mechanism of Xuezhikang is likely to be involved in the inhibition of hepatic expression of TNF-α.⁴⁸ Thus, Xuezhikang has been recommended in attempting to treat those patients with hyperlipidemia intolerant to other statins or with elevated liver/muscle enzymes induced by other statins. ⁴⁹

In the Xuezhikang, flavonoids have different levels of protection effects on liver damage caused by a variety of reasons, and the protective mechanisms were related to enzyme antioxidant function,⁵⁰ inhibiting the release of TNF-α,⁵¹ and the role of cell apoptosis. Furthermore, selenium may have some preventive effects in alcoholic cirrhosis.⁵² A large number of research reports in China and abroad indicate that selenium is closely related to the emergence, development, and prognosis of liver disease.

Anticancer Effects

The CCSPS study found that Xuezhikang could reduce the risk of death from cancer.¹³ After observing the effects of Xuezhikang, the product after removal of lovastatin (PG [product after]), and lovastatin on the inhibition of colon carcinoma in situ and metastatic tumor cells, researchers in David Geffen School of Medicine Center for Human Nutrition from the University of California found that not only Xuezhikang and lovastatin had inhibitory effects on tumor cells, but also PG had these effects, which demonstrated that the antitumor effect in Xuezhikang is a synergetic result of lovastatin and other useful elements.⁵³

Supplementing the diet of tumor-bearing mice or rats with oils containing n-3 fatty acids can slow the growth of various types of cancers, including lung, colon, mammary, and prostate. The efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, irinotecan (CPT-11), 5-fluorouracil, and tamoxifen, and of radiation therapy has been improved when the diet included n-3 fatty acids. Some potential mechanisms for the activity of n-3 fatty acids against cancer include modulation of eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility to apoptosis, and estrogen signaling. In humans, n-3 fatty acids have also been used to suppress cancer-associated cachexia and to improve the quality of life.⁵⁴ PUFAs could also promote the absorption and storage of anticancer drugs, and enhance anticancer drug concentration in tumor cells to increase their efficacy.⁵⁵ Supplementation with EPA significantly reduced cyclooxygenase 2 concentrations,⁵⁶ which also had beneficial effects for cancer prevention.

Moreover, recent studies showed that flavonoids can exhibit significant antitumor activities, and the combination treatment with some active flavones can change the antitumor effects. Some natural flavonoids and chalcone derivates can reverse the multidrug resistance of tumor cells.⁵⁷ Activating and upregulating caspase-3, modulating Bax/Bcl-2 expression level and intracellular Ca²⁺ level, decreasing the mitochondrial transmembrane potential, and promoting the release of cytochrome C are involved in the induction of apoptosis in cancer cells by the compounds, which is associated with the regulatory factors, such as p53, eukaryotic protein kinases (EPK), nuclear factor κ-B, and so on.⁵⁸ In addition, some flavonoids-enriched diets can modulate immune function and appear to be protective against DNA damage.

Furthermore, another component of Xuezhikang, selenium, is one of the trace elements with the effects of anticancer and preventing cancer. Its mechanisms are multifaceted, including antioxidative damage, regulation of gene expression and cell cycle to promote apoptosis of cancer cells, stabilizing the structure of DNA, and enhancing immune function against cancer as well as being intermediary in the metabolism of certain chemical carcinogens.⁵⁹ In addition, ergosterin has already been known to have antitumor effects.^60,61

Improving Insulin Resistance

Xuezhikang can significantly lower levels of fasting serum insulin and C peptide, and raise insulin sensitivity index in patients with hypertension complicated with dyslipidemia, suggesting it can improve insulin sensitivity for patients with hypertension during lipid-lowering therapy.⁶²

As main components in Xuezhikang, n-3 PUFAs can regulate the activity of key transcription factors to regulate gene expression in lipid metabolism and improve insulin sensitivity of type 2 diabetes mellitus to prevent diabetic complications.⁶³ Six (6) weeks of supplementation with n-3 PUFAs reduced the postprandial decrease in macrovascular function and meanwhile improved postprandial microvascular function.⁶⁴ Furthermore, flavonoids also have a significant effect in the improvement of insulin resistance,⁶⁵ and many associated drugs have already been put into clinical practice. Also, it was reported that magnesium deficiency can lead to reduction of insulin sensitivity⁶⁶ and affect the stability of glucose metabolism. Thus, increasing the intake of magnesium plays an important role in prevention of non-insulin-dependent diabetes mellitus and its complications.⁶⁷ Moreover, selenium reduces the production of oxygen free radicals in the body by glutathione peroxidase to prevent further oxidative damage in the body and the insulin A, B between the two peptide chains for ensuring the complete molecule structure and function of insulin to play a role in lowering blood glucose. In addition, selenium also has inhibitory effects on complications of diabetes such as osteoporosis and retinopathy. ⁶⁸

Inhibiting Ventricular Remodeling

Xuezhikang has shown beneficial effects on reversing hypertensive left ventricular hypertrophy (LVH) and improving heart function in patients with hypertension.⁶⁹ Combined therapy with Xuezhikang and valsartan can improve LVH and heart rate turbulence parameters, and lessen the damage on the autonomous nervous system.⁷⁰ Long-term therapy with Xuezhikang remarkably improved left ventricular diastolic function, probably mediated through antifibrotic and anti-inflammatory effects.⁷¹ The mechanism of the protective effect on ventricular remodeling might be mainly from natural lovastatin⁷² in Xuezhikang.

Neural Regulation and Protection Effects

Xuezhikang significantly reduced the infarct volume and improved the functional recovery compared to vehicle, and significantly decreased the malondialdehyde (MDA) accumulation after reperfusion. NG-nitro-l-arginine methyl ester partially inhibited the protective effect of Xuezhikang but nearly completely abolished the protective effect of simvastatin. The beneficial effects are partly due to the statins and other components in Xuezhikang.⁷³

Since it enhances protein synthesis in hippocampal neurons and increasing cell differentiation, an α-linolenic acid–enriched diet has certain effects on nutrition and health care for the brain.⁷⁴ Furthermore, higher plasma EPA was associated with a lower severity of depressive symptomatology in elderly subjects, especially those taking antidepressants.⁷⁵ For other components, γ-aminobutyric acid can reduce damage of brain neurons caused by massive release of glutamate.⁷⁶ Magnesium can significantly reduce mortality in patients with ischemic brain injury, and promote the recovery of neurological function. In an acute state of cerebral infarction, magnesium is a neural- protective agent of high clinical value.⁷⁷

Kidney Protection Effects

The efficacy of Xuezhikang has been investigated in patients with nephritic syndrome and hyperlipidemia, and the results found that Xuezhikang could regulate the levels of lipid and had potential effects of kidney protection.⁷⁸ Adding Xuezhikang in routine therapy could strengthen the efficacy and control the progression of proteinuria and glomerular lesion effectively.⁷⁹

Lovastatin, the main component of Xuezhikang, was demonstrated to have the effect of renal fibrosis prevention through the activation of Rho GTPases.⁸⁰ It has been also reported that n-3 PUFAs can slow down the progression of kidney diseases by lipid-lowering, anti-inflammation, inhibition of oxidative stress, improving hemodynamics, intervention of cell proliferation, and signal transduction.⁸¹ α-Linolenic acid can improve kidney function, reduce urinary calcium excretion, and inhibit calcium oxalate crystal formation in kidney, which may have some value in the prevention and treatment of urolithiasis.⁸²

Others

Combined use of Xuezhikang with antihypertensive therapy could increase the circulating endothelial progenitor cells and improve their function in essential hypertensive patients with blood pressure controlled by antihypertensive drugs, leading to benefits independent of pressure-lowering effects.⁸³ Xuezhikang stimulated new bone formation in bone defects in vivo and increased bone cell formation in vitro.⁸⁴ Flavonoids and statins have been shown to promote bone formation, and thus may influence peak bone and decrease the risk of osteoporosis in later life.^85,86 In addition, the InCHIANTI study⁸⁷ showed that low plasma selenium is independently associated with poor skeletal muscle strength in community-dwelling older adults. Another study demonstrated that an increased concentration of long-chain n-3 PUFAs in serum, especially docosahexaenoic acid, may protect against atrial fibrillation.⁸⁸

The clinical benefits of Xuezhikang in cardiovascular disease and other chronic conditions as well as potential synergetic mechanism by pharmacological effects of different components in Xuezhikang are summarized in Tables 1 and 2.

Table 1.

Clinical Benefits of Xuezhikang in Cardiovascular Disease and Other Chronic Conditions

No.	Clinical benefits	Study	Design	Sample	Control	Duration	Effect of Xuezhikang
1	Lipid profiles modulation	Liu J 2006¹²	Meta-analysis	99 Randomized trials	—	—	The lipid modification effects appeared to be similar to pravastatin, simvastatin, lovastatin, atorvastatin, or fluvastatin
2	Anti-atherosclerosis	Zhao SP 2004²³	Randomized control trial (RCT)	50 Coronary heart disease patients	Placebo	6 weeks	Reducing proportion of atherosclerotic substance in the plaque; Improving endothelial function through its potent anti-inflammatory and lipid-lowering effects to set more mature collagen and more stable fibrous cap
		Lu L 2009²⁴	RCT	88 Essential hypertensive(EH) patients	Antihypertensive drug and pravastatin	8 weeks
		Fan XF 2010²⁵	RCT	84 Patients with nonalcoholic fatty liver disease and hyperlipidemia	Polyene-phosphatidylcholine capsule	24 weeks	Lowering the serum levels of inflammatory factors such as tumor necrosis factor-alpha and interleukin-6 (IL-6).
		Liu JD 2006²⁶	RCT	90 patients with unstable angina (UA)	Blank	3 days	Reducing the serum levels of serum oxidized low-density lipoprotein-cholesterol (ox-LDL), and C-reactive protein (CRP).
		Yao QH 2003²⁷	RCT	103 patients with UA (69 male)	Vitamin E	4 months	Lowering the serum levels of fibrinogen.
		Huang J 2006²⁸	Case– control trial	69 patients with acute coronary syndrome and 30 healthy people	Blank	2 weeks	Reducing the serum levels of high-sensitivity CRP, matrix metalloproteinase-9.
		Jian J 1999²⁹	RCT	91 patients with hyperlipidemia	Gemfibrozil	8 weeks	Regulating the balance between thromboxane and prostacyclin
3	Liver protection	Yao ZL 2006⁴⁷	RCT	62 patients with fatty liver	Blank	14 months	Relieving clinical syndromes and improving liver function.
4	Anti-cancer	CCSPS¹³	RCT	4870 patients	Placebo	4.5 years	Reducing the risk of death for cancer.
5	Improving insulin resistance	Dai XH 2000⁶²	RCT	64 patients with hypertension and dyslipidemia	Efamol	2 months	Lowering levels of fasting serum insulin and C peptide, raising.
6	Inhibiting ventricular remodeling	Wang JM 2000⁶⁹	RCT	42 patients with hypertention and left ventricular hypertrophy(LVH)	Enalapril	8 weeks	Reversing hypertensive LVH and improving heart function in patients with hypertension.
		Gong C 2010⁷⁰	RCT	90 patients with hypertention and LVH	Valsartan	2 years	Improve LVH and heart rate turbulence parameters, and lessening the damage on the autonomous nervous system.
		Ye P 2009⁷¹	RCT	55 hypertensive patients with normal blood LDL-C level	Placebo and blank	72 weeks	Improving left ventricular diastolic function, probably mediated through antifibrotic and anti-inflammatory effects.
7	Kidney protection	Cao ZX 2007⁷⁸	RCT	58 patients with nephritic syndrome and hyperlipidemia	Blank	8 weeks	Regulating the levels of lipid and had potential effects of kidney protection.
		Liu ZX 2007⁷⁹	RCT	94 patients with youth obesity	Blank	8 weeks	Strengthening the efficacy and controlling the progression of proteinuria and glomerular lesion effectively.
8	Others	Lu L 2009⁸³	RCT	88 EH patients	Antihypertensive drug and pravastatin	8 weeks	Combined use of Xuezhikang with the anti-hypertensive therapy could lead to benefits independent of pressure-lowering effects.

Table 2.

Potential Synergetic Mechanism by Pharmacological Effects of Different Components in Xuezhikang

No.	Effective components	Clinical benefits	Study	Study type	Results
1	Natural statins	Overall lipid profiles modulation	Huang Z 2010^a	Review	Statins, especially lovastatin, can reduce endogenous cholesterol synthesis, and increase the activity of low-density lipoprotein (LDL) receptor on the surface of liver cells to promote the clearance of LDL through feedback mechanisms.
		Anti-atherosclerosis	Laufs U 1998³⁰	In vitro	Lovastatin could upregulate endothelial constitutive nitric oxide synthase (ecNOS) expression predominantly by post-transcriptional mechanisms.
		Anticancer	Hong MY 2008⁵³	In vivo	Not only Xuezhikang and lovastatin had inhibitory effects on tumor cells, but also product after removal of lovastatin (PG) had, which demonstrated that the antitumor effect in Xuezhikang is a synergetic result of lovastatin and other useful elements.
		Inhibiting ventricular remodeling	Ye P 2009⁷¹	In vivo	The mechanism of the protective effect on ventricular remodeling might be mainly from natural lovastatin in Xuezhikang.
		Kidney protection	Patel S 2006⁸⁰	In vitro	Lovastatin was demonstrated to have the effects of renal fibrosis prevention through the activation of ρGTPases.
		Bone formation	Marini H 2008⁸⁵	In vivo	Statins have been shown to promote bone formation, thus it may be possible to influence peak bone and to decrease the risk of osteoporosis in later life.
2	Unsaturated fatty acids	Overall lipid profiles modulation	Phillipson BE 1985¹⁷	In vivo	Polyunsaturated fatty acids (PUFAs) can decrease triglycerides (TG), reduce the rate of lipid shuttle driven by cholesteryl ester transfer protein, increase high-density lipoprotein (HDL), reduce small LDL production, and get the cholesterol out of the vessel wall.
			Dai Y 2009¹⁸	In vivo	α-Linolenic acid and γ-linolenic acid, their effects on serum levels of total cholesterol (TC), TG, and high-density lipoprotein-cholesterol (HDL-C) were significant.
			OPTILIP¹⁹	In vivo	An increased intake of n-3 long-chain PUFAs caused the reduction in plasma triacylglycerol and favorable changes in LDL size
			Dai Y 2009¹⁸	In vivo	Diet enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce blood levels of neutral lipids, TC, LDL, very low-density lipoprotein, and increase HDL.
			Sadovsky R 2009²⁰	In vivo	Intake of omega-3-acid ethyl esters can significantly decrease serum TG, along with plasma concentrations of certain lipoproteins up to 45%.
			COMBOS 2008²¹	In vivo	Significant improvements were confirmed across a range of lipid indicators by taking PUFAs in combination with statin.
2	Unsaturated fatty acids	Anti-athero sclerosis	Arntzenius AC 1985³¹	In vivo	N-3 PUFAs, another main component of Xuezhikang, can directly or indirectly play a role in the immune system, and contribute to slowing the progression of atherosclerosis.
			Carpentier YA 2006³²	In vivo	N-3 PUFAs modulate inflammation, platelet activation, endothelial functions, and so on.
			He K 2009³³	In vivo	The dietary intake of long-chain n-3 PUFAs was inversely associated with concentrations of interleukin-6 (IL-6), matrix metalloproteinase-3.
			Vedin I 2008³⁴	In vivo	Reduced the release of interleukin-1β (IL-1β), granulocyte colony-stimulating factor.
			He K 2008³⁵	In vivo	Reflecting lower levels of inflammation and endothelial activation for a lower prevalence of subclinical atherosclerosis.
			Hilpert KF 2007³⁶	In vitro	Unsaturated fatty acids differentially affected concentrations of apoB-containing lipoprotein subclasses to attenuate the impairment of endothelial function.
			Zhao G 2007³⁷	In vivo	Increased intakes of α-linolenic acid exerted anti-inflammatory effects by inhibiting IL-6, IL-1β, and TNF-α production in cultured peripheral blood mononuclear cells.
			Djoussé L 2003³⁸	In vivo	Higher consumption of total linolenic acid was associated with the lower prevalence odds of carotid plaques and with lesser thickness of segment-specific carotid intima-media thickness.
			Bouwens M 2009³⁹	In vivo	The intake of EPA and DHA for 26 weeks could alter the gene expression profiles of peripheral blood mononuclear cells (PBMCs) to a more anti-inflammatory and anti-atherogenic status.
2	Unsaturated fatty acids	Anticancer	Hardman WE 2004⁵⁴	In vivo	The efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, irinotecan (CPT-11), 5-fluorouracil, and tamoxifen, and of radiation therapy has been improved when the diet included n-3 fatty acids.
			Jiang WG 1998⁵⁵	In vitro	PUFAs could also promote the absorption and storage of anticancer drugs, and enhance anticancer drug concentration in tumor cells to increase their efficacy.
			Mehta SP 2008⁵⁶	In vivo	Supplementation with EPA significantly reduced cyclooxygenase 2 concentrations, which also had beneficial effects for cancer prevention.
		Improving insulin resistance	Carpentier YA 2006⁶³	In vivo	N-3 PUFAs can regulate the activity of key transcription factors to regulate gene expression in lipid metabolism and improve insulin sensitivity of type 2 diabetes mellitus to prevent diabetic complications.
			Stirban A 2010⁶⁴	In vivo	Six weeks of supplementation with n-3 PUFAs reduced the postprandial decrease in macrovascular function and meanwhile improved postprandial microvascular function.
		Neural regulation	Tian F 2009⁷⁴	In vitro	Enhancing protein synthesis in hippocampal neurons and increasing cell differentiation, α-linolenic acid-enriched diet has certain effects on nutrition and health care for brain.
			Féart C 2008⁷⁵	In vivo	Higher plasma EPA was associated with a lower severity of depressive symptomatology in elderly subjects, especially those taking antidepressants.
2	Unsaturated fatty acids		Pan YH 2001⁷⁶	In vivo	γ-Aminobutyric can reduce damage of brain neurons caused by massive release of glutamate.
		Kidney protection	Qian JL 2009⁸¹	In vivo	n-3 PUFAs can slow down the progression of kidney diseases by lipid-lowering, anti-inflammation, inhibition of oxidative stress, improving hemodynamics, intervention of cell proliferation, and signal transduction.
			Wang J 2004⁸²	In vitro	α-Linolenic acid can improve kidney function, reduce urinary calcium excretion, inhibit calcium oxalate crystal formation in kidney.
		Anti–atrial fibrillation	Virtanen JK 2009⁸⁸	In vivo	An increased concentration of long-chain n-3 PUFAs in serum, especially DHA, may protect against atrial fibrillation.
3	Flavonoids	Overall lipid profiles modulation	Jahromi MAF 1993²²	In vitro	Most flavonoids can reduce levels of TG, TC, and LDL.
		Anti-atherosclerosis	Xiao LZ 2004⁴⁰	In vitro	Protecting blood vessels though inhibiting platelet aggregation, anti-inflammatory, and antioxidant effects.
			Loke WM 2008⁴¹	In vivo	Dietary flavonoids, such as quercetin and epicatechin, can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function.
3	Flavonoids	Anti-atherosclerosis	Fuchs D 2007⁴²	In vivo	Flavonoids-enriched diet could reduce the levels of soluble vascular cell adhesion molecule-1 and increase the anti-inflammatory response in blood mononuclear cells.
			Nasca MM 2008⁴³	In vivo	Flavonoids caused an improvement in endothelial function that may reflect an overall improvement in the underlying inflammatory process underlying atherosclerosis.
		Liver protection	Tipoe GL 2010⁵⁰	In vitro	Flavonoids have different levels of protection effects on liver damage caused by a variety of reasons, and the protective mechanism was related to antioxidant function of enzyme.
			Kim MH 2010⁵¹	In vitro	It inhibited the release of TNF-α, and the role of cell apoptosis.
		Anticancer	Zhu RX 2010⁵⁷	Review	Some natural flavonoids and chalcone derivates can reverse the multidrug resistance of tumor cells.
			Zeng S 2009⁵⁸	Review	Activating and up-regulating caspase-3, modulating Bax/Bcl-2 expression level and intracellular Ca2+ level, decreasing the mitochondrial transmembrane potential and promoting the release of cytochrome C are involved in the induction of apoptosis in cancer cells by the compounds, which is associated with the regulatory factors, such as p53, eukaryotic protein kinases (EPK), nuclear factor kappa-B (NF-κB), and so on.
		Improving insulin resistance	Liu ZM 2010⁶⁵	In vivo	Flavonoids also have a significant effect in the improvement of insulin resistance, and many associated drugs have already been put into clinical practice.
		Bone formation	Marini H 2008⁸⁵	In vivo	Flavonoids have been shown to promote bone formation, and thus may influence peak bone and decrease the risk of osteoporosis in later life.
4	Trace element: magnesium	Anti-atherosclerosis	Li JJ 2003⁴⁴	Review	Many animal experiments show that magnesium has an anti-atherosclerosis effect, the mechanisms of which may be reducing lipemia, protecting blood vessels, decreasing free radical and lipid peroxide, and affecting the level of hormone.
		Improving insulin resistance	Barbagallo M 2007⁶⁶	Review	Magnesium deficiency can lead to reduction of insulin sensitivity affecting the stability of glucose metabolism.
			Kim DJ 2010⁶⁷	Review	Increasing the intake of magnesium plays an important role in prevention of non-insulin-dependent diabetes mellitus and its complications.
		Neural regulation	Tymianski M 1996⁷⁷	In vitro	Magnesium can significantly reduce the mortality in patients with injury of ischemic brain, and promote the recovery of neurological function. In acute state of cerebral infarction, magnesium is a neural-protective agent of high clinical value.
5	Trace element: selenium	Anti-atherosclerosis	Yun BS 2002⁴⁶	In vivo	Selenium supplementation increases the activity of anti-oxidative glutathione peroxidase 1 in endothelial cells of patients, which may also protect against the progress of arteriosclerosis.
		Liver protection	Aaseth J 1980⁵²	Review	Selenium may have some preventive effects in alcoholic cirrhosis.
		Anticancer	Shen DL 2008⁵⁹	Review	Selenium's anti-cancer mechanisms are multifaceted, including anti-oxidative damage, regulation of gene expression and cell cycle to promote apoptosis of cancer cells, stabilizing the structure of DNA and enhancing immune function against cancer as well as intermediary in the metabolism of certain chemical carcinogens.
		Improving insulin resistance	Zhang M 2009⁶⁸	In vitro	Selenium also has inhibitory effects on complications of diabetes such as osteoporosis and retinopathy.
		Bone formation	InCHIANTI study⁸⁷	In vivo	Low plasma selenium is independently associated with poor skeletal muscle strength in community-dwelling older adults.
6	Ergosterol	Overall lipid profiles modulation	Subbiah MT 1973⁶⁰	Review	Ergosterol can compete with the cholesterol absorption site to interfere with the absorption of cholesterol, reducing exogenous cholesterol.
		Anticancer	Kahols K 1989⁶¹	In vitro	Ergosterol proved to be active against Walker 256 carcinosarcoma and MCF-7 breast cancer cell lines.
7	Sterins	Anti-atherosclerosis	Yun BS 2002⁴⁶	In vitro	Anti-oxidative effects of sterins may also have some value in atherosclerosis prevention.

Huang Z, Li DD. Recent advances in the studies of lovastatin. Chin J Biochem Pharmaceutics 2010;31:144.

The controversy on polypill has never stopped since the first conception in 2003.⁸⁹ As a natural compound medicine, the remarkable clinical benefits and multicomponents synergetic mechanism of Xuezhikang make it a successful paradigm of polypill. Although lovastatin is the main component in lowering blood lipid, other ingredients in Xuezhikang also work together to reach the goal of overall lipid regulation and additional clinical benefits. In fact, the concept of polypill happens to coincide with the theory of compound prescription in Traditional Chinese Medicine (TCM), which originated in China more than 2000 years ago. It is one of the representative characteristics and strengths of TCM to treat patients by compound prescription through the "monarch, minister, assistant, and guide" compatibility of various herbal medicines to achieve multitarget intervention with efficacy-enhancing and toxicity-reducing effects. The compound prescription based on TCM pattern diagnosis contains a wealth of ideas about "individualized medicine," which might have valuable implications for future development of an individualized polypill.

There might be some limitations in this review. Since most studies reported positive results here, the publication bias could not be excluded. However, this article focused on the synergistic mechanisms of different components in Xuezhikang to contribute multiple clinical benefits as a natural polypill, rather than a systematic review on the available clinical evidences of Xuezhikang. With the progress of in-depth research, it is believed, there will be more clinical benefits of Xuezhikang to be discovered, and polypill is anticipated to be a more effective and feasible way for treating complicated diseases.

Footnotes

Acknowledgments

Dr. Hao Xu conceived this article to review the clinical benefit of Xuezhikang and its multicomponents synergetic mechanism as a natural polypill. Dr. Yan Feng and Dr. Hao Xu prepared and drafted the manuscript. Dr Keji Chen provided constructive suggestions and made modification to the manuscript.

Disclosure Statement

There are no conflicts of interest.

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