Available online 15 April 2024

Author links open overlay panel, , , , , , , , , , , , , , , , , , ABSTRACTBackground

The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes.

Methods

TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2’s participants.

Results

At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) μg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) μg/L and 0.30 (0.18, 0.51) μg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset.

Conclusions

TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population.

Section snippetsBACKGROUND

Established therapies to reduce risk for cardiovascular disease (CVD), such as reducing glycemia and blood pressure, anti-platelet therapy, cholesterol-lowering and other evidence-based medications and procedures form the backbone for patients with coronary atherosclerosis.1 Patients with diabetes have much greater risk for CVD than those without, including recurrent events. The results of edetate disodium-based (disodium ethylenediamine tetra-acetic acid or Na2EDTA) chelation in patients with

Study overview

TACT2 (ClinicalTrials.gov identifier NCT02733185) is a randomized, double-masked, placebo-controlled, multicenter (88 sites across USA, Canada), 2 × 2 factorial trial testing the effectiveness of 40 infusions of a multi-component edetate disodium solution compared with placebo, and of an oral, high-dose multi-vitamins and minerals (OMVM) supplement compared with placebo.11

The trial chronology and organization have been described in detail.11 Participants were eligible if they were 50 years or

RESULTS

Of 1000 randomized TACT2 participants, 933 participants had blood and/or urine metal measurements, and 849 participants had both urine and blood metals measured at baseline (Supplemental Figure 1). There were no major differences in demographic, medication use, or clinical characteristics in the subset of participants with metals measured compared to the overall TACT2 study population and to the 67 participants without metals measured (Table 1).

DISCUSSION

Adult men and women with a prior myocardial infarction and diabetes across the US and Canada who participated in the TACT2 study showed a high burden of CVD risk factors and use of medication to treat CVD and diabetes. Compared to the original TACT subpopulation with diabetes, TACT2 had more female and non-white participants and participants with hypertension; a greater use of statins and insulin, but fewer prior smokers and those with a prior anterior myocardial infarction. The burden of

CRediT authorship contribution statement

Ana Navas-Acien: Writing – original draft, Visualization, Supervision, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Regina M. Santella: Writing – review & editing, Supervision, Resources, Methodology, Investigation. Bonnie R. Joubert: Writing – review & editing, Supervision, Project administration, Methodology, Formal analysis. Zhen Huang: Writing – original draft, Visualization, Validation, Formal analysis, Data curation. Yuliya Lokhnygina:

Acknowledgements

The National Center for Complementary and Integrative Health (NCCIH), the National Heart Lung and Blood Institute (NHLBI), the National Institute for Diabetes Digestive and Kidney diseases (NIDDK), and the National Institute of Environmental Health Sciences (NIEHS) provided funding and supervision for TACT2, under award numbers: 1UG3AT009149, 5UH3AT009149, 2UH3AT009150, 5R01AT009273 and 2U24AT009150.The Centers for Disease Control and Prevention performed metal analyses on biological specimens

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