Two late-breaking clinical trials addressing cardiovascular outcomes in patients with diabetes were presented this week at the American College of Cardiology meeting in Atlanta, USA. One of these trials looked at the effects of the hyperactivation of the polyol pathway on diabetic cardiomyopathy (DbCM) and the other the effects of chelation therapy in patients with diabetes and prior myocardial infarction.

ARISE-HF:  A Selective Aldose Reductase Inhibitor (AT-001) for the Treatment of Diabetic Cardiomyopathy

The hyperactivation of the polyol pathway results in dysregulation and eventually cell death. 

AT-001 works by preventing the enzyme, aldose reductase, from breaking down glucose into sorbitol, which damages cardiac tissue leading to myocardial stiffening and eventually heart failure. 

Treating patients with DbCM and reduced exercise capacity at high risk for heart failure could limit the progression of DbCM reflected in the stabilization of peak VO2. The ARISE-HF trial randomized 691 patients with Type 2 diabetes, stage B heart failure and no known atherosclerotic disease to two doses of AT-001 or placebo.  The study’s primary endpoint was the difference in (peak VO2) between the placebo group and AT-001 from an initial exercise test to study end at 15 months. 

The average difference in peak VO2 between the two groups was 0.3, which was not statistically significant, and the secondary endpoints also did not reach statistical significance. 

A preplanned subgroup analysis, based on previous studies’ confounders, found a statistically significant effect of treatment in patients who were not taking SGLT2 inhibitors or GLP-1 agonists.

While the study results were not positive, Dr James Januzzi of Harvard Medical School discussed the unmet need in these patients; ”Their dramatically reduced peak VO2 is indicative of a highly impaired population with a high likelihood of progression to symptomatic heart failure […] It may be that, although our patients had early-stage diabetic cardiomyopathy, because their blood glucose was so well controlled the condition was progressing very slowly.” 

The study was funded by Applied Therapeutics, which manufactures AT-100.

TACT2: Effect Of Edetate Disodium Based Chelation Infusions on Cardiovascular Events In Post-MI Patients With Diabetes

Lead and cadmium are recognized risk factors for atherosclerosis. Previously the TACT trial utilizing Edetate disodium (EDTA) as a lead and cadmium chelator, demonstrated a reduction in cardiovascular events in patients with a prior MI (633 with diabetes) compared to placebo (HR=0.82, p=0.035) (HR=0.59, p=0.0002 in patients with diabetes). 

TACT2 was a double-blind factorial designed trial assessing EDTA specifically in post MI patients with diabetes. 

1000 patients received forty (40) weekly edetate disodium or placebo infusions and oral low-dose vitamin and mineral supplements with a minimum follow-up 2.5 years (median 48 months).

The primary endpoint was a composite of time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. 

EDTA chelation produced >60% reduction in blood lead levels  but did not result in a significant clinical benefit on the primary or secondary endpoints or on all-cause mortality.

When asked why TACT2 did not demonstrate similar benefits to TACT1, Dr Gervasio Lamas of Mount Sinai Medical Center indicated participants in TACT2 may have had more advanced diabetes, reducing the trial’s ability to meaningfully impact clinical outcomes. Participants’ baseline lead levels were also significantly lower in TACT2. 

“Our method of treatment was effective at reducing lead, even in patients starting with low lead levels, and it was safe,” Lamas said. “In most countries outside of North America and western Europe, lead remains a serious cardiovascular and neurological problem.”

Funded by the National Institutes of Health.

References:

Radcliffe Cardiology, Dr Gervasio Lamas, 7 Apr 2024, ACC.24: Chelation Therapy in Post-MI Pts with Diabetes: TACT2, Accessed 7 April 2024. 

American College of Cardiology, 7 Apr 2024, Chelation Therapy Does Not Improve Outcomes after Heart Attack [Press Release].  

Radcliffe Cardiology, Dr James Januzzi, Harriette Van Spall, 8 Apr 2024, ACC 24 Late-Breaker Discussion: The ARISE-HF Trial, Accessed 8 April 2024. 

American College of Cardiology, 8 Apr 2024, New Drug Fails to Improve Diabetes-Related Heart Failure [Press Release].