Rebecca B. Costello

Omega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future Research A Report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop

Compared with prehistoric times, the ratio of n-6 to n-3 fatty acids in the modern diet has increased ≈10-fold to 20:1.1,2 A substantial body of evidence suggests that n-3 polyunsaturated fatty acids (PUFAs) provide cardiovascular protection and prevent arrhythmias.3–5 This has led to the recommendation by the American Heart Association that all adults eat fatty fish at least 2 times per week and that patients with coronary heart disease (CHD) are advised to consume ≈1 g/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combined.6,7 The evidence base is not entirely consistent, and a number of randomized trials have failed to show a protective effect of n-3 PUFAs against arrhythmias.8–10 This has led to some uncertainty regarding the appropriate recommendations for their use.11 The present review originates from the Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements on August 29–30, 2005, and includes the findings from the recently published trials. Data from epidemiological studies, randomized clinical trials, animal studies, and basic science mechanistic studies on the role of n-3 PUFAs in arrhythmia prevention are examined. Areas in which the data are conflicting or our current knowledge is lacking are emphasized. Fatty acids are classified by the length of the carbon chain (long chain, n=20 to 22; intermediate chain, n=18) and the number of double bonds (saturated, monounsaturated, polyunsaturated).1,2 For PUFAs, the location of the first double bond relative to the -CH3 or omega (n-) end is given. Long- and intermediate-chain fatty acids must be ingested as part of the diet because they cannot be synthesized by humans and are therefore referred to as essential. The most common dietary fatty acids include (1) the omega-6 linoleic acid …

Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory from the American Heart Association

Multiple randomized controlled trials (RCTs) have assessed the effects of supplementation with eicosapentaenoic acid plus docosahexaenoic acid (omega-3 polyunsaturated fatty acids, commonly called fish oils) on the occurrence of clinical cardiovascular diseases. Although the effects of supplementation for the primary prevention of clinical cardiovascular events in the general population have not been examined, RCTs have assessed the role of supplementation in secondary prevention among patients with diabetes mellitus and prediabetes, patients at high risk of cardiovascular disease, and those with prevalent coronary heart disease. In this scientific advisory, we take a clinical approach and focus on common indications for omega-3 polyunsaturated fatty acid supplements related to the prevention of clinical cardiovascular events. We limited the scope of our review to large RCTs of supplementation with major clinical cardiovascular disease end points; meta-analyses were considered secondarily. We discuss the features of available RCTs and provide the rationale for our recommendations. We then use existing American Heart Association criteria to assess the strength of the recommendation and the level of evidence. On the basis of our review of the cumulative evidence from RCTs designed to assess the effect of omega-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events, we update prior recommendations for patients with prevalent coronary heart disease, and we offer recommendations, when data are available, for patients with other clinical indications, including patients with diabetes mellitus and prediabetes and those with high risk of cardiovascular disease, stroke, heart failure, and atrial fibrillation.

Dietary guidance in heart failure: a perspective on needs for prevention and management.

The role that dietary factors play in preventing heart failure (HF) and in improving prognosis is increasingly recognized, indicating a need for well-grounded guidelines that can provide recommendations for daily nutrient intakes. At present, however, the state of dietary guidance is more satisfactory for persons at risk of HF (Stages A and B) than for those with a diagnosis of HF (Stages C and D). For individuals at risk of HF, a good starting point is provided by governmental and professional society guidance directed at dietary management of cardiovascular risk factors such as hypertension, hyperlipidemia, and obesity. These dietary recommendations are consonant with epidemiologic research suggesting that improving risk factor profiles likely will lower the risk of developing HF. For patients with diagnosed HF, however, little information is available to define optimal nutrient intakes and optimal food patterns. Dietary services have been shown useful in improving clinical outcomes, but nutritional management must be individualized to the patient’s needs and must accommodate pharmacologic therapy, multiple co-morbidities, the possible need for nutritional supplements, repeated hospitalizations, salt and fluid retention, voluntary vs. involuntary weight loss, and other nutritional issues relevant to the aged population who comprise the majority of HF patients. Progress in the field will require well-designed clinical investigations addressing nutrient intake, nutrient metabolism, and nutritional status while mindful of the complex pathophysiology of HF.

The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature.

A systematic review was conducted using Samueli Institute’s Rapid Evidence Assessment of the Literature (REAL©) process to determine the evidence base for melatonin as an agent to optimize sleep or improve sleep quality, and generalize the results to a military, civilian, or other healthy, active, adult population. Multiple databases were searched yielding 35 randomized controlled trials (RCTs) meeting the review’s inclusion criteria, which were assessed for methodological quality as well as for melatonin effectiveness. The majority of included studies were high quality (83.0%). Overall, according to Grading Recommendations, Assessment Development and Evaluation (GRADE) methodology, weak recommendations were made for preventing phase shifts from jet lag, for improving insomnia in both healthy volunteers and individuals with a history of insomnia, and for initiating sleep and/or improving sleep efficacy. Based on the literature to date, no recommendations for use in shift workers or to improve hormonal phase shift changes in healthy people can be made at this time. Larger and longer-duration RCTs utilizing well characterized products are needed to warrant melatonin recommendations in young, healthy adults.

The Circulating Concentration and 24-h Urine Excretion of Magnesium Dose- and Time-Dependently Respond to Oral Magnesium Supplementation in a Meta-Analysis of Randomized Controlled Trials

BACKGROUND Accurate determination of Mg status is important for improving nutritional assessment and clinical risk stratification. OBJECTIVE We aimed to quantify the overall responsiveness of Mg biomarkers to oral Mg supplementation among adults without severe diseases and their dose- and time responses using available data from randomized controlled trials (RCTs). METHODS We identified 48 Mg supplementation trials (n = 2131) through searches of MEDLINE and the Cochrane Library up to November 2014. Random-effects meta-analysis was used to estimate weighted mean differences of biomarker concentrations between intervention and placebo groups. Restricted cubic splines were used to determine the dose- and time responses of Mg biomarkers to supplementation. RESULTS Among the 35 biomarkers assessed, serum, plasma, and urine Mg were most commonly measured. Elemental Mg supplementation doses ranged from 197 to 994 mg/d. Trials ranged from 3 wk to 5 y (median: 12 wk). Mg supplementation significantly elevated circulating Mg by 0.04 mmol/L (95% CI: 0.02, 0.06) and 24-h urine Mg excretion by 1.52 mmol/24 h (95% CI: 1.20, 1.83) as compared to placebo. Circulating Mg concentrations and 24-h urine Mg excretion responded to Mg supplementation in a dose- and time-dependent manner, gradually reaching a steady state at doses of 300 mg/d and 400 mg/d, or after ~20 wk and 40 wk, respectively (all P-nonlinearity ≤ 0.001). The higher the circulating Mg concentration at baseline, the lower the responsiveness of circulating Mg to supplementation, and the higher the urinary excretion (all P-linearity < 0.05). In addition, RBC Mg, fecal Mg, and urine calcium were significantly more elevated by Mg supplementation than by placebo (all P-values < 0.05), but there is insufficient evidence to determine their responses to increasing Mg doses. CONCLUSIONS This meta-analysis of RCTs demonstrated significant dose- and time responses of circulating Mg concentration and 24-h urine Mg excretion to oral Mg supplementation.

Do Cinnamon Supplements Have a Role in Glycemic Control in Type 2 Diabetes? A Narrative Review

Cinnamon (Cinnamomum sp) has been suggested to help patients with type 2 diabetes mellitus (T2DM) achieve better glycemic control, although conclusions from meta-analyses are mixed. To evaluate whether the use of cinnamon dietary supplements by adults with T2DM had clinically meaningful effects on glycemic control, as measured by changes in fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c), a comprehensive PubMed literature search was performed. Eleven randomized controlled trials were identified that met our inclusion criteria that enrolled 694 adults with T2DM receiving hypoglycemic medications or not. In 10 of the studies, participants continued to take their hypoglycemic medications during the cinnamon intervention period. Studies ranged from 4 to 16 weeks in duration; seven studies were double-blind. Cinnamon doses ranged from 120 to 6,000 mg/day. The species of cinnamon used varied: seven used Cinnamomum cassia or Cinnamomum aromaticum, one used Cinnamomum zeylanicum, and three did not disclose the species. Because of the heterogeneity of the studies, a meta-analysis was not conducted. All 11 of the studies reported some reductions in FPG during the cinnamon intervention, and of the studies measuring HbA1c very modest decreases were also apparent with cinnamon, whereas changes in the placebo groups were minimal. However, only four studies achieved the American Diabetes Association treatment goals (FPG <7.2 mmol/L [130 mg/dL] and/or HbAlc <7.0). We conclude that cinnamon supplements added to standard hypoglycemic medications and other lifestyle therapies had modest effects on FPG and HbA1c. Until larger and more rigorous studies are available, registered dietitian nutritionists and other health care professionals should recommend that patients continue to follow existing recommendations of authoritative bodies for diet, lifestyle changes, and hypoglycemic drugs.

In the Midst of Confusion Lies Opportunity: Fostering Quality Science in Dietary Supplement Research

The Office of Dietary Supplements (ODS) was established at the National Institutes of Health (NIH) by Congress through the Dietary Supplement Health and Education Act (DSHEA) of 1994. The mission of the ODS is to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, stimulating and supporting research, disseminating research results and educating the public, all in an effort to foster an enhanced quality of life and health for the U.S. population. In pursuit of this mission, ODS takes into account an array of dietary supplement ingredients and products. This includes vitamin and mineral supplements and botanicals, as well as non-nutrient supplements. Toward that end, ODS has taken a number of steps. In collaboration with other Institutes and Centers at NIH, ODS has established a network of Dietary Supplement Research Centers around the country that provide the focus for multidisciplinary research efforts; it supports research activities and scientific conferences, it supports evidence-based reviews of supplements, and it maintains a public database of scientific literature on dietary supplements. The lack of credible information from well-controlled studies of many dietary supplements raises issues of caution and concern. The ODS is committed to providing and disseminating accurate and reliable scientific information on dietary supplements.

Chromium supplements for glycemic control in type 2 diabetes: limited evidence of effectiveness

Some adults with type 2 diabetes mellitus (T2DM) believe that chromium-containing supplements will help control their disease, but the evidence is mixed. This narrative review examines the efficacy of chromium supplements for improving glycemic control as measured by decreases in fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c). Using systematic search criteria, 20 randomized controlled trials of chromium supplementation in T2DM patients were identified. Clinically meaningful treatment goals were defined as an FPG of ≤7.2 mmol/dL, a decline in HbA1c to ≤7%, or a decrease of ≥0.5% in HbA1c. In only a few randomized controlled trials did FPG (5 of 20), HbA1c (3 of 14), or both (1 of 14) reach the treatment goals with chromium supplementation. HbA1c declined by ≥0.5% in 5 of 14 studies. On the basis of the low strength of existing evidence, chromium supplements have limited effectiveness, and there is little rationale to recommend their use for glycemic control in patients with existing T2DM. Future meta-analyses should include only high-quality studies with similar forms of chromium and comparable inclusion/exclusion criteria to provide scientifically sound recommendations for clinicians.

A Free New Dietary Supplement Label Database for Registered Dietitian Nutritionists

The Academy of Nutrition and Dietetics recognizes the importance of including dietary supplements in assessing and planning dietary intakes.1 Dietary supplement (DS) use in the United States has increased markedly during the last 30 years and is now widespread across all segments of society.2,3,4,5,6 Today, over half of adults and a third of US children have used one or more DS within the past 30 days, with multi-vitamin, multi-mineral (MVMM) products especially common.7, 8 Since supplements are now major sources of several nutrients such as calcium and vitamin D in American diets, it is important for registered dietitians and nutritionists (RDNs) to include their contributions when assessing intakes or planning diets.9,10,11 Likewise, for national nutrition surveillance the contributions to nutrient intakes from supplements must be considered in order to identify groups at dietary risk because their intakes fall below the estimated average requirement (EAR) or above the upper tolerable intake level (UL).12 For example, when supplements are included in assessments, the proportion of the United States population that is below the EAR is much less for several vitamins11 and fewer women are “at risk” (defined as below the EAR) for folate intake than when they are not.13,14 For some nutrients, like folic acid, the UL is established based solely for the form that comes from fortificants in foods and in dietary supplements. RDNs, epidemiologists, and public health officials also need accurate dietary supplement databases in order to evaluate possible associations between nutrient intake and disease outcomes. The National Health and Nutrition Examination Survey (NHANES) dietary supplement label database contains label-derived information from supplement products that is updated every two years. Information contained in the database is driven by what is reported by survey participants. The currently available database contains supplement label information for products reported from 1999–2010. While the NHANES DS database provides useful information, it is not comprehensive and is more likely to contain commonly used supplements and less likely to contain infrequently used supplements.15 In fact, MVMM products account for only about half of all supplements used.3 Additionally, not all information from the label is recorded and released in the database. For example, the NHANES database does not contain information such as health claims, other ingredients and warning statements that may have been on the label.

Is Nutrient Content and Other Label Information for Prescription Prenatal Supplements Different from Nonprescription Products

BACKGROUND Prenatal supplements are often recommended to pregnant women to help meet their nutrient needs. Many products are available, making it difficult to choose a suitable supplement because little is known about their labeling and contents to evaluate their appropriateness. OBJECTIVE To determine differences between prescription and nonprescription prenatal supplements available in the United States regarding declared nutrient and nonnutrient ingredients and the presence of dosing and safety-related information. DESIGN Using two publicly available databases with information about prenatal supplement products, information from prescription and nonprescription product labels were extracted and evaluated. For the 82 prescription and 132 nonprescription products, declared label amounts of seven vitamins and minerals, docosahexaenoic acid (DHA), the presence of other nonnutrient components, and the presence of key safety and informational elements as identified in two Department of Health and Human Services Office of Inspector General (OIG)s 2003 reports were compiled and compared. RESULTS Compared with nonprescription products, prescription products contained significantly fewer vitamins (9±0.2 vs 11±0.3; P≤0.05) and minerals (4±0.1 vs 8±0.3; P≤0.05). Declared amounts of folic acid were higher in prescription products, whereas vitamin A, vitamin D, iodine, and calcium were higher in the nonprescription products. Amounts of iron, zinc, and DHA were similar. Virtually all products contained levels of one or more nutrients that exceeded the Recommended Dietary Allowances for pregnant and/or lactating women. Product type also influenced ingredients added. Fewer prescription products contained botanical ingredients (6% prescription vs 33% nonprescription) and probiotics (2% prescription vs 8% nonprescription). Only prescription products contained the stool softener docusate sodium. CONCLUSIONS Our analysis of prenatal supplements indicates that prescription and nonprescription supplements differ in terms of declared composition and nutrient strength, but have labels that are similarly sparse regarding aspects of use such as dosing information.