Chelation therapy for cardiovascular disease

Editor-In-Chief: Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; Associate Editor(s)-in-Chief:  Rim Halaby, M.D. [2], Ian Ergui, B.Sc.

To read more about chelation therapy click here.

Synonyms and keywords: Chelation therapy, EDTA, post-myocardial infarction, diabetes

## Overview[edit | edit source]

Chelation is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. Chelation therapy, which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.[1][2] Common chelators include penicillamine, which binds copper and can be used to treat Wilson’s disease, deferoxamine, which binds iron and is used in the treatment of thalassemia and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,[3] patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,[4] or sickle cell disease and transfusion acquired iron-overload,[5] to name a few instances.

Ethylene diamine tetraacetic acid (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of atherosclerotic disease. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.

## Chelation Therapy and CVD[edit | edit source]

The use of chelation therapy as a treatment for atherosclerotic disease dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.[6] Later studies by Kitchell were less positive,[7][8] and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of chelation therapy for cardiovascular disease (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.[9]

For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.[10] Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving endothelium-dependent forearm blood flow.[11] A systematic review of four randomized clinical trials on chelation therapy and peripheral artery occlusive disease reported no benefit associated with chelation therapy.[12] The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, follow up was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.[13] The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.[14] Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for cardiovascular disease and other diagnoses.

In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function (creatinine 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium EDTA combined with ascorbic acid, B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, stroke, MI, coronary revascularization, and hospitalization for angina. A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for statins in post-MI patients (NNT=16 for the secondary prevention of a major coronary event). The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.[15]

TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and diabetes (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).[16] Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–MI patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.

These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.[17] The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the NIH.

## Mechanism of Action[edit | edit source]

Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.[18] Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.[1] While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.[19] This evidence is strongest for lead and cadmium.[20][21][22] Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].[20] Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].[23] Heavy metals may play a role in the development of cardiovascular disease through a number of different mechanisms.[24] Heavy metals include transition metals such as cadmium, mercury, manganese, chromium, cobalt, nickel, iron, and copper, metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.[25][26][27] Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,[28] endothelial cell dysfunction,[29] and hypertension.[30] Heavy metal exposure is also associated with genetic and epigenetic manifestations. Cadmium promotes atherosclerosis and endothelial dysfunction through multiple genetic changes.[31] One of the mechanisms involves DNA strand breaks and damage with subsequent apoptosis in endothelial cells.[31] Also, maternal lead exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of DNA methylation early in life.[32]

Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of chelation therapy may result from enhanced excretion of heavy metals, and subsequent reduction in processes listed above. Additionally, in patients with diabetes, a reduction in the metal-catalyzed formation of reactive oxygen species, formation of advanced glycation end-products, and lipid peroxidation has been postulated.[33] Metal detoxification in the context of diabetes possibly decreases inflammation and oxidative stress that characterize atherosclerosis.[34] Recent research, including chelation-activity assays, indicates that many common diabetes drugs, such as metformin and aldose reductase inhibitors, could possibly have some chelating properties.[35][36][37]

The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as ascorbic acid, B-vitamins and magnesium, thought to have a protective effect on endothelial cells,[38] making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.

## Future Studies[edit | edit source]

TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.

## Side Effects[edit | edit source]

Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.

* Arrhythmias
* Autoimmune diseases
* Bone marrow
* Convulsions
* Depression
* Fever
* Heart failure
* Hypocalcemia
* Hypoglycemia
* Hypotension
* Prolonged bleeding time
* Renal failure
* Respiratory arrest
* Tetany
* Trace metal deficiency
* Vitamin deficiency[13][15]

## Landmark Trials[edit | edit source]

* TACT

* TACT 2 [3] (link to press release [4])

## References[edit | edit source]

1. ↑ 1.0 1.1 Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA (2001). "EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc". Biol Trace Elem Res. 83 (3): 207–21. doi:10.1385/BTER:83:3:207. PMID 11794513.CS1 maint: Multiple names: authors list (link)
2. ↑ Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125
3. ↑ CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [1]
4. ↑ Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases (2011). "Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases". Hepatology. 54 (1): 328–43. doi:10.1002/hep.24330. PMC 3149125. PMID 21452290.CS1 maint: Multiple names: authors list (link)
5. ↑ NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)
6. ↑ CLARKE CN, CLARKE NE, MOSHER RE (1956). "Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid". Am J Med Sci. 232 (6): 654–66. PMID 13372537.CS1 maint: Multiple names: authors list (link)
7. ↑ KITCHELL JR, MELTZER LE, SEVEN MJ (1961). "Potential uses of chelation methods in the treatment of cardiovascular diseases". Prog Cardiovasc Dis. 3: 338–49. PMID 13756462.CS1 maint: Multiple names: authors list (link)
8. ↑ KITCHELL JR, PALMON F, AYTAN N, MELTZER LE (1963). "The treatment of coronary artery disease with disodium EDTA. A reappraisal". Am J Cardiol. 11: 501–6. PMID 14033183.CS1 maint: Multiple names: authors list (link)
9. ↑ Villarruz MV, Dans A, Tan F (2002). "Chelation therapy for atherosclerotic cardiovascular disease". Cochrane Database Syst Rev (4): CD002785. doi:10.1002/14651858.CD002785. PMID 12519577.CS1 maint: Multiple names: authors list (link)
10. ↑ Olszewer E, Carter JP (1988). "EDTA chelation therapy in chronic degenerative disease". Med Hypotheses. 27 (1): 41–9. PMID 3144646.
11. ↑ Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR (1999). "Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function". Clin Exp Pharmacol Physiol. 26 (11): 853–6. PMID 10561804.CS1 maint: Multiple names: authors list (link)
12. ↑ Ernst E (1997). "Chelation therapy for peripheral arterial occlusive disease: a systematic review". Circulation. 96 (3): 1031–3. PMID 9264515.
13. ↑ 13.0 13.1 Ernst E (2000). "Chelation therapy for coronary heart disease: An overview of all clinical investigations". Am Heart J. 140 (1): 139–41. doi:10.1067/mhj.2000.107548. PMID 10874275.
14. ↑ Lewin MR (1997). "Chelation therapy for cardiovascular disease. Review and commentary". Tex Heart Inst J. 24 (2): 81–9. PMC 325409. PMID 9205980.
15. ↑ 15.0 15.1 Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL; et al. (2013). "Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial". JAMA. 309 (12): 1241–50. doi:10.1001/jama.2013.2107. PMID 23532240.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
16. ↑ Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y; et al. (2014). "The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT)". Circ Cardiovasc Qual Outcomes. 7 (1): 15–24. doi:10.1161/CIRCOUTCOMES.113.000663. PMC 4111470. PMID 24254885.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
17. ↑ Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ; et al. (2014). "2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons". J Am Coll Cardiol. 64 (18): 1929–49. doi:10.1016/j.jacc.2014.07.017. PMID 25077860.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
18. ↑ WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM (1962). "Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle". Surgery. 52: 793–5. PMID 14000694.CS1 maint: Multiple names: authors list (link)
19. ↑ Agarwal S, Zaman T, Tuzcu EM, Kapadia SR (2011). "Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006". Angiology. 62 (5): 422–9. doi:10.1177/0003319710395562. PMID 21421632.CS1 maint: Multiple names: authors list (link)
20. ↑ 20.0 20.1 Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E (2006). "Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults". Circulation. 114 (13): 1388–94. doi:10.1161/CIRCULATIONAHA.106.628321. PMID 16982939.CS1 maint: Multiple names: authors list (link)
21. ↑ Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E (2004). "Lead, cadmium, smoking, and increased risk of peripheral arterial disease". Circulation. 109 (25): 3196–201. doi:10.1161/01.CIR.0000130848.18636.B2. PMID 15184277.CS1 maint: Multiple names: authors list (link)
22. ↑ Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W; et al. (2013). "Cadmium exposure and incident cardiovascular disease". Epidemiology. 24 (3): 421–9. doi:10.1097/EDE.0b013e31828b0631. PMID 23514838.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
23. ↑ Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E (2012). "Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population". Environ Health Perspect. 120 (7): 1017–22. doi:10.1289/ehp.1104352. PMC 3404657. PMID 22472185.CS1 maint: Multiple names: authors list (link)
24. ↑ Vaziri ND, Khan M (2007). "Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension". Clin Exp Pharmacol Physiol. 34 (9): 920–5. doi:10.1111/j.1440-1681.2007.04644.x. PMID 17645641.
25. ↑ Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D (1984). "Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids". Proc Natl Acad Sci U S A. 81 (12): 3883–7. PMC 345326. PMID 6587396.CS1 maint: Multiple names: authors list (link)
26. ↑ Heinecke JW, Rosen H, Chait A (1984). "Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture". J Clin Invest. 74 (5): 1890–4. doi:10.1172/JCI111609. PMC 425370. PMID 6501577.CS1 maint: Multiple names: authors list (link)
27. ↑ Morgan J, Leake DS (1995). "Oxidation of low density lipoprotein by iron or copper at acidic pH". J Lipid Res. 36 (12): 2504–12. PMID 8847477.
28. ↑ Dursun N, Arifoglu C, Süer C, Keskinol L (2005). "Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels". Biol Trace Elem Res. 104 (2): 141–9. doi:10.1385/BTER:104:2:141. PMID 15894814.CS1 maint: Multiple names: authors list (link)
29. ↑ Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H (1995). "Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead". Arch Environ Contam Toxicol. 28 (2): 168–72. PMID 7710289.CS1 maint: Multiple names: authors list (link)
30. ↑ Vaziri ND (2008). "Mechanisms of lead-induced hypertension and cardiovascular disease". Am J Physiol Heart Circ Physiol. 295 (2): H454–65. doi:10.1152/ajpheart.00158.2008. PMC 2519216. PMID 18567711.
31. ↑ 31.0 31.1 Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B; et al. (2009). "Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance". Arterioscler Thromb Vasc Biol. 29 (9): 1392–8. doi:10.1161/ATVBAHA.109.190082. PMID 19556524.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
32. ↑ Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X; et al. (2015). "Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren". Sci Rep. 5: 14466. doi:10.1038/srep14466. PMC 4586440. PMID 26417717.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
33. ↑ Lamas GA, Ackermann A (2000). "Clinical evaluation of chelation therapy: is there any wheat amidst the chaff?". Am Heart J. 140 (1): 4–5. doi:10.1067/mhj.2000.107549. PMID 10874253.
34. ↑ Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013
35. ↑ Nagai R, Murray DB, Metz TO, Baynes JW (2012). "Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications". Diabetes. 61 (3): 549–59. doi:10.2337/db11-1120. PMC 3282805. PMID 22354928.CS1 maint: Multiple names: authors list (link)
36. ↑ Frizzell N, Baynes JW (2014). "Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma". Clin Chem Lab Med. 52 (1): 69–75. doi:10.1515/cclm-2012-0881. PMID 23612664.
37. ↑ Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K; et al. (2012). "Cellular responses to the metal-binding properties of metformin". Diabetes. 61 (6): 1423–33. doi:10.2337/db11-0961. PMC 3357267. PMID 22492524.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
38. ↑ Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.

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