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Health Protocols

Cholesterol Management

Nutritional Approaches to Managing Blood Lipids and Lipoproteins

Nutritional approaches to blood lipid and lipoprotein management mirror many of the strategies of conventional therapies. Dietary modifications aim to reduce the intake and uptake of fats and cholesterol from the diet. The inclusion of specific dietary compounds with cholesterol-lowering (hypocholesterolemic) or cardioprotective properties may also reduce cardiovascular disease risk by several different mechanisms.

Diet is an important determinant of cardiovascular disease risk; both conventional and alternative approaches advocate dietary and lifestyle changes as the first step in meeting lipid management goals. The National Cholesterol Education Program (NCEP) developed the Therapeutic Lifestyle Changes (TLC) diet42 for medical professionals to help patients pursue nutritional options for lowering cholesterol. The TLC diet recommends no more than 25 to 35 percent of daily calories from total fat, with up to 20 percent as monounsaturated, 10 percent as polyunsaturated, and less than 7 percent as saturated fats. This relatively high allotment of fat calories allows for increased unsaturated fat intake like omega-3 fatty acids in place of carbohydrates for patients with metabolic syndrome.

Carbohydrates and proteins should provide 50-60 percent and 15 percent, of total calories, respectively. Optional dietary guidelines include the addition of 10-25 grams of soluble fiber, and 2 grams of plant sterols per day. Total calories are adjusted to maintain body weight and prevent weight gain, and enough moderate exercise to burn at least 250 calories per day is recommended.

Although not designed as a hypocholesterolemic diet, the DASH (Dietary Approaches to Stop Hypertension) eating plan encourages many of the same heart-healthy eating habits.43 The first DASH eating plan (originally called the “combination diet”) focused on fruits, vegetables, and whole grains, and was especially high in fiber (31 grams/day) and potassium (4.7 grams / day), and low in animal products. Ironically, the original DASH was not a low sodium diet (allowing up to 3 grams/day), but was nonetheless hypotensive44. The low-sodium DASH diet has demonstrated even greater hypotensive effects when limiting sodium to 1.5 grams/day.45 Recall that hypertension is a major coronary heart disease factor. Hypertension magnifies the danger posed by excess LDL by damaging the endothelial barrier, allowing increased permeability.

Caloric restriction (CR) is the dramatic reduction of dietary calories (by up to 40%), to a level short of malnutrition.46 Restriction in energy intake slows down the body’s growth processes, causing it to instead focus on protective repair mechanisms; the overall effect is an improvement in several measures of wellbeing. Observational studies have tracked the effects of CR on lean, healthy individuals, and have demonstrated that moderate CR (22-30% decreases in caloric intake from normal levels) improves heart function, reduces markers of inflammation (C-reactive protein, tumor necrosis factor (TNF)), reduces risk factors for cardiovascular disease (LDL-C, triglycerides, blood pressure) and reduces diabetes risk factors (fasting blood glucose and insulin levels).47,48,49,50 Preliminary results of the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study, a long-term multicenter trial on the effects of calorie-restricted diets in healthy, overweight volunteers51 has shown that moderate CR can reduce several cardiovascular risk factors (LDL-C, triglycerides, and blood pressure, C-reactive protein).52

Replacing Lost Hormones to Achieve Optimal Cholesterol Levels

Due to the role of cholesterol as a precursor to steroid hormones, some researchers have speculated that the elevation in cholesterol seen with advancing age is a compensatory effort by the body to restore levels of hormones to more youthful levels.

In a small clinical trial, Dr. Sergey Dzugan, and Dr. Arnold Smith, found that restoring youthful hormone levels with the use of bioidentical hormone replacement therapy (BHRT) resulted in a significant reduction in cholesterol levels in 20 individuals with high cholesterol.53

Hormone replacement therapy has been shown to reduce cardiovascular risk in aging women,54 and aging men with lower testosterone levels are at significantly greater risk for heart disease.55 Thus, aging individuals should consider optimizing their hormone levels in order to reduce cardiovascular risk. More information on this topic can be found in Life Extension’s Hormone Replacement Therapy protocols for Men and Women.

Nutrients for Lipid Management

There are several nutrients that have been identified as potential agents for promoting a favorable lipid profile; many of them work by the same principles as conventional therapies (such as reducing cholesterol synthesis, or interfering with cholesterol absorption in the gut). Several also have additional activities (antihypertensive, inhibition of LDL-oxidation, antiinflammatory) that complement their cholesterol-lowering activity and lend to their overall reductions in fatal and non-fatal cardiovascular events.

Inhibiting Cholesterol Synthesis

Pantethine and its metabolites appear to act on the body’s fat and cholesterol metabolism pathways. Pantethine is a derivative of pantothenic acid (vitamin B5), and can serve as a source of the vitamin. One notable function of vitamin B5 is its conversion into coenzyme A, a necessary factor in the metabolism of fatty acids into cellular energy. The pantethine derivative cysteamine may also function to reduce the activity of liver enzymes that produce cholesterol and triglycerides.56 Studies of pantethine consumption have demonstrated significant reductions in total- and LDL cholesterol (up to 13.5%), triglycerides, and elevation of HDL-C in hypercholesterolemic subjects (individuals with high cholesterol)57,58 and diabetic subjects59 when taken at 900-1,200 mg/day, although significant effects on triglycerides have been observed at dosages as low as 600 mg/day.60

Red yeast rice is a traditional preparation of rice fermented by the yeast Monascus purpureus. The yeast produces metabolites (monacolins) that are naturally-occuring HMG-CoA Reductase inhibitors (one of these, monacolin K, is chemically identical to lovastatin61). A comprehensive review of 93 randomized trials including nearly 10,000 patients has demonstrated that commercial preparations of red yeast rice produced reduction in total cholesterol, LDL-C, triglycerides, and an increase in HDL-cholesterol.62 A long-term (4.5 year) multicenter study of nearly 5,000 patients with a previous heart attack and high total cholesterol levels demonstrated that a commercial red yeast rice preparation reduced the incidence of major coronary events, including nonfatal heart attack and cardiovascular mortality, when compared to placebo.63 Red yeast rice extracts have also been shown to be well tolerated and effective in lowering LDL in patients with statin intolerance.64,65

Due to regulations regarding their labeling in the US, standardization of commercial red yeast rice preparations for monacolins is problematic, thus levels of monacolins can vary dramatically between red yeast rice products.66 There are some standardized red yeast rice products that are standardized for monacolin K content.

Garlic has been substantiated by several human trials, particularly its ability to support favorable blood lipid profiles. Three separate analyses of 32 blinded, controlled human trials of garlic consumption in healthy or patients with high cholesterol and triglycerides confirm significant reductions in total cholesterol by an average of 7.3 mg/dL, and triglycerides by an average of 4.2 mg/dL.67,68,69 While the average cholesterol reductions across all human studies are modest, greater reductions in total cholesterol were realized in patients who were initially hyperlipidemic or hypertriglycemic (>11 mg/dL reduction), took the extract for over 12 weeks (11 mg/dL reduction), or took a garlic powder (as opposed to an oil or aged extract; 12 mg/dL reduction).70

Garlic also reduces systolic- and diastolic- blood pressure (SBP and DBP) in hypertensive individuals, and systolic blood pressure in persons with normal blood pressure. A recent review and analysis of 11 controlled human trials of garlic showed a mean decrease of 4.6 ± 2.8 mm Hg for SBP in the garlic group compared to placebo, while the mean decrease in the hypertensive subgroup was 8.4 mm Hg for SBP and 7.3 mm Hg for DBP.71

Indian Gooseberry (Amla; Emblica officinalis) has been used traditionally as a nutrient-dense food in Indian regions, and in Ayurvedic medicine for treating a variety of conditions. Modern scientific inquiry has revealed considerable evidence in support of the medicinal use of this nutritional powerhouse. Analytical studies on extracts of Indian Gooseberry highlight its potent antioxidant properties;72 animal studies carry these findings forward by showing that orally administered amla extract significantly reduce levels of oxidized LDL.73,74 In human studies, extracts of amla have been shown to attenuate elevations in LDL, total cholesterol, and triglycerides, and boost levels of protective HDL.75 In a study examining the antioxidant activity of amla extract in subjects with metabolic abnormalities, four months of supplementation was shown to dramatically bolster plasma antioxidant power and suppress oxidative stress.76

Studies suggest that amla extract may also protect against LDL glycation by modulating blood glucose levels. In diabetic patients amla not only significantly reduced post-prandial glucose levels, but also lowered lipid and triglyceride levels over a 21 day period77. In an animal model of metabolic syndrome induced by a high fructose diet, concomitant administration of amla extract reined in rising cholesterol and triglyceride levels, and also significantly repressed the expression of inflammation-related genes, which are typically elevated in metabolic syndrome models.78 Extracts of the antioxidant-rich fruit also reduce levels of advanced glycation end products (AGEs), which are formed by the same process as glycated LDL.79 By limiting the amount of LDL particles that become glycated, amla may help maintain proper cellular uptake of cholesterol and reduce the amount of LDL-C available to infiltrate the arterial wall.

Gynostemma pentaphyllum. Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to treat several chronic conditions, including diabetes and inflammatory disorders. Its effects are due in part to its ability to activate a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK).158,159 This enzyme, which affects glucose metabolism and fat storage, has been called a “metabolic master switch” because it controls numerous metabolic pathways.160,161

Activation of AMPK stimulates glucose uptake in muscles and beta oxidation, in which fatty acids are broken down, while reducing the production of fat and cholesterol in the liver.158 It can also prevent damage to blood vessel lining (endothelial) cells caused by oxidized LDL (“bad”) cholesterol.162 AMPK activation reduces cholesterol and triglyceride levels.163,164

G. pentaphyllum stimulates AMPK activation and affects cholesterol levels in the blood and liver. A study in obese mice showed eight weeks of supplementation with G. pentaphyllum led to weight loss and improvements in glucose metabolism and cholesterol levels. Mice treated with 150 mg/kg (about 900 mg for an adult human) or 300 mg/kg (about 1800 mg for an adult human) of the extract had total cholesterol reductions of 14.2% and 7.1%, respectively, compared with the control group.158

Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels.165,166 Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity.167,168 Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway.169-171 Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging.167

Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury.172 Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level.173

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo.170 In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation.174 Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism.191

Inhibiting Absorption of Dietary Cholesterol

Soluble Fibers include non-digestable and fermentable carbohydrates, and their sufficient intake has been associated with lower prevalence of cardiovascular disease.81 When included as part of a low-saturated fat/low cholesterol diet, they can lower LDL-C by 5-10% in hypercholesterolemic and diabetic patients, and may reduce LDL-C in healthy individuals as well.82 The cholesterol-lowering properties of soluble oat fiber, psyllium, pectin, guar gum, ß-glucans from barley, and chitosan are substantiated by dozens of controlled human clinical trials. 83,84,85 Soluble fibers lower cholesterol by several potential mechanisms.86 They may directly bind bile acids or dietary cholesterol, preventing/disrupting their absorption. Their high viscosities (measure of a liquids thickness) and effects on intestinal motility may slow or limit macronutrient uptake. They can also increase satiety, which can limit overall energy intake.

Prebiotics, a subset of soluble fiber, have gained attention in recent years in their ability to be selectively fermented by gut flora for a diversity of potential health-promoting benefits. The fermentation of prebiotic fibers into short-chain fatty acids such as acetate, butyrate, or propionate may inhibit cholesterol synthesis in the liver.87 In human trials, the prebiotic fibers inulin and dextrin have induced reductions in serum levels of total cholesterol (-9% and -2% for inulin and dextrin, respectively), LDL-C (-1 % for dextrin), and triglycerides (-21% for inulin).88,89

Plant sterols (phytosterols) are steroid compounds found in plants that function similarly to cholesterol in animals (as components of plant cell membranes, and precursors to plant hormones). Like cholesterol, they can exist as free molecules or as sterol- esters. Esters of sterols have a higher activity and better fat solubility, which allows for lower effective dosages (2-3 g/day as opposed to 5-10 g/day for unesterified sterols).90 Sterols themselves are poorly absorbed from the diet, but because of their chemical similarity to cholesterol, they are thought to compete with cholesterol for absorption in the intestines, which has the net effect of reducing LDL levels.91 Sterols may also reduce cholesterol production in the liver, reduce the synthesis of VLDLs, increase LDL particle size, and increase LDL uptake from the blood92,93 HDL and/or very low-density lipoproteins are generally not affected by sterol intake.94

There have been numerous studies of the effects of sterol esters on reducing mean total cholesterol and LDL-C cholesterol in healthy, hypercholesterolemic, and diabetic individuals. An analysis of 57 trials involving over 3600 individuals has reported an average LDL-C reduction of 9.9% at a mean intake of 2.4 g sterol esters/day.95 Sufficient evidence of the cholesterol-lowering effects of sterols has prompted the US Food and Drug Administration to permit the health claim that sterol esters may be associated with a reduced risk of coronary heart disease, when taken at sufficient levels in the context of a healthy diet, one of only 12 permissible health claims granted by this organization96 The NCEP97 and American Heart Association98 both support the use of sterols in their dietary recommendations.

Guggul/Gum guggul, the resin of the Commiphora mukul tree, has a history of traditional usage in Ayurvedic medicine and is widely used in Asia as a cholesterol-lowering agent. Guggulipid is a lipid extract of the gum that contains plant sterols (guggulsterones E and Z), the proposed bioactive compounds.99 In an analysis of 20 human studies on guggulipid, most of the evidence support a significant reduction in serum total cholesterol, LDL, and triglycerides, as well as an elevation in HDL.100 However, most of these studies were small, and had significant design flaws (such as lack of controls or statistical analysis). More recent studies, with better designs, have produced conflicting results. The first, a 36 week study of the effects of 25 mg of guggulsterones on 61 hypercholesterolemic patients demonstrated significant reductions of total cholesterol by 11.7%, LDL by 12.5%, and triglycerides by 15%.101 A second study revealed an opposite effect; this larger (103 patient) study looked at low- (25 mg) and high- (50 mg) dose guggulsterones on blood lipid parameters for eight weeks, and observed increases in LDL-C (4% and 5% for the low and high dose groups, respectively).102 In the most recent study, 12 week administration of 540 mg raw guggul demonstrated modest reductions in both total cholesterol and HDL (3-6%), although the clinical significance of this outcome is not clear.103

Soy protein has value as an anti-hypercholesterolemic agent not only because of the potential lipid-lowering effects of its included isoflavones (which may increase the amount of LDL receptors and help to clear LDL particles from the blood), but also for its potential as an alternative to other high fat/high cholesterol protein sources. A 1995 meta-analysis of 38 controlled human clinical trials (30 conducted on hypercholesterolemic patients) revealed that compared to animal protein, an average intake of 47g/day of soy protein resulted in significant improvements in blood lipid/lipoprotein parameters. Across the studies there were observable average reductions in total cholesterol (9%), LDL-C (12.9%), triglycerides (10.5%), and VLDL-C (2.6%), as well as a non-significant increase in HDL-C (2.4%)104 These data were the foundation for the FDA approval of the food-labeling health claim for soy protein in the prevention of CHD.105

More recently, a second meta-analysis of 41 soy protein studies (including 32 new studies performed after 1995) confirmed the anti-hypercholesterolemic properties of soy protein. The average reductions in blood lipids were smaller (5.3% for total cholesterol, 4.3% for LDL-C, 6.3% for triglycerides, and a 0.8% increase in HDL-C), but this analysis was limited to studies that used soy protein isolates (which contain no cholesterol-lowering fiber).106 Some of this difference may also be explained by baseline lipid levels; persons with moderate to severe hypercholesterolemia showed the largest decreases in serum cholesterol when soy is added to the diet.107

Isoflavone-enriched soy proteins may have additiona lipid-lowering benefits. In the 11 human trials that compare isoflavone-enriched soy to isoflavone-free soy, the enriched soy products (which delivered an average of 102 mg isoflavones/day) lowered total and LDL cholesterol more than isoflavone-free soy, by 1.7% and 3.5%, respectively.108

Inhibiting Oxidation and Glycation of LDL

Coenzyme Q10 (CoQ10). The generation of chemical energy in the form of ATP by the mitochondrial electron transport chain is essential for the existence of life as we know it. Delicate endothelial cells that line the arterial walls depend on healthy mitochondrial function to control blood pressure and vascular tone. Oxidized or glycated LDL can sabotage endothelial mitochondrial function and damage the endothelial barrier, setting the stage for the atherosclerotic cascade to initiate.109,110 CoQ10 is an integral component of mitochondrial metabolism, serving as an intermediary transporter between two major check points along the road to ATP production. Interestingly, CoQ10 is also the only known endogenously synthesized lipid soluble antioxidant,111 and is thus incorporated into LDL particles, where it serves to protect against oxidation. Because of these dual roles insufficient levels of CoQ10 expedite atherogenesis from two angles – by limiting mitochondrial efficiency in endothelial cells and leaving LDL particles vulnerable to oxidative damage.

As noted above, statin drugs, which are typically used to treat high cholesterol, ironically also suppress levels of CoQ10 in the blood.112 Individuals taking a statin drug should always supplement with CoQ10.

Carotenoids are common constituents of the LDL particle. ß-carotene is the second most abundant antioxidant in LDL; other common dietary carotenoids (lycopene, lutein) may be transported by LDL particles as well.113 Together, these three carotenoids have an indispensable role in the protection of LDL particles from oxidative damage; their serum levels have been demonstrated to be the most predictive of the degree of LDL oxidation in humans.114 Carotenoids may also possess additional lipid-lowering activities independent of their antioxidant potential. The best-studied in this respect is lycopene; an analysis of 12 human trials of lycopene reveals an average reduction in LDL-C of approximately 12%.115 Potential mechanisms for this action are suppression of cholesterol synthesis by the inhibition of the HMG-CoA reductase enzyme, or an increase in the rate of LDL degradation.116 Astaxanthin, a carotenoid found in some fish and marine oils, can increase HDL.117

Vitamin E. Natural tocopherols and tocotrienols together form vitamin E. These fat-soluble antioxidants have been studied for decades and are known to protect against some cardiovascular events. Vitamin E strongly inhibits the oxidation of LDL particles.118,119

Alpha tocopherol is the best known form of vitamin E and is found in the largest quantities in blood and tissue. It is critical, however, for anyone supplementing with vitamin E to make sure they are also getting adequate gamma tocopherol each day. The key benefit is gamma tocopherol’s ability to dramatically reduce inflammatory threats, a major cause of virtually all degenerative diseases. One of the most important benefits of gamma tocopherol is its ability to improve endothelial function by increasing nitric oxide synthase, the enzyme responsible for producing vessel-relaxing nitric oxide.120 One major way it produces this effect is by sponging up destructive reactive nitrogen species, such as peroxynitrite.121 In fact, gamma tocopherol is able to “trap” a variety of reactive nitrogen species and halt their negative effects on a host of cellular processes.122

Supplementation in humans with 100 mg per day of gamma tocopherol showed resulted in a reduction in several risk factors for vascular disease such as platelet aggregation and LDL cholesterol levels.123

Pomegranate is now widely viewed as a superfruit with a myriad of health benefits, and rightfully so; dozens of placebo controlled clinical trials have been carried out on pomegranate juice, or pomegranate extract. With respect to lipid management, the efficacy of pomegranate is rivaled by very few natural compounds. The high concentration of polyphenols (particularly punicalagins) in pomegranate make it an ideal ingredient for suppressing LDL oxidation.124,125

Consumption of pomegranate polyphenols significantly lowered total and LDL cholesterol concentrations while maintaining HDL levels in subjects with elevated cholesterol profiles.126 Pomegranate also suppresses immunoreactivity against oxidized LDL, a mechanisms which would be expected to limit plaque formation in the intimia.127 In fact, this is exactly what was shown in a long-term study of pomegranate consumption. Subjects received either pomegranate juice or placebo for three years; in the group receiving the placebo, carotid intima media thickness (cIMT; a measure of atherosclerosis) increased by 9% one year after study initiation, while in the group receiving pomegranate, cIMT was reduced by an astonishing 30%. Moreover, pomegranate significantly reduced oxidized LDL concentrations, and increased serum antioxidant activity, compared to placebo, while simultaneously lowering blood pressure. This study also showed that pomegranate nearly doubled the activity of paraoxonase-1 (PON-1), an antiatherogenic enzyme that optimizes the function of HDL and protects lipids from oxidative damage.128 Both groups in this study continued on standard therapy that may have included statins, anti-hypertensives, etc.

Polyphenols are a diverse set of phytonutrients that are ubiquitous in the diet. Polyphenol intake has been associate with lower risk of cardiovascular mortality, and may partially explain the health benefits of several common foods (tea, fruits, vegetables, wine, chocolate).129 Flavonoids, the largest and best studied class of polyphenols, include catechins from green tea and chocolate, theaflavins from black tea, soy isoflavones, flavan-3-ol polymers from red wine, and anthocyanidins from grapes and berries. A systematic analysis of over 130 human studies of flavonoids revealed significant improvements in endothelial function (cocoa and black tea polyphenols) and blood pressure (anthocyanidins, isoflavones, cocoa); however, only green tea catechins exhibited significant cholesterol (LDL-C) lowering in this analysis (averaging about 9 mg/dL over 4 studies).130 Subsequently, a study of black tea extract in 47 mildly hypercholesterolemic Japanese men and women demonstrated an 8% reduction in total cholesterol and 13% drop in LDL-C after 3 months.131

Other polyphenolic compounds with significant lipid modification potential based on human studies include methylated citrus flavonoids (polymethoxyflavones), which were shown to lower total-cholesterol, LDL-C, and triglycerides by 27%, 25%, and 31%, respectively when combined with tocotrienols in a small pilot trial.132 Additionally, the red wine polyphenol resveratrol was shown to incorporate into the LDL particles of human volunteers following ingestion of a high-resveratrol wine, potentially acting as a resident antioxidant.133 This is consistent with resveratrol’s role in the prevention of LDL oxidation observed in humans.134

Curcumin has a variety of protective roles in CVD, potentially reducing oxidative stress, inflammation, and the proliferations of smooth muscle cells and monocytes. 95 Small human trials studies have revealed the effects of curcumin on reducing in lipid peroxidation135,136 and plasma fibrinogen,137 both factors in the progression of atherosclerosis.138 Curcumin may also reduce serum cholesterol by increasing the production of the LDL receptor,139,140 but despite successes in animal models, human data on the antihypercholesterolemic effects of curcumin is conflicting. A small study of 10 healthy volunteers revealed significant decreases in lipid oxidation products (-33%) and total cholesterol (-12%), with a concomitant increase in HDL-C (29%) when using 500 mg curcumin daily for 7 days.141 In two subsequent studies, low-dose curcumin showed a non-significant trend toward lowering total- and LDL-C in acute coronary patients,142 while high dose-curcumin (1-4 g/day) exhibited non-significant increases in total-, LDL-, and HDL cholesterol.143

Enhancing Cholesterol Elimination

Artichoke has traditional usage as a liver protectant and choleretic (compound that stimulates bile flow). In stimulating bile flow, artichoke may aid the body in the disposal of excess cholesterol. In vitro studies suggest its anti-atherosclerotic effects may also be linked to an antioxidant capacity that reduces LDL oxidation, or the ability of one of its constituents, luteolin, to indirectly inhibit HMG-CoA reductase.144

In addition to several uncontrolled human studies and case reports,145 several randomized, controlled trials support the ability of artichoke extract to lower total- and/or LDL-cholesterol. In one trial, artichoke extract (1800 mg/day) for six weeks reduced total cholesterol (-9.9%) and LDL-C (-16.6%) in 71 hypercholesterolemic patients, with no differences in HDL-C or triglycerides.146 In another, also in hypercholesterolemic patients, 1280 mg artichoke extract per day for 12 weeks reduced total cholesterol by 6.1% when compared with a control group. Changes in LDL-C, HDL-C, and triglycerides were insignificant.147 Some studies indicate artichoke supplementation can raise HDL levels.192,193 Artichoke extract also improved parameters of endothelial function in a small human trial.150

Optimizing the Lipid Profile

Niacin/Nicotinic acid (vitamin B3) is an essential nutrient with roles throughout human metabolism. At dosages substantially above the recommended daily intake (RDI), prescription niacin treatments can significantly raise HDL-C (by 30-35% in some cases, at dosages averaging 2.25 grams/day).149,150 Niacin can also change the distribution of LDL by increasing the amount of large buoyant LDL and reducing the amount of small dense LDL.151 Niacin can also reduce the susceptibility of LDL to oxidation.152

In 2010, the results of seven published studies on the effects of niacin therapy were combined to examine the overall effect. This meta-analysis is considered more powerful than an individual study because it increases the sample size. The results showed that patients taking niacin (compared with a placebo) had significant reductions in nonfatal myocardial infarction and and transient ischemic attack.153

On May 26, 2011, the National Institutes of Health stopped a clinical trial of a prescription-strength level of niacin one year prior to its projected completion. The participants were 3400 patients with stable heart disease, well-controlled LDL, and elevated triglycerides. They added high dose, extended release niacin to their statin therapy. The level of niacin used in the study was much higher than that contained in dietary supplements. As shown in previous studies, the niacin drug successfully elevated HDL and lowered triglycerides, but failed to reduce the risk for heart attack or stroke. The findings of this trial highlight the multifactorial pathology of cardiovascular disease; Life Extension believes that had these patients been receiving antioxidants like CoQ10 to reduce LDL oxidation, pomegranate to improve endothelial function, and fish oil to regulate triglyceride levels there would have been a strong reduction in risk. Mainstream media outlets have used this study as a basis for headlines suggesting that niacin is ineffective for promoting cardiovascular health. However, the lesson that should be taken from these findings is that optimal cardiovascular protection requires a multi-modal approach, and should not be limited to one or two interventions.

Fish Oil, is a source of omega-3 fatty acids (eicosapentaenoic acid -- EPA, and docosahexaenoic acid -- DHA), which cannot be synthesized by humans but are nonetheless essential for several metabolic processes. Aside from reductions in the risk of cardiovascular mortality and non-fatal cardiovascular events (supported by studies of tens of thousands of moderate and high risk patients)154, fish oil fatty acids significantly reduce serum triglycerides. Forty-seven studies, comprising over 15,000 patients, have confirmed an average triglyceride reduction of 30 mg/dL, at an average intake of 3.35g EPA+DHA over 24 weeks.155 Triglycerides were reduced in a dose-dependent manner, and were dependent on baseline levels (reductions of greater than 40% were observed in patients with the highest starting triglyceride levels). Slight increases in LDL-C and HDL-C were also observed in these studies, although other large analyses failed to detect any significant effects of fish oil on cholesterol.156 The mechanism by which EPA + DHA lowers triglycerides thought to be by slowing the release of VLDL particles into the plasma, or increasing lipid degradation and clearance of triglyceride-rich lipoproteins from the blood.157 Lowering triglyceride levels is a known strategy for increasing the amount of large buoyant LDL and reducing the amount of small dense LDL.

Prescription fish oil uses a highly concentrated EPA+DHA fish oil ester that provides a dosage of 3.36 g of omega-3 in 4 capsules; its degree of triglyceride reduction (up to 45%) is similar to non-prescription fish oil at a similar dose (usually requiring several more capsules.)157 Non-prescription fish oil supplements sell at a fraction of the price of prescription fish oil and usually require one or more additional capsules to be taken daily to obtain the same amount of EPA/DHA.

Alpha-cyclodextrin is a soluble fiber from corn that has received much attention for its ability to bind to dietary fats and prevent their absorption.175-177 In early animal research, rats fed a high-fat diet had reductions in triglyceride and total cholesterol levels when alpha-cyclodextrin was added to their food. The addition of alpha-cyclodextrin resulted in less weight gain, reductions in plasma cholesterol and triglycerides, restored insulin sensitivity, and normalized leptin levels.176 Results from an animal study found alpha-cyclodextrin lowered total cholesterol, with an apparent ability to selectively lower pro-atherogenic apoB lipoprotein, while leaving protective HDL cholesterol unchanged. Studies in rodent models have also revealed alpha-cyclodextrin may have a special affinity to bind atherogenic saturated and trans-fatty acids rather than unsaturated fatty acids.177,178

Beneficial effects of alpha-cyclodextrin have been borne out in human studies. For instance, in a double-blind placebo-controlled clinical trial, 66 obese diabetic patients took either 2 g alpha-cyclodextrin or placebo with each fatty meal for three months. At the end of the study, subjects with hypertriglyceridemia in the alpha-cyclodextrin group had reductions in total cholesterol levels, while cholesterol levels rose in the placebo group. Adiponectin levels rose in the alpha-cyclodextrin group but fell in the placebo group; and subjects in the alpha-cyclodextrin group maintained their weight, while those in the placebo group gained weight.179 In a controlled clinical trial in 28 healthy adults, taking alpha-cyclodextrin with fat-containing meals for 30 days resulted in significant reductions in levels of total cholesterol, LDL cholesterol, and weight. Weight loss was over 90% greater in the alpha-cyclodextrin group compared with the control group. Insulin and apolipoprotein B levels also fell in the alpha-cyclodextrin group. Importantly, no adverse effects were reported. Alpha-cyclodextrin forms a complex with fats, and while it does increase excretion of fat in the stool, it does not appear to cause the fecal incontinence commonly seen with use of medications that block dietary fat digestion.175,177,180

Probiotics are increasingly recognized for their critical role in regulating immune activity, reducing inflammation throughout the body, and have attracted interest for their ability to reduce LDL cholesterol and cardiovascular risk. A review of research found that, of the probiotic strains studied, Lactobacillus reuteri (L. reuteri) NCIMB 30242 has excellent evidence for reducing cardiac risk by safely lowering levels of total and LDL cholesterol as well as markers of inflammation.181

In a randomized controlled trial, 114 participants with high cholesterol levels who were otherwise healthy consumed either a probiotic yogurt providing 2.8 billion colony forming units of microencapsulated L. reuteri NCIMB 30242 or a control yogurt daily for six weeks. The L. reuteri group had reductions in total cholesterol (9%) and LDL-cholesterol (5%), levels relative to the placebo yogurt group. ApoB100, which at high levels is associated with vascular disease, was significantly reduced in the L. reuteri group.182,183 In another controlled clinical trial on 127 healthy adults with high cholesterol levels, subjects received either capsules of L. reuteri NCIMB 30242 or placebo for nine weeks. Those taking the L. reuteri probiotic had a greater than 9% drop in total cholesterol and a drop in LDL cholesterol levels of over 11.5% compared with placebo. The ratio of apoB-100 to apoA-1 fell by 9% in the L. reuteri-supplemented group compared with placebo. The apoB-100:apoA-1 ratio is a strong predictor of cardiovascular risk, particularly in overweight and obese individuals.184,185 High-sensitivity C-reactive protein and fibrinogen, additional markers of cardiovascular risk, were also significantly reduced relative to placebo.186 Interestingly, later analyses of the results from this study identified two other attributes of L. reuteri: subjects taking the probiotic experienced general improvement in functional gastrointestinal symptoms187 and a significant increase in levels of vitamin D compared with placebo.188

Although the exact mechanism by which L. reuteri NCIMB 30242 improves lipid levels has not yet been fully characterized, it is known that intestinal microbes have a role in regulating cholesterol transport and metabolism, and this effect may in part depend on an ability to break down bile acids in the digestive tract.181,186 Bile acids have a close relationship with intestinal microbiota and help regulate cholesterol synthesis and lipid and glucose metabolism.189,190 By increasing bile acid breakdown and excretion, L. reuteri is thought to stimulate cholesterol-dependent bile acid production in the liver, removing cholesterol from circulation.190

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