Hemodynamic Impact of an Ephedra-free Multicomponent Weight Loss Supplement
Abstract and Introduction
Purpose: The effect of Metabolife Ephedra-Free on blood pressure (BP) and hemodynamics was studied.
Methods: Healthy volunteers were randomly assigned to take a single dose of Metabolife Ephedra-Free or matching placebo and then crossed over to the opposite treatment after a seven-day washout period. BP was measured at baseline and one, three, and five hours after administration. Cardiac index, systemic vascular resistance index (SVRI), and total thoracic fluid content were determined in a subgroup of subjects.
Results: Twenty patients (mean ± S.D. age, 24.8 ± 1.9 years) completed the study. No significant differences in systolic or diastolic BP were found between the Metabolife Ephedra-Free and placebo groups. In the subgroup (n = 8), SVRI was higher (but not significantly so) in the Metabolife Ephedra-Free group than in the placebo group at one hour (2162.5 ± 421.1 versus 1934.6 ± 344.2 dyn · sec · cm-5 · m2); the difference was significant at five hours (1981.6 ± 293.3 versus 1765.1 ± 340.3 dyn · sec · cm-5 · m2).
Conclusion: Single doses of Metabolife Ephedra-Free did not affect BP in healthy young volunteers. SVRI did not exceed the normal range but was elevated at five hours compared with SVRI in placebo recipients.
We previously found that Metabolife 356 (Metabolife International Inc, San Diego, CA), an ephedra-containing supplement with 16 other ingredients, elevated systolic blood pressure (SBP) in humans by 5 mm Hg compared with placebo. This finding may explain the 18 anecdotal cases of myocardial infarction and 24 cerebrovascular accidents associated with Metabolife 356. The Food and Drug Administration (FDA) banned ephedra-containing supplements, leading consumers to look for alternatives. Metabolife Ephedra-Free (Metabolife International) contains two ingredients that were present in Metabolife 356, namely chromium 150 µg and caffeine 54 mg, as well as new ingredients, such as Garcinia cambogia extract (active ingredient, hydroxycitric acid), green tea extract (active ingredients, caffeine and polyphenols, including epigallocatechin-3-gallate), yerba mate extract (active ingredient, caffeine), minerals (calcium, sodium, and potassium), modified cellulose, maltodextrin, dicalcium phosphate, stearic acid, sodium bicarbonate, silica, dextrin, citric acid, dextrose, lecithin, and sodium citrate.
Most of the ephedra-free products currently on the market contain some combination of G. cambogia, green tea extract, yerba mate extract, and bitter orange. Metabolife Ephedra-Free is thus a reasonable model for supplements taken for weight loss without using bitter orange extract.
Caffeine is generally known to increase SBP, and catechin polyphenols in green tea may enhance caffeine's actions or have some direct caffeine-like effects that may increase BP.[4,5] However, the epigallocatechin-3-gallate in green tea has been found not to affect BP, other catechin polyphenols reduce BP by releasing nitric oxide, and G. cambogia lowered SBP in an animal study.[6-10] The amount of each ingredient in Metabolife Ephedra-Free is not disclosed, the potential for interactions between ingredients has not been adequately determined, and the exact mechanism or BP effect of all constituents has not been worked out. The potential impact of Metabolife Ephedra-Free on BP is unknown.
The purpose of our study was to evaluate the effect of Metabolife Ephedra-Free on BP and hemodynamics.
This was a randomized, double-blind, placebo-controlled crossover study conducted from January to May 2004. This study was approved by the institutional review board of the University of Connecticut. Written informed consent was required, and all study procedures were conducted in accordance with the ethical standards for research in human subjects.
We evaluated healthy adults (≥18 years) who expressed interest in participating in the study. Subjects were excluded for cardiac rhythm other than normal sinus rhythm, history of atrial or ventricular arrhythmia, family history of premature sudden cardiac death, left ventricular hypertrophy, atherosclerosis, hypertension, palpitations, T-wave abnormalities, baseline linear QTc-interval greater than 440 msec, thyroid disease, type 1 or 2 diabetes mellitus, recurrent headaches, depression, any psychiatric or neurologic disorder, history of alcohol or drug abuse, renal or hepatic dysfunction, concurrent use of anticoagulants or monoamine oxidase inhibitors, or unwillingness to sign the informed-consent form. We used patient histories to determine these exclusion criteria. Pregnant or lactating females were also excluded; urine dipstick tests were used to confirm absence of pregnancy. For at least 12 hours before administration, subjects abstained from caffeine (all sources, including diet and medications), herbal products (including bitter orange extract), ephedra, and stimulants (including systemic and topical decongestants, ephedrine, and nonprescription products).
Subjects were randomly assigned to receive Metabolife Ephedra-Free (lot number 169094A, expiration date April 2005) or placebo according to a random permuted-block method with a block size of four patients per group. To minimize effects of circadian variation, patients completed all parts of the study at the same time of day.
Subjects received one capsule of either Metabolife Ephedra-Free or matching placebo. To maintain blinding, the original Metabolife Ephedra-Free tablets were reformulated by using empty capsules (Capsugel, Pfizer Inc., Morris Plains, NJ) and lactose monohydrate powder (Humco Corporation, Texarkana, TX). Each opaque Metabolife Ephedra-Free capsule for the study had the contents of one Metabolife Ephedra-Free tablet. After a seven-day washout period, subjects returned to the study center and received the opposite treatment. All subjects maintained their usual diet during the washout period and returned without significant changes in their general health. BP was evaluated immediately before capsule ingestion and 1, 3, and 5 hours after ingestion. These intervals were based on the half-life of caffeine (3 hours). In a recent study of the pharmacokinetics of polyphenols from green tea consumed by healthy volunteers, epigallocatechin-3-gallate had half-lives of 2.3 hours (after an 800-mg dose) and 3.1 hours (400 mg). Multiple combinations of polyphenols from green tea have half-lives of 3.3 hours (800 mg of epigallocatechin-3-gallate as polyphenols) and 4.0 hours (400 mg) after a single dose. The epigallocatechin-3-gallate dose of 800 mg is approximately equivalent to 24 120-mL cups of green tea. Metabolife Ephedra-Free is recommended to be taken as often as three times a day during waking hours. A complete hemodynamic profile was obtained at the same experimental time points (before and 1, 3, and 5 hours after ingestion) in a subgroup of eight subjects (the last eight subjects enrolled).
The primary endpoints were maximum SBP and diastolic blood pressure (DBP) attained during the five-hour study. BP was measured manually with a mercury sphygmomanometer. Two readings were obtained for each time point and averaged. The same investigator determined BP for the same subject throughout the study to minimize interinvestigator variation.
In the subgroup, secondary endpoints included maximum values for cardiac index, thoracic fluid content, and systemic vascular resistance index (SVRI) over five hours. These values were obtained by bioelectrical impedance cardiography (Bio-Z, Cardiodynamics International Corporation, San Diego, CA), an FDA-approved, noninvasive equivalent to the Swan-Ganz catheter. To measure and calculate hemodynamics, sensors were placed bilaterally over the base of the neck and the thorax at the level of the xiphoid process, while an oscillometric cuff connected to the device was placed 2.5 cm above the antecubital crease, with the bladder of the cuff over the brachial artery. Measurements were obtained when the waveform indicator displayed signal strength of 75-100%.
At each hemodynamic time point after capsule ingestion, subjects were asked if they had had any potential adverse effects since the preceding measurement. If a potential adverse effect was identified, the subject was asked whether he or she still had the adverse effect reported previously and whether it was worse or better than previously.
Continuous data are reported as means and standard deviations. Continuous data were compared between groups by using a paired t test. A p value of ≤0.05 was considered significant. A prespecified power analysis assumed that an intergroup difference of 4 ± 4 mm Hg in either SBP or DBP would be significant. An α of 0.05 and a power of 0.8 indicated that the necessary sample size was 10 patients. The SBP difference was based on a study by Corea et al. The standard deviation was based on our previous work.
Of 24 subjects screened, 3 refused to sign the consent form and 1 met the exclusion criteria. Twenty patients (mean ± S.D. age, 24.8 ± 1.9 years, 60% male) enrolled in and completed the study. No difference in SBP or DBP was noted between Metabolife Ephedra-Free and placebo at baseline or maximum ( ). When each time period (one, three, and five hours after administration) was compared separately between groups, the Metabolife Ephedra-Free group had a higher DBP at one hour than the placebo group (73.4 ± 8.6 versus 70.5 ± 9.1 mm Hg [p = 0.0539]), but BP returned to baseline by three hours.
Blood Pressure Changes in Study Groups
|Variable||Mean ± S.D. Blood Pressure (mm Hg)a|
|Metabolife Ephedra-Free Group (n = 20)||Placebo Group (n = 20)|
|Systolic blood pressure|
|Baseline||115.4 ± 10.1||114.2 ± 11.3|
|Maximumb||121.3 ± 12.6||118.9 ± 10.2|
|Diastolic blood pressure|
|Baseline||71.1 ± 9.9||70.0 ± 7.9|
|Maximum||74.6 ± 8.5||73.4 ± 7.2|
aNone of the differences between groups were significant.
bMeasured at intervals up to five hours after administration.
In the eight-patient subgroup, SVRI was higher (but not significantly so) in the Metabolife Ephedra-Free group than in the placebo group at one hour (2162.5 ± 421.1 versus 1934.6 ± 344.2 dyn · sec · cm-5 · m2 [p = 0.056]); the difference was significant at five hours (1981.6 ± 293.3 versus 1765.1 ± 340.3 dyn · sec · cm-5 · m2 [p = 0.041]) compared with the placebo group (normal physiological range of 1337-2483 dyn · sec · cm-5 · m2). Cardiac index was significantly higher in the Metabolife Ephedra-Free group at baseline (p = 0.018). No significant differences in cardiac index occurred at any time after administration, although there was a nonsignificant reduction at five hours. When the change from baseline was evaluated, no differences in cardiac index were observed between groups.
Adverse events were mild, with headache (one subject in each group), gastrointestinal upset (one subject in each group), sweating (one subject in the Metabolife Ephedra-Free group), palpitations (one subject in the Metabolife Ephedra-Free group), and jitteriness (one subject in the Metabolife Ephedra-Free group) being reported.
We found no significant alterations in BP resulting from the use of Metabolife Ephedra-Free. We found a nonsignificant increase in SVRI at one hour and a significant increase at five hours, suggesting additional vasoconstriction above that noted with placebo. No subjects exceeded the normal range for SVRI, and the average was still well within the normal range at all times.
In a previous investigation, we found that caffeine 400 mg significantly increased SPB by 9 mm Hg at three hours compared with placebo in healthy young subjects.
The hemodynamic effects of green tea are not well defined. Green tea contains caffeine, and some of the green tea polyphenols may have caffeine-like effects. However, different polyphenols may act differently on smooth muscle in the vasculature. Epigallocatechin-3-O-methygallate produced a dose-dependent hypotensive effect in hypertensive rats, mediated in part by inhibition of angiotensin-converting enzyme. Epigallocatechin-3-O-methygallate 10 mg/kg was superior to captopril 10 mg/kg at reducing BP in this study. Another potential mechanism of BP reduction by polyphenols in green tea is the release of nitric oxide. Epigallocatechin-3-gallate, one of primary polyphenols in green tea, did not alter BP in stroke-prone hypertensive rats after long-term exposure. In contrast, another study in 20 normotensive men (mean ± S.D. age, 56.2 ± 1.1 years) found that those drinking green tea had a slightly higher SBP (5.5 mm Hg; 95% confidence interval, -1.4 to 12.4 mm Hg) and DBP (3.1 mm Hg; 95% confidence interval, 1.8 to 8.4) 30 minutes after ingestion than those consuming caffeine, but the effect was transient. Plasma caffeine concentrations were 2.44 mg/L for the green tea group and 2.58 mg/L for the caffeine group. In hypertensive rats, green tea reduced SBP and DBP significantly, but the effects gradually diminished over the three weeks of the trial. The net effect might depend on the relative contribution of the BP-enhancing and -reducing polyphenols in the individual products.
In old, obese, diabetic rats, treatment with (-)-hydroxycitric acid 200 mg/day reduced SBP by 13 mm Hg compared with controls at three weeks. After the dose was doubled to 400 mg, further SBP reductions (3-5 mm Hg) were noted at weeks 4-6. It is not known whether the weight loss that occurred in these rats affected the results.
Given the impact of the individual ingredients on BP, the lack of effect of Metabolife Ephedra-Free has a variety of possible explanations. The doses of caffeine, green tea, and G. cambogia are not known. It may be that the caffeine doses are relatively low or that the caffeine effect on BP is counterbalanced by the other ingredients. Pharmacokinetic or pharmacodynamic effects of drug interactions might account for the attenuation of the caffeine effect or accentuate the hypotensive effects of some of the other components. Since Metabolife Ephedra-Free has so many components, we cannot specifically say that any individual ingredient has acceptable cardiac safety when used alone. What we can state is that single doses of Metabolife Ephedra-Free have better cardiovascular safety than single doses of the ephedra-containing Metabolife 356. Metabolife 356 increased SPB significantly in a study with almost identical methodology.
Our study has several limitations. We monitored patients for only five hours. Given the lack of clear pharmacokinetic data for virtually all of the ingredients, we cannot comment on the effects of a single dose after this period. Our results suggest it is unlikely that subsequent BP alteration would have occurred. We used only a single dose of the product rather than evaluating the effects of repeated administration, so we can speculate only as to the long-term effects. We cannot be certain that overdoses of the product will not yield adverse BP or SVRI effects. Given the elevations in SVRI, people should be strongly cautioned to ingest only recommended doses. If the SVRI effects are dose related, SVRI may exceed the normal range among patients overdosing on the product. This would be especially dangerous for cardiac patients. We studied young, healthy volunteers. We do not know if Metabolife Ephedra-Free is effective as a weight-loss supplement, but weight loss in obese patients, by itself, is associated with BP reductions. We do not know if this product alters cholesterol levels, clotting factor concentrations, inflammatory mediators, liver function, or the cytochrome P-450 system. As with all dietary supplements, research into these unknown areas are needed before a full assessment of the cardiovascular safety of the product can be elucidated. Finally, since the ingredients are not disclosed, we cannot be sure that the ingredient amounts will not be altered over time or that active ingredients are consistent from batch to batch. However, it is unlikely that the ingredients will change radically, given the complexity associated with formulation.
Single doses of Metabolife Ephedra-Free did not affect BP in healthy young volunteers. SVRI did not exceed the normal range but was elevated at five hours compared with SVRI in placebo recipients.
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