Clinical Briefs With Comments from Russell H. Greenfield, MD
Clinical Briefs
With Comments from Russell H. Greenfield, MD, Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.
Tea Time Will Never Be the Same Again: Tea and Milk
Source: Lorenz M, et al. Addition of milk prevents vascular protective effects of tea. Eur Heart J 2007;28:219-223.
Goal: To determine whether milk impacts the cardioprotective effects of drinking tea.
Study design: Controlled crossover clinical trial together with in vitro data.
Subjects: Healthy, postmenopausal women recruited through advertisements (n = 16, mean age 59.5 years).
Methods: Subjects were instructed to abstain from drinking tea for four weeks prior to and during the study. During the trial, participants drank 500 mL of boiled water (control), freshly brewed black tea with 10% water, or black tea with 10% skim milk while they enjoyed a croissant for breakfast. Tea preparation was standardized. Subjects underwent three clinical evaluations after fasting overnight, each at least three days apart from one another. Flow-mediated dilation (FMD) and nitro-mediated dilation (NMD, referring to measurements taken after 0.4 mg sublingual nitroglycerin spray and reflecting endothelial independent vasodilatation), were measured before and two hours post-ingestion of the beverages using high-resolution vascular ultrasound following cuff occlusion of the forearm for five minutes. Changes in brachial artery diameter were measured every 15 seconds for up to two minutes. Bench studies were also performed. Bovine aortic endothelial cells were treated with black tea, milk, and milk proteins, and vasorelaxation studies were performed using isolated rat thoracic aorta rings. In cell culture experiments, the production of nitric oxide in response to tea with or without milk was measured.
Results: Tea ingestion significantly increased FMD compared to control, but this effect was abolished with the addition of milk. Tea's effects on NMD (endothelial independent vasodilatation), however, were not affected by the addition of milk. Tea significantly increased endothelial nitric oxide synthase (eNOS) activity in cell culture, but addition of 10% milk completed eliminated the rise in eNOS activity. Experiments with single milk proteins showed that casein (all three forms tested) blunted eNOS activity in a manner similar to milk. In contrast, albumin, lactalbumin, and lactoglobulin had little effect on eNOS activity. Further study showed that tea-induced eNOS phosphorylation, which regulates eNOS activity, is blocked by both milk and single milk caseins. Tea relaxed pre-contracted aortic rings, which was prevented by the NOS-inhibitor L-NAME. Similarly, 10% milk also completely inhibited tea-induced relaxation. When β-casein was added to tea, aortic ring relaxation was likewise inhibited, whereas bovine serum albumin had little effect. Additional studies showed that addition of 10% milk selectively and markedly decreased concentrations of various catechins in the supernatant of centrifuged tea, whereas content of caffeine and gallic acid was unaffected, suggesting a complex formation between catechins and milk proteins.
Conclusion: Milk may counteract the favorable health effects of tea on vascular function.
Study strengths: Human exposure, cell culture, and functional models assessed; degree of detail.
Study weaknesses: Lack of generalizability (subjects were healthy postmenopausal women); very small sample size.
Of note: Ten percent milk was added to black tea to mimic common practice in the United Kingdom; vegetarians and regular drinkers of large amounts of tea were excluded from the study; participants had to have normal values on screening parameters that included lipid levels, blood pressure, thyroid-stimulating hormone, and body mass index; worldwide, tea is second only to water in terms of public consumption; data suggest that polyphenols possess a high binding affinity for proteins high in proline, such as caseins; prior data indicate that adding milk to tea inhibits tea's antimutagenic actions; studies assessing milk's effect on the antioxidant capacity of tea have yielded conflicting results.
We knew that: Tea exerts antioxidant, vasodilatory, and anti-inflammatory effects; the health effects of tea have been tied to its flavonoid content, especially catechins; studies suggest that tea drinking is inversely related to cardiovascular disease morbidity and mortality; FMD is evoked by nitric oxide generated by eNOS during a short period of shear stress; eNos is important for ischemia-mediated arteriogenesis and blood flow stimulated angiogenesis; the major catechin in tea (epigallocatechin-3-gallate) induces eNOS activation in endothelial cells and leads to vasorelaxation in rat aortic rings; tea polyphenols have long been known to interact with milk proteins.
Comments: Until recently, nowhere in the West has the ritual enjoyment of drinking tea become so ingrained in society as in Britain. Indeed, with positive trials of the health benefits of tea piling up over recent years it's clear the Brits (as well as traditional Asian peoples long before) have been on to something. Surprising it is, however, to find that the genteel manner of enjoying afternoon tea with milk appears to counteract important health benefits of tea drinking on endothelial function. Additional studies should be performed that examine other types of tea, but the results of this small, yet in-depth, study raise questions that few would have considered prior. For those who drink tea for their hearts, it may be best to eschew milk. For those who drink tea for their souls, a little milk remains permissible.
What to do with this article: Keep a hard copy in your file cabinet.
Adults, Herbs, and Evidence-based Medicine
Source: Bardia A, et al. Use of herbs among adults based on evidence-based indications: Findings from the National Health Information Survey. Mayo Clin Proc 2007;82:561-566.
Goal: To examine indications that consumers report for taking individual herbs, determine whether these are in accordance with available evidence, and identify factors that predict evidence-based use.
Design: Cross-sectional complex survey (data taken from the Alternative Health/Complementary and Alternative Medicine [CAM] supplement of the 2002 National Health Interview Survey, or NHIS).
Subjects: Survey respondents who used a single popular herbal remedy to treat a specific medical condition within the prior 12 months (n = 609, of whom 65% were women, mean age 41 years).
Methods: Data were extracted from the survey with particular emphasis on answers regarding use of herbs in the prior year, and if so whether they were employed to address a specific medical condition. Subjects were asked to specify the clinical indication for use of the herb from a list of 73 specific health conditions. They were also asked to list independently herbs they took during the previous year from a list of 35 commonly used botanicals. Only responses from subjects who used a single herb from the list of 35 and who said they were taking it to address a specific malady were included in the analysis. Ultimately, analysis was limited to individuals who took one of six herbs in the prior 12 months (echinacea, garlic, ginseng, kava, soy, and St. John's wort).
Results: Overall 54.9% of respondents used herbs consistent with evidence-based medicine (EBM) guidelines (range of 68% for echinacea to 4% for ginseng); however, only about one-third of people using garlic, kava, soy, or St. John's wort did so in accordance with EBM guidelines. For five of the herbs (not echinacea, for which no such pattern was identified), older, non-Hispanic white women with higher levels of education were more likely to use the agents in an evidence-based manner.
Conclusion: More than 60% of adult respondents to a nationally representative survey used a sampling of commonly consumed single herbal remedies to address specific health conditions in ways not supported by the scientific literature.
Study strengths: Large sample size; multivariable logistic regression analysis.
Study weaknesses: Response rate to the Alternative Health/CAM supplement was not noted; analysis only possible for use of a single herb, when clinical experience suggests that many people use more than one herbal remedy at a time, or combination therapy; no information provided on specific products used by respondents, dosages employed, or perceived efficacy.
Of note: The response rate to the overall 2002 NHIS questionnaire was almost 75%; a single database was used to develop the evidence-based standards for herb use as applied in this study; sales of dietary supplements have increased more than any other segment of CAM since the 1990s; data suggest that consumers believe their conventional medical doctors are not in favor of supplement use; the survey employed in this study distinguished "natural herbs" from vitamins and minerals; the 10 most commonly endorsed herbs in the survey were noted to be echinacea, ginseng, ginkgo, garlic, St. John's wort, peppermint, ginger, soy, ragweed, and kava; the authors were not able to assess ginkgo for claudication, dementia or cerebral insufficiency, nor were they able to assess ginger for nausea and vomiting, because these conditions were not listed in the survey's 73 specific health conditions; the database employed for this study did not identify any established use of peppermint; it is striking that ragweed was listed as one of the 10 most commonly endorsed herbs in the survey; ginseng for "mental performance" was not assessed in this trial, only its use in the setting of diabetes; despite a spate of articles questioning its efficacy against the common cold, echinacea remains the single most popular herbal remedy in the United States.
We knew that: Most people do not discuss their use of CAM therapies, including supplements, with their conventional doctors; in addition, conventional medical providers are often not well-versed in CAM therapies, including the use of supplements; the NHIS is a large, nationally representative household survey that uses a national sample of the civilian, non-institutionalized U.S. population, sampling approximately 30,000 adults each year (with over-sampling of both black and Hispanic populations); the NHIS has been conducted continuously since 1957, and data are released annually; the survey includes a core set of questions with additional questions asked periodically, and detailed questions asked of one randomly selected adult and one child per household; the Dietary Supplement Health and Education Act (DSHEA) of 1994 established that dietary supplements be regulated under an FDA category different from both foods and drugs; under DSHEA, supplement labels can only claim that the product contained therein supports the "structure and function of the body," and cannot offer claims that the supplement can help "diagnose, treat, cure, or prevent any disease."
Clinical import: The authors of this study call for health care professionals to proactively educate consumers regarding existing evidence either for or against the use of specific herbs to address health conditions. Such a call is laudable, and problematic. The majority of conventional medical practitioners has little or no knowledge of the proper use of supplements, is uncertain where to turn for credible information in this regard, and is struggling to stay up to date in their own fields let alone learn about CAM therapies. In addition, data suggest that the majority of practicing physicians do not follow EBM guidelines with respect to specific therapeutic interventions, thus it cannot be surprising that the lay public often pays little heed to the medical research, choosing to rely more on personal experience, tradition, and popular opinion than on professional advice. The study itself is significantly flawed in ways delineated, but the underlying theme that people are using CAM therapies without guidance from, or at least partnership with, their conventional doctors is important to emphasize, even though already commonly accepted.
What to do with this article: Remember that you read the abstract.
One Does not Equal Two—Cinnamon and Diabetes Mellitus
Source: Altschuler JA, et al. The effect of cinnamon on A1C among adolescents with type I diabetes. Diabetes Care 2007;30:813-816.
Goal: To determine the effect of cinnamon on glycemic control in adolescents with Type 1 diabetes mellitus (DM).
Study design: Prospective, randomized, double-blind, placebo-controlled study performed over 90 days.
Subjects: Adolescents with Type 1 DM (n = 72, with 57 completing the trial) treated as outpatients.
Methods: Subjects were randomized to receive either 1 g/d of cinnamon in pill form or placebo (a lactose pill). A three-month supply was provided to participants at the time of enrollment, and instructions were offered to take the pills at the same time each day. Subjects were asked to maintain a logbook of insulin usage during the course of the study. Primary outcome measures were total A1c and change in A1c. Additional endpoints included total daily insulin use and adverse events. Subjects were called every two weeks both to assess compliance and collect data.
Results: No statistically significant differences were identified between the two groups with respect to total daily insulin intake, final mean A1c, mean change in A1c, or number of hypoglycemic episodes. With respect to the last parameter, however, subjects in the cinnamon group experienced 39% more hypoglycemic episodes than those in the placebo arm, but the result did not reach statistical significance.
Conclusion: Cinnamon is not effective for improving glycemic control in adolescents with Type 1 DM.
Study strengths: Compliance assessed by regular phone contact in addition to pill count (however, level of compliance is not stated in the paper); intention-to-treat analysis.
Study weaknesses: Source of cinnamon and type is not detailed except to say that the pills were prepared by the University of California-San Francisco Investigational Pharmacy; significant dropout rate; short duration of trial.
Of note: Adolescents with Type 1 DM were chosen for study because they are deemed a high-risk group; adolescents have unique challenges in trying to maintain adequate glycemic control that include increasing insulin resistance, and both physiologic (rapid growth) and psychosocial issues; data point to an increase in A1c in those with DM from age 13 to 19 years; for inclusion, subjects had to have carried the diagnosis of Type 1 DM for at least 18 months and have avoided inpatient care for at least 12 months; in this study, A1c levels were taken from medical records at the time of enrollment and then repeated approximately 90 days later; a subject in the cinnamon arm experienced a hypoglycemic seizure one day after enrollment and withdrew from the study; study results tended to favor the placebo group.
We knew that: A1c (also called glycohemoglobin) provides an estimate of blood sugar control over the prior few months, and is the single best predictor for risk of complications in people with either Type 1 and Type 2 DM; specialists typically recommend that people with DM keep their A1c as close to 6% or below as possible (4-6% is considered normal); a slim majority of studies has shown that cinnamon may be an effective aid in achieving enhanced glycemic control for people with Type 2 DM; results of a number of in vitro studies suggest that cinnamon may sensitize individuals to the effects of insulin, with some researchers hypothesizing the presence of a synergistic effect; other researchers posit that cinnamon may actually increase endogenous insulin production; the majority of data supporting a therapeutic benefit of cinnamon in the setting of Type 2 DM focuses on fasting blood sugar, which contributes relatively little to A1c.
Comments: While the potential benefit of adding cinnamon to the diet for people with Type 2 DM has long been considered, the same cannot be said for the setting of Type 1 DM. Many practitioners simply assumed that cinnamon must be good for anyone with "diabetes," though the basis for specific therapeutic intervention differs considerably between Types 1 and 2. The present study raises questions about the efficacy of cinnamon for people with either type of DM, but is far from definitive. One major concern is the type of cinnamon employed by the pharmacists. To lump all forms of cinnamon together is simplistic, if not misguided, as there are many. The majority of data showing a beneficial effect on blood sugar has used Cassia cinnamon. The form of cinnamon employed in this trial was not disclosed. To their credit, the researchers do question whether a larger dose of cinnamon might be necessary to show an effect in Type 1 DM, and note that a 90-day intervention is shorter than the typical 120-day lifespan of the human red blood cell (thus potentially having an impact on A1c). In addition, it is interesting to note the statistically nonsignificant rate of hypoglycemia in the cinnamon group (39%), a rate that would certainly be deemed clinically significant. The questions raised by this trial are important, but further research is clearly warranted.
What to do with this article: Keep a copy of the abstract on your computer.
Greenfield RH. Tea time will never be the same again: Tea and milk. Altern Med Alert 2007;10(6):70-71. Greenfield RH. Adults, herbs, and evidence-based medicine. Altern Med Alert 2007;10(6):71-72. Greenfield RH. One does not equal twoCinnamon and diabetes mellitus. Altern Med Alert 2007;10(6):72.Subscribe Now for Access
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