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Chromium

Common Name(s): Chromium chloride, Chromium nicotinate, Chromium picolinate

Clinical Overview

See also: Basaglar

Use

Chromium supplementation has been studied for a variety of indications, especially diabetes and weight loss, but clinical studies have shown inconsistent results. The role of supplemental chromium remains controversial.

Dosing

The currently accepted value for chromium dietary intake is 25 mcg/day for women and 35 mcg/day for men. Daily dosages used in clinical trials for periods of up to 9 months range as follows: brewer's yeast up to 400 mcg/day; chromium chloride 50 to 600 mcg/day; chromium nicotinate 200 to 800 mcg/day; chromium picolinate 60 to 1,000 mcg/day. The potential for genotoxic effects exists at higher dosages.

Contraindications

None well documented. Renal failure may be considered a relative contraindication.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Limited animal experimentation showed skeletal and neurological defects in the offspring of mice fed chromium picolinate.

Interactions

None well documented.

Adverse Reactions

Ingestion or exposure to certain forms of chromium may cause or contribute to GI irritation and ulcers, dermatitis, hemorrhage, circulatory shock, and renal tubule damage.

Toxicology

No risk of genotoxicity at appropriate dosages over the short-term exists for chromium as a dietary supplement. However, at higher dosages, such as those used in trials evaluating the efficacy of chromium in glycemic control, concern exists for potential genotoxic effects.

Source

Chromium (Cr) is abundant in the earth's crust and is found in concentrations ranging from 100 to 300 ppm.1 Industrially, it is obtained from chrome ore, among other sources. The organic form of chromium exists in a dinicotino-glutathionine complex in natural foods, which is better absorbed than the inorganic form. Good dietary sources of chromium include brewer's yeast, liver, potatoes with skin, beef, fresh vegetables, and cheese.2

History

Chromium is a steel-gray lustrous metal that is important as an additive in the manufacture of steel alloys (chrome steel, chrome-nickel steel, stainless steel) and greatly increases the durability and corrosion resistance of these metals; hence its use in metal prosthetic implants. Synthetically-produced 51Cr is used as a tracer in various hematologic disorders and in the determination of blood volume.3 As chromium is considered to be important for normal glucose metabolism, a number of over-the-counter products promote the use of chromium, alone or in combination with glucose tolerance factor, to improve carbohydrate utilization. The effectiveness of these products has not been established, although they represent sources of chromium.

Chemistry

Chromium has an atomic weight of 51.996. The element may occur in compounds in di-, tri-, or hexavalent forms. Hexavalent chromium is the highest oxidation state of elemental chromium. Trivalent chromium is the most stable oxidation state for chromium, and this form is found in common nutritional supplements, generally as the picolinate salt.4, 5 A number of naturally occurring isotopes have been identified, the most common of which is 52Cr (approximately 84% of the isotopes). 51Cr has a half-life of approximately 28 days. Many chromium salts are industrial hazards.6

Uses and Pharmacology

To date, no chromium-containing biomolecules have been definitively described, and no clinical manifestation of trivalent chromium deficiency in humans has been established.4, 7 The argument for chromium supplementation relies on evidence from case reports of resolution of diabetic symptoms refractory to insulin via chromium added to total parenteral nutrition, and experiments in which animals deficient in chromium exhibited impaired glucose metabolism.4, 5, 8, 9

Binge eating

Data from a 6-month, double-blind, pilot randomized clinical trial (n = 24) support efficacy of chromium picolinate to improve manifestations and psychopathology of binge eating disorder. After a 1-month placebo run-in to eliminate placebo responders, overweight adults with binge eating disorder were randomly assigned to chromium 1,000 mcg/day (high-dose), chromium 600 mcg/day (moderate dose), or placebo. Although statistical power was limited, fasting glucose was reduced significantly in both treatment groups versus placebo; binge eating and related psychopathology, symptoms of depression, and weight were also reduced more in the chromium groups, but these data did not reach statistical significance. Both doses were well tolerated.55

Diabetes

Chromium may influence glucose metabolism by increasing the number of insulin receptors or by binding insulin to receptors.7, 10, 11, 12 The US Food and Drug Administration concludes that, based on very limited credible evidence, chromium picolinate may reduce the risk of insulin resistance and therefore may reduce the risk of type 2 diabetes.8, 13

A number of systematic reviews and meta-analyses have been conducted to determine the effect of chromium on glycemic control, although large, quality trials are limited.7, 8, 10, 14, 49 The majority of studies have found no effect on measured outcomes, with a few studies contributing to the positive observed effects.8, 15 Variations of preparations used in the trials and study conditions make generalization of the results difficult.8, 10 A meta-analysis that used mean gain scores to take changes in fasting glucose of both the treatment as well as placebo groups into account found no significant effect of supplemental chromium in diabetic (n = 440) or nondiabetic (n = 369) adults. Doses ranged from 200 to 1,000 mcg/day among 5 preparations.59 The American Diabetes Association (ADA) standards of medical care in diabetes statement (2015) states that evidence is insufficient to support routine use of micronutrients, such as chromium, to improve glycemic control in diabetic patients (low-quality evidence).61

In patients with diabetes, chromium supplementation may produce a modest increase in glycemic control.7, 8, 10, 14, 16, 60, 63 A 2007 review found a significant reduction in fasting blood glucose, but not hemoglobin A1c (HbA1c). This review pooled data from studies using more than 250 mcg/day of chromium for at least 3 months.49 In 2014, a systematic review and meta-analysis identified 25 randomized, controlled trials comparing chromium mono- or combination therapy versus placebo in diabetic patients. Chromium therapy significantly improved HbA1c, fasting plasma glucose, HDL-C, and triglycerides, especially with chromium picolinate and especially with doses over 200 mcg/day.56 Another study found 400 mcg/day of chromium chloride to significantly improve fasting plasma glucose, waist circumference, ALT, and insulin sensitivity.60 However, a meta-analysis published November 2014 of 14 randomized controlled trials that evaluated chromium effects in adults with type 2 diabetes mellitus identified statistically significant improvements in fasting plasma glucose (−19.23 mg/dL), but not HbA1c, with administration of brewer's yeast. No significant effects were found with the other chromium formulations (ie, chromium chloride, chromium picolinate, or chromium yeast). Dosages ranged from 126 to 1,000 mcg given 1 to 3 times daily for 8 to 24 weeks.64 In women with the endocrine-metabolic disorder polycystic ovary syndrome, significant improvement was seen with 8 weeks supplementation of chromium picolinate 200 mcg/day compared to placebo in mean insulin levels (−3.6 vs +3.6 microunits/mL, respectively) as well as with assessments on insulin resistance, beta cell function, and insulin sensitivity.62 Among healthy trial participants, chromium supplementation did not have an effect on glycemic control.7, 8, 10, 17

A 3-month, double-blind, placebo-controlled study (n = 74 evaluable) compared 2 different salts of chromium, chromium dinicocysteinate (CDNC) and chromium picolate (CP), at doses of 400 mcg/day in adults with type 2 diabetes mellitus. No significant improvement was seen with either chromium product for HbA1c or fasting blood glucose. The CDNC group had significant reductions in insulin resistance, protein oxidation, and TNF-alpha. No significant change in these was seen for CP.50

A single-blind, placebo-controlled, 3-month study (n = 40) compared brewer’s yeast 9 g plus chromium 42 mcg to control (plain brewer’s yeast without chromium) in adults with newly diagnosed type 2 diabetes mellitus. Mean reductions in HbA1c, serum triglycerides, and low-density lipoprotein-cholesterol (LDL-C) were significantly greater in the treatment group compared with contol.51 This study was not included in the most recent evidence review because of the low chromium dose.

Limited studies evaluating the effect of a combination of chromium picolinate (600 mcg/day) and biotin have shown improved glycemic control in type 2 diabetes.18, 19, 20

Chromium-deficient patients may be more likely to show a positive response; however, most patients with diabetes are not chromium deficient.7, 10 The effects of chromium on corticosteroid-induced diabetes have been studied.21 Chromium picolinate 1,000 mcg daily decreased the QTc interval in patients with type 2 diabetes.11, 22

As a component of medical nutrition therapy for patients with type 1 or type 2 diabetes, the American Diabetes Association Standards of Care (2014) does not recommend routine supplementation with micronutrients such as chromium to improve glycemic control (low-quality evidence).58

Hyperlipidemia

Results of the limited number of quality clinical trials are equivocal. Positive results have been reported in a review of the effects of chromium picolinate in type 2 diabetes14 and in obese participants.13 However, a systematic review and other reviews reported no effect in type 2 diabetes.8, 15, 16 Limited studies evaluating combined chromium picolinate and biotin supplementation in type 2 diabetes have shown improved lipid profiles.19, 20, 23, 24 As previously mentioned, a combination of brewer’s yeast 9 g plus chromium 42 mcg per day significantly reduced serum triglycerides, and LDL-C in addition to HbA1c.51 The lipid profile (triglycerides, very low-density lipoprotein [VLDL], and total cholesterol) was significantly improved compared to placebo in Iranian women with polycystic ovary syndrome administered chromium picolinate 200 microg/day for 8 weeks in a randomized, double-blind, placebo-controlled trial.62

A randomized, placebo-controlled, 8-week pediatric study (n = 120, 9 ± 4 years of age) evaluated 2 chromium 1.2 mg products, chromium polynicotinate (CPNC) and chromium policosanol (CPC), and glucomannan (GM) in hypercholesterolemia. Patients were randomized to 1 of 5 groups: placebo, CPNC, CPC, GM, CPNC with GM, or CPC with GM. No significant lipid-lowering benefit was seen with any of the 3 monotherapy groups (CPNC, CPC, GM). The CPNC-GM group, but not the CPC-GM group, had significant reductions in total cholesterol and LDL-C.52

Ischemic heart disease

The clinical practice guideline from the American College of Physicians/American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society of Thoracic Surgeons regarding management of stable ischemic heart disease (2012) recommend that treatment with garlic, coenzyme Q10, selenium, or chromium should not be used with the intent of reducing cardiovascular risk or improving outcomes in patients with stable ischemic heart disease (strong recommendation; low-quality evidence).48

Osteoporosis

Limited studies in postmenopausal women suggest a role for chromium in prevention of osteoporosis.31, 32

Polycystic ovary syndrome

Because polycystic ovary syndrome (PCOS) is a metabolic-endocrine disease and data suggest benefit on insulin and lipid metabolism with chromium supplementation, a double-blind, randomized, placebo-controlled trial investigated the effect of chromium administration in 64 Iranian women with PCOS. Patients were encouraged to follow their usual diet and activity levels. After 8 weeks of chromium picolinate 200 mcg/day, significant improvement was seen with chromium supplementation compared to placebo in mean insulin levels (−3.6 vs +3.6 microunits/mL, respectively) as well as with assessments on insulin resistance, beta cell function, and insulin sensitivity (P < 0.01 for all). Similar results were seen with the within-group analysis for the chromium group whereas the placebo within-group data revealed significant increases in these parameters. Secondary endpoints of changes to triglycerides, VLDL-cholesterol, and total cholesterol were also significantly improved with chromium. No side effects were reported.62 Body mass index (BMI), insulin, and free testosterone were significantly improved with chromium supplementation in women with PCOS in a meta-analysis of 7 studies enrolling 351 women. Sample sizes ranged from 5 to 92 and chromium was administered at either 200 or 1,000 mcg/day for a duration of 8 to 24 weeks. No significant changes were observed for fasting blood sugar, total testosterone, dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), or lutenizing hormone (LH).65

Refractory mood disorders

Case reports of 8 patients have shown clinical response to chromium monotherapy for chronic refractory mood disorders. These include patients with bipolar II disorder, dysthymic disorder, and major and minor depression.29, 30

Weight loss

A meta-analysis of the effects of chromium picolinate in weight reduction found few quality trials available for inclusion. A small positive effect of chromium was found in 2 trials. A reduction of 1.1 to 1.2 kg over 10 to 13 weeks was estimated versus placebo (200 or 400 mcg chromium picolinate daily).25 Two reviews found no effect on lean muscle mass, muscle strength, or body composition.26, 27 A systematic review pooled data only from randomized, double-blind, placebo-controlled studies (11 studies, n = 866). Median benefit was statistically significant compared with placebo (−0.50 kg [95% confidence interval, −0.97 to −0.03]), but clinically modest (0.06% of total body weight loss compared with baseline).53 A 2014 systematic review and meta-analysis found a significant, albeit of questionable clinical significance, effect of chromium picolinate compared with placebo on weight loss when data from 6 randomized controlled trials (N = 392) were pooled; the mean difference was −1.1 kg (P = 0.001). The dose-based analysis (200 to 1,000 mcg) revealed no difference among doses. Lack of evidence was available to determine safety. All studies were of low quality.57

A randomized, placebo-controlled, 6-week pediatric study (n = 25, 9 to 12 years of age) evaluated chromium chloride 400 mcg/day. Participants also received nutritional education and 90 minutes of aerobic exercise 3 times per week during the study. No significant difference was seen for body mass index. Compared with placebo, significant improvements in insulin sensitivity, lean body mass, and percent body fat were observed in the treatment group.54

Dosing

The currently accepted value for chromium dietary intake is 25 mcg/day for women and 35 mcg/day for men.4, 33 Daily dosages used in clinical trials for periods of up to 9 months range as follows8, 10, 25, 27: brewer's yeast of up to 400 mcg; chromium chloride 50 to 600 mcg; chromium nicotinate 200 to 800 mcg; chromium picolinate 60 to 1,000 mcg. At the higher end of the range, the potential for genotoxic effects may outweigh potential benefits.4, 5

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Limited animal experimentation showed skeletal and neurological defects in the offspring of mice fed chromium picolinate.4, 34

Interactions

None well documented. A study conducted among patients with HIV taking antiretroviral therapy found an increased urinary excretion of chromium. A correlation between decreased serum chromium levels and metabolic abnormalities in HIV-infected patients taking antiretroviral therapy was observed.17

Adverse Reactions

Trivalent chromium compounds found in foods show little or no toxicity.

Adverse effects reported in clinical trials include watery stools, vertigo, headache, and urticaria.53 Oral ingestion of chromate salts may lead to irritation of the GI tract (eg, nausea, ulcers, vomiting), hemorrhage, and circulatory shock. Renal damage, including acute tubular necrosis, has been observed following occupational exposure to chromium. Liver necrosis is also possible.35, 36 Rhabdomyolysis has been reported for chromium picolinate and combination products containing chromium.28, 37

A case report of acute oral poisoning with hexavalent chromium (as potassium dichromate) noted ulceration in the gastric fundus as well as renal tubule toxicity, but noted normal glomerular filtration and creatinine clearance. The use of large doses of parenteral ascorbic acid is controversial in the management of chromium poisoning. Although experimental evidence suggests that hexavalent chromium is reduced by ascorbic acid to a less soluble form and therefore, a less toxic trivalent form, this possibility has not been supported with clinical evidence and may lead to worsened nephrotoxicity due to increased oxaluria.36

Topical effects following exposure to chromium and chromates may lead to eczematous dermatitis and ulceration. Ulceration and perforation of the nasal septum have also occurred.38, 39

Isolated incidents of deleterious effects of chromium picolinate supplementation in humans have been reported, but their significance is difficult to ascertain.26

Increased levels of serum chromium have been reported for patients with chronic renal failure receiving metal-on-metal prosthetic implants, but with no negative effect on renal function.40

Toxicology

Hexavalent chromium, having the highest oxidation state of elemental chromium, is a well-established carcinogen.4, 5, 41 Trivalent chromium, the most stable oxidation state for chromium, is generally found in common nutritional supplements as the picolinate.4, 5 Oxidation of trivalent chromium complexes within the extracellular fluid, with resultant cellular uptake of the reactive hexavalent chromium species, is the main concern with chromium supplementation.4

A review of toxicological studies does not indicate a risk of genotoxicity with short-term chromium at low dosages as a dietary supplement.4, 5 However, at higher dosages, such as those used in trials evaluating the efficacy of chromium in glycemic control, the potential for genotoxic effects may outweigh potential benefits.4, 5

However, toxicological studies should be interpreted carefully, because the toxic effects are dependent on the general chemistry of the ligand or complex being tested, as well as the treatment conditions and media used.4 In bacterial mutagenicity assays, trivalent chromium compounds appear to be largely inactive.5 Mixed results have been reported for short-term bioassays using cultured mammalian cells, and an increasing number of mutagenic and genotoxic effects are being published.5 In monkeys fed hexavalent chromium for 180 days at levels common in industrial settings, resultant oxidative stress in the testes was considered to be responsible for spermatozoa toxicity.42 Limited animal experimentation showed skeletal and neurological defects in the offspring of mice fed chromium picolinate during pregnancy or lactation.4, 34

Concern regarding the release of chromium from metal implants (ie, total knee and hip arthroplasty) has been studied.40, 43, 44, 45, 46, 47 Studies conducted for periods of up to 6 years have shown initial increases in chromium serum levels, but not erythrocyte levels, probably as a result of corrosion of the implant surface and wear. Peak chromium levels were reported at 9 months, with a gradual decline thereafter in 1 study.47 A gender difference was also reported in 1 study; higher levels of serum chromium were noted in women.43 No evidence of systemic toxic effect or mutagenicity was found in patients in any of these studies43, 44, 45, 46, 47 including in those with chronic renal failure.40

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