US Pharm. 2024;49(9):33-37.

ABSTRACT: Hypertension and dyslipidemia affect nearly one-half of adults in the United States, and as patients become more motivated to take charge of their health, the use of dietary supplements to help treat these conditions is increasing. Pharmacists should be aware of dietary supplement products with supportive evidence—although limited—of efficacy for hypertension and dyslipidemia. These products include garlic, potassium, blue-green algae, L-arginine, vitamin C, and fish oil for hypertension and fish oil, niacin, red yeast rice, and berberine for dyslipidemia. Patients should be informed about the current evidence regarding the benefits of these dietary supplements so that they have realistic treatment expectations, understand possible adverse events, and are aware of potential drug interactions.

Hypertension and hyperlipidemia are common conditions in the United States, with staggering estimates of nearly one-half of all U.S. adults having high blood pressure (BP) and one-half having lipid abnormalities.1,2 Frequently, these populations overlap. Patients are increasingly motivated to take charge of their health, often turning to dietary supplements to achieve positive outcomes. Pharmacists are on the front line of dietary supplement use and should be knowledgeable about the evidence for and limitations of these products. This article will review dietary supplements that have the most supportive evidence for hypertension and lipid disorders. These include garlic, potassium, blue-green algae (BGA), L-arginine, vitamin C, and fish oil for hypertension and fish oil, niacin, red yeast rice (RYR), and berberine for dyslipidemia.

Hypertension

Garlic: Garlic plays an important role in the modern diet, and its medicinal properties have long been documented. Garlic has both cardioprotective and BP-reducing effects.3 Its mechanism of action is tied to its hydrogen sulfide production and the presence of allicin, which has angiotensin II–inhibiting and vasodilating effects.4 A meta-analysis concluded that garlic was superior to placebo for lowering BP, with a reduction in systolic BP (SBP) of 8.6 ± 2.2 mmHg in patients with hypertension.3 Most of the studies used garlic powder in dosages of 600 mg to 900 mg daily, although in some cases up to 2,400 mg daily was used. Many studies had small sample sizes and no standardized dosing.3 A double-blind, placebo-controlled, dose-response trial of 12 weeks’ duration found that aged garlic extract capsules at a dosage of 480 mg daily reduced SBP by 11.8 ± 5.4 mmHg.5

Garlic is typically well tolerated, and common side effects include bloating, flatulence, body odor, and reflux. Consideration should be given to potential drug interactions. Garlic may have antiplatelet effects and increased risk of bleeding if combined with anticoagulant or antiplatelet medications. Small clinical studies have demonstrated a mean AUC decrease of 51% for saquinavir when it was taken with garlic caplets and a 39% decrease in CYP2E1 activity when it was taken with garlic oil.6,7 These results raise concern over garlic’s effects on the CYP450 system. Garlic should be used with caution in conjunction with medications that undergo CYP metabolism. More studies of potential interactions are warranted.

Potassium: Higher dietary potassium intake is associated with a lower risk of developing hypertension, and it has been shown to reduce BP in patients with diagnosed hypertension. A higher potassium level appears to blunt the effects of sodium. A lower sodium-potassium ratio is associated with lower BP compared with sodium or potassium individually.8 Potassium’s role in BP reduction is recognized by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guideline.8 The guideline reports BP reductions of 4 mmHg to 5 mmHg in hypertensive patients and 2 mmHg in normotensive patients.9 Dosing varies, but the ACC/AHA guideline recommends a dietary potassium intake of 3,500 mg to 5,000 mg daily.8,9 Dietary sources of potassium include bananas, potatoes, spinach, and carrots. Potassium tends to be well tolerated; however, side effects may include abdominal pain, belching, diarrhea, flatulence, nausea, and vomiting. Rare but serious side effects associated with hyperkalemia include arrhythmia, heart block, hypotension, and confusion.10 Concomitant potassium supplementation with medications that increase potassium, including ACE inhibitors, angiotensin receptor blockers (ARBs), and potassium-sparing diuretics, should be avoided.

Blue-Green Algae: BGA (also known as spirulina) may lower BP, but its mechanism of action is not well understood. It has been hypothesized that BGA’s high potassium content leads to this antihypertensive effect.11 A meta-analysis of five randomized, controlled trials involving hypertensive patients who took 1 g to 8 g of BGA daily found an average SBP reduction of 4.6 mmHg and diastolic BP (DBP) reduction of 4.29 mmHg compared with placebo.12 In one randomized, controlled trial, hypertensive patients who were taking 2 g of BGA daily experienced a significant reduction in BP (6/5 mmHg) after 3 months.13

One consideration with BGA is the number of capsules or tablets to be taken. BGA is available in various strengths (e.g., 400 mg, 500 mg, 1,000 mg), so patients should be instructed on the correct amount to consume to achieve the desired 5-mmHg BP reduction. Patients should take 1 g of BGA for at least 12 weeks to achieve full effectiveness. BGA is generally well tolerated, but possible side effects include abdominal cramping, nausea, vomiting, and diarrhea.

L-Arginine: L-arginine is an amino acid found naturally in foods such as red meat, poultry, fish, and dairy. It is metabolized into nitric oxide (NO), causing NO-induced vasodilation and a mild reduction in BP. L-arginine also acts in the renin-angiotensin-aldosterone system by inhibiting ACE activity; this enhances the BP-lowering effect by reducing the conversion of angiotensin I to angiotensin II, resulting in less vasoconstriction and water and sodium retention.14 The effect of L-arginine on hypertension has been studied at dosages of 4 g to 24 g daily; however, daily dosages of 9 g or lower have the best evidence, and 3 g orally three times daily is recommended.15 A meta-analysis investigating the effect of L-arginine in patients with and without hypertension showed significant reductions of SBP by 6.40 mmHg and DBP by 2.64 mmHg.16 L-arginine effectively lowered BP regardless of resting BP category, although it was found that BP reduction was not significant in patients who were obese.16 Most studies of L-arginine have been of short duration.

Current data suggest that L-arginine becomes ineffective for reducing BP after 24 days of use.15 This is a major limitation for the treatment of chronic hypertension, and more positive evidence would be needed before long-term use can be recommended. Common adverse effects include abdominal pain, bloating, nausea, headache, and flushing.16 L-arginine has caused hyperkalemia in patients with renal insufficiency or failure; therefore, caution should be exercised when it is used in combination with ACE inhibitors and ARBs.15 Patients who have recently experienced a myocardial infarction should avoid L-arginine supplements, as research shows an increased mortality risk in patients who started taking L-arginine within 3 to 21 days of first ST-elevation myocardial infarction.17 Also, L-arginine should be discontinued at least 2 weeks prior to elective surgery, as it can complicate BP control during the procedure.15

Vitamin C: Vitamin C’s antihypertensive effects were first reported in the literature in 1946.18 This vitamin is thought to lower BP through its antioxidant properties by reducing oxidative stress and enhancing endothelial function. In a meta-analysis of 29 clinical trials, vitamin C was found to significantly reduce SBP by 4.85 mmHg and DBP by 1.67 mmHg in hypertensive patients in a pooled analysis; however, these studies had small sample sizes.19 The dosing of vitamin C supplements was quite varied, ranging from 60 mg to 4,000 mg daily (median: 500 mg daily).19 The most commonly available strengths are 500 mg to 1,000 mg, and this range could be taken orally once daily for hypertension. Vitamin C is generally well tolerated, with adverse effects more likely to occur at dosages exceeding 2 g daily. Side effects of vitamin C supplementation may include abdominal cramps, esophagitis, heartburn, headache, nausea, vomiting, and diarrhea.18

Fish Oil for Hypertension: There is evidence that fish oil is beneficial against both hypertension and hyperlipidemia. Fish oil is the dietary source of two omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplements contain varying amounts of EPA and DHA, which may affect a product’s efficacy for lowering BP. Compared with EPA, DHA may have greater BP effects because of its ability to reduce circulating levels of vasodilatory mediators.20 One study using 4 g of EPA/DHA for 4 months in mildly hypertensive patients showed a BP reduction of 6/5 mmHg.21 Fish oil has also been shown more effective in patients with untreated hypertension, with a lesser effect seen in patients who were taking antihypertensive medications at baseline.22 Based on the variety of fish oil supplement use evidenced in the literature, further research is required before a conclusive strength and frequency can be recommended for lowering patients’ BP. The most common adverse effects of fish oil supplementation include abdominal pain, heartburn, diarrhea, and eructation. Fish oil may interact with antiplatelet and anticoagulant medications to increase the risk of bleeding, and it may enhance side effects from sirolimus, cyclosporine, and tacrolimus.

Hyperlipidemia

Fish Oil for Hyperlipidemia: It has been found that fish oil is effective for lowering triglycerides (TG) in patients with severe hypertriglyceridemia (>500 mg/dL). The effect of fish oil on TG is due to an increase in VLDL clearance, reduced VLDL synthesis and secretion, increased fatty acid oxidation, reduced fatty acid synthesis, diversion of fatty acids to phospholipid synthesis, downregulation of fatty acid esterifying enzymes, and increased hepatic uptake of TG.23,24 The AHA has stated that a dosage of 4 g daily is clinically useful for lowering TG by 20% to 30%.23 Because the EPA/DHA content of dietary fish oil supplements is variable and frequently is low, the AHA supports the use of prescription omega-3 fatty acids to ensure the quality needed to achieve expected outcomes.23 The potential drug interactions and adverse effects of fish oil used for hyperlipidemia are the same as for hypertension (as discussed above).

Niacin: This form of vitamin B3 is found in many foods, including red meat, poultry, dairy, and green vegetables. Dosages of 500 mg daily or higher are FDA approved for treatment of primary hyperlipidemia and mixed dyslipidemia. Niacin appears to exert its cardioprotective effects by reducing fibrinogen concentrations in plasma and potentially stimulating fibrinolysis. It can bind G protein–coupled receptors on adipocytes, inhibit free fatty acid release from adipose tissue, and inhibit cyclic adenosine monophosphate production, which controls the activity of TG lipase.25 In dosages of 1 g daily or higher, niacin can reduce LDL by 25%, decrease TG by 20% to 50%, and increase HDL by 13% to 35%. Dietary supplements are available for purchase at lower strengths; however, these strengths have not been shown to improve lipid levels; therefore, patients should aim for a total daily dose of 500 mg to 1,000 mg.26

Niacin is well tolerated, and the most common side effects of supplementation are flushing, abdominal pain, constipation, diarrhea, and heartburn. Some rare but serious side effects are hepatotoxicity, myopathy, and vision changes. Niacin is contraindicated in patients with significant or unexplained hepatic disease, and it should be used with caution in patients with alcoholism, gallbladder disease, or hepatic dysfunction.27

Red Yeast Rice: RYR, a rice product fermented with Monascus purpureus yeast, contains monacolins, one of which, monacolin K, is chemically identical to the hyperlipidemia medication lovastatin. A meta-analysis involving 1,012 subjects that compared RYR with statins found that RYR was more effective in lowering TG, comparable in lowering LDL and HDL, and less effective in lowering total cholesterol at dosages of 200 mg to 4,800 mg daily.28 Additional meta-analyses have found that RYR may lower LDL by 21 mg/dL to 29 mg/dL and TG by 20 mg/dL to 27 mg/dL and increase HDL by 3 mg/dL compared with placebo.28 RYR supplements may contain up to 10 mg to 20 mg of monacolin K. Importantly, the FDA considers RYR products that contain statin-like components to be unapproved, illegal medications. It is not known how the varying quantities of monacolin K in RYR may affect cholesterol levels. The use of RYR is not mentioned in the most recent ACC/AHA hyperlipidemia guidelines. RYR may cause abdominal discomfort, diarrhea, dizziness, flatulence, headache, heartburn, myopathy, and nausea. There have been reports of hepatotoxicity and rhabdomyolysis, likely due to varying quantities of monacolin K in the supplement.29 Additionally, cases of nephrotoxicity caused by contaminated RYR have been reported. Patients looking into RYR should consider whether a prescription statin would be a better-quality product that would result in better outcomes.

Berberine: Berberine has been used in traditional Chinese medicine for thousands of years. This isoquinolone alkaloid isolated from plants of the genus Berberis has been studied for the treatment of many metabolic conditions. Berberine’s mechanism of action for lipid lowering is thought to be via upregulation in LDL receptors and suppression of proprotein convertase subtilisin/kexin type 9. A systematic review of clinical trials concluded that berberine—alone or in combination with other supplements—lowered LDL by an average of 20% to 30%.30 The typical berberine dosage was 500 mg twice daily.30 Berberine appears to be well tolerated, with the most common side effects being abdominal pain, flatulence, nausea, and vomiting. Drug interactions are an important consideration, as berberine has been shown to decrease CYP enzyme activity in clinical trials. Renal transplant patients in a clinical pharmacokinetic study who were taking berberine had a 29.3% higher blood concentration of cyclosporine compared with those not taking berberine; this was attributed to berberine’s inhibition of CYP3A4 in the liver or small intestine.31 Repeat administration in a two-phase, randomized-crossover clinical study of healthy males showed a decrease in CYP2D6, 2C9, and 3A4 activity.32 Berberine has been studied for its blood glucose– and BP-lowering effects, and it may attenuate the effects of antidiabetic and antihypertensive medications. It is unknown whether berberine confers any benefit in risk reduction of atherosclerotic cardiovascular disease.

The Pharmacist’s Role

Patients are increasingly more proactive regarding their health. Pharmacists, especially those in the community pharmacy setting, are often asked for dietary supplement recommendations. Pharmacists should ensure the safe use of products and consider patient-specific factors, goals, and preferences when formulating a recommendation. Dietary supplements are not FDA approved, and therefore they typically have limited evidence documenting benefits and potential for variability in quality. Despite this, pharmacists should be aware of whatever evidence does exist and help steer patients toward products that will help them meet their goal. Whenever possible, products that have undergone third-party testing should be recommended. It may be reasonable for patients to try garlic, potassium, BGA, L-arginine, vitamin C, or fish oil for hypertension and fish oil, niacin, RYR, or berberine for dyslipidemia. Patients should be educated on these dietary supplements’ current evidence of benefit so that they have realistic expectations for treatment, potential adverse events, and drug interactions.

REFERENCES

1. American Heart Association. Facts about high blood pressure. www.heart.org/en/health-topics/high-blood-pressure/the-facts-about-high-blood-pressure. Accessed June 13, 2024.
2. Tóth PP, Potter D, Ming EE. Prevalence of lipid abnormalities in the United States: the National Health and Nutrition Examination Survey 2003-2006. J Clin Lipidol. 2012;6(4):325-330.
3. Ried K. Garlic lowers blood pressure in hypertensive individuals, regulates serum cholesterol, and stimulates immunity: an updated meta-analysis and review. J Nutr. 2016;146(2):s389-s396.
4. Ried K, Frank OR, Stocks NP, et al. Effect of garlic on blood pressure: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2008;8(1):13.
5. Ried K, Frank OR, Stocks NP. Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial. Eur J Clin Nutr. 2013;67(1):64-70.
6. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34(2):234-238.
7. Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002;72(3):276-287.
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APHA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension. 2018;71(6):1269-1324.
9. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology joint committee on clinical practice guidelines. Circulation. 2023;148(9):e9-e119.
10. Potassium. NatMed Pro [subscription database]. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=851. Accessed June 13, 2024.
11. Lee EH, Park JE, Choi YJ, et al. A randomized study to establish the effects of Spirulina in type 2 diabetes mellitus patients. Nutr Res Pract. 2008;2(4):295-300.
12. Machowiec P, Ręka G, Maksymowicz M, et al. Effect of Spirulina supplementation on systolic and diastolic blood pressure: systematic review and meta-analysis of randomized controlled trials. Nutrients. 2021;13(9):3054.
13. Miczke A, Szulinska M, Hansdorfer-Korzon R, et al. Effects of spirulina consumption on body weight, blood pressure, and endothelial function in overweight hypertensive Caucasians: a double-blind, placebo-controlled, randomized trial. Eur Rev Med Pharmacol Sci. 2016;20(1):150-156.
14. Wu G, Meininger CJ. Arginine nutrition and cardiovascular function. J Nutr. 2000;130(11):2626-2629.
15. L-arginine. NatMed Pro [subscription database]. Accessed June 13, 2024. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=875. Accessed June 13, 2024.
16. Shiraseb F, Asbaghi O, Bagheri R, et al. Effect of L-arginine supplementation on blood pressure in adults: a systematic review and dose-response meta-analysis of randomized clinical trials. Adv Nutr. 2022;13(4):1226-1242.
17. Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (Vintage MI) randomized clinical trial. JAMA. 2006;295(1):58-64.
18. Vitamin C. NatMed Pro [subscription database]. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1001. Accessed June 13, 2024.
19. Juraschek SP, Guallar E, Appel LJ, Miller ER III. Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2012;95(5):1079-1088.
20. Mori TA, Watts GF, Burke V, et al. Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men. Circulation. 2000;102(11):1264-1269.
21. Prisco D, Paniccia R, Bandinelli B, et al. Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients. Thromb Res. 1998;91(3):105-112.
22. Campbell F, Dickinson HO, Critchley JA, et al. A systematic review of fish-oil supplements for the prevention and treatment of hypertension. Eur J Prev Cardiol. 2013;20(1):107-120.
23. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation. 2019;140(12):e673-e691.
24. Fish oil. NatMed Pro [subscription database]. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=993#background. Accessed June 13, 2024.
25. Karpe F, Frayn KN. The nicotinic acid receptor—a new mechanism for an old drug. Lancet. 2004;363(9424):1892-1894.
26. Niacin. NatMed Pro [subscription database]. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=924#effectiveness. Accessed June 13, 2024.
27. Niacin. Clinical Pharmacology [subscription database]. www.clinicalkey.com/pharmacology/monograph/1473?n=Niacin%2C+Niacinamide. Accessed June 13, 2024.
28. Li P, Wang Q, Chen K, et al. Red yeast rice for hyperlipidemia: a meta-analysis of 15 high-quality randomized controlled trials. Front Pharmacol. 2022;12:819482.
29. Red yeast rice. NatMed Pro [subscription database]. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=925. Accessed June 13, 2024.
30. Koppen LM, Whitaker A, Rosene A, Beckett RD. Efficacy of berberine alone and in combination for the treatment of hyperlipidemia: a systematic review. J Evid Based Complementary Altern Med. 2017;22(4):956-968.
31. Wu X, Li Q, Xin H, et al. Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. Eur J Clin Pharmacol. 2005;61(8):567-572.
32. Guo Y, Chen Y, Tan ZR, et al. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012;68(2):213-217.

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