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Women’s Functional & Integrative Medicine Professional Training

Metabolism and Cardiovascular II: Supplement Support

MODULE 17

Supplement Support

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Garlic• Garlic supplements have shown promise in the treatment of uncontrolled hypertension, lowering

blood pressure (BP) by about 10 mmHg systolic and 8 mmHg diastolic, similar to BP medication.

• A meta-analysis of 26 studies found that garlic significantly reduced total cholesterol and triglyceride levels but not HDL and LDL, while other report that raw and aged garlic reliably reduce total cholesterol and LDL-C, while increasing HDL-C.

• Compared with the placebo groups, serum total cholesterol and triglyceride levels in the garlic group were reduced by 0.28 mmol and 0.13 mmol, respectively.

• The benefits of garlic were greater for individuals who used it long-term and who had higher baseline total cholesterol levels. Garlic powder and aged garlic extract were more effective in reducing serum total cholesterol levels, and garlic oil was more effective in lowering serum triglyceride levels.

• Garlic’s BP lowering effects are due to enhanced NO signaling and due to its hydrogen sulfide (H2S) signaling which in turn relaxes blood vessels and lowers blood pressure.

• In those with elevated cholesterol (>200 mg/dL, >5.5 mmol/L), consistently consuming garlic for two months or more can moderately reduce total as well as low-density lipoprotein (LDL) cholesterol and can slightly bump up high-density lipoprotein (HDL).

Integr Blood Press Control. 2014; 7: 71–82. • Eur J Clin Nutr. 2013 Jan; 67(1): 64–70.

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• Side effects of garlic supplements, reported by about a third of participants in these trials, were generally mild, and included burping, gas, and reflux in the first few weeks of the trial. 4%–6% of users may experience more severe GI disturbances with therapeutic dosages. Lower tolerance of sulfur-containing foods such as garlic, onion, and leek may be reversed by supplementation with molybdenum and/or vitamin B12, often deficient in affected individuals

• Several dietary and genetic factors, including folate, vitamin B6, and vitamin B12 deficiency, and known genetic variants of the MTHFR and CBS genes, influence the efficiency of H2S production, and could be important contributors to hypertension in these individuals, which may also explain individual responsiveness to garlic supplementation seen in clinical trials.

• Safety: There is a low risk of interaction even at high doses with warfarin, however there is a potentially harmful interaction of garlic with protease inhibitors in antiretroviral therapy.

• Dose: Aged garlic two capsules daily containing 480 mg each daily, or approximately two cloves of garlic per meal or 10 g/day have been estimated to release sufficient H2S for maintaining the balanced blood vessel constriction

.Nutr Rev. 2013 May;71(5):282-99.

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Artichoke• Artichoke extract contains cynaroside and its

derivative called luteolin. Both of these constituents seem to block HMG-CoA reductase, similar to statin medications in lowering cholesterol.

• There is some preliminary evidence supporting artichokes’ ability to lower LDL cholesterol by 23% over a 6-week period.

• A 12-week study consisting of 75 patients used 1,280 mg of artichoke leaf extract and demonstrated its effectiveness in decreasing cholesterol. The study found a 4.2% decrease in total cholesterol for the artichoke leaf extract group, compared to a 1.9% decrease in the placebo group.

• A 6-week study consisting of 143 patients with hyperlipoproteinemia used 1,800 mg of artichoke leaf extract per day. The study found

these doses helped prevent atherosclerosis, cardiovascular disease and helped lower total cholesterol and LDL. No adverse effects were seen. In the artichoke group, total cholesterol was lowered over 18% and LDL was lowered over 22% versus the placebo group where total cholesterol was lowered only 8.6% and LDL was lowered 7.9%.

• Safety: Other than inducing flatulence and the remote possibility of an allergic reaction, artichoke appears to be safe with no known drug-herb interactions.

• Dose: Recommended to eat the food. If this is not possible, the dose of Artichoke Extract is 1800 mg in divided doses (600 mg three times/day or 900 mg twice/day).

Cochrane Database Syst Rev. 2002;(3)(3):CD003335. • Arzneimittelforschung. 2000;50(3):260-265. • Phytomedicine. 2008 Sep; 15(9):668-75.

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Glucomannan• Evidence from randomized controlled trials (RCTs) suggests the consumption of konjac

glucomannan (KJM), a viscous soluble fiber, for improving LDL-cholesterol concentrations. It has also been suggested that the cholesterol-lowering potential of KJM may be greater than that of other fibers.

• A systematic review and meta-analysis aimed to assess the effect of KJM on LDL cholesterol, non-HDL cholesterol, and apolipoprotein B.

• Twelve studies (n = 370), 8 in adults and 4 in children, met the inclusion criteria.

• KJM significantly lowered LDL cholesterol and non-HDL cholesterol.

• Data from 6 trials suggested no impact of KJM on apolipoprotein B.

• Our findings support the intake of ∼3 g KJM/d for reductions in LDL cholesterol and non-HDL cholesterol of 10% and 7%, respectively.

• Dose: 1-4 gm/day

Am J Clin Nutr. 2017 May;105(5):1239-1247.

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Hibiscus• In vitro studies show Hibiscus sabdariffa L., an ingredient found in many herbal tea blends and

other beverages, has ‘antioxidant’ properties, and, in animal models, extracts of its calyces have demonstrated hypocholesterolemic and antihypertensive properties.

• Appears to have evidence to support its role in reducing blood pressure in persons with elevated blood pressure. It may be this through ACE inhibitory potential (although this is admittedly weak) or benefitting the endothelium via nitric oxide related mechanisms (appears to be in better accordance with the amount of anthocyanins that reach the blood).

• Reductions in both diastolic and systolic blood pressure have been noted, and for the most part appear to be reliable in presence although not so much in magnitude of benefit (ie. blood pressure is reliably reduced, but the degree of reduction seems to vary).

• In regards to diabetes and blood glucose control, H. sabdariffa appears to have limited evidence to support these claims but the evidence is so far in support.

https://examine.com/supplements/hibiscus-sabdariffa • J Nutr. 2010 Feb;140(2):298-303.Planta Med. 2007 Jan;73(1):6-12. • J Hum Hypertens. 2009 Jan;23(1):48-54. • Phytomedicine. 2010 Jun;17(7):500-5. doi: 10.1016 •

J Ethnopharmacol. 1999 Jun;65(3):231-6.• Phytomedicine. 2004 Jul;11(5):375-82. • J Nutr. 2010 Feb;140(2):298-303.

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• Safety: Higher doses of H. sabdariffa do exert toxic effects, although none of these toxic effects have been reported in humans (that being said, they have not conclusively been disproven either). It would be prudent to avoid taking too much Roselle, especially since many benefits of Roselle (elaborating on in complete summary) are not dose-dependent above the lowest observable toxic dose of 2.2g/150lb human

• Dose: Tea: 6 grams in 250 mL of water taken 2-3 times per day. Supplemental: taken according to the content of anthocyanins; 10mg of anthocyanins derived from H. sabdariffa (which would be 1g of a 1% extract or 500mg of a 2% extract) appears to be effective.

• Higher doses are associated with toxicity in rats, and it would be prudent to not exceed the above doses unnecessarily.

https://examine.com/supplements/hibiscus-sabdariffa • J Nutr. 2010 Feb;140(2):298-303.Planta Med. 2007 Jan;73(1):6-12. • J Hum Hypertens. 2009 Jan;23(1):48-54. • Phytomedicine. 2010 Jun;17(7):500-5. doi: 10.1016 •

J Ethnopharmacol. 1999 Jun;65(3):231-6.• Phytomedicine. 2004 Jul;11(5):375-82. • J Nutr. 2010 Feb;140(2):298-303.

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Myo-inositol• Eighty outpatient postmenopausal women, affected by metabolic syndrome, were enrolled

in a 12-month study.

• All the women were evaluated for serum glucose, insulin, HOMA-IR (Homeostasis Model Assessment-Insulin Resistance), triglycerides, total and high density lipoprotein cholesterol, body mass index (BMI), waist circumference and blood pressure at baseline and after 12 months of treatment.

• All women were treated with a low-energy diet, and then they were randomly assigned to myo-inositol 2 g BID (n = 40) or placebo (n = 40).

• With the exception of BMI and waist circumference, after 12 months of treatment, all the parameters studied showed a significant improvement in the myo-inositol group compared to the control group.

• At the end of the study, in the myo-inositol group, the number of women without metabolic syndrome was eight (20%) whereas, in the control group, only one woman no longer had the metabolic syndrome after 12 months of diet.

Climacteric. 2012 Oct;15(5):490-5.

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Curcumin• While all preliminary evidence, an increasing number of studies support the following

actions for curcumin:

o Reduction in BP

o Increased HDL-C

o Reduced LDL-C and triglycerides

• 80mg of a bioavailability enhanced curcumin supplement has been reported to increase nitric oxide in serum by 40% or so, which is significantly larger than many other dietary supplements.

• A decrease in lipid peroxidation and oxidative stress markers results from regular curcumin use.

Phytother Res. 2011 Nov;25(11):1721-6. • Nutr J. 2012 Sep 26;11:79.J Clin Psychopharmacol. 2008 Feb;28(1):110-3.

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Ginseng• A placebo-controlled, double-blind clinical trial was conducted in which 72 menopausal

women who were given either 3 gm red ginseng containing 60 mg of ginsenosides/day or placebo for 3 months. KI and MRS were used to assess subjective symptoms and CV risk factors were assessed with lipid testing, CRP, carotid artery intima-media thickness.

• Serum estradiol levels were also tested.

• After the 12 week the KI for the RG group reduced from 18.93 to 13.32 compared with the placebo from 15.21 to 15.10. The MRS score dropped from 12.45 to 8.32 in the ginseng group compared with 10.23 to 9.26 in the placebo group.

• RG led to a significant decrease in T-Chol from 138.11 to 108.82 compared with the placebo, from 128.52 to 128.03. LDL was also significant with no differences in HDL or CRP.

• Carotid intima-media thickness was significantly reduced in the red ginseng group compared with the placebo group.

Menopause. 2012 Apr;19(4):461-6.

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Bergamot• Bergamot is the common name of the fruit Citrus bergamia Risso

(family Rutaceae) which differs from other Citrus fruits in the composition and content of several distinct flavonoids, such as neoeriocitrin, neohesperidin, naringin (the latter also found in grapefruit)

• Three flavanones extracted from the bergamot peel act like statins. In addition, naringin, as well as neoeriocitrin and rutin have been reported to be active in animal models of atherosclerosis and have been shown to inhibit the oxidation of LDL.

• Animal studies have shown that constituents in this plant reduce cholesterol levels by modulating the activities of HMG-CoA reductase and acyl CoA:cholesterol O -acyltransferase (ACAT), binds to bile acids and increases the turnover rate of blood and liver cholesterol, and improves fecal excretion of sterols in rats.

• In vitro studies in human hepatoma cell line (HepG2) have shown that naringenin and hesperetin reduce the availability of lipids for the assembly of apolipoprotein (apo) B-containing lipoproteins. improved overall insulin sensitivity and glucose tolerance

• Two clinical trials (n=77, n=80) in patients with mixed dyslipidemia or moderate hypercholesterolemia received Bergamot products. After 6 months reductions in T-chol, LDL-C, and Tgs were observed, along with increased HDL.

• Currently there is not enough scientific information to determine an appropriate range of doses for bergamot. As discussed above, few clinical studies using bergamot have been performed and the doses ranged from 500 to 1000 mg/daily (in one study 650 mg twice daily). Some authors reported that in the absence of guidelines for the dosage of bergamot two to four 500 mg of extract in capsules is recommended to be taken once or twice a day for a month, while after that one capsule daily is enough to maintain this supplement in the blood.

• Bergamot appears safe to take with all other medications. However, caution is advised when using other supplements that also may decrease blood glucose, and medications which increase sensitivity to sunlight (photosensitizing drugs).

• Further, data suggests that bergamot induces complex effects on metabolic regulation and could be considered as an alternative treatment in patients who are intolerant to statins; its lipid and glycemic effects may result in a reduction of CV risk.

Phytomedicine 23 (2016) 1175–1181 • Front Pharmacol. 2015; 6: 299.

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Grapeseed Extract

• A randomized, double-blind, placebo-controlled study was conducted in almost 100 women between the ages of 40 and 60 years old. 40% to 48% were premenopausal and 52% to 60% perimenopausal, postmenopausal or surgically menopausal.

• Women were randomized to receive grape seed extract tablets that contained either 100 mg per day or 200 mg/day of proanthocyanidins or placebo for a total of 8 weeks.

• Significant changes were observed in hot flashes, anxiety, insomnia, increased muscle mass and reduced blood pressure.

• 100 mg and 200 mg were both found to be effective.

Menopause. 2014;21(9):990996.

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Relora

• A pilot clinical study with a small sample size (n=28), and high attrition indicated that obese subjects who eat in response to stress may benefit from proprietary extracts of M officinalis and P amurense at 250 mg TID x 6 weeks.

• Possible upregulation of DHEA

• The mechanism of action appears to be through reduction of cortisol levels and possibly perceived stress, thereby helping participants maintain body weight. Bedtime cortisol levels decreased in the treatment group and increased in the placebo group.

Altern Ther Health Med. 2006 JanFeb;12(1):504.

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Pantetheine• Pantethine, a naturally occurring derivative of

pantothenic acid (vitamin B5) is a precursor of coenzyme A, with an antiperoxidation effect in vivo, is purported, based on a large number of animal studies, to raise HDL, lower LDL and Tgs, and reduce arterial wall plaque.

• It is known to be well tolerated and B5 is ubiquitous in the diet and also produced by intestinal bacteria.

• In one study evaluating the cholesterol-lowering effectiveness of pantethine in women in perimenopausal age, 24 hypercholesterolemic women (total serum cholesterol greater than or equal to 240 mg/dl were treated with 900 mg/day of pantethine.

• After 16 weeks of treatment, significant reductions of total cholesterol, LDL-cholesterol and LDL-C/HDL-C

ratio could be observed.

• No remarkable changes of the main laboratory parameters (fasting blood sugar, BUN., creatinine, uric acid) were seen.

• Efficacy percentages of the treatment were about 80%.

• None of the patients reported adverse reactions and the authors concluded that pantethine should be considered in the long-term treatment of lipid derangements occurring in the perimenopausal age.

• Dose 450 mg BID x 4-12 months to see effectiveness.

Minerva Medica [01 Jun 1990, 81(6):475-479]

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Pueraria mirifica

• Postmenopausal women given Pueraria mirifica for two months had improved lipid profiles compared to a placebo control group. HDL increased 34% while LDL decreased 17% in the group receiving the Pueraria.

• Believed due to phytosterol constituents.

• Other studies have not been able to demonstrate improved blood lipids with this herb.

Journal of Restorative Medicine, Volume 1, Number 1, 1 September 2012, pp. 91-95(5)

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What About Red Yeast Rice (RYR)? • RYR is made by fermenting white rice with

the yeast, Monascus purpureus. The fermentation process turns the yeast red and produces mevinic acids. One of these acids is called monacolin K or mevinolin which is also found in the statin drug, lovastatin.

• These acids inhibit HMG CoA reductase and reduce cholesterol production from the liver. Red yeast also contains sterols, including beta-sitosterol (also found in vegetables), isoflavones (also found in soy), and monounsaturated fatty acids (also found in olive oil).

• The cholesterol-lowering effects likely are a combination of the statin-like mevinic acids

and its other plant-based constituents.

• A randomized trial compared 40 mg of simvastatin + educational pamphlet to Red Yeast Rice 1200 mg twice daily, fish oil (~ 3.5 gms daily) and a 12 week program that focused on the importance of a Mediterranean diet, exercise and relaxation.

• After 12 weeks, there was a 39% reduction of LDL in the simvastatin group and a 42% reduction in the RYR + lifestyle group.

• Research in China has shown that those patients who had a previous MI who were randomized to RYR had a decreased incidence of cardiac events and death.

Ann Intern Med. 2009;150(12):830-9, W147-9.

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• Inappropriate fermentation practice can result in the chemical citrinin which is a nephrotoxin. Monacolins block the production of cholesterol. Because red yeast rice preparations rarely declare their monacolin K content, understanding dose-related efficacy and side-effect risks in red yeast rice is practically impossible.

• Red yeast rice has been reported to occasionally have the same serious side effects as statins, including myopathy, rhabdomyolysis, and hepatotoxicity. To complicate matters further, different batches of red yeast rice crops may contain citrinin and additional toxic chemicals if they are grown with insecticides or pesticides.

• The problem is, 1) In a study published in

October 2010 in the Archives of Internal Medicine, 12 red yeast rice products were analyzed for their monacolin and citrinin content. The results of the analyses demonstrated a high variability of the content of both substances. 2) The U.S. Food and Drug Administration (FDA) has determined that red yeast rice products that contain more than trace amounts of monacolin K are unapproved new drugs and cannot be sold legally as dietary supplements.

• Dose: It’s recommended to take 1200 to 1800 mg twice daily. (3.6 g RYR = 6 mg of lovastatin)

American Journal of Medicine. October 2017, Volume 130, Issue 10, Pages 1148–1150

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Ok, and Then There’s Niacin• High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to

be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation.

• Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25% and has been shown in multiple surrogate end point studies to reduce CV risk.

• However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects.

• Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events.

• While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures.

Curr Atheroscler Rep. 2015 Aug; 17(8): 521. • N Engl J Med. 2014;371:203–212.Cleveland Clinic Journal of Medicine. 2012 January;79(1):38-43

FINIS!

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