Diabetes Drug Aleglitazar Fails to Reduce Ischemic Outcomes in Diabetics with Recent ACS

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In patients with type 2 diabetes and recent acute coronary syndromes (ACS), adding the dual peroxisome proliferator-activated receptor (PPAR) agonist aleglitazar to standard therapy does not reduce the risk of cardiovascular death or other ischemic outcomes, according to a study presented March 30, 2014, at the American College of Cardiology/i2 Scientific Session in Washington, DC, and simultaneously published online ahead of print in the Journal of the American Medical Association.

For the AleCardio trial, conducted at 720 hospitals in 26 countries between February 2010 and May 2012, A. Michael Lincoff, MD, of the Cleveland Clinic (Cleveland, OH), and colleagues randomized 7,226 patients with type 2 diabetes and a recent ACS (76% MI) to standard therapy plus placebo (n = 3,610) or aleglitazar (150 μg daily; n = 3,616).

The trial was terminated in July 2013 in response to a greater percentage of specific adverse events in the aleglitazar group. The median follow-up was 104 weeks. More patients in the aleglitazar group than the placebo group discontinued the study drug prematurely (29.3% vs 25.3%).

No Efficacy Seen

Occurrence of the primary efficacy endpoint (composite of cardiovascular death, nonfatal MI, or nonfatal stroke) was similar between the groups, with aleglitazar showing no detectable effect on the rates of any of the individual components of the primary endpoint or any of the secondary endpoints. However, aleglitazar was associated with reductions in hospitalizations for unstable angina and unplanned revascularization (table 1).

Table 1. Efficacy Endpoints

 

Aleglitazar
(n = 3,616)

Placebo
(n = 3,610)

HR (95% CI)

P Value

Primary Efficacy Endpoint

9.5%

10.0%

0.96 (0.83-1.11)

0.57

Hospitalizations
for Unstable Angina

3.3%

4.3%

0.75 (0.59-0.96)

0.02

Unplanned Revascularization

11.0%

13.8%

0.79 (0.69-0.90)

< 0.001


Compared with the placebo, aleglitazar reduced glycated hemoglobin levels, and more patients achieved a glycated hemoglobin level of < 7% (both P < 0.001). Additionally, the need for initiation of permanent insulin therapy was lower with aleglitazar than placebo (P = 0.02).

Aleglitazar patients also saw greater increases in HDL cholesterol levels from baseline compared with the placebo as well as greater impact on triglyceride levels, which decreased by 23.9% with aleglitazar and increased by 10.9% with the placebo (both P < 0.001).

The aleglitazar group had more GI hemorrhages, renal dysfunction, and hypoglycemic events than the placebo group with trends toward increased rates of bone fracture and rehospitalization for heart failure (table 2).

Table 2. Safety Endpoints

 

Aleglitazar
(n = 3,616)

Placebo
(n = 3,610)

HR (95% CI)

P Value

Bone Fractures

2.3%

1.8%

  1.30 (0.94-1.80)

0.11

GI Hemorrhage

2.4%

1.7%

1.44 (1.03-2.00)

0.03

Renal Dysfunction

7.4%

2.7%

2.85 (2.25-3.60

< 0.001

Rehospitalization for HF

3.4%

2.8%

1.22 (0.94-1.59)

0.14

Hypoglycemic Events

17%

11%

  1.60 (1.41-1.82)

< 0.001

 
“The only unprecedented adverse effect was gastrointestinal hemorrhage, and none of the safety signals were overwhelming,” Dr. Lincoff said in a press release. “The issue was futility of cardiovascular superiority.”

The End of the Road?

Aleglitazar is a dual PPAR agonist with balanced affinity for the PPAR-α and PPAR-γ subtypes. In the SYNCHRONY and AleNephro phase 2 trials, aleglitazar significantly reduced glycated hemoglobin, triglycerides, and LDL cholesterol and increased HDL cholesterol.

Dr. Lincoff said the study “highlights the difficulty in predicting cardiovascular outcomes using metabolic endpoints, particularly with drugs that affect a complex spectrum of pathways and multiple-gene activators.

“This study may well mark the end of this class of drug being tested clinically,” he added.

Study Details

Among the 90% of enrolled patients in whom the diagnosis of diabetes had been established prior to the index hospitalization, the mean time between diagnosis and study entry was 8.6 years.

 


Source:
Lincoff AM, Tardif J-C, 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;Epub ahead of print.

 

 

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Disclosures
  • The trial was sponsored by Hoffmann-La Roche.
  • Dr. Lincoff reports receiving research grants from AstraZeneca, CSL Laboratories, Eli Lilly, Regado, Roche, Takeda, and Vivus through his institution.

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