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.
CoQ10, ecSOD, hike! CoQ10 and CAD
Source: Tiano L, et al: Effect of coenzyme Q10 administration on endothelial function and extracellular superoxide dismutase in patients with ischaemic heart disease: a double-blind, randomized controlled study. Eur Heart J. 2007;28:2249-2255.
Goal: To determine whether or not supplementation with oral coenzyme Q10 (CoQ10) improves extracellular superoxide dismutase (ecSOD) activity and endothelium-dependent (ED) vasodilation in subjects with coronary artery disease (CAD).
Study Design: Double-blind, randomized, controlled trial.
Subjects: People with CAD whose events (CABG, PTCA/myocardial infarction) occurred at least 3 months prior to enrollment (n = 38 with 33 men, mean age, 55 years); data available for analysis on 33 subjects (including all those in the active intervention group).
Methods: Subjects were randomized to 2 groups; one received CoQ10 100 mg orally 3 times daily, while the other received placebo in the same dosing schedule, each for one month. At baseline and at the end of one month, subjects underwent brachial artery ED assessment (fasting state), cardiopulmonary exercise testing, and measurement of endothelium-bound ecSOD activity. With regard to the latter, baseline venous samples were obtained and then a 5,000 U heparin bolus was administered IV. Blood samples for ecSOD were obtained at 1, 3, 5, 7, and 10 minutes after infusion.
Results: Supplementation resulted in a 4-fold increase in plasma CoQ10 levels. EcSOD activity increased from 17.3 to 22.4 in the CoQ10 group, compared with a change from 16.6 to 17.3 in the placebo group. Increases in ecSOD activity were most notable for those subjects with the lowest baseline levels of endothelium-bound ecSOD.
Baseline flow-mediated dilation was strongly correlated with endothelium-bound ecSOD activity, and ED relaxation improved in the CoQ10 group, but not the placebo group. Enhanced ED relaxation was linked to increases in plasma CoQ10. Improvements in other cardiopulmonary parameters were also statistically greater in the group receiving CoQ10.
Conclusion: Oral supplementation with CoQ10 300 mg daily for one month results in improved endothelial function and endothelium-bound ecSOD activity in subjects with known CAD.
Study strengths: Employ of multiple measures of cardiovascular function; unique focus on ecSOD.
Study weaknesses: Small sample size; short study duration.
Of note: CoQ10 has been shown to improve ED in people with diabetes mellitus; subjects in this trial had normal left ventricular ejection fractions (EF) with a mean EF = 58% (normal typically considered 55-70%); recent data suggest that CoQ10 improves cardiac contractility in people with ischemic heart disease; people engaged in cardiac rehabilitation were not eligible for participation in this study; medications were not changed throughout the study, including beta blockers; ecSOD is specifically released from the endothelium into the plasma by heparin bolus injection.
We knew that: CoQ10 has been suggested to have antioxidant and mitochondrial bioenergetic actions; some studies have shown beneficial effects on cardiac performance in people with heart failure or CAD; ecSOD is a major antioxidant enzyme system of blood vessel walls, and ecSOD activity is reduced in people with CAD; low levels of ecSOD would suggest increased susceptibility to oxidative stress; ED vasodilation is strongly correlated with endothelium-bound ecSOD levels; the highest tissue concentrations of ecSOD are found in blood vessels, the lung, kidney and uterus; endothelial dysfunction of peripheral vasculature correlates well with coronary arterial endothelial dysfunction.
Comments: The findings of this study are certainly intriguing, but as my radiologist friends often advise, "this requires further clinical correlation."
CoQ10 has been under intense research scrutiny for over 4 decades because of its potential for increasing cellular energy levels, and potent antioxidant activity. Like the current study, however, many CoQ10 trials utilize creative diagnostics, but are plagued by methodologies rife with small numbers of participants and short durations of intervention. There is promise of benefit in the use of CoQ10 for people with established cardiovascular disease, but the topic cries out for definitive study. Aside from CoQ10's expense and the potential for its interacting with warfarin, there is little reason to recommend against its use in the setting of CAD and heart failure. It would be so much better, however, if in these settings there were definitive reason to actively promote its use. That time has still not arrived. If CoQ10 is to assume an important role in the management of cardiovascular disorders, researchers must better bridge the gap between clinical potential and clinical performance.
What to do with this article: Keep a copy on your computer.
MDs and DS: Are Regulations Understood?
Source: Ashar BH, et al: Physicians' understanding of the regulation of dietary supplements. Arch Intern Med. 2007;167:966-969.
Goal: To assess the level of physician understanding of US dietary supplement (DS) regulation and the process of adverse event reporting (AER). In addition, to determine whether or not an interactive online curriculum could be a useful physician tool in this regard.
Subjects: Internal medicine residents and attendings from 15 different residency training programs.
Methods: A didactic module on DS regulation was developed with a focus on 5 content objectives as follows: 1) DS do not require approval before being sold; 2) Efficacy data are not needed before DS are sold; 3) Safety data are not needed before DS are sold; 4) No current regulations exist to ensure product quality of DS; 5) Adverse events due to DS should be reported through the FDA MedWatch system. Pre- and post-training multiple choice tests were developed based on clinical cases (5 questions each, with one question per content objective) by a varied group of experts in their fields. Post-test answers could not be accessed until the training module was completed. The training module was made available to 1,541 residents. Pretest performance assessed baseline understanding of DS regulation, and together with results of the post-test were used to evaluate the effectiveness of the online teaching tool.
Results: A total of 335 physicians completed the entire training module, including pre- and post-tests, with 90% being residents (21% were interns, 34% were PGY-2s, 35% were PGY-3s, and 10% were attendings). At baseline, understanding of the fundamentals of DS regulation was demonstrably low, with an average pretest score of but 59%. Over 1/3 of participants were unaware that DS do not require FDA approval before being marketed and sold. Few (approximately 40%) were aware that AER related to use of DS should go through the FDA MedWatch system. Upon completion of the online module, however, average post-test scores rose to 91%. Test scores did not improve with increasing level of residency training, although attending physicians did score significantly higher on two of the 5 content objectives.
Conclusion: In this sample of physicians in training and attendings, knowledge of DS regulation and AER was poor, but an online DS educational module significantly improved awareness and understanding of key concepts.
Study strengths: Random pilot testing before actual study began; analysis based on years of training / experience; tested for participation bias.
Study weaknesses: Poor participation rate (22%); a sample of 5 test questions may not adequately assess knowledge of key concepts of regulation.
Of note: The FDA MedWatch program is used to monitor the safety of drugs, devices, biologicals, and DS; while reportedly uncommon, instances of adulteration or contamination of DS have been documented, and there exist concerns that such problems are underreported; until recently, the source of most inquiries into the safety of specific DS was consumers; studies have shown that healthcare practitioners desire more education on Complementary and Alternative Medical (CAM) therapies; a growing number of medical schools have incorporated select aspects of CAM therapies into the curriculum, most often as electives, but some as part of the standard course of study; some educators have proposed that understanding of governmental regulation of DS be considered a core competency for medical school curricula in integrative medicine.
We knew that: The Dietary Supplement Health and Education Act (DSHEA) of 1994 established regulation of vitamins, supplements and herbs as DS, permitting such products to be marketed and sold without prior FDA approval, and without requiring completion of safety and efficacy studies; DSHEA also enabled the FDA to establish Good Manufacturing Practices (GMPs) for DS, similar to those in place for pharmaceuticals, although such regulations have yet to be fully enacted.
Comments: The attitudes of conventional Western medical practitioners towards DS run the gamut from benign neglect to support to antagonism, but the fact that our patients are using DS is now undeniable. Patients can turn to the teenaged health food store clerk, the Internet, or popular books and periodicals for advice on how they should use DS, or they can turn to their doctors. Indeed, when surveyed, users of DS would prefer to get credible, non-judgmental information on DS from their doctors. In order to serve patients well, healthcare practitioners must possess fundamental knowledge regarding DS use, of which regulation and standardization would seem paramount so that appropriate recommendations can be made and AER undertaken appropriately. This information is still not readily taught to medical students and residents, so the development of a curriculum to address this shortcoming is very important. This study has flaws, but the authors are to be commended.
What to do with this article: Keep a hard copy in your file cabinet.
Fish with Sugar? O-3s and Childhood Type 1 Diabetes
Source: Norris JM, et al. Omega-3 polyunsaturated fatty acid intake and islet cell autoimmunity in children at increased risk for type 1 diabetes. JAMA. 2007;298:1420-1428.
Goal: To determine whether development of islet cell autoimmunity (IA) is associated with dietary omega-3 (O-3) and omega-6 (O-6) fatty acid intake in children.
Study Design: Prospective, longitudinal observation study (the Diabetes Autoimmunity Study in the Young, or DAISY) conducted between 1994-2000, as well as a related case-cohort study examining risk of IA according to polyunsaturated fatty acid (PUFA) content of red blood cell membranes.
Subjects: Children at risk for type 1 diabetes (DM) defined as either possessing a high DM risk HLA genotype, or having a parent or sibling with DM (n = 1,770). The case-cohort part of the trial involved 244 subjects.
Methods: Two groups of children were followed, the first being unaffected first-degree relatives of patients with type 1 DM who were identified and recruited between birth and 8 years of age, and the second group being babies screened at birth for the presence of diabetes-susceptibility alleles in the HLA region. Dietary intake of PUFAs was assessed starting at age one year using a validated 111-item semiquantitative food frequency questionnaire (FFQ). Starting at age 2 years, or at enrollment if older than age 2, the FFQ was administered annually, during which parents were asked to recall the children's diets over the prior year (dietary advice was not provided). Intakes of PUFAs were calculated based on established food composition values. Children recruited at birth were tested for autoantibodies to pancreatic islet antigens at 9, 15 and 24 months, and annually thereafter. Those recruited at a later age had blood drawn at the time of study enrollment and then annually. Children who tested positive for any of the autoantibodies were then placed on an accelerated schedule of blood draws. Random blood glucose and glycolated hemoglobin were also obtained at each clinic visit. Timing of introduction of cereal into the infant diet was evaluated as well. The primary study outcome of interest was risk of IA defined as being positive on 2 consecutive visits at least 3 months apart, and at trial's end, for antibodies against insulin, glutamic acid decarboxylase (produced by pancreatic islet cells), or insulinoma-associated antigen-2, or by having DM at the last clinic visit.
Results: Mean age at follow-up was 6.2 years. A total of 58 children developed IA, and after adjustment for potential confounding factors, total O-3 intake (but not marine PUFA intake) was inversely related to risk of IA (Hazard Ratio, or HR, =0.45), an association strengthened when outcome was limited to those positive for 2 or more autoantibodies (HR=0.23). Total O-6 intake was not associated with increased risk for IA. Vitamin D intake was found to be neither a covariate nor a confounder. Results of the case-cohort trial showed that O-3 content of erythrocyte membranes was inversely correlated with risk of IA (HR=0.63). No association between timing of introduction of cereal and risk of IA was identified.
Conclusion: Higher dietary intake of O-3 fatty acids as reported on repeated FFQs is associated with a reduced risk of IA in children who are otherwise at increased genetic risk for type 1 DM. In addition, a higher proportion of O-3s in red blood cell membranes is also associated with decreased risk for IA.
Study strengths: Dietary intake data were dynamically updated with each IA event; in a subset of subjects aged 1-3 years (n = 68), results of FFQs were compared to four 24-hour food recalls collected from parents throughout the year; assessment of vitamin D intake as potential confounder; consideration of supplements and vitamins, as well as sociodemographic factors.
Study weaknesses: Challenges inherent in the use of annual FFQs (recall bias, etc.); staggered enrollment meant differing amounts of data available for each child.
Of note: In a prior, retrospective study, infant supplementation with cod liver oil was associated with a decreased risk of type 1 DM; cod liver oil is often quite high in vitamin A, as well as vitamin D; experts believe that both genetic and environmental factors play a role in initiation of the autoimmune process at work in the development of type 1 DM; in addition, dietary factors have been implicated, with some studies suggesting that vitamin D intake may play a protective role; no attempt was made to assess dietary intake of subjects during the first year of life; a prior study suggested that early introduction of cereal into the infant diet was associated with an increased risk of IA; erythrocyte samples were not available until 2000, so the number of IA cases in the case-cohort analysis was lower.
We knew that: Type 1 DM is an autoimmune disease characterized by destruction of the insulin-producing beta cells of the pancreatic islets; the clinical phase of type 1 DM is preceded by an asymptomatic period of variable duration during which autoantibodies to beta cells and their antigens are detectable in the blood; a number of studies suggest that O-3s dampen local and systemic inflammatory responses, leading some to believe that the Western diet traditionally low in O-3s may predispose to development of type 1 DM; alpha-linolenic acid (ALA) is the principal O-3 in Western diets, and serves in a limited capacity as a precursor for EPA and DHA (most commonly found in cold water fish); linoleic acid is the most abundant O-6 in the Western diet, and competes with ALA for key enzymes involved in fatty acid metabolism and subsequent conversion to either pro- or anti-inflammatory prostaglandins and related molecules; O-3s reduce levels of oxidative stress in the body.
Comments: The burdens for individuals with DM, both acute and chronic, are relatively well known, but what may not be is the increasing burden on society. Expenses associated with the care of people with diabetes are skyrocketing, with the annual cost associated with treating complications of DM now averaging $10,000 per person. For the individual as well as the healthcare system as a whole, such a circumstance seems unsustainable. As with most chronic maladies, the focus needs to be on prevention as well as treatment, which is what makes the published report at hand so important.
Compelling data have long been accumulating on potential neurodevelopmental and anti-inflammatory benefits with increasing dietary intake of omega-3 fatty acids in childhood, but the results of this article call for nothing less than our rapt attention. To be sure, the authors of this important paper are quick to state that further research is warranted, but their excitement is palpable - "...omega-3 supplementation could become a mainstay for early intervention to safely prevent development of type 1 diabetes." May it be so.
What to do with this article: Make copies to hand out to your peers.
CoQ10, ecSOD, hike! CoQ10 and CAD, MDs and DS: Are Regulations Understood?, and Fish with Sugar? O-3s and Childhood Type 1 DiabetesSubscribe Now for Access
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