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Health Protocols

Cholesterol Management

Integrative Interventions

Artichoke

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 mechanisms of action may be linked to reduction of LDL oxidation, or the ability of one of its constituents, luteolin, to indirectly inhibit HMG-CoA reductase.74

Several randomized controlled trials support the ability of artichoke extract to lower total- and/or LDL cholesterol. In one trial, artichoke extract (1,800 mg/day) for six weeks reduced total cholesterol (-9.9%) and LDL cholesterol (-16.6%) in 71 hypercholesterolemic patients, with no differences in HDL cholesterol or triglycerides.75 In another trial in hypercholesterolemic patients, 1,280 mg artichoke extract per day for 12 weeks reduced total cholesterol by 6.1% when compared with a control group. Changes in LDL cholesterol, HDL cholesterol, and triglycerides were insignificant.76 Some studies indicate artichoke supplementation can raise HDL levels.77,78 Artichoke extract also improved parameters of endothelial function in a small trial.79

Pantethine

Pantethine, a derivative of pantothenic acid (vitamin B5), can serve as a source of the vitamin. Pantethine and its metabolites appear to act on the body’s fat and cholesterol metabolism pathways. 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.80 Studies of pantethine consumption have demonstrated significant reductions in total cholesterol and LDL cholesterol (up to 13.5%), triglycerides, and elevation of HDL cholesterol in people with high cholesterol81,82 and diabetic individuals83 when taken at 900‒1,200 mg/day, although significant effects on triglycerides have been observed at dosages as low as 600 mg/day.84 A well-controlled clinical trial demonstrated that, when added to a diet low in saturated fat and cholesterol, pantethine provided an additional reduction in total cholesterol and LDL.85

Indian Gooseberry (Amla)

Indian gooseberry or amla, a common name for the plant Phyllanthus emblica (Emblica officinalis), has been used traditionally in Indian Ayurvedic medicine for a variety of conditions.86 In animal models, Indian gooseberry has demonstrated powerful antioxidant and anti-inflammatory effects.87 For instance, in an animal model of metabolic syndrome induced by a high-fructose diet, administration of amla extract controlled rising cholesterol and triglyceride levels and significantly reduced the expression of some inflammation-related genes typically elevated in metabolic syndrome.88

Several clinical trials have demonstrated that Indian gooseberry extract favorably influences blood lipids and cholesterol. Healthy and diabetic volunteers given 2 or 3 grams per day of Indian gooseberry for three weeks experienced significant decreases in total cholesterol and triglycerides.87 A head-to-head comparison between amla and simvastatin (Zocor) in 60 hyperlipidemic individuals demonstrated similar effects on lipid profile.89 In individuals with type 2 diabetes, doses of either 250 or 500 mg of an amla extract standardized to 60% low molecular weight hydrolyzable tannins, taken twice daily, significantly lowered total cholesterol, LDL and VLDL cholesterol, triglycerides, and significantly raised HDL cholesterol levels compared to both baseline and placebo.90 In a 12-week trial in 15 overweight or obese adults who were 36 years old on average, 500 mg twice daily of this same high-tannin extract had a significant beneficial impact on markers of cardiovascular risk. Compared with baseline, the amla extract reduced calculated LDL cholesterol, total cholesterol/HDL ratio, and hs-CRP levels.91

Garlic

Garlic’s benefits have been substantiated by several human trials, particularly its ability to support favorable blood lipid profiles. Three separate analyses of 32 blinded and controlled human trials of garlic consumption in healthy individuals or those with high cholesterol and triglycerides confirmed significant reductions in total cholesterol by an average of 7.3 mg/dL, and triglycerides by an average of 4.2 mg/dL.92-94 While average cholesterol reductions across human studies were modest, greater reductions in total cholesterol were realized in patients who initially had high cholesterol or triglycerides (>11 mg/dL) and who took the extract for over 12 weeks (11 mg/dL).92

A comprehensive review of 39 primary trials concluded that prolonged (greater than two months) use of garlic preparations appeared effective in reducing total cholesterol and LDL in individuals with elevated cholesterol and had a low rate of side effects.95

Garlic also reduces systolic and diastolic blood pressure in hypertensive individuals, and systolic blood pressure in persons with normal blood pressure. A review and analysis of 11 placebo-controlled human trials of garlic showed a mean decrease of 4.6 mm Hg for systolic blood pressure in the garlic group; the mean decrease in a hypertensive subgroup was 8.4 mm Hg for systolic blood pressure and 7.3 mm Hg for diastolic blood pressure.96

Gynostemma pentaphyllum (G. 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).97,98 This enzyme, which affects glucose metabolism and fat storage, has been called a “metabolic master switch” because it controls numerous metabolic pathways.99,100

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.97 It can also prevent damage to blood vessel lining (endothelial) cells caused by oxidized LDL.101

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 1,800 mg for an adult human) of the extract had total cholesterol reductions of 14.2% and 7.1%, respectively, compared with the control group.97 In a 12-week placebo-controlled trial of G. pentaphyllum in healthy obese men and women, abdominal fat, body weight, overall body fat and percent body fat were all significantly reduced compared with placebo.100

Hesperidin

Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels.102,103 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.104,105 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 AMPK pathway.106-108 Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging.104

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 hesperidin daily improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury.109 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.110

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg 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 hs-CRP,111 as well as significant decreases in levels of total cholesterol, ApoB, and markers of vascular inflammation relative to placebo.107 In another randomized controlled trial in overweight adults with evidence of 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.112 In yet another randomized controlled trial including 75 heart attack patients who received 600 mg hesperidin or placebo daily for four weeks, those taking hesperidin had significant improvements in HDL cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism.113

Plant Sterols

Plant sterols are steroid compounds found in plants that function similarly to cholesterol in animals (ie, as components of plant cell membranes, and precursors to plant hormones).114 Like cholesterol, they can exist as free molecules or sterol esters. Esters of sterols have a higher activity and better fat solubility, which allows for lower effective dosages (2‒3 grams/day as opposed to 5‒10 grams/day for unesterified sterols).115 Sterols themselves are poorly absorbed from the diet, but because of their chemical similarity to cholesterol, are thought to compete with cholesterol for absorption in the intestines, which has the net effect of reducing LDL levels.116 Sterols may also reduce cholesterol production in the liver, reduce the synthesis of VLDLs, increase LDL particle size, and increase LDL uptake from the blood.117,118 HDL is generally not affected by sterol intake.119

There have been numerous studies of the effects of sterol esters on reducing mean total cholesterol and LDL cholesterol in healthy, hypercholesterolemic, and diabetic individuals. An analysis of 57 trials involving over 3,600 individuals reported an average LDL cholesterol reduction of 9.9% at a mean intake of 2.4 grams sterol esters/day.120 This benefit extends to sterol supplements delivered in tablet form.114 Sufficient evidence for the cholesterol-lowering effects of sterols prompted the U.S. Food and Drug Administration (FDA) to permit the health claim that sterol esters may be associated with a reduced risk of CHD, when taken at sufficient levels in the context of a healthy diet.121 The National Cholesterol Education Program122 and American Heart Association123 both support the use of sterols in their dietary recommendations. A comprehensive review by a lipid expert panel suggests plant sterols alone or in combination with other dietary supplements and/or ezetimibe could be considered as alternatives or add-on therapy to statins.124

Guggul/gum guggul

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.125 Evidence of inconsistent quality suggest guggul supplementation may help improve the lipid profile, but better-designed trials are needed to clarify efficacy.125-131

Soluble Fibers

Soluble fibers include non-digestible and fermentable carbohydrates, and their sufficient intake has been associated with lower prevalence of cardiovascular disease.119 When included as part of a low-saturated fat/low-cholesterol diet, they can lower LDL cholesterol, generally by roughly 5‒10%, in hypercholesterolemic and diabetic patients, and may reduce LDL cholesterol in healthy individuals as well.132 The cholesterol-lowering properties of soluble oat fiber, psyllium, pectin, guar gum, beta-glucans from barley, and chitosan are substantiated by dozens of controlled human clinical trials.133-135 A 2015 review of 17 randomized controlled trials concluded that beta-glucan consumption significantly reduced total cholesterol and LDL in hypercholesterolemic individuals without any reported adverse effects.136 Soluble fibers lower cholesterol by several potential mechanisms.133 They may directly bind bile acids or dietary cholesterol, preventing/disrupting their absorption. Their high viscosities (measure of a liquid’s thickness) and effects on intestinal motility may slow or limit macronutrient uptake. They can also increase satiety, which can limit overall energy intake.

Alpha-cyclodextrin

Alpha-cyclodextrin, a soluble fiber derived from corn, has received much attention for its ability to bind to dietary fats and prevent their absorption.137-139 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.138 Results from an animal study found alpha-cyclodextrin lowered total cholesterol, with an apparent ability to lower ApoB-containing lipoproteins, 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.139,140

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 grams 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.141 In a controlled clinical trial in 28 healthy adults, taking alpha-cyclodextrin with fat-containing meals for 30 days resulted in significant reductions in total cholesterol, LDL cholesterol, and weight. Weight loss was over 90% greater in the alpha-cyclodextrin group than the control group. Insulin and ApoB 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.137,139,142

A randomized controlled study in 2016 gave a group of healthy participants alpha-cyclodextrin supplements or placebo. While there was no change overall in basic lipid parameters (total cholesterol, LDL, HDL, triglycerides), there was a 10% drop in small-dense LDL, considered to be more atherogenic.143 In an animal model of atherosclerosis, adding alpha-cyclodextrin to a Western diet decreased aortic plaque formation.144

Coenzyme Q10 (CoQ10)

The generation of chemical energy in the form of ATP by mitochondria is an essential biological function. Delicate endothelial cells that line 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.145,146 CoQ10 is an integral component of mitochondrial metabolism, serving as an intermediary transporter between two major check points in ATP production. Interestingly, because CoQ10 is lipid soluble, it is incorporated into LDL particles, where it serves to protect against oxidation. Insufficient levels of CoQ10 expedite atherogenesis by limiting mitochondrial efficiency in endothelial cells and leaving LDL particles vulnerable to oxidative damage. Statin drugs, which are typically used to treat high cholesterol, ironically also suppress levels of CoQ10 in the blood.147 Individuals taking a statin drug should always supplement with CoQ10.

In a randomized, controlled, double-blind trial, the addition of 200 mg CoQ10 daily in people taking statins and omega-3 fatty acids improved a range of cardiovascular risk factors. Total cholesterol, systolic blood pressure, and inflammatory markers (hs-CRP and interleukin-6) were all significantly reduced, while internal antioxidant defenses increased and statin-related adverse effects diminished.148

A 2018 review of randomized clinical trials in patients with coronary artery disease concluded that supplementation with CoQ10 reduces total cholesterol and increases HDL. This study also detected a trend for CoQ10 to reduce LDL and Lp(a).149 A previous review also found that CoQ10 supplementation reduced Lp(a).150

Carotenoids

Carotenoids are common constituents of the LDL particle. Beta-carotene is the second most abundant antioxidant in LDL; other common dietary carotenoids (lycopene, lutein) may be transported by LDL particles as well.28 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.151 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 revealed an average reduction in LDL cholesterol of approximately 12%.152 Potential mechanisms for this action are suppression of cholesterol synthesis by inhibition of the HMG-CoA reductase enzyme or an increase in the rate of LDL degradation.153 In an animal model, lycopene attenuated neointimal hyperplasia, a process that has a negative effect on the long-term success of balloon angioplasty of arteries.154 In another animal model, supplementing virgin olive oil with lycopene had an additive beneficial effect on blood lipids and even resulted in a decrease in body weight gain.155 A systematic review of human intervention trials that studied the consumption of tomato products and lycopene supplementation found that these interventions have beneficial effects of blood lipids and vascular function.156

Vitamin E

Natural tocopherols and tocotrienols together form vitamin E. These fat-soluble antioxidants have been studied for decades. Vitamin E inhibits the oxidation of LDL particles.157,158

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. 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.159 One major way it produces this effect is by sponging up destructive reactive nitrogen species, such as peroxynitrite.160 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.161

Supplementation in humans with 100 mg per day gamma-tocopherol resulted in a reduction in several risk factors for vascular disease (eg, platelet aggregation and LDL cholesterol levels).162

Tea Polyphenols

Polyphenols are a diverse set of phytonutrients that are ubiquitous in the diet. Both green and black tea contain polyphenols. Green tea catechins exhibited significant cholesterol (LDL) lowering in an analysis of several studies (averaging about 9 mg/dL over four studies).163 A meta-analysis corroborated green tea’s beneficial effects on total cholesterol and LDL as well as systolic blood pressure.164 A head-to-head comparison of green tea versus the diabetes medication metformin in obese women at risk of developing diabetes found that green tea performed better at lowering total cholesterol and LDL.165 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 cholesterol after three months.166 In a series of preclinical studies, black tea theaflavins effectively reduced total cholesterol, LDL, and triglycerides.167

Pomegranate

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.168,169

Consumption of pomegranate polyphenols significantly lowered total and LDL cholesterol concentrations while maintaining HDL levels in subjects with elevated cholesterol profiles.170 Pomegranate also suppresses immunoreactivity against oxidized LDL, a mechanism which would be expected to limit plaque formation in the intimia.171 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 placebo group, carotid intima media thickness (cIMT; a measure of atherosclerosis) increased by 9% one year after study initiation, while cIMT decreased 30% in the pomegranate group. Pomegranate also significantly reduced oxidized LDL concentrations and increased serum antioxidant activity, compared with placebo, while simultaneously lowering blood pressure. Moreover, pomegranate nearly doubled the activity of paraoxonase-1 (PON-1), an antiatherogenic enzyme that optimizes HDL function and protects lipids from oxidative damage.172 Both groups continued on standard therapy that may have included statins, anti-hypertensives, etc.

In a randomized controlled clinical trial, women with metabolic syndrome were given polyphenol-rich pomegranate juice or water. Women who received the juice were found to have significantly lower levels of an oxidative stress marker and higher levels of healthy monounsaturated fatty acids in their red blood cell membranes. Plasma levels of the pro-inflammatory fat arachidonic acid were reduced in juice group.173 Consumption of pomegranate juice was shown to lower atherosclerosis risk factors in hemodialysis patients in another randomized placebo-controlled trial.174 In a trial on 48 overweight or obese participants, 1,000 mg pomegranate extract daily improved total cholesterol, LDL cholesterol, and HDL cholesterol levels as well as several other markers of metabolic health and inflammation.175

Curcumin

The active ingredient in turmeric (and also the main compound that gives it its bright yellow color), curcumin has a variety of protective roles in CVD, potentially reducing oxidative stress, inflammation, and the proliferation of smooth muscle cells and monocytes. Ninety-five small human trials have revealed the effects of curcumin on reducing lipid peroxidation176,177 and plasma fibrinogen,178 both factors in the progression of atherosclerosis.179 Curcumin may also reduce serum cholesterol by increasing the production of the LDL receptor,180,181 but despite successes in animal models, human data on the anti-hypercholesterolemic 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 cholesterol (29%) when using 500 mg curcumin daily for seven days.182 In two subsequent studies, low-dose curcumin showed a non-significant trend toward lowering total cholesterol and LDL cholesterol in acute coronary patients,183 while high dose-curcumin (1‒4 grams/day) exhibited non-significant increases in total-, LDL-, and HDL cholesterol.184

An analysis of seven randomized controlled trials concluded that turmeric and curcumin were effective in lowering LDL cholesterol and triglycerides without any serious side effects.185 When compared with placebo, supplementation with turmeric led to a reduction in body mass index, total cholesterol, and triglycerides in a study of patients with type 2 diabetes.111 A similar study involving individuals with metabolic syndrome found curcumin had a beneficial effect on lipid parameters (decreased LDL and increased HDL).186

Fish Oil

Fish oil has long been used as a nutritional supplement to support cardiovascular health. It contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids have been shown to positively modulate several aspects of cholesterol and lipid metabolism. For instance, omega-3 fatty acids may beneficially affect reverse cholesterol transport. Omega-3 fatty acids are thought to accomplish this by influencing HDL remodeling and promoting excretion of cholesterol components via the liver and gallbladder.187 Increasing omega-3 fatty acid intake also helps keep the omega-6 to omega-3 fatty acid ratio in a healthy balance. The evolutionary human diet contained roughly equal amounts of omega-6 and omega-3 fatty acids, whereas today’s Western diet typically contains much more omega-6 fats. An imbalance too heavily favoring omega-6 is associated with increased risk for a variety of diseases, including cardiovascular disease.188 In addition to eating healthful foods rich in omega-3s, supplementation is an effective method of balancing the ratio.

In a review of 22 studies on supplemental or prescription fish oil preparations that evaluated the effects of EPA and DHA on blood lipids, DHA was found to decrease triglyceride levels by 6.8% and increase HDL levels by 5.9%.189 Although DHA is known to slightly elevate LDL levels, high-dose DHA has been shown to increase LDL turnover and LDL particle size190 (larger LDL particles may not promote atherosclerosis as much as small LDL particles). In a rigorous clinical trial, 4 grams daily of a prescription-only drug form of EPA called icosapent ethyl (Vascepa) reduced the risk of cardiovascular events in people with high triglycerides who were taking statins.191

In mid-2019, the U.S. FDA responded to a health petition and stated it would not object a qualified health claim for omega-3 fatty acids despite concluding that “the evidence is inconsistent and inconclusive.” One variant of the qualified health claim to which the FDA has not objected reads as follows:

  • “Consuming EPA and DHA combined may reduce the risk of CHD (coronary heart disease) by lowering blood pressure.”

Probiotics

Probiotics, which are increasingly recognized for their role in regulating immune activity and reducing inflammation throughout the body, 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 reuteri192 NCIMB 30242 has been shown to lower levels of total and LDL cholesterol as well as markers of inflammation.193

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 (CFUs) 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. ApoB-100, which at high levels is associated with vascular disease, was significantly reduced in the L. reuteri group.194,195 In another controlled clinical trial on 127 healthy adults with high cholesterol levels, subjects received either L. reuteri NCIMB 30242 capsules or placebo for nine weeks. Those taking L. reuteri had a greater than 9% drop in total cholesterol and greater than 11.5% drop in LDL cholesterol levels 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.196,197 Fibrinogen and hs-CRP, additional markers of cardiovascular risk, were also significantly reduced relative to placebo.198 Interestingly, later analyses of the study results noted that subjects taking the probiotic experienced general improvement in functional gastrointestinal symptoms199 and a significant increase in vitamin D levels compared with placebo.200

Although the exact mechanism by which L. reuteri NCIMB 30242 improves lipid levels has not 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.193,198 Bile acids have a close relationship with intestinal microbiota and help regulate cholesterol synthesis and lipid and glucose metabolism.201,202 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.202

An analysis of 30 randomized controlled trials encompassing over 1,600 subjects found those treated with probiotics had on average 7.8 point-lower total cholesterol and 7.3 point-lower LDL levels than those not treated.203 Another review concluded L. acidophilus-specific probiotics were particularly effective in lowering LDL levels.204 Furthermore, a systematic review of all Lactobacillus strains used in randomized controlled trials found that on average, Lactobacillus use shaved about five points off total cholesterol and four points off LDL cholesterol.192 A review of probiotic use in the type 2 diabetes population205 found that significant reductions in total cholesterol, triglycerides, LDL, and blood pressure were associated with supplementation.206

Prebiotics

Prebiotics, a subset of soluble fiber, have gained attention for their ability to be selectively fermented by gut flora for a variety 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.133 In human trials, the prebiotic fibers inulin and dextrin induced reductions in serum levels of total cholesterol (-9% and -2% for inulin and dextrin, respectively), LDL cholesterol (-1 % for dextrin), and triglycerides (-21% for inulin).207,208

Red Yeast Rice

Red yeast rice is a traditional preparation of rice fermented by the yeast Monascus purpureus. The yeast produces metabolites (monacolins) that are naturally-occurring HMG-CoA reductase inhibitors (one of these, monacolin K, is chemically identical to lovastatin).209 A comprehensive review of 93 randomized trials including nearly 10,000 patients demonstrated that commercial preparations of red yeast rice produced reductions in total cholesterol, LDL cholesterol, triglycerides, and an increase in HDL cholesterol.210 A multicenter well-controlled trial which compared a red yeast rice extract called Xuezhikang to placebo demonstrated a 27% decrease in LDL.211 And a review of 22 clinical trials supported Xuezhikang’s use to reduce death and heart attack risk when added to conventional treatment for CHD.212 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 with placebo.213 Red yeast rice extracts have also been shown to be well tolerated and effective in lowering LDL in patients with statin intolerance214,215 and safe and effective in LDL-lowering even in younger individuals.216 Because of this evidence, the International Lipid Expert Panel recommended red yeast rice’s use in those whose LDL target has not been reached due to statin intolerance.124

Due to regulations regarding their labeling in the United States, standardization of commercial red yeast rice preparations for monacolins is problematic, thus levels of monacolins can vary dramatically between red yeast rice products.217

Bergamot

Likely indigenous to the Calabria region of Italy, bergamot is a fruit considered by most experts to be a hybrid of sour orange and lemon, or perhaps a natural mutation of lemon. Bergamot’s essential oils contain flavonoid glycosides which have statin-like effects6 and also naringin, which has been shown in an animal model to inhibit the oxidation of LDL and increase the fecal excretion of cholesterol.50 A small clinical trial in people with high cholesterol showed bergamot juice extract reduced total cholesterol, LDL and triglycerides; decreased the presence of small, dense LDL; and led to significant shrinkage of atherosclerotic plaque in the carotid arteries.218 A trial that enrolled 98 people with elevated blood lipids found that 12 weeks of supplementation with a formula based on bergamot extracts led to reduced triglycerides and greater weight loss compared with placebo.219 Bergamot may also compliment statin drugs. An open-label placebo-controlled trial enrolled 77 people with elevated LDL cholesterol and triglycerides and randomized them into four groups: 1) placebo, 2) 10 mg or 20 mg daily of rosuvastatin, 3) bergamot polyphenols, and 4) bergamot polyphenols plus 10 mg rosuvastatin. The researchers found that the bergamot polyphenols enhanced the lipid-lowering effect of rosuvastatin.220

Niacin and Lipid Management

The story of niacin in the context of lipid management and cardiovascular medicine has evolved substantially over the last several decades. Early trials conducted in the 1970s and ‘80s found niacin helped reduce cardiovascular risk. Subsequently, clinical use of niacin increased, and the FDA granted approval in 1997 for the use of niacin to reduce risk in people with a history of a cardiovascular event. Approved indications later expanded to include lipid management in some people who had not had a cardiovascular event, including use in combination with statins. However, the FDA withdrew some approved indications in 2016 after two large trials showed niacin did not reduce risk when added to statins. Niacin remains FDA approved for lipid management in people not taking statins.221

Reliable published data shows niacin favorably modulates the lipid profile, primarily affecting HDL and triglycerides.222 However, niacin therapy has not been consistently shown to reduce the rate of cardiovascular events.223 Niacin may be helpful for managing lipids when used alone by people who have experienced a cardiovascular event and are not using statins.221 Some doctors may recommend niacin for people with stubbornly high triglycerides despite trying other interventions.

Niacin may be a helpful addition to an overall cardiovascular risk management strategy in people not taking statins. A qualified physician should be consulted to determine whether niacin is a reasonable option for people with elevated lipids who do not wish to take statin drugs, those with statin resistance, or those unable to tolerant statins.

It is important to keep in mind that niacin often causes an unpleasant flushing effect. This reaction is transient and typically consists of skin reddening, burning, and tingling, and can be quite unpleasant. Some people report developing a tolerance to the niacin flush or a diminished reaction with continued use.


Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.

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