Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus - AleCardio

Mar 30, 2014
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
F. Hoffmann-La Roche
Date Presented:
01/01/2014
Date Published:
01/01/2014
Date Updated:
03/30/2014
Original Posted Date:
03/30/2014
References

Description:

The goal of the trial was to evaluate treatment with the peroxisome proliferator-activated receptor (PPAR) dual-agonist aleglitazar compared with placebo among type 2 diabetic patients hospitalized for an acute coronary syndrome. Aleglitazar is a dual agonist of PPAR-α and -γ receptors. The primary effect of PPAR-α activation is to improve plasma lipid profile, while the primary effect of PPAR-γ activation is to improve insulin sensitivity.

Hypothesis:

The hypothesis is that aleglitazar will reduce adverse cardiovascular outcomes.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients with type 2 diabetes hospitalized for acute coronary syndrome

    Number of enrollees: 7,226
    Duration of follow-up: 104 weeks
    Mean patient age: 61 years
    Percentage female: 27%

Exclusions:

  • Heart failure class II-IV
  • Heart failure hospitalization in the last 12 months
  • Severe peripheral edema
  • Chronic kidney disease
  • Fasting triglycerides >400 mg/dl
  • Treatment with a fibrate or thiazolidinedione
  • Liver disease
  • Anemia

Primary Endpoints:

  • Primary efficacy endpoint: cardiovascular death, MI, or stroke
  • Primary safety endpoint: hospitalization from heart failure, or change in renal function

Secondary Endpoints:

  • Cardiovascular death, MI, stroke, or hospitalization for unstable angina
  • All-cause death, MI, or stroke
  • Unplanned coronary revascularization

Drug/Procedures Used:

Patients with type 2 diabetes and hospitalized for an acute coronary syndrome were randomized to aleglitazar 150 µg (n = 3,616) versus placebo (n = 3,610).

Concomitant Medications:

Aspirin (98%), ADP receptor inhibitor (89%), and statin (92%)

Principal Findings:

Overall, 7,226 patients were randomized. The mean age was 61 years, 27% were women, mean duration of diabetes was 8.6 years, mean body mass index was 29 kg/m2, mean glycated hemoglobin was 7.8%, mean low-density lipoprotein cholesterol (LDL-C) was 79 mg/dl, qualifying event was ST-segment elevation myocardial infarction (STEMI) in 39%, non-STEMI in 36%, and unstable angina in 25%.

At a median of 104 weeks, the trial was terminated early due to futility for efficacy and increased safety endpoints. At the time the trial was stopped, 74% of predicted events had been adjudicated.

Compared with placebo, aleglitazar was associated with improvements in glycated hemoglobin, triglycerides, and high-density lipoprotein cholesterol; however, it was associated with an increase in LDL-C.

The primary efficacy outcome of cardiovascular death, MI, or stroke occurred in 9.5% of the aleglitazar group versus 10% of the placebo group (p = 0.57).

- Unstable angina hospitalization: 3.3% vs. 4.3% (p = 0.02), respectively
- Unplannned revascularization: 11.0% vs. 13.8% (p < 0.001), respectively
- Hospitalization for heart failure: 3.4% vs. 2.8% (p = 0.14), respectively
- Gastrointestinal (GI) hemorrhage: 2.4% vs. 1.7% (p = 0.03), respectively
- Renal dysfunction: 7.4% vs. 2.7% (p < 0.001), respectively
- Bone fracture: 2.3% vs. 1.8% (p = 0.11), respectively
- Peripheral edema: 14.0% vs. 6.6% (p < 0.001), respectively

Interpretation:

Among type 2 diabetic patients hospitalized for an acute coronary syndrome, the use of the PPAR-αγ dual-agonist aleglitazar in addition to standard therapy was not beneficial. Aleglitazar did not reduce adverse cardiovascular events, despite favorable effects on glycated hemoglobin, HDL-C, and triglyceride levels. In fact, aleglitazar was associated with an excess of safety events: GI hemorrhage, renal dysfunction, and peripheral edema, and a nonsignificant excess in hospitalization for heart failure and bone fracture.

A possible explanation for the lack of efficacy includes the high prevalence of statins and good baseline lipid control. Also, an increase in LDL-C might have negated beneficial effects from HDL-C and triglyceride lowering. It is unknown if the same results would have been observed among patients with newly diagnosed diabetes and less established atherosclerotic disease. The reduction of macrovascular events in diabetic patients remains challenging.

References:

Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial. JAMA 2014;311:1515-25.

Presented by Dr. A. Michael Lincoff at the American College of Cardiology Scientific Session, Washington, DC, March 30, 2014.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Fractures, Bone, Edema, Insulin Resistance, Peroxisome Proliferator-Activated Receptors, Glycated Hemoglobin A, Cholesterol, Body Mass Index, Heart Failure, Oxazoles, Medical Futility, Triglycerides, Hospitalization


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