Functional medicine: Focusing on imbalances in core metabolic processes

The Trial to Assess Chelation Therapy (TACT) was the first large, double-­blinded, placebo-controlled RCT to test post-­myocardial infarction (MI) disodium EDTA infusions (weekly 3-hour infusions for 30 weeks followed by 10 infusions 2 to 8 weeks apart).⁸⁶ Despite the chelation group having a modest reduction in the primary composite endpoint (hazard ratio [HR] = 0.82; 95% CI, 0.69-0.99; P = .035),⁸⁶ especially in those with diabetes (HR = 0.59; 95% CI, 0.44-0.79; P < .001; number needed to treat [NNT] = 6.5),⁸⁷ the authors concluded these results were insufficient to support routine disodium EDTA chelation post MI. Moreover, the 2014 Guidelines for Chronic Ischemic Heart Disease only upgraded chelation therapy from “not recommended” to “uncertain.”⁸⁸

Nevertheless, to put into perspective the magnitude of chelation’s treatment effect post MI in patients with diabetes, it can be compared to standard-of-care statin RCTs for secondary prevention, reported as follows. The absolute risk reduction (ARR) of coronary events with statin therapy in a high genetic risk group (the group with the greatest ARR) was 6.03% in the CARE trial and 6.87% in the PROVE IT-TIMI 22 trial, corresponding to a calculated NNT (1/ARR) of 16.6 and 14.6 respectively.⁸⁹

In order to understand the hesitancy to accept chelation therapy as a reasonable CVD treatment,⁵⁹ one must balance the modest effect demonstrated by TACT with its limitations, the greatest of which was the unusually large proportion of patients who withdrew their consent or were lost to follow-up (~18%).⁸⁶ However, it is important to note that some patients withdrew after experiencing a primary endpoint and that at least 50% more were from the placebo group than the chelation group,⁸⁶ rather than the reverse that was erroneously reported by Fihn et al.⁸⁸ Unblinding was possible, but there were no significant differences in serious adverse events between groups.

Furthermore, since withdrawn subjects had similar CVD risk profiles, more withdrawals in the placebo arm increases the likelihood of more unrecorded primary outcome events in the placebo arm than treatment arm. One possibility is that these could have accentuated the benefit of chelation therapy, and that missing data reduced the reported efficacy. Because of TACT’s profound findings for those with diabetes post MI, the TACT2 Phase 3 clinical trial underway through 2022 will further clarify chelation’s utility for treating stable ischemic heart disease specifically in this group.

Chronic, lowdose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.

Interestingly, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors themselves inhibit advanced glycation end products (AGE) formation in diabetes, most likely via chelation. Increased protein glycation and accumulation of AGEs on tissue proteins during hyperglycemia (the Maillard reaction) are hypothesized to be fundamental in the pathogenesis of diabetic vascular complications. Consequently, chronic, low-dose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.⁹⁰

ACKNOWLEDGEMENT
The authors thank Ariel Pomputius, MLIS, for contributing to the literature searches during manuscript preparation.

CORRESPONDENCE
Frank A. Orlando, MD, UF Health Family Medicine – Springhill, 4197 NW 86th Terrace; forlando@ufl.edu