The Natural Treatment of Hypertension
Marion Wofford, MD, MPH, University of Mississippi Medical Center, Division of Hypertension, 2500 North State Street, Jackson, MS 39216 E-mail: email@example.com
The goal of this review is to evaluate the efficacy of commonly available dietary supplements in the treatment of hypertension, using the average blood pressure reduction achieved with the implementation of lifestyle modifications as a standard. For this reason, the authors focus on the antihypertensive potential of these agents rather than pharmacology, pharmacokinetics, adverse effects, or supplement-drug interactions. For the purpose of this review, dietary supplements are defined as exhibiting some evidence of benefit if a systolic blood pressure reduction of 9.0 mm Hg or greater and/or a diastolic blood pressure reduction of 5.0 mm Hg or greater has been observed in previously published, peer-reviewed trials. These defining limits are based on the average blood pressure reduction associated with the implementation of certain lifestyle modifications. Agents with some evidence of benefit include coenzyme Q10, fish oil, garlic, vitamin C, and L-arginine.
Dietary supplements have become the focus of debate among suppliers, the health care community, government regulatory agencies, and the general public. While being used for centuries to treat a wide variety of health conditions, contemporary concerns primarily surround the issues of safety and efficacy. In 1994, the US Food and Drug Administration defined “dietary supplement” in the Dietary Supplement Health and Education Act as “a product taken by mouth that contains a ‘dietary ingredient’ intended to supplement the diet.”1 Dietary ingredients May include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Supplements May also be extracts or concentrates of those substances.1 Because dietary supplements are easily accessible and because of the frequent misinterpretation that all natural products are also safe, patients May choose these agents for blood pressure control. Self-treatment with dietary supplements without the supervision of a health care provider May be very dangerous.2 For example, patients often utilize garlic in the treatment of hypertension, and garlic is known to interact with numerous medications. Garlic May enhance the anticoagulant effects of warfarin and the hypoglycemic effects of oral diabetic agents. Concomitant use with garlic can also result in decreased serum levels of several drugs used in the treatment of human immunodeficiency virus.3 Health care providers must be familiar with the available supplements used, for example, to “support a healthy cardiovascular system” and address the appropriate use of supplements with patients along with issues like medication interactions. Information of questionable reliability is readily available to the public and providers must be prepared to authoritatively answer questions concerning these agents.4
In a recent analysis tracking the amount and quality of information available on the Internet, out of 2600 Web sites identified by using the search terms “high blood pressure” and “treatment,” 58% focused on alternative therapies and only 36% discussed conventional antihypertensive drugs. In the same study, it was noted that 12 of the 14 herbs listed on the Internet as effective remedies for high blood pressure have actually been shown to raise blood pressure in valid scientific studies.5 A survey conducted in Alabama in 2000 revealed that 46% of the population was taking nutritional supplements and 26% were taking herbal supplements.6 As self-treatment with dietary supplements continues to increase in popularity, health care providers must be responsible for educating patients about the efficacy, or lack of efficacy, of these agents.
The goal of this review is to evaluate the efficacy of dietary supplements in the treatment of hyper-tension, using as a benchmark the average blood pressure reduction noted with the incorporation of lifestyle modifications. For this reason, only the antihypertensive potential of these agents, rather than pharmacology, pharmacokinetics, adverse effects, or drug interactions, is discussed.
A list of potential natural antihypertensive agents was initially identified. This list was generated by a review of those agents included in The Review of Natural Products7 and the Natural Medicines Comprehensive Database3 as having potential benefits in hypertension. These were utilized because of their widespread acceptance as reputable and accurate sources of information regarding the study of natural products. The following agents were identified: coenzyme Q10 (CoQ10), ubiquinone, garlic, arginine, fish oil, hawthorn, olive oil, vitamin C, vitamin E, skullcap, barberry, betel nut, bishop's weed, bitter melon, cat's claw, celery, Eleutherococcus, gotu kola, guar gum, herbal diuretics, hibiscus, holly, jiaogulan, procaine, lemongrass, mistletoe, morinda, Nigella sativa, oil of evening primrose, passion flower, periwinkle, reishi mushroom, rhubarb, saffron, stevia, veratrum, white hellebore, willard water, withania, yellow root, yohimbine, and yucca. A Medline search of the published literature was then conducted using each identified agent. The following additional search terms were also used: “hypertension,”“alternative medicine,” and “dietary supplement.” The searches were limited using the parameters 1999-2003, human, and English language (this May be a limitation of the study).
Many sources claim that specific alternative therapies or supplements are efficacious in the treatment of hypertension; however, the degree of antihypertensive efficacy is rarely impressive when compared with the blood pressure reduction that can be documented with the incorporation of lifestyle modifications. For example, in the Dietary Approaches to Stop Hypertension (DASH) trial it was noted that the DASH combination diet significantly (p<0.05) lowered both systolic blood pressure (SBP) and diastolic blood pressure (DBP), with an overall decrease in SBP of 11.4 mm Hg and DBP of 5.5 mm Hg in hypertensive individuals.8 The DASH combination diet is rich in fruits, vegetables, and low-fat dairy products.
Weight loss and sodium reduction have also been shown to decrease blood pressure. The phase II Trials of Hypertension Prevention9 observed that a weight loss of 4.3-4.5 kg along with a concomitant decrease in sodium excretion of 50 mmol/d was associated with an SBP decrease of 4.0 mm Hg and a DBP decrease of 2.8 mm Hg at 6 months.
A more recent randomized, controlled trial assessed the efficacy of simultaneously implementing diet, exercise, and weight loss.10 Forty-four hypertensive, overweight adults, taking a single blood pressure medication, were randomized to one of two groups. The lifestyle group ate a low-calorie, low-sodium diet based on the DASH diet and participated in moderate intensity exercise three times weekly. The control group continued their previous lifestyle. The lifestyle group lost an average of 4.9 kg in 9 weeks. Reductions in daytime blood pressure readings were 12.1 mm Hg systolic and 6.6 mm Hg diastolic.10
Based on the average reduction of blood pressure noted in those trials, dietary supplements are defined as possessing some evidence of benefit when an SBP reduction of 9.0 mm Hg or greater and/or a DBP reduction of 5.0 mm Hg or greater can be documented. The cut-off limits are based on a simple average of the blood pressure reduction noted in the three trials just discussed. Dietary supplements with little or no evidence of benefit are those that either have little or no literature to support efficacy or those that prove to decrease SBP by less than 9.0 mm Hg and/or decrease DBP by less than 5.0 mm Hg. According to these parameters, five agents meet the criterion of some evidence of benefit in the treatment of hypertension, while the other agents noted have little or no evidence of benefit to promote efficacy. The agents with some evidence of benefit include CoQ10, fish oil, garlic, vitamin C, and L-arginine (Table).
AGENTS WITH SOME EVIDENCE OF BENEFIT
The Natural Medicines Comprehensive Database3 has five potential categories of efficacy: effective, likely effective, possibly effective, possibly ineffective, or likely ineffective. The database uses evidence-based articles from Medline to classify each indication for each agent. CoQ10 falls into the category of possibly effective in the treatment of hypertension.
It has been theorized that most hypertensive patients have a significant deficiency of CoQ10. It is now understood that CoQ10 May lower blood pressure by correcting an endogenous provitamin deficiency.11 Tran et al.11 reviewed eight different trials that measured the decrease in blood pressure following differing doses of CoQ10. All eight trials showed some degree of reduction in blood pressure, although the amount of reduction was not consistent among the trials.11
A randomized, double-blind trial conducted by Singh et al.12 suggested that administration of 60 mg CoQ10 twice daily to patients already receiving conventional antihypertensive medications provides protection to pancreatic β cells, liver cells, arterial smooth muscle cells, and endothelial cells through its antioxidative action. Group A received CoQ10 at the previously defined dose. Group B received a B-vitamin complex. There were 30 patients in Group A and 29 patients in Group B. Patients were followed for 8 weeks. The CoQ10 group showed a 16 mm Hg reduction in SBP and a 9 mm Hg reduction in DBP. Reductions in the following indices were also noted in the CoQ10 group: fasting insulin and glucose levels, triglycerides, and lipid peroxides. In addition, increases in the following indices were noted: high-density lipoprotein cholesterol; vitamins A, C, and E; and beta carotene. Group B only benefited with an increase in vitamin C and beta carotene.
Coenzyme Q10 has also shown some benefit in the treatment of isolated systolic hypertension. A cohort of 46 men and 37 women with isolated systolic hypertension were enrolled in a 12-week randomized, double blind, placebo-controlled trial. The treatment group received 60 mg CoQ10 twice daily. The reduction of SBP in the treatment group was 17.8±7.3 mm Hg. The reduction of SBP in the placebo group was only 1.7 mm Hg.13
The Natural Medicines Comprehensive Database gives fish oil a rating of possibly effective when used orally for hypertension. The omega-3 fatty acids (eicosapentoic acid and docosahexanoic acid) in fish oils potentially lower blood pressure by directly modulating the intracellular calcium ion, which signals vascular smooth muscles to dilate.3
Sixteen hypertensive men and 16 normotensive men were randomly assigned to receive either eicosapentoic acid and docosahexanoic acid or olive oil as a placebo for a period of 4 months. After 2 months, SBP decreased by 6 mm Hg and DBP decreased by 5 mm Hg in fish oil-treated hypertensives and normotensives.14
Yosefy et al.15 examined the efficacy of dietary fish oil supplementation in obese patients with hypertension and dyslipidemia, with and without diabetes mellitus. Twenty nondiabetic patients who were obese, hypertensive, and dyslipidemic participated in a 13-day unblinded study. Participants fasted for four 20-hour periods on Days 1, 5, 9, and 13. Fish oil concentrate, in the form of a tablet containing 180 mg eicosapentaenoic acid and 120 mg docosahexanoic acid, was administered as 15 capsules daily for the 13 days (a high dose that often causes side effects). In addition, the patients were placed on the American Heart Association Step I diet, which includes cholesterol intake less than 300 mg with 50% of total daily energy intake coming from carbohydrates, 30% from fat, and 20% from protein. In the nondiabetic group, SBP decreased by 12.7 mm Hg and DBP decreased by 7.9 mm Hg. At a later time, 19 type 2 diabetic patients (controlled with sulfonylureas) who were obese, hypertensive, and dyslipidemic underwent the same study protocol. In the diabetic group, SBP decreased by 15.7 mm Hg and DBP decreased by 7.6 mm Hg.
In contrast to the benefits attributed to fish oil supplementation in the treatment of hypertension and dyslipidemia in obese patients, no benefit could be observed in the prevention of pregnancy-induced hypertension. In six multicenter trials, women with high-risk pregnancies were randomly assigned to receive fish oil or olive oil in identical capsules from 20-33 weeks until delivery. Fish oil had no effect on the occurrence of pregnancy-induced hypertension.16
The Natural Medicines Comprehensive Database rates garlic as possibly effective when taken orally for hypertension. Fresh, intact garlic cells contain the amino acid alliin, which is considered to be the most active constituent. When the intact cells are broken, alliin is converted to allicin by the enzyme allinase. Garlic is thought to be effective in the treatment of hypertension by causing smooth muscle relaxation and vasodilation.3
A meta-analysis of trials evaluating the efficacy of garlic in the treatment of high blood pressure showed that garlic decreases SBP by 7.7 mm Hg and DBP by 5.0 mm Hg when compared with placebo. The optimum dosage of garlic for the treatment of hypertension has yet to be established and the use of garlic in the treatment of hypertension remains controversial.17 Several studies have alluded to the fact that garlic is effective in the treatment of hypertension18,19 whereas a placebo-controlled study reported that it has no effect on blood pressure.20 These contradictions are probably due to variations in treatment protocols, duration of therapy, and formulation utilized; however, a recent study argued that the results warrant using standardized formulations of garlic.21 Although garlic does fit the working definition of some evidence of benefit, the studies that allude to its efficacy include humans in small, uncontrolled studies. Before recommending garlic in the treatment of hypertension, more well developed studies showing positive outcomes on blood pressure are needed.
Vitamin C (ascorbic acid) is listed as possibly effective in the treatment of hypertension in the Natural Medicines Comprehensive Database.3 The probable mechanism of action for vitamin C is that it functions as an antioxidant to enhance the synthesis or prevent the breakdown of nitric oxide.14
A study conducted by Duffy et al. 22 noted that vitamin C added to conventional medication lowered SBP effectively, but had no effect on DBP.
A randomized, placebo-controlled study conducted in 39 patients concluded that vitamin C is effective in the treatment of hypertension. Patients were randomized to receive either placebo or ascorbic acid in a one-time loading dose of 2 g, then 500 mg daily for 30 days. SBP decreased by approximately 13 mm Hg in the ascorbic acid group after 30 days. However, the reduction in DBP was not statistically significant. There was no change in the placebo group.14
According to the Natural Medicines Comprehensive Database, L-arginine receives a rating of likely ineffective in the treatment of hypertension.3 It has however, been found to have potential in the treatment of hypertension in several small pilot studies, and thus fits the working definition of having some evidence of benefit.23–25
The amino acid L-arginine serves as the substrate for nitric oxide synthesis in the body. Nitric oxide is an endothelium-derived relaxing factor that is essential for regulating vascular tone. By supplementing L-arginine, more nitric oxide is produced. Nitric oxide then stimulates angiogenesis and inhibts endothelin-1 release, leukocyte adhesion, platelet aggregation, and superoxide generation.26
A single-blind, crossover trial, conducted in six healthy volunteers, measured the effect of arginine-rich diets on blood pressure. Patients were separated into three groups. Group 1 served as the control group and received a diet relatively low in L-arginine. Group 2 received an L-arginine-rich diet based on natural foods such as dry legumes and nuts. Group 3 received a diet identical to that of the control group plus L-arginine supplementation. The patients receiving L-arginine-rich diets (Groups 2 and 3) showed a significant reduction in blood pressure, with a decrease in SBP of 6.2 mm Hg more than the control group and a decrease in DBP of 5.0 mm Hg more than the control group.24
A pilot study conducted by Kelly et al.27 showed that oral L-arginine had favorable effects on both SBP and DBP in hypertensive kidney transplant and hemodialysis patients. Six normotensive individuals and 10 kidney transplant patients received 9 g L-arginine daily for 9 days, then 18 g L-arginine daily for 9 additional days. Six hemodialysis patients and four peritoneal dialysis patients received the same dose for 14 days. Five kidney transplant patients received 30 mL canola oil daily in addition to L-arginine. Blood pressure, creatinine clearance, and serum creatinine level were measured at baseline, 9 days, and 18 days. Hemodialysis patients were noted to have a decrease in SBP of approximately 28.7 mm Hg.27 DBP also decreased, but to a lesser extent. Renal function remained the same in all groups. Canola oil had no effect on blood pressure.
A larger, prospective, randomized, double blind trial conducted in 35 people with essential hypertension showed less promising results. Patients were randomized to receive either 6 g L-arginine or placebo. Acute changes in blood pressure were noted, but long-term effects warrant further investigation.28
A prospective, crossover trial was conducted in six patients with type 2 diabetes mellitus and mild hypertension. The patients received 3 g arginine hourly for 10 hours on either day 2 or day 3 of the study. Blood pressure was measured between 5 a.m. and 4 p.m. SBP and DBP decreased by 12 mm Hg and 6.2 mm Hg, respectively. The antihypertensive effect was temporary, however. Blood pressure dropped within 2 hours of initiating arginine and returned to the previous value within 1 hour of stopping arginine. According to this study, arginine May be useful for temporarily decreasing blood pressure in type 2 diabetics.23
As the latter two studies demonstrate, arginine is only effective in acute situations. For example, intravenous arginine has been used to lower pulmonary vascular resistance and cardiac output in infants with pulmonary hypertension.27
AGENTS WITH LITTLE OR NO EVIDENCE OF BENEFIT
Hawthorn is a member of the Rosaceae family and is used most often in Europe for the treatment of heart failure.29 A recent well developed trial looked at the hypotensive effect of hawthorn extract and magnesium in mild, essential hypertension. Subjects were randomized to one of four groups: 600 mg magnesium, 500 mg hawthorn leaf extract, a combination of both magnesium and hawthorn leaf extract, and placebo. At the end of 10 weeks, analysis of variance showed no difference in decline of blood pressure in any of the four groups. Although factorial contrast analysis showed evidence of promising reduction in resting DBP in the hawthorn group at 10 weeks, there was no definitive evidence to support the use of hawthorn extract in the treatment of hypertension.30
Vitamin E in the treatment of hypertension received a rating of possibly ineffective in the Natural Medicines Comprehensive Database.3
Vitamin E seems to have no effect on blood pressure in patients with controlled hypertension. A randomized, controlled, open-label trial measured both clinic and 24-hour ambulatory blood pressure in 142 patients with controlled hypertension. Ambulatory blood pressure showed no change in SBP and a DBP decrease of only 1.6 mm Hg.31
The Heart Outcomes Prevention Evaluation (HOPE) Study32 enrolled a total of 2545 women and 6996 men aged 55 years or older who were at high risk for cardiovascular disease. They were randomly assigned to receive 400 IU vitamin E daily or matching placebo along with either ramipril or matching placebo for approximately 4.5 years. There was no significant difference in cardiovascular events between those receiving vitamin E and those receiving placebo.32
A review of recent Medline citations finds that five dietary supplements demonstrate evidence of some benefit in the treatment of mild hypertension. CoQ10, fish oil, garlic, vitamin C, and L-arginine all fit the working definition of some evidence of benefit. These agents have shown to be at least as effective as the incorporation of lifestyle modifications. However, these agents should not replace the implementation of recommended lifestyle changes, including proper diet, exercise, and weight loss.
Although the trials mentioned here were published in peer-reviewed journals, many have major limitations. Many of the trials contained a small number of participants and were conducted for short periods of time. The agents with some evidence of benefit should be further studied in large, placebo-controlled, double-blind studies to definitively say that the supplements are effective. In addition, it is important to note that not all of the supplements utilized in the studies were appropriately standardized. Additional studies must be conducted before claiming absolute proven efficacy.
There are no data which demonstrate that the five dietary supplements discussed are more beneficial than currently recommended antihypertensive drugs.33 These dietary supplements May be considered as adjuvant therapy but not as initial treatment for stage 1 or higher hypertension.
Patients must realize that “natural” products are not necessarily “safe.” They must also realize that self-treatment with dietary supplements without the supervision of a health care provider can be potentially dangerous. Because these agents do exert pharmacologic effects on the body, they are capable of producing adverse effects and supplement-drug interactions. Despite a few supplements demonstrating evidence for efficacy, several fundamental limitations of essentially all dietary supplement clinical trials must be acknowledged. Many of the studies have a small sample size, are of short duration, and lack a placebo or control group. Additionally, supplements are rarely analyzed for consistent product content before use in a clinical trial.34 Significant variations have been noted between manufacturer label claims and actual product content.35–39 Thus, even agents found to have some evidence of benefit by this review will likely have varying efficacy depending on the individual product consumed by the patient. Finally, no dietary supplement has demonstrated evidence for protection against the long-term sequelae of hypertension, such as stroke, myocardial infarction, renal failure, and others.
Our review is not without limitations. Only English-language research published in Medline-indexed journals was included in the review. However, much of the literature on dietary supplements is published in journals not indexed in Medline. Animal data was also excluded, and some dietary supplements May demonstrate antihypertensive efficacy in animal models or have in vitro data suggesting possible antihypertensive actions. Also, only articles published between 1999 and 2003 were included in our Medline search and additional, well developed trials May have been published before this time frame. In addition, many meta-analyses utilized in the research do not clearly state the blood pressure reduction of the placebo groups. Finally, the inclusion of only Medline-indexed articles is a limitation because even Medline-indexed journals have published numerous poor studies of arguable design on the topic of dietary supplements. For example, the lack of standardized products, the possibility of content variation, and the lack of product analysis before and during the clinical investigation May be limitations of the articles reviewed.
It is the responsibility of health care providers to identify and convey concerns about these agents to the public. Before recommending a dietary supplement, a provider should explain the risks that May be associated with these agents and review the potential for product variance as well as lack of effect. Most importantly, health care providers must remember that our first priority is primum non nocere, that is, to do no harm.
Most of the supplements we researched show little or no evidence of benefit when compared with lifestyle modifications. The agents that May show some evidence of benefit (e.g., CoQ10, fish oil, garlic, vitamin C, and L-arginine) May be utilized as adjuncts to lifestyle modifications and conventional medications as long as the patient does not experience any adverse effects or supplement-drug interactions and the patient does not depend on the agents as definitive treatment. These agents should never be used as “safe” alternatives to conventional medications and they should not be used without the supervision of a health care provider. If not properly treated, hypertension can result in significant adverse sequelae.33
In addition to efficacy, health care providers must be aware of the potential for drug interactions, contraindications, and adverse effects associated with the specific dietary supplements. Garlic, for example, has the potential to interact with oral anticoagulants and oral antidiabetic medications, among others.3 It is imperative that health care providers ask patients if they are taking dietary supplements. Patients May often think they do not have to inform their health care provider about these products because they are “safe” and “natural.” The public must be educated about dietary supplements and understand the importance of reviewing these supplements with their health care provider, despite their easy availability without a prescription.