Effect of BET Protein Inhibition With Apabetalone on Cardiovascular Outcomes in Patients With Acute Coronary Syndrome and Diabetes - BETonMACE

Contribution To Literature:

The BETonMACE trial showed that apabetalone is not superior to placebo on a background of optimal medical therapy in reducing adverse cardiovascular outcomes among patients with type 2 diabetes mellitus and recent acute coronary syndrome.

Description:

The goal of the trial was to assess the safety and efficacy of apabetalone, a drug that results in BET protein inhibition, among patients with diabetes mellitus and acute coronary syndrome.

Study Design

During the run-in phase, patients received either 40-80 mg of atorvastatin or 20-40 mg of rosuvastatin for 1-2 weeks. Following this, eligible patients were randomized in a 1:1 fashion to either apabetalone 100 mg BID (n = 1,212) or placebo (n = 1,206).

  • Total screened: 3,937
  • Total number of enrollees: 2,425
  • Duration of follow-up: 26 months
  • Mean patient age: 62 years
  • Percentage female: 26%

Inclusion criteria:

  • Type 2 diabetes mellitus
  • Acute coronary syndrome 7-90 days prior
  • Low high-density lipoprotein cholesterol (HDL-C) (<40 mg/dl for males, <45 mg/dl for females)

Exclusion criteria:

  • Planned further coronary revascularization
  • Previous or current diagnosis of heart failure
  • Coronary artery bypass grafting within 90 days
  • Estimated glomerular filtration rate <30 or need for dialysis
  • Cirrhosis

Other salient features/characteristics:

  • Duration of diabetes mellitus: 8.4 years
  • ST-segment elevation myocardial infarction (STEMI): 38%
  • Hemoglobin A1c: 7.4%; baseline low-density lipoprotein cholesterol (LDL-C): 70%
  • Percutaneous coronary intervention for acute coronary syndrome: 79%
  • High-intensity statin: 90%; dual antiplatelet therapy: 88%
  • SGLT-2 inhibitor: 12.4%

Principal Findings:

The primary outcome, cardiovascular death, MI, or stroke for apabetalone vs. placebo, was 10.3% vs. 12.4% (p = 0.11).

  • Cardiovascular death (excluding death from undetermined cause)/MI/stroke: 9.3% vs. 11.6% (p = 0.06)

Secondary outcomes for apabetalone vs. placebo:

  • Cardiovascular death/MI: 9.2% vs.11.5% (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)

Interpretation:

The results of this trial indicate that apabetalone, a drug that results in BET protein inhibition, is not superior to placebo on a background of optimal medical therapy in reducing adverse cardiovascular outcomes among patients with type 2 diabetes mellitus and recent acute coronary syndrome. It appears that the trial was a bit underpowered to show a benefit due to lower than expected event rates. Salutary effects on metabolic parameters, particularly HDL-C, were observed. The incidence of transaminitis was higher with this drug.

References:

Presented by Kausik K. Ray at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS

Keywords: AHA19, AHA Annual Scientific Sessions, Acute Coronary Syndrome, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Dyslipidemias, Hemoglobin A, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolic Syndrome X, Myocardial Infarction, Percutaneous Coronary Intervention, Primary Prevention, Stroke


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