'Extraordinary' Chelation Effects in Diabetes Propel TACT into Spotlight Again

Shelley Wood

November 19, 2013

DALLAS, TX — The Trial to Assess Chelation Therapy (TACT), dubbed by one observer as "the most controversial CVD trial in a long time," is stepping back into the limelight today with findings from a substudy that may prove just as astounding as the primary study results.

In a prespecified analysis of patients with diabetes in TACT, Dr Esteban Escolar (Mount Sinai Medical Center, Miami Beach, FL) and colleagues, with TACT principal investigator Dr Gervasio A Lamas (Mount Sinai Medical Center), found a highly significant 15% absolute decrease in risk of the primary composite end point among diabetic patients in the chelation arm compared with patients treated with placebo infusions.

Escolar presented the diabetes substudy here today at the American Heart Association 2013 Scientific Sessions . The analysis was also published simultaneously in Circulation: Cardiovascular and Quality Outcomes[1].

"When we broke the composite down to look at our secondary end points, we found that we had about a 40% reduction in total mortality, a 40% reduction in recurrent MI, and about a 50% reduction in mortality [in patients with diabetes]," Lamas said in an interview with heartwire . Acknowledging that TACT was a "surprising" trial to begin with, "it turns out . . . the more detail you look into, the more extraordinary the effects."

Proceeding with TACT

As previously reported by heartwire , TACT found that patients randomized to a regimen involving up to 40 separate three-hour infusions of a chelation-therapy solution (disodium ethylenediaminetetraacetic acid [EDTA], ascorbic acid, magnesium chloride, potassium chloride, sodium bicarbonate, B vitamins, procainamide, and a small amount of standard heparin) experienced an 18% drop in the trial's primary end point (all-cause death, reinfarction, stroke, revascularization, or hospitalization for angina) compared with patients randomized to a placebo infusion. All patients in TACT were aged 50 or older and had had a prior MI.

At the time, investigators noted that the benefit of chelation appeared stronger in patients with self-reported diabetes.

To investigate this further, Lamas and colleagues looked more closely at diabetes patients, including not only the 538 who self-reported having diabetes in the original trial, but an additional 95 patients taking an oral diabetes treatment or insulin or who had a fasting blood glucose >6.99 mmol/L.

As with the original TACT results, all of the end points in the diabetes substudy favored the chelation-treated patients. To reduce one instance of the primary end point in the chelation group with diabetes, the number needed to treat was 6.5 patients over 5 years.

Importantly, there was no reduction in events in the nondiabetes patients, which investigators say may explain why the primary study results were not quite robust enough to deflect ongoing controversy over the trial.

"We really found no evidence that nondiabetics benefited in this study," Lamas said simply. "So if we do another study, it would be targeted at patients with diabetes. Right now, I would be reluctant to think of this as a treatment for nondiabetes patients. We have to keep an open mind. This is a very old treatment, but it is a new experiment."

Clinical End Points in Patients With Diabetes, by Randomization

End point Chelation (%) Placebo (%) Hazard ratio (95% CI) p
Primary end point 25 38 0.59 (0.44–0.79) <0.001
Death 10 16 0.57 (0.36–0.88) 0.011
MI 5 10 0.48 (0.26–0.88) 0.015
Coronary revascularization 15 20 0.68 (0.48–0.99) 0.042
Stroke 1 1 1.19 (0.27–5.30) 0.829

 

More Healthy Skepticism, Less Negativity

Lamas acknowledged that cardiologists have greeted the TACT results with skepticism and/or derision but argues that the results are actually intuitive for diabetologists and epidemiologists, who over years of researching diabetes complications have demonstrated that accumulation of advanced-glycation end products involves metal-catalyzed oxygen chemistry for their formation. As such, chelation of metal ions may be that much more important in diabetes patients, explaining the magnitude of benefit in this group. Indeed, note Lamas and colleagues in their paper, some common diabetes medications actually have chelating properties.

"The reason this is exciting is—if this is borne out by additional experimentation—it is a way of treating the complications of diabetes that we have simply missed the boat on for decades, not knowing that metal chemistry was needed to form the advanced-glycation end products," Lamas enthused. "If you look at these results depicted in these graphs, there is simply nothing like it. You show it to endocrinologists and they go bananas. Whether or not future studies show this to be true, the fact that it might be true is reason enough for there to be scientific interest in this."

Commenting on the study for heartwire , Dr Darren McGuire (UT Southwestern Cardiology, Dallas) called the results "as surprising and intriguing as the primary TACT trial results."

"Although overall a relatively small trial, 200 primary cardiovascular events were ascertained in this diabetes mellitus subset, yielding respectable statistical power and precision, though I agree with the authors that these observations will require confirmation prior to consideration for broad clinical application," he observed.

McGuire was less fired up over the theory that chelation effects on glycation end products could be mediating the benefit, telling heartwire, "That proposal . . . is simply not supported by the existing database demonstrating little to no net CV benefits of modification of glycation end products; at least not via pharmacologic glucose lowering."

Another point for further investigation, noted McGuire, was that the infusion contained not only EDTA, but nine other "bioactive constituents that could each contribute to or even account for the observed benefits."

Still, he concluded, "these are really interesting observations, and hopefully we will have further investigation into this area."

Another Chelation Trial?

The original TACT trial wrestled with enrollment, ultimately taking over a decade to yield results, in part because cardiologists were absolutely convinced that chelation was a load of horse hockey.

Lamas, for his part, believes the unexpected results from the overall TACT study, followed by these even more astounding findings in diabetic patients, may be enough to drive a swift and decisive new study focused on diabetic subjects.

"I think if this brings out healthy skepticism, as opposed to bias and negativity, then we've gone a long way toward having a scientific discourse."

As for who might fund such a trial, Lamas said: ''There's only one organization that could do this, and that's the National Institute of Health. And at the end of it all, who is going to benefit from money saved by all the end points in diabetes that don't occur, even if the treatment is half as effective as these data suggest? If you do the math, it will pay for itself. When ideas are meritorious, they tend to rise to the top."

Lamas disclosed that from 2000 to 2003 he served as a consultant to OmniComm, the electronic data-capture company used in the trial. The other investigators had no disclosures.

See also:

Chelation Therapy: Promising for Diabetic Patients but Disruptive to the Medical Establishment

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