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PHILADELPHIA -- Investigational apabetalone was not better than placebo on a background of optimal medical therapy for reducing adverse cardiovascular (CV) outcomes in patients with type 2 diabetes and recent acute coronary syndrome (ACS), researchers reported here.

After 26 months of follow-up in the BETonMACE trial, 12.4% of patients on placebo experienced the primary efficacy endpoint -- a composite of CV death, non-fatal myocardial infarction (MI), or stroke -- versus 10.3% of the patients treated with apabetalone (P=0.11), said Kausik Ray, MD, MBChB, of Imperial College London.

When deaths of undetermined cause were eliminated from the calculations, the reduction in events among patients on apabetalone was 21% (P=0.06), still failing to attain statistical significance, he reported in a presentation at the American Heart Association (AHA) meeting.

A number of prespecified secondary endpoints similarly trended toward significance, but because of the failure of the primary endpoint, Ray said these findings should be looked at cautiously:

• CV death/MI: 9.2% for apabetalone vs 11.5% for placebo (P>0.05)
• Stroke: 1.4% vs 1.4% (P>0.05)
• All-cause mortality: 5.0% vs 5.7% (P>0.05)
• Change in HDL-C from baseline at 100 weeks: 16.2% vs 10.4% (P=0.001)
• Change in LDL-C from baseline at 100 weeks: 11.5% vs 14.9% (P=0.35)

He suggested those positive findings might give researchers hints as where to go if apabetalone research in this setting continues. "This was the first cardiovascular outcomes trial assessing the potential of epigenetic modification with BET protein inhibition," Ray stated. "Favorable trends were observed for the primary endpoint and key components with a nominal difference in heart failure hospitalization."

Svati Shah, MD, of Duke University School of Medicine in Durham, North Carolina, commented that "Apabetalone is an interesting small molecule with novel mechanism of action...There is a suggestion of effects on heart failure and other subgroups, and while there may be cautious optimism, apabetalone is not ready for use in patients."

She suggested that the trial was hampered by small numbers; future clinical trials with the agent should try to recruit more participants.

For inclusion, patients had to have type 2 diabetes, ACS 7 to 90 days prior, and low HDL cholesterol (<40 mg/dL for males; <45 mg/dL for females). Nearly three-fourths had an MI diagnosis; the remainder had unstable angina. The time from the index ACS event until randomization into the study was 28 days.

During the run-in phase of the trial, patients (about age 62; 74% men; BMI 30.2) received either 40-80 mg of atorvastatin (Lipitor) or 20-40 mg of rosuvastatin (Crestor) for 1 to 2 weeks. Eligible patients were randomized in a 1:1 fashion to either apabetalone 100 mg BID (n=1,212) or placebo (n=1,206).

In her discussion, Shah explained that BET proteins are a key element in the molecular cascade that can modulate gene expression. BET inhibition was considered as a weapon to disrupt that inflammation cascade, which could, in turn, have potential clinical utility in targeting residual risk among the high-risk patients. She noted that with apabetalone showed potential for reducing markers of inflammation, and for reducing cardiac events.

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