Recommendation grades (A-D) and levels of evidence (1-4) are defined at the end of the "Major Recommendations" field. The table below summarizes the conclusions that follow for specific dietary supplements and nutraceuticals (DS/N).
Coenzyme Q10
Coenzyme Q10 (CoQ10) has beneficial effects for mitochondrial disorders, congestive heart failure (CHF), and ischemia-reperfusion injury (Grade C). For these indications, physicians may recommend it in situations in which the patient has not gained sufficient improvement from conventional therapy, providing there is no reasonable anticipation of adverse effects. No persuasive data compel this task force to endorse the use of CoQ10 in a wide variety of other claimed benefits, including performance enhancement, retardation of the aging process, immune system enhancement, diabetes mellitus, hypertension, or cancer (Grade D).
Flavonoids, Isoflavones, and Ipriflavone
Researchers reviewed more than 1,000 articles on phytoestrogens for a 30-year period and found 74 relevant studies to examine in detail. They concluded that insufficient evidence was available to recommend phytoestrogens instead of traditional hormone replacement therapy or to endorse any specific recommendations about particular phytoestrogen products. The guideline developers agree with this conclusion (Grade D). Nevertheless, it would be prudent to recommend a diet high in legumes and cereals to women who are at risk for cardiovascular disease or estrogen-dependent malignant lesions or who are perimenopausal (Grade A). In particular, ample conclusive level 1 and 2 data support the beneficial effect of soy protein in patients at risk for cardiovascular disease (Grade A). There are also conclusive level 2 and 3 data concerning isoflavones or ipriflavone and osteoporosis (Grade B). Overall, increasing the dietary consumption of fruit, vegetables, and certain beverages containing flavonoids (tea and red wine) seems prudent as part of a healthful diet. Currently, however, specific quantitative recommendations cannot be made for the general population.
Phytosterols
The use of phytosterols has been investigated in patients with hypercholesterolemia and found to reduce low-density lipoprotein (LDL) cholesterol levels. Conclusive level 1 data have accrued because of the numerous prospective, randomized, controlled trials (PRCTs) that have been conducted. The American Association of Clinical Endocrinologists (AACE), in agreement with the American Heart Association Nutrition Committee, recommends the use of phytosterols in patients with hypercholesterolemia and in patients requiring secondary prevention after an atherosclerotic event (Grade A). All treated patients must be monitored for sitosterolemia in case they are heterozygotes. Patients with normal cholesterol levels may also take phytosterols if they and their physicians are aware of the potential risks of sitosterolemia (Grade C). AACE does not recommend the use of phytosterols for the treatment or prevention of malignant disease, inasmuch as only inconclusive level 3 data exist for this indication (Grade D).
Saw Palmetto
Only two strong studies support the use of saw palmetto extract in patients with benign prostatic hypertrophy. Clinical toxicities related to the use of this product seem to be minimal. Therefore, with conclusive level 2 data available, saw palmetto extract may be recommended for patients with benign prostatic hypertrophy who refuse conventional therapy or in whom conventional therapy fails (Grade B). AACE does not support the proactive (first-line) recommendation of saw palmetto extract in any patient who has prostate cancer or prostate enlargement or who simply requests prevention of either of these two conditions by use of this approach rather than conventional therapy.
Glutamine
Glutamine is a nontoxic, physiologically important agent that is beneficial in critical illness (Grade A). Glutamine may protect the gastrointestinal mucosa in the setting of acute stress and surgical treatment (Grade B). This effect is most prominent in low-birth-weight neonates receiving parenteral nutrition support. Glutamine also seems to be effective in the treatment of oral mucositis and stomatitis associated with both localized radiation therapy and systemic chemotherapy (Grade C) and in the decrease of occurrence of peripheral neuropathy after paclitaxel therapy (Grade C). Other effects attributed to glutamine supplementation are not clearly defined. Data supporting enhancement of the immune system are weak and inconclusive at best (Grade D). Glutamine seems to have no benefit as an energy-providing performance-enhancing agent (Grade D). Use of glutamine in patients with liver disease and impaired ureagenesis is associated with hyperammonemia. Otherwise, published reports have provided no clear evidence of major toxic effects associated with either enteral or parenteral supplementation with glutamine.
Taurine
A derivative form of taurine, N-acetylhomotaurine, has demonstrated effectiveness in the treatment of alcohol abuse (Grade B). Emerging clinical data support the addition of taurine to parenteral nutrition when hepatopathy cannot be explained by any other mechanism (Grade C). No published data clearly support any other beneficial or therapeutic activity of supplemental taurine in healthy adults or pathologic states (Grade D). In neonates, taurine appears to be an essential amino acid during stress ("conditionally essential") (Grade C).
Carnitine
In the rare cases of primary carnitine deficiency, carnitine therapy is effective (Grade A). In secondary carnitine deficiency, carnitine therapy has limited proven value (Grade C). Level 2 and 3 data regarding carnitine as a performance-enhancing or ergogenic (energy-providing) agent are available, but not all studies show conclusive evidence of benefit (Grade C). Trials of carnitine used in the treatment of congestive heart failure are emerging and appear encouraging (Grade C). Similar results have been noted in the treatment of cardiac and peripheral vascular ischemic disease (Grade C), as well as for the use of carnitine in patients with anemia associated with chronic renal disease who are receiving hemodialysis (Grade C). Finally, carnitine therapy may be useful in patients treated with valproic acid for seizure disorders (Grade C). No clear evidence has shown appreciable toxic effects associated with use of carnitine.
Creatine
Contradictory level 1, 2, and 3 evidence of a proenergy effect, reflected by improved performance, exists for creatine for any type of exertion, although the weight of evidence favors a beneficial effect (Grade C). Claims for efficacy in the treatment of congestive heart failure are inconclusive (Grade D). Limited data indicate that careful dosing of creatine may diminish symptoms associated with McArdle's disease (glycogen storage disease type V) (Grade C).
Chondroitin
Chondroitin sulfate, administered for a long-term period, probably has some beneficial action in restoring cartilage damaged by osteoarthritis (Grade B). Additional data investigating the combination of chondroitin sulfate and glucosamine in the management of osteoarthritis are reviewed in the original guideline document and do not affect this recommendation.
Glucosamine
Glucosamine may be an effective treatment for osteoarthritis. Several large metareviews have demonstrated such benefit but have failed to meet level 1 criteria. In addition, several level 2 and 3 studies of glucosamine demonstrate benefit in the treatment of osteoarthritis (Grade B). Therefore, glucosamine may be recommended for those patients refusing, or not responding to, conventional therapy for acute osteoarthritis, administered alone or in combination with chondroitin sulfate.
Omega-3 Fatty Acids, Including Fish Oils
Polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) appear to be useful in the treatment of hypertriglyceridemia and the prevention of cardiovascular events (Grade A). Efficacy in inflammatory bowel disease is supported by level 3 evidence (Grade C). Adverse effects may be noted at dosages larger than 3 g/day.
Probiotics
Probiotics may be used safely in patients with antibiotic-associated diarrhea and recurrent Clostridium difficile colitis. The level 1, 2, and 3 data are inconclusive, with the weight of evidence favoring demonstrable benefit (Grade C). Chronic pouchitis flare-ups apparently are prevented by a mixed-organism probiotic, as reported in recent, conclusive level 2 studies (Grade B).
Dehydroepiandrosterone Sulfate (DHEAS)
Although many level 3 scientific reports have focused on dehydroepiandrosterone sulfate (DHEAS), the data are insufficient to support the use of DHEAS in healthy adults in any circumstance at the current time (Grade D). In 1999, it was argued in an editorial that DHEAS may be used as part of replacement therapy in women with adrenal insufficiency; however, as intuitive as this application seems, confirmation of efficacy with level 1 data is necessary (Grade D).
Androstenedione
The available data do not support the use of androstenedione or androstenediol for performance-enhancing effects (Grade D). In fact, deleterious effects on the lipid profile are suggested by the data. The addition of other herbal compounds with unproven efficacy seems to be a marketing ploy to entice purchase of these dietary supplements and nutraceuticals. Any agent that directly or indirectly increases androgen levels should be avoided in men with prostate cancer until clinical trials demonstrate its safety.
Table. Summary of Evidence-based Indications for Dietary Supplements and Nutraceuticals Reviewed in these Guidelines
Androstenedione
- Grade D: performance; body composition
Carnitine
- Grade A: primary deficiency
- Grade C: secondary deficiency; performance; cardiac; renal; valproate use
Choline
- Grade A: pregnancy; breast feeding
- Grade C: hyperhomocysteinemia; total parenteral nutrition (TPN)-induced hepatopathy
- Grade D: memory
Chondroitin
- Grade B: osteoarthritis
- Grade D: cognition; cardiovascular; renal stones
Coenzyme Q10
- Grade C: mitochondrial disorder; congestive heart failure; ischemia-reperfusion injury
- Grade D: performance; antiaging; immunity; diabetes mellitus; hypertension; cancer
Creatine
- Grade C: ergogenic; McArdle's disease
- Grade D: congestive heart failure
Dehydroepiandrosterone sulfate (DHEAS)
- Grade D: androgen replacement; performance; antiaging; libido; immunity; body composition
Glucosamine
Glutamine
- Grade A: critical illness
- Grade C: stomatitis
- Grade D: Crohn's disease; immunity; cancer; performance
Melatonin
- Grade C: sleep/jet lag; menopause (mood)
- Grade D: cancer
Omega-3 fatty acids
- Grade A: cardiovascular
- Grade B: high triglycerides
- Grade C: inflammatory bowel disease (IBD)
- Grade D: immunity; human immunodeficiency virus (HIV); hypertension; behavior; asthma; rheumatoid arthritis; psoriasis; chronic fatigue syndrome
Phytosterols
- Grade A: high cholesterol; secondary prevention of atherosclerosis
- Grade D: normal cholesterol; cancer; chronic disease
Probiotics
- Grade B: chronic pouchitis
- Grade C: antibiotic-related diarrhea; C. difficile colitis
Saw palmetto
- Grade B: benign prostatic hyperplasia (BPH)
Flavinoids
- Grade A: coronary artery disease (CAD) risk reduction
- Grade B: osteoporosis
- Grade D: hormone replacement; hot flashes; cognitive therapy; antiaging
Taurine
- Grade B: chronic alcoholism
- Grade C: total parenteral nutrition-induced hepatopathy
- Grade D: congestive heart failure; diabetes mellitus; dyslipidemia
Antidiabetic indications
alpha-Lipoic acid
American ginseng
- Grade D: glycemic control
Chromium
- Grade A: chromium deficiency
- Grade D: glycemic control; dyslipidemia; obesity
gamma-Linolenic acid
Ginkgo biloba
- Grade D: peripheral neuropathy; erectile dysfunction; intermittent claudication
Momordica charantia
- Grade D: glycemic control
Vanadium
- Grade D: glycemic control
Vitamin E
- Grade D: cardiovascular risk
Definitions:
Recommendation Grades
Grade A
>1 conclusive level 1 publications demonstrating benefit >> risk
Recommended for indications reflected by the publications; can be used with other conventional therapy or as "first-line" therapy
Grade B
No conclusive level 1 publication
>1 conclusive level 2 publications demonstrating benefit >> risk
Recommended for indications reflected by the publications if the patient refuses or fails to respond to conventional therapy; must monitor for adverse effects, if any; can be recommended as "second-line" therapy
Grade C
No conclusive level 1 or 2 publication
>1 conclusive level 3 publications demonstrating benefit >> risk
OR
No risk at all and no benefit at all
Recommended for indications reflected by the publications if the patient refuses or fails to respond to conventional therapy, provided there are no significant adverse effects; "no objection" to recommending their use
OR
"no objection" to continuing their use
Grade D
No conclusive level 1, 2, or 3 publication demonstrating benefit >> risk
Conclusive level 1, 2, or 3 publications demonstrating risk >> benefit
Not recommended
Patient is advised to discontinue use
Levels of Evidence
Level 1
Prospective, randomized, controlled trials—large
- Data derived from a substantial number of trials, with adequate power, involving a substantial number of subjects and outcome data
- Large meta-analyses using raw or pooled data or incorporating quality ratings
- Well-controlled trial at one or more medical centers
- Consistent pattern of findings in the population for which the recommendation is made (generalizable data)
- Compelling nonexperimental, clinically obvious evidence (for example, use of insulin in diabetic ketoacidosis); "all-or-none" indication
Level 2
Prospective, randomized, controlled trials—limited body of outcome data
- Limited number of trials, small population sizes in trials
- Well-conducted single prospective cohort study
- Limited but well-conducted meta-analyses
- Inconsistent findings or results not representative for the target population
- Well-conducted case-controlled study
Level 3
Other experimental outcome data and nonexperimental data
- Nonrandomized, controlled trials
- Uncontrolled or poorly controlled trials
- Any randomized clinical trial with one or more major or three or more minor methodologic flaws
- Retrospective or observational data
- Case reports or case series
- Conflicting data with weight of evidence unable to support a final recommendation
Level 4
Expert opinion
- Inadequate data for inclusion in above categories; situation necessitates an expert panel's synthesis of the literature and a consensus
- Experience-based information
- Theory-driven conclusions
