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Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management
Accepted Manuscript Title: Preventing Cardiovascular Heart Disease: Promising Nutraceutical and non-Nutraceutical Treatments for Cholesterol Management Authors: T.P. Johnston, T.A. Korolenko, M. Pirro, A. Sahebkar PII: DOI: Reference:
S1043-6618(16)31430-X http://dx.doi.org/doi:10.1016/j.phrs.2017.04.008 YPHRS 3559
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
29-12-2016 20-3-2017 7-4-2017
Please cite this article as: Johnston TP, Korolenko TA, Pirro M, Sahebkar A.Preventing Cardiovascular Heart Disease: Promising Nutraceutical and nonNutraceutical Treatments for Cholesterol Management.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2017.04.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Preventing Cardiovascular Heart Disease: Promising Nutraceutical and non-Nutraceutical Treatments for Cholesterol Management
T.P. Johnston1, T.A. Korolenko2, M. Pirro3, A. Sahebkar4 1
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108-2718, USA. [email protected] 2
Institute of Physiology and Fundamental Medicine, Timakov St. 4, Novosibirsk, 630117, Russia. [email protected] 3
Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy. [email protected] 4
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran. [email protected]
Corresponding Author: Thomas P. Johnston, Ph.D. Division of Pharmaceutical Sciences School of Pharmacy University of Missouri-Kansas City Rm. 4243, HSB 2464 Charlotte Street Kansas City, MO 64108-2718, USA. 816-235-1624 (telephone) 816-235-5779 (fax) [email protected]
Graphical_Abstract
Non-statin Rx
Synthetic/biological
Natural
PCSK9 inhibitors
Injection (Sc)
MTTP inhibitors
Oral
ApoB ASOs
Injection (Sc)
CETP inhibitors
Oral
RVX-208
Oral
β-Glucan
Oral
Glucomannan
Oral
Sterols/stanols
Oral
Berberine
Oral
Curcuminoids
Oral
ABSTRACT
Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease.
Atherosclerosis resulting from hypercholesterolemia causes many
serious cardiovascular diseases.
Statins are generally accepted as a treatment of choice for
lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients.
Ezetimibe improves cholesterol-lowering efficacy and provides mild
additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and
several
therapeutic
hypercholesterolemia.
agents
not
derived
from
‘natural’
sources,
to
treat
Keywords: Cardiovascular disease; Hypercholesterolemia; Nutraceuticals
1.
Hypercholesterolemia and Its Relation to Cardiovascular Disease Atherosclerotic cardiovascular disease (ASCVD) is the major cause of mortality in
industrialized countries. In the United States, CVD is still the leading cause of mortality, which accounted for about 24 percent of all deaths in 2014 (1). Serum total cholesterol levels are directly related to coronary artery disease and low-density-lipoprotein cholesterol (LDL-C) is involved in the pathogenesis of the atherosclerotic changes that occur in the vascular wall (2). Based on data collected from 2005 to 2008, over half of all adults in the United States have elevated cholesterol values and about one-third have elevated LDL-C levels (1).
The
atherosclerotic process begins early in life (3,4,5) and typically progresses to adult CVD. Genetic and environmental factors seem to contribute to the development of CVD (6). Pharmacologic treatment of hypercholesterolemia for both primary and secondary prevention of cardiovascular disease is well accepted.
Statins are the cornerstone of
pharmacotherapy for hypercholesterolemia owing to their undisputed effectiveness in reducing plasma LDL-C levels as well as lipid-independent pleiotropic actions such as anti-thrombotic, antioxidant, and anti-inflammatory properties. While statins have been used routinely for the primary and secondary prevention of CVD, there are additional primary and adjunctive treatments that are being used to modify atherogenic plasma lipid profiles. The desire for other primary and adjunctive hypolipidemic agents stems from the fact that some statin-treated patients develop statin intolerance which mainly manifests as statin-associated muscle symptoms (SAMS) with a spectrum of symptoms ranging from myalgias to life-threatening rhabdomyolysis, although the likelihood of developing the latter condition is quite small. For completeness sake, it should be mentioned that high-dose statin therapy has been associated with a slightly, but significantly, increased risk of the development of new-onset diabetes (7,8).
Moreover, there is compelling evidence suggesting the presence of a considerable residual risk of CVD in statin-treated patients, even those attaining therapeutic LDL-C goals. While the use of non-statins to treat hypercholesterolemia includes bile acid-binding resins and ezetimibe, these agents will not be discussed. In particular, hypocholesterolemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors will be discussed, as well as yeast polysaccharides (e.g., beta-glucans and mannans) and additional natural compounds (nutraceuticals) (e.g., glucomannans, plant sterols, berberine, and red yeast rice).
2.
Therapeutic Agents from Natural Sources Over the past two decades, there has been a surge of interest to use natural products
for the management of hypercholesterolemia. Evidence from numerous randomized controlled trials (RCTs) and meta-analyses has also confirmed the hypolipidemic efficacy as well as safety of certain nutraceuticals. Here, some of the most important hypocholesterolemic nutraceuticals will be discussed. The slightly water-soluble, wall-yeast polysaccharide known as zymosan has been shown to decrease atherogenic serum lipids in experimental lipemia induced in mice, although the hypolipidemic effects of zymosan, which is composed primarily of β-glucan and mannan, are still poorly understood (9).
The former component; namely, β-glucan, has previously been
shown to exhibit a hypolipidemic effect in a well-documented mouse model known as the poloxamer 407 (P-407)-induced hyperlipidemic mouse model of atherogenesis (10,11). However, the overall cholesterol-lowering efficacy of β-glucan has been modest, as confirmed in two large meta-analyses (Table 1) (12,13). Its hypocholesterolemic effect is attributed to its ability to swell after oral ingestion, form a gel, and then bind with cholesterol and prevent its absorption.
Mannan, which belongs to a class of immunomodulators of polysaccharide origin, has been shown to stimulate macrophages in vivo through its interaction with the mannose receptor (14-17). Polysaccharides, unlike statins, are natural stimulators of macrophages, which cause the macrophages to increase their endocytic activity (18,19,20).
Following endocytosis by
macrophages, these branched polysaccharides have the capacity to „activate‟ LDL- and scavenger-receptors and increase the uptake of atherogenic LDL-cholesterol, as well as other lipoproteins with modified chemical structures.
It has also been suggested that excess
cholesterol may potentially be removed from atherosclerotic plaque by activated macrophages (21). Glucomannan fiber, obtained from Amorphophallus konjac tubers, has been documented to function as both a hypolipidemic (22-25) and hypoglycemic agent (24,26,27). Because glucomannan swells in the presence of water to form a viscous gel, it delays gastric emptying time and, consequently, decreases the postprandial surge in plasma glucose and insulin (28,29).
A decrease in the postprandial insulin concentration suppresses hepatic
cholesterol synthesis (30) through a reduction in insulin-induced 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity (31).
As with several plant-derived anti-
hypercholesterolemic compounds (e.g., psyllium fiber), glucomannan appears to increase not only fecal weight (26), but also the excretion of bile acids into the feces (25,32).
Since
cholesterol is normally excreted into bile, the decrease in the plasma concentration of bile acids (32) and the subsequent excretion of bile acids into the feces contributes to the cholesterollowering action of glucomannan (23,33,34). In conclusion, glucomannan, like other soluble fibers (oats, guar gum, pectin, and psyllium), has been touted for its beneficial effects on the risk of coronary heart disease (28).
This claim has been supported by a meta-analysis which
concluded that glucomannan beneficially lowered [weighted mean difference (WMD)] total cholesterol (WMD: -19.3 mg/dl), LDL-cholesterol (WMD: -16.0 mg/dl), triglycerides (WMD: -11.1 mg/dl), body weight (WMD: -0.79 kg), and fasting blood glucose (WMD: -7.4 mg/dl), but not
HDL-cholesterol or blood pressure (Table 1) (35).
These authors further concluded that
pediatric patients, patients receiving dietary modification, and patients with impaired glucose metabolism did benefit from glucomannan, but not to the same degree (35). Plant sterols have also been evaluated as cholesterol-lowering agents since the early 1950s (36). Plant sterols (mainly sitosterol and campesterol) and stanols (mainly sitostanol and campestanol) occur in several plant-based foods, most notably in vegetable oils, nuts, breads, seeds, margarines, cereals, vegetables, and fruits (37,38). Plant-derived sterols have now been unequivocally established as effective compounds with which to lower serum cholesterol (Table 1) (39-42). In fact, similar to ezetimibe, plant sterols lower LDL-cholesterol concentrations by inhibiting cholesterol absorption from the intestine (43,44). Yoshida et al. investigated the antihypercholesterolemic effects of dietary supplementation with plant sterols and/or glucomannan to determine whether these supplements would both improve the overall lipid profile and modulate cholesterol biosynthesis in mildly hypercholesterolemic Type II diabetic and nondiabetic subjects (45).
These investigators concluded that both glucomannan alone and a
combination of glucomannan and plant sterols substantially improves plasma LDL-cholesterol concentrations in Type II diabetic patients, but, as mentioned above, not to the same extent as in non-diabetic patients (45). In summary, experimental and clinical evidence has shown that plant sterols/stanols can ameliorate plasma levels of total cholesterol, LDL-cholesterol, and triglycerides (Table 1) (46). Berberine is a natural alkaloid found in plants of Berberis species. It has several properties, including anti-infective, anti-tumoral, and metabolic.
A beneficial influence of
berberine on lipid profiles, including cholesterol- and triglyceride-lowering effects, have been observed along with a favorable impact on insulin sensitivity.
Several meta-analyses have
confirmed the positive effects of berberine on multiple lipid parameters (Table 1) (47,48,49), which might be related to its stimulatory action on the JNK/c-jun pathway and its inhibitory effect on PCSK9 expression. Additionally, it has been reported that berberine upregulates LDL
receptors similar to statin drugs, as well as affects 5’-adenosine monophosphate activated protein kinase (AMPK); a key enzyme that plays a role in cellular energy homeostasis and affects how the body regulates cholesterol, blood pressure, and blood glucose (50). While producing a less atherogenic plasma lipid profile is extremely significant, it is also important to emphasize that improving other pertinent factors that contribute to CVD is just as significant as berberine’s capacity to correct plasma lipid derangements. For example, berberine also exhibits antihypertensive, inotropic, and antiarrhythmic properties (50). Cicero et al., using a dietary combination of berberine, chlorogenic acid (obtained from decaffeinated Green coffee, Coffea canephora; decreases cholesterol by upregulating the gene expression of peroxisome proliferation-activated receptor alpha), and tocotrienols (isolated from Elaeis guineensis; reduce cholesterol by blocking HMGCoA reductase activity by a different mechanism than statins) to treat overweight patients with mixed hyperlipidemia for 8 weeks (51). This study revealed that treatment of the patients with the above nutraceutical combination improved not only all lipid parameters evaluated, but also improved metabolic and biochemical indices aimed at measuring insulin sensitivity and blood glucose, as well as liver steatosis (51). Red yeast rice is probably the most potent natural cholesterol-lowering agent, possibly because of its content in multiple substances positively affecting cholesterol metabolism. Accordingly, red yeast rice contains at least 10 monacolins, including monacolin K (which is chemically identical to lovastatin), plant sterols, fibers, and niacin, which all may have some cholesterol-lowering efficacy (52). A large number of RCTs, included in several meta-analyses, have confirmed the beneficial effects of red yeast rice on cholesterol levels (Table 1) (53,54). Despite the natural origin of red yeast rice, the presence of monacolin K may explain the occurrence of side effects to muscle when higher doses have been used.
A combination of natural lipid-lowering agents has been developed in recent years in order to reduce their doses, improve tolerability, and target multiple lipid risk factors. In this regard, nutraceutical combinations containing both berberine and red yeast rice have been tested mostly in patients with hypercholesterolemia and have demonstrated promising results (55,56,57). Additional combinations of lipid-lowering natural compounds have also been evaluated in moderately hypercholesterolemic patients, which include red yeast rice + coenzyme Q10, as well as the four-combination dietary regimen that includes monacolin K (isolated from Chinese red yeast rice; reversible inhibitor of HMG-CoA reductase) + guggul
resin
(obtained
from
Commiphora
mukal;
inhibits
hepatic
cholesterol
biosynthesis, enhances hepatic uptake of both LDL and VLDL, and increases biliary excretion of cholesterol) + octacosanols (isolated from Saccharum officinarum; inhibits hepatic cholesterol biosynthesis and increases the catabolism of LDL) + silymarin (obtained from Silybum marianum; possesses anti-inflammatory and lipid-lowering properties that are still not well understood).
As mentioned above, creating a less
atherogenic plasma lipid profile is extremely important, but the nutraceutical combinations described above were also assessed for their ability to improve other relevant factors that contribute to CVD (e.g., arterial stiffness and endothelial function). Endothelial ‘dysfunction’ has been known for years to contribute to the eventual development of CVD (58). Along the lines of endothelial function, Cicero et al. demonstrated that a red yeast rice (10 mg monacolins) + coenzyme Q10 (30 mg) dietary regimen consumed for 6 months by moderately hypercholesterolemic patients improved the plasma lipid profile, endothelial reactivity, and arterial stiffness relative to patients ingesting a placebo (59). Cicero et al. also reported that when the 4-combination dietary regimen described above was evaluated in moderately hypercholesterolemic patients for eight weeks, a significant reduction in total cholesterol, LDL-C, high-sensitivity C-reactive protein (hs-CRP), and
endothelial function (as measured by pulse volume displacement used to induce reactive hyperemia) was observed in nutraceutical-treated patients vs. placebo-treated patients (60). Curcuminoids are another example of naturally occurring lipid-modifying agents. These polyphenolic compounds, present in turmeric, are endowed with numerous health benefits. As it pertains to ASCVD and hyperlipidemia, there is extensive evidence, including data from RCTs, which shows the cholesterol- and triglyceride-lowering effect of curcuminoids (61,62,63). The triglyceride-lowering effect of curcuminoids makes these phytopharmaceuticals an ideal adjunct to statins owing to the role of hypertriglyceridemia in explaining the residual CVD risk following statin therapy, and also the weak effect of statins on plasma triglyceride levels (Table 1) (64). Additionally, since curcuminoids can stimulate the biogenesis and function of mitochondria (65), and possess analgesic activity (66), their concomitant adjunctive use with statins could lessen the likelihood of SAMS and statin intolerance. Lastly, it is important to emphasize the role of curcumin as it pertains to inflammation and ASCVD. Since ASCVD has been referred to as an inflammatory disease, it is extremely noteworthy that curcumin inhibits tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1), which are key inflammatory mediators involved with numerous inflammatory diseases. In fact, recent evidence – including meta-analyses of randomized controlled trials – has shown a significant effect of curcumin in lowering circulating TNF, IL-6 and MCP-1 concentrations (67-69). These anti-inflammatory effects, when exerted at the site of arterial wall, play an important role in attenuating vascular inflammation and endothelial dysfunction (70).
3.
Therapeutic Non-Statin Agents Not Derived from Natural Sources
Several newer and/or investigational non-statin agents have been evaluated that utilize different mechanisms of action to decrease cholesterol.
Mipomersen is an antisense
oligonucleotide that complements the mRNA of the apolipoprotein B-100 (APOB) gene (71,72,73). Antisense oligonucleotides “hybridize” with the mRNA species of interest and form a cDNA-mRNA complex (72,73).
Essentially, the mRNA cannot be translated into protein.
Therefore, the decrease in apolipoprotein B-100 protein decreases the availability for LDL synthesis, and consequently, plasma LDL is reduced (71,72,73).
The dosing regimen for
mipomersen is weekly subcutaneous injections and this agent has only been approved to date for homozygous familial hypercholesterolemia (HoFH) (74). The microsomal triglyceride transfer protein (MTTP) inhibitors are represented by lomitapide. MTTP normally transfers triglycerides to the endoplasmic reticulum where newlysynthesized apolipoproteins are added to make a chylomicron or VLDL particle (75). It should be mentioned that cholesterol is also absorbed, subsequently esterified, and then packed into chylomicrons in the intestine or VLDL particles in the liver.
The mechanism of action for
lomitapide is to inhibit MTTP. Since MTTP is required for chylomicron and VLDL assembly and secretion, a decrease in their production interferes downstream in the formation of LDL-C (75,76). Thus, plasma LDL-C is reduced as a result. One drawback to the use of lomitapide is the significant adverse effect of increased aminotransferase levels and the potential for hepatotoxicity (hepatic steatosis that could progress to cirrhosis) (77). Similar to the antisense oligonucleotide mipomersen, lomitapide has only been approved to date for treatment of HoFH. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represents a major advance in the treatment of dyslipidemia and a promising option for those patients with severe types of genetic dyslipidemias; in particular, FH (76,78,79). Briefly, PCSK9 is a member of the proteinase K family and binds to the LDL receptor resulting in its degradation (80). Naturally, this action would decrease the uptake and metabolism of LDL from the blood, which subsequently results in an increase of LDL-C levels in the plasma (78,80). The rationale behind
the use of the PCSK9 inhibitor, which is itself a monoclonal antibody, is to recognize PCSK9, bind to it, and render PCSK9 inactive and incapable of destroying LDL receptors. Intact LDL receptors are then free to scavenge more LDL particles from the circulation and the plasma levels of LDL-C are significantly reduced (76,78,80).
Alirocumab and evolocumab are two
PCSK9 inhibitors (both are human monoclonal antibodies) approved in 2015 for the treatment of patients with ASCVD, heterozygous FH (HeFH) or HoFH, who require additional lowering of plasma LDL-C (81,82,83). In Phase II trials, alirocumab was shown to decrease LDL-C by up to 73% (84), but it should be noted that both agents are expensive and the cost-effectiveness of these drugs is questionable, since evolocumab and alirocumab are injected subcutaneously every 2 or 4 weeks. Thus, another injectable PCSK9 inhibitor, ALN-PCS, is under development. ALN-PCS, by turning off PCSK9 synthesis in the liver, has been developed to produce a cholesterol-lowering effect lasting for more than 140 days with a single dose (85). Results from most strategies aimed at increasing plasma HDL-C levels in order to reduce cardiovascular risk have produced disappointing results. RVX-208 is an orally active small molecule being developed to increase HDL functionality. In a series of novel studies, RVX-208 has been shown to target multiple processes, including reverse cholesterol transport, thrombosis, and inflammation, which may have a role in the lower incidence of RVX-208induced major cardiovascular events in the ASSURE and SUSTAIN trials (86). Lastly, another non-statin investigational class of compounds includes the cholesteryl ester transfer protein (CETP) inhibitors (87). CETP, a glycoprotein synthesized in the liver, normally mediates the transfer of cholesteryl esters from larger subfractions of HDL (i.e., HDL2) to triglyceride-rich lipoproteins and LDL in exchange for a molecule of triglyceride (87). Following HDL2‟s enrichment with triglycerides, it becomes more susceptible to catabolism by the liver (88). Some examples of hypolipidemic agents in the CETP inhibitor category include torcetrapib, anacetrapib, dalcetrapib, and evacetrapib, although it should be mentioned that these agents are not without risk, since clinical trials with torcetrapib were halted in 2006 due to
increased mortality (89). When either these inhibitors are evaluated in laboratory animals, or a genetic mutation occurs in the gene that encodes for the synthesis of CETP in humans, the result is similar; specifically, greater levels of HDL and reduced levels of LDL-C, although there are conflicting reports as to whether this modulation in the levels of HDL and LDL-C that occur from a CETP mutation in humans leads to an increased or decreased risk of CVD. It must be mentioned that due to the failure of dalcetrapib and evacetrapib, there are numerous review articles appearing in the literature that do not support the rationale for the continued development of CETP inhibitors (90,91,92,93). Nevertheless, the CETP inhibitors represent yet another strategy of interfering with cholesterol metabolism in an attempt to reduce LDL-C and increase HDL, although their clinical efficacy in the treatment of hypercholesterolemia remains in question.
4.
Concluding Remarks We have discussed hypercholesterolemia and its impact on the development of ASCVD.
Next we presented the use of yeast polysaccharides, natural compounds, and various newer and investigational non-statin agents with which to treat hypercholesterolemia and consequently reduce the development of ASCVD. All of these synthetic and naturally-derived hypolipidemic compounds/therapies represent alternative treatment strategies with which to decrease serum cholesterol, especially the plasma concentration of LDL-C, in an attempt to prevent ASCVD in subjects who are statin-resistant, statin-intolerant, or suffer from a high residual risk despite attainment of their LDL-C goal with statin therapy. The majority of the compounds discussed in this mini-review are aimed at disrupting one or more key steps involved with lipid metabolism and cholesterol turnover in humans.
Nevertheless, additional supporting evidence from
outcome trials is warranted to elucidate the impact of the above mentioned agents on cardiovascular events and endpoints.
It is suggested that the intentional pharmacological
manipulation of tissue and serum lipid concentrations, the deliberate inhibition or activation of
key enzymes associated with both lipid synthesis and metabolism, and the desire to prevent the absorption and/or hasten the excretion of sterol-based compounds should only be viewed as one strategy to modify or influence the incidence of ASCVD.
Clearly, other non-
pharmacological means of minimizing ASCVD include a healthy lifestyle that promotes regular daily exercise and strict adherence to a nutritious diet that minimizes/eliminates the ingestion of foodstuffs high in carbohydrates, sugar, and trans-fats. Taken together, these strategies could greatly reduce the incidence of dyslipidemia and ASCVD in all cultures.
DISCLOSURE POLICY (COMPETING INTEREST)
The authors‟ declare that there is no conflict of interest, including any financial, personal, or other relationships with people or organizations within 3 years of beginning the submitted work that could inappropriately influence, or be perceived to influence, the work.
TERMS OF SUBMISSION STATEMENT FROM THE AUTHOR(S)
The authors‟ declare that this paper has not been published elsewhere and is not presently under consideration for publication by any other journal. This mini-review is approved by all authors. Furthermore, if the review is accepted for publication, it will not be published elsewhere in the same form, in English or any other language, including electronically without the written consent of the copyright-holder.
ROLE OF THE FUNDING SOURCE
There was no financial support provided for the preparation of this article and, therefore, no influence in the study design; the collection, analysis, or interpretation of data; in the writing of the article; and in the decision to submit the article. As per the submission instructions for Pharmacological Research, “This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors”.
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Table 1: Summary of meta-analyses of randomly-controlled trials (RCT) demonstrating the alteration in plasma lipids mediated by compounds derived from natural sources Natural compound
Beta-glucan
No. of RCT arms
No. of subjects
11
591
Dose range
TC a
Plant sterols/stanols
14
20
(mg/dL)
Red yeast rice
Curcuminoids
11
13
10
TG a
Ref.
(mg/dL)
(mg/dL) (mg/dL)
3-13 g/day
531
1273
1.2-15.1 g/day
1.5-2.8 g/day (sterol/stanol) 0.45-3.2 g/day (phytosterol/sterol ester)
Berberine
HDL-C a
-11.64 (-15.13, 8.15)
Glucomannan
LDL-C a
874
804
223
0.6-1.5 g/day
0.2-3.6 g/day
0.045-6.0 g/day
-10.48 (13.2, 7.76)
NS
NS
94
95
-19.28
-15.99
-1.36
-11.08
(-24.30, 14.26)
(-21.31, 10.67)
(-3.37, 0.66)
(-22.07, 0.09)
-13.90
-13.51
(-17.76, 10.04)*
(-18.15, 8.49)*
-23.55
-25.10
+1.93
-44.25
(-32.05, 15.06)*
(-29.34, 20.85)*
(+0.77, +3.47)*
(-61.06, 27.43)*
-37.45
-33.59
+3.09
-20.35
(-43.63, 30.89)*
(-39.77, 27.41)*
(-0.77, +7.34)
(-27.43, 12.39)*
+8.97
+16.15
-0.59
-1.29
(-4.56, +22.51)
(-4.43, +36.74)
(-1.66, +0.49)
(-9.05, +6.48)
NS
-8.85
96
(-14.16, 2.65)*
* Indicates a significant effect; ** Indicates a systematic review; NS: not stated a. indicates weight combined mean value TC = total cholesterol; LDL-C = low-density-lipoprotein cholesterol; high-density-lipoprotein cholesterol; TG = triglycerides
48
97
98
S1043-6618(16)31430-X http://dx.doi.org/doi:10.1016/j.phrs.2017.04.008 YPHRS 3559
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
29-12-2016 20-3-2017 7-4-2017
Please cite this article as: Johnston TP, Korolenko TA, Pirro M, Sahebkar A.Preventing Cardiovascular Heart Disease: Promising Nutraceutical and nonNutraceutical Treatments for Cholesterol Management.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2017.04.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Preventing Cardiovascular Heart Disease: Promising Nutraceutical and non-Nutraceutical Treatments for Cholesterol Management
T.P. Johnston1, T.A. Korolenko2, M. Pirro3, A. Sahebkar4 1
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108-2718, USA. [email protected] 2
Institute of Physiology and Fundamental Medicine, Timakov St. 4, Novosibirsk, 630117, Russia. [email protected] 3
Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy. [email protected] 4
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran. [email protected]
Corresponding Author: Thomas P. Johnston, Ph.D. Division of Pharmaceutical Sciences School of Pharmacy University of Missouri-Kansas City Rm. 4243, HSB 2464 Charlotte Street Kansas City, MO 64108-2718, USA. 816-235-1624 (telephone) 816-235-5779 (fax) [email protected]
Graphical_Abstract
Non-statin Rx
Synthetic/biological
Natural
PCSK9 inhibitors
Injection (Sc)
MTTP inhibitors
Oral
ApoB ASOs
Injection (Sc)
CETP inhibitors
Oral
RVX-208
Oral
β-Glucan
Oral
Glucomannan
Oral
Sterols/stanols
Oral
Berberine
Oral
Curcuminoids
Oral
ABSTRACT
Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease.
Atherosclerosis resulting from hypercholesterolemia causes many
serious cardiovascular diseases.
Statins are generally accepted as a treatment of choice for
lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients.
Ezetimibe improves cholesterol-lowering efficacy and provides mild
additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and
several
therapeutic
hypercholesterolemia.
agents
not
derived
from
‘natural’
sources,
to
treat
Keywords: Cardiovascular disease; Hypercholesterolemia; Nutraceuticals
1.
Hypercholesterolemia and Its Relation to Cardiovascular Disease Atherosclerotic cardiovascular disease (ASCVD) is the major cause of mortality in
industrialized countries. In the United States, CVD is still the leading cause of mortality, which accounted for about 24 percent of all deaths in 2014 (1). Serum total cholesterol levels are directly related to coronary artery disease and low-density-lipoprotein cholesterol (LDL-C) is involved in the pathogenesis of the atherosclerotic changes that occur in the vascular wall (2). Based on data collected from 2005 to 2008, over half of all adults in the United States have elevated cholesterol values and about one-third have elevated LDL-C levels (1).
The
atherosclerotic process begins early in life (3,4,5) and typically progresses to adult CVD. Genetic and environmental factors seem to contribute to the development of CVD (6). Pharmacologic treatment of hypercholesterolemia for both primary and secondary prevention of cardiovascular disease is well accepted.
Statins are the cornerstone of
pharmacotherapy for hypercholesterolemia owing to their undisputed effectiveness in reducing plasma LDL-C levels as well as lipid-independent pleiotropic actions such as anti-thrombotic, antioxidant, and anti-inflammatory properties. While statins have been used routinely for the primary and secondary prevention of CVD, there are additional primary and adjunctive treatments that are being used to modify atherogenic plasma lipid profiles. The desire for other primary and adjunctive hypolipidemic agents stems from the fact that some statin-treated patients develop statin intolerance which mainly manifests as statin-associated muscle symptoms (SAMS) with a spectrum of symptoms ranging from myalgias to life-threatening rhabdomyolysis, although the likelihood of developing the latter condition is quite small. For completeness sake, it should be mentioned that high-dose statin therapy has been associated with a slightly, but significantly, increased risk of the development of new-onset diabetes (7,8).
Moreover, there is compelling evidence suggesting the presence of a considerable residual risk of CVD in statin-treated patients, even those attaining therapeutic LDL-C goals. While the use of non-statins to treat hypercholesterolemia includes bile acid-binding resins and ezetimibe, these agents will not be discussed. In particular, hypocholesterolemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors will be discussed, as well as yeast polysaccharides (e.g., beta-glucans and mannans) and additional natural compounds (nutraceuticals) (e.g., glucomannans, plant sterols, berberine, and red yeast rice).
2.
Therapeutic Agents from Natural Sources Over the past two decades, there has been a surge of interest to use natural products
for the management of hypercholesterolemia. Evidence from numerous randomized controlled trials (RCTs) and meta-analyses has also confirmed the hypolipidemic efficacy as well as safety of certain nutraceuticals. Here, some of the most important hypocholesterolemic nutraceuticals will be discussed. The slightly water-soluble, wall-yeast polysaccharide known as zymosan has been shown to decrease atherogenic serum lipids in experimental lipemia induced in mice, although the hypolipidemic effects of zymosan, which is composed primarily of β-glucan and mannan, are still poorly understood (9).
The former component; namely, β-glucan, has previously been
shown to exhibit a hypolipidemic effect in a well-documented mouse model known as the poloxamer 407 (P-407)-induced hyperlipidemic mouse model of atherogenesis (10,11). However, the overall cholesterol-lowering efficacy of β-glucan has been modest, as confirmed in two large meta-analyses (Table 1) (12,13). Its hypocholesterolemic effect is attributed to its ability to swell after oral ingestion, form a gel, and then bind with cholesterol and prevent its absorption.
Mannan, which belongs to a class of immunomodulators of polysaccharide origin, has been shown to stimulate macrophages in vivo through its interaction with the mannose receptor (14-17). Polysaccharides, unlike statins, are natural stimulators of macrophages, which cause the macrophages to increase their endocytic activity (18,19,20).
Following endocytosis by
macrophages, these branched polysaccharides have the capacity to „activate‟ LDL- and scavenger-receptors and increase the uptake of atherogenic LDL-cholesterol, as well as other lipoproteins with modified chemical structures.
It has also been suggested that excess
cholesterol may potentially be removed from atherosclerotic plaque by activated macrophages (21). Glucomannan fiber, obtained from Amorphophallus konjac tubers, has been documented to function as both a hypolipidemic (22-25) and hypoglycemic agent (24,26,27). Because glucomannan swells in the presence of water to form a viscous gel, it delays gastric emptying time and, consequently, decreases the postprandial surge in plasma glucose and insulin (28,29).
A decrease in the postprandial insulin concentration suppresses hepatic
cholesterol synthesis (30) through a reduction in insulin-induced 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity (31).
As with several plant-derived anti-
hypercholesterolemic compounds (e.g., psyllium fiber), glucomannan appears to increase not only fecal weight (26), but also the excretion of bile acids into the feces (25,32).
Since
cholesterol is normally excreted into bile, the decrease in the plasma concentration of bile acids (32) and the subsequent excretion of bile acids into the feces contributes to the cholesterollowering action of glucomannan (23,33,34). In conclusion, glucomannan, like other soluble fibers (oats, guar gum, pectin, and psyllium), has been touted for its beneficial effects on the risk of coronary heart disease (28).
This claim has been supported by a meta-analysis which
concluded that glucomannan beneficially lowered [weighted mean difference (WMD)] total cholesterol (WMD: -19.3 mg/dl), LDL-cholesterol (WMD: -16.0 mg/dl), triglycerides (WMD: -11.1 mg/dl), body weight (WMD: -0.79 kg), and fasting blood glucose (WMD: -7.4 mg/dl), but not
HDL-cholesterol or blood pressure (Table 1) (35).
These authors further concluded that
pediatric patients, patients receiving dietary modification, and patients with impaired glucose metabolism did benefit from glucomannan, but not to the same degree (35). Plant sterols have also been evaluated as cholesterol-lowering agents since the early 1950s (36). Plant sterols (mainly sitosterol and campesterol) and stanols (mainly sitostanol and campestanol) occur in several plant-based foods, most notably in vegetable oils, nuts, breads, seeds, margarines, cereals, vegetables, and fruits (37,38). Plant-derived sterols have now been unequivocally established as effective compounds with which to lower serum cholesterol (Table 1) (39-42). In fact, similar to ezetimibe, plant sterols lower LDL-cholesterol concentrations by inhibiting cholesterol absorption from the intestine (43,44). Yoshida et al. investigated the antihypercholesterolemic effects of dietary supplementation with plant sterols and/or glucomannan to determine whether these supplements would both improve the overall lipid profile and modulate cholesterol biosynthesis in mildly hypercholesterolemic Type II diabetic and nondiabetic subjects (45).
These investigators concluded that both glucomannan alone and a
combination of glucomannan and plant sterols substantially improves plasma LDL-cholesterol concentrations in Type II diabetic patients, but, as mentioned above, not to the same extent as in non-diabetic patients (45). In summary, experimental and clinical evidence has shown that plant sterols/stanols can ameliorate plasma levels of total cholesterol, LDL-cholesterol, and triglycerides (Table 1) (46). Berberine is a natural alkaloid found in plants of Berberis species. It has several properties, including anti-infective, anti-tumoral, and metabolic.
A beneficial influence of
berberine on lipid profiles, including cholesterol- and triglyceride-lowering effects, have been observed along with a favorable impact on insulin sensitivity.
Several meta-analyses have
confirmed the positive effects of berberine on multiple lipid parameters (Table 1) (47,48,49), which might be related to its stimulatory action on the JNK/c-jun pathway and its inhibitory effect on PCSK9 expression. Additionally, it has been reported that berberine upregulates LDL
receptors similar to statin drugs, as well as affects 5’-adenosine monophosphate activated protein kinase (AMPK); a key enzyme that plays a role in cellular energy homeostasis and affects how the body regulates cholesterol, blood pressure, and blood glucose (50). While producing a less atherogenic plasma lipid profile is extremely significant, it is also important to emphasize that improving other pertinent factors that contribute to CVD is just as significant as berberine’s capacity to correct plasma lipid derangements. For example, berberine also exhibits antihypertensive, inotropic, and antiarrhythmic properties (50). Cicero et al., using a dietary combination of berberine, chlorogenic acid (obtained from decaffeinated Green coffee, Coffea canephora; decreases cholesterol by upregulating the gene expression of peroxisome proliferation-activated receptor alpha), and tocotrienols (isolated from Elaeis guineensis; reduce cholesterol by blocking HMGCoA reductase activity by a different mechanism than statins) to treat overweight patients with mixed hyperlipidemia for 8 weeks (51). This study revealed that treatment of the patients with the above nutraceutical combination improved not only all lipid parameters evaluated, but also improved metabolic and biochemical indices aimed at measuring insulin sensitivity and blood glucose, as well as liver steatosis (51). Red yeast rice is probably the most potent natural cholesterol-lowering agent, possibly because of its content in multiple substances positively affecting cholesterol metabolism. Accordingly, red yeast rice contains at least 10 monacolins, including monacolin K (which is chemically identical to lovastatin), plant sterols, fibers, and niacin, which all may have some cholesterol-lowering efficacy (52). A large number of RCTs, included in several meta-analyses, have confirmed the beneficial effects of red yeast rice on cholesterol levels (Table 1) (53,54). Despite the natural origin of red yeast rice, the presence of monacolin K may explain the occurrence of side effects to muscle when higher doses have been used.
A combination of natural lipid-lowering agents has been developed in recent years in order to reduce their doses, improve tolerability, and target multiple lipid risk factors. In this regard, nutraceutical combinations containing both berberine and red yeast rice have been tested mostly in patients with hypercholesterolemia and have demonstrated promising results (55,56,57). Additional combinations of lipid-lowering natural compounds have also been evaluated in moderately hypercholesterolemic patients, which include red yeast rice + coenzyme Q10, as well as the four-combination dietary regimen that includes monacolin K (isolated from Chinese red yeast rice; reversible inhibitor of HMG-CoA reductase) + guggul
resin
(obtained
from
Commiphora
mukal;
inhibits
hepatic
cholesterol
biosynthesis, enhances hepatic uptake of both LDL and VLDL, and increases biliary excretion of cholesterol) + octacosanols (isolated from Saccharum officinarum; inhibits hepatic cholesterol biosynthesis and increases the catabolism of LDL) + silymarin (obtained from Silybum marianum; possesses anti-inflammatory and lipid-lowering properties that are still not well understood).
As mentioned above, creating a less
atherogenic plasma lipid profile is extremely important, but the nutraceutical combinations described above were also assessed for their ability to improve other relevant factors that contribute to CVD (e.g., arterial stiffness and endothelial function). Endothelial ‘dysfunction’ has been known for years to contribute to the eventual development of CVD (58). Along the lines of endothelial function, Cicero et al. demonstrated that a red yeast rice (10 mg monacolins) + coenzyme Q10 (30 mg) dietary regimen consumed for 6 months by moderately hypercholesterolemic patients improved the plasma lipid profile, endothelial reactivity, and arterial stiffness relative to patients ingesting a placebo (59). Cicero et al. also reported that when the 4-combination dietary regimen described above was evaluated in moderately hypercholesterolemic patients for eight weeks, a significant reduction in total cholesterol, LDL-C, high-sensitivity C-reactive protein (hs-CRP), and
endothelial function (as measured by pulse volume displacement used to induce reactive hyperemia) was observed in nutraceutical-treated patients vs. placebo-treated patients (60). Curcuminoids are another example of naturally occurring lipid-modifying agents. These polyphenolic compounds, present in turmeric, are endowed with numerous health benefits. As it pertains to ASCVD and hyperlipidemia, there is extensive evidence, including data from RCTs, which shows the cholesterol- and triglyceride-lowering effect of curcuminoids (61,62,63). The triglyceride-lowering effect of curcuminoids makes these phytopharmaceuticals an ideal adjunct to statins owing to the role of hypertriglyceridemia in explaining the residual CVD risk following statin therapy, and also the weak effect of statins on plasma triglyceride levels (Table 1) (64). Additionally, since curcuminoids can stimulate the biogenesis and function of mitochondria (65), and possess analgesic activity (66), their concomitant adjunctive use with statins could lessen the likelihood of SAMS and statin intolerance. Lastly, it is important to emphasize the role of curcumin as it pertains to inflammation and ASCVD. Since ASCVD has been referred to as an inflammatory disease, it is extremely noteworthy that curcumin inhibits tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1), which are key inflammatory mediators involved with numerous inflammatory diseases. In fact, recent evidence – including meta-analyses of randomized controlled trials – has shown a significant effect of curcumin in lowering circulating TNF, IL-6 and MCP-1 concentrations (67-69). These anti-inflammatory effects, when exerted at the site of arterial wall, play an important role in attenuating vascular inflammation and endothelial dysfunction (70).
3.
Therapeutic Non-Statin Agents Not Derived from Natural Sources
Several newer and/or investigational non-statin agents have been evaluated that utilize different mechanisms of action to decrease cholesterol.
Mipomersen is an antisense
oligonucleotide that complements the mRNA of the apolipoprotein B-100 (APOB) gene (71,72,73). Antisense oligonucleotides “hybridize” with the mRNA species of interest and form a cDNA-mRNA complex (72,73).
Essentially, the mRNA cannot be translated into protein.
Therefore, the decrease in apolipoprotein B-100 protein decreases the availability for LDL synthesis, and consequently, plasma LDL is reduced (71,72,73).
The dosing regimen for
mipomersen is weekly subcutaneous injections and this agent has only been approved to date for homozygous familial hypercholesterolemia (HoFH) (74). The microsomal triglyceride transfer protein (MTTP) inhibitors are represented by lomitapide. MTTP normally transfers triglycerides to the endoplasmic reticulum where newlysynthesized apolipoproteins are added to make a chylomicron or VLDL particle (75). It should be mentioned that cholesterol is also absorbed, subsequently esterified, and then packed into chylomicrons in the intestine or VLDL particles in the liver.
The mechanism of action for
lomitapide is to inhibit MTTP. Since MTTP is required for chylomicron and VLDL assembly and secretion, a decrease in their production interferes downstream in the formation of LDL-C (75,76). Thus, plasma LDL-C is reduced as a result. One drawback to the use of lomitapide is the significant adverse effect of increased aminotransferase levels and the potential for hepatotoxicity (hepatic steatosis that could progress to cirrhosis) (77). Similar to the antisense oligonucleotide mipomersen, lomitapide has only been approved to date for treatment of HoFH. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represents a major advance in the treatment of dyslipidemia and a promising option for those patients with severe types of genetic dyslipidemias; in particular, FH (76,78,79). Briefly, PCSK9 is a member of the proteinase K family and binds to the LDL receptor resulting in its degradation (80). Naturally, this action would decrease the uptake and metabolism of LDL from the blood, which subsequently results in an increase of LDL-C levels in the plasma (78,80). The rationale behind
the use of the PCSK9 inhibitor, which is itself a monoclonal antibody, is to recognize PCSK9, bind to it, and render PCSK9 inactive and incapable of destroying LDL receptors. Intact LDL receptors are then free to scavenge more LDL particles from the circulation and the plasma levels of LDL-C are significantly reduced (76,78,80).
Alirocumab and evolocumab are two
PCSK9 inhibitors (both are human monoclonal antibodies) approved in 2015 for the treatment of patients with ASCVD, heterozygous FH (HeFH) or HoFH, who require additional lowering of plasma LDL-C (81,82,83). In Phase II trials, alirocumab was shown to decrease LDL-C by up to 73% (84), but it should be noted that both agents are expensive and the cost-effectiveness of these drugs is questionable, since evolocumab and alirocumab are injected subcutaneously every 2 or 4 weeks. Thus, another injectable PCSK9 inhibitor, ALN-PCS, is under development. ALN-PCS, by turning off PCSK9 synthesis in the liver, has been developed to produce a cholesterol-lowering effect lasting for more than 140 days with a single dose (85). Results from most strategies aimed at increasing plasma HDL-C levels in order to reduce cardiovascular risk have produced disappointing results. RVX-208 is an orally active small molecule being developed to increase HDL functionality. In a series of novel studies, RVX-208 has been shown to target multiple processes, including reverse cholesterol transport, thrombosis, and inflammation, which may have a role in the lower incidence of RVX-208induced major cardiovascular events in the ASSURE and SUSTAIN trials (86). Lastly, another non-statin investigational class of compounds includes the cholesteryl ester transfer protein (CETP) inhibitors (87). CETP, a glycoprotein synthesized in the liver, normally mediates the transfer of cholesteryl esters from larger subfractions of HDL (i.e., HDL2) to triglyceride-rich lipoproteins and LDL in exchange for a molecule of triglyceride (87). Following HDL2‟s enrichment with triglycerides, it becomes more susceptible to catabolism by the liver (88). Some examples of hypolipidemic agents in the CETP inhibitor category include torcetrapib, anacetrapib, dalcetrapib, and evacetrapib, although it should be mentioned that these agents are not without risk, since clinical trials with torcetrapib were halted in 2006 due to
increased mortality (89). When either these inhibitors are evaluated in laboratory animals, or a genetic mutation occurs in the gene that encodes for the synthesis of CETP in humans, the result is similar; specifically, greater levels of HDL and reduced levels of LDL-C, although there are conflicting reports as to whether this modulation in the levels of HDL and LDL-C that occur from a CETP mutation in humans leads to an increased or decreased risk of CVD. It must be mentioned that due to the failure of dalcetrapib and evacetrapib, there are numerous review articles appearing in the literature that do not support the rationale for the continued development of CETP inhibitors (90,91,92,93). Nevertheless, the CETP inhibitors represent yet another strategy of interfering with cholesterol metabolism in an attempt to reduce LDL-C and increase HDL, although their clinical efficacy in the treatment of hypercholesterolemia remains in question.
4.
Concluding Remarks We have discussed hypercholesterolemia and its impact on the development of ASCVD.
Next we presented the use of yeast polysaccharides, natural compounds, and various newer and investigational non-statin agents with which to treat hypercholesterolemia and consequently reduce the development of ASCVD. All of these synthetic and naturally-derived hypolipidemic compounds/therapies represent alternative treatment strategies with which to decrease serum cholesterol, especially the plasma concentration of LDL-C, in an attempt to prevent ASCVD in subjects who are statin-resistant, statin-intolerant, or suffer from a high residual risk despite attainment of their LDL-C goal with statin therapy. The majority of the compounds discussed in this mini-review are aimed at disrupting one or more key steps involved with lipid metabolism and cholesterol turnover in humans.
Nevertheless, additional supporting evidence from
outcome trials is warranted to elucidate the impact of the above mentioned agents on cardiovascular events and endpoints.
It is suggested that the intentional pharmacological
manipulation of tissue and serum lipid concentrations, the deliberate inhibition or activation of
key enzymes associated with both lipid synthesis and metabolism, and the desire to prevent the absorption and/or hasten the excretion of sterol-based compounds should only be viewed as one strategy to modify or influence the incidence of ASCVD.
Clearly, other non-
pharmacological means of minimizing ASCVD include a healthy lifestyle that promotes regular daily exercise and strict adherence to a nutritious diet that minimizes/eliminates the ingestion of foodstuffs high in carbohydrates, sugar, and trans-fats. Taken together, these strategies could greatly reduce the incidence of dyslipidemia and ASCVD in all cultures.
DISCLOSURE POLICY (COMPETING INTEREST)
The authors‟ declare that there is no conflict of interest, including any financial, personal, or other relationships with people or organizations within 3 years of beginning the submitted work that could inappropriately influence, or be perceived to influence, the work.
TERMS OF SUBMISSION STATEMENT FROM THE AUTHOR(S)
The authors‟ declare that this paper has not been published elsewhere and is not presently under consideration for publication by any other journal. This mini-review is approved by all authors. Furthermore, if the review is accepted for publication, it will not be published elsewhere in the same form, in English or any other language, including electronically without the written consent of the copyright-holder.
ROLE OF THE FUNDING SOURCE
There was no financial support provided for the preparation of this article and, therefore, no influence in the study design; the collection, analysis, or interpretation of data; in the writing of the article; and in the decision to submit the article. As per the submission instructions for Pharmacological Research, “This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors”.
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Table 1: Summary of meta-analyses of randomly-controlled trials (RCT) demonstrating the alteration in plasma lipids mediated by compounds derived from natural sources Natural compound
Beta-glucan
No. of RCT arms
No. of subjects
11
591
Dose range
TC a
Plant sterols/stanols
14
20
(mg/dL)
Red yeast rice
Curcuminoids
11
13
10
TG a
Ref.
(mg/dL)
(mg/dL) (mg/dL)
3-13 g/day
531
1273
1.2-15.1 g/day
1.5-2.8 g/day (sterol/stanol) 0.45-3.2 g/day (phytosterol/sterol ester)
Berberine
HDL-C a
-11.64 (-15.13, 8.15)
Glucomannan
LDL-C a
874
804
223
0.6-1.5 g/day
0.2-3.6 g/day
0.045-6.0 g/day
-10.48 (13.2, 7.76)
NS
NS
94
95
-19.28
-15.99
-1.36
-11.08
(-24.30, 14.26)
(-21.31, 10.67)
(-3.37, 0.66)
(-22.07, 0.09)
-13.90
-13.51
(-17.76, 10.04)*
(-18.15, 8.49)*
-23.55
-25.10
+1.93
-44.25
(-32.05, 15.06)*
(-29.34, 20.85)*
(+0.77, +3.47)*
(-61.06, 27.43)*
-37.45
-33.59
+3.09
-20.35
(-43.63, 30.89)*
(-39.77, 27.41)*
(-0.77, +7.34)
(-27.43, 12.39)*
+8.97
+16.15
-0.59
-1.29
(-4.56, +22.51)
(-4.43, +36.74)
(-1.66, +0.49)
(-9.05, +6.48)
NS
-8.85
96
(-14.16, 2.65)*
* Indicates a significant effect; ** Indicates a systematic review; NS: not stated a. indicates weight combined mean value TC = total cholesterol; LDL-C = low-density-lipoprotein cholesterol; high-density-lipoprotein cholesterol; TG = triglycerides
48
97
98