Effect of the Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonist Aleglitazar on Risk of Cardiovascular Disease in Patients With Type 2 Diabetes - SYNCHRONY

Jun 18, 2009
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Trial Sponsor:
F Hoffmann-La Roche AG (Switzerland)
Date Published:
01/01/2009
Date Updated:
06/18/2009
Original Posted Date:
06/18/2009
References

Description:

Several dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonists have been clinically developed; however, toxic effects have impeded development beyond phase III clinical trials. The SYNCHRONY study was a phase II clinical trial that sought to assess the therapeutic dose of aleglitazar that would be associated with the best safety and efficacy profile.

Hypothesis:

The study would identify the dose associated with the best safety and efficacy profile for aleglitazar in patients with type 2 diabetes.

Study Design

Study Design:

Patients Screened: 899
Patients Enrolled: 332
NYHA Class: I/II: 4%
Mean Follow Up: 16 weeks
Mean Patient Age: 52.6-56.9 years
Female: 59

Patient Populations:

  • Age 18-75 years
  • Diagnosis of type 2 diabetes mellitus
  • Oral antidiabetic-naive or previous treatment with a maximum of two antidiabetic agents (none at maximum dose)
  • HbA1c <10% at screening, and between 7% and 10% at prerandomization visit
  • Fasting blood glucose >126 mg/dl at screening, and ≤234 mg/dl at prerandomization visit

Exclusions:

  • Type I diabetes
  • Impaired liver or renal (creatinine ≥2.0 mg/dl) functioning
  • Anemia
  • Uncontrolled hypertension
  • Myocardial infarction or stroke within the past 6 months
  • New York Heart Association class III/IV congestive heart failure
  • Any other serious illness
  • Patients treated with lipoprotein-modifying therapies (i.e., fibrates) within 1 month before screening, apart from stable (1 month or longer) statin therapy

Primary Endpoints:

  • Efficacy:
    • Absolute change in HbA1c from baseline to 16 weeks
  • Safety:
    • Cardiovascular events
    • Peripheral edema
    • Body weight change
    • Renal function

Secondary Endpoints:

  • Change from baseline in fasting plasma glucose
  • Change from baseline in fasting lipid profile

Drug/Procedures Used:

After the placebo run-in period, patients were randomly assigned to double-blind treatment with one of four daily doses of aleglitazar (50 µg, 150 µg, 300 µg, or 600 µg) or matching placebo, each of which was given as a combination of two aleglitazar or placebo-matched capsules, or to open-label 45 mg of pioglitazone.

Concomitant Medications:

Aspirin (14.6%), statins (15.2%), angiotensin-receptor blockers (5.3%), and angiotensin-converting enzyme inhibitors (36.6%)

Principal Findings:

A total of 322 patients were randomized, 55 to each of the four doses of aleglitazar, 55 to placebo, and 57 to pioglitazone. Baseline characteristics were fairly similar. The mean duration of diabetes mellitus ranged from 2.3 to 4.6 years, with a mean baseline glycated hemoglobin (HbA1c) of 7.9-8.06%. Mean fasting blood glucose ranged from 170 to 184 mg/dl, and mean LDL ranged from 121 to 135 mg/dl. About one-half of all patients had received previous monotherapy treatment for diabetes, with similar numbers of the remaining patients controlled with diet alone or with a combination of oral antidiabetic drugs.

Aleglitazar was associated with a significant reduction in baseline HbA1c compared with placebo in a dose-dependent fashion, from -0.36% (95% confidence interval [CI] 0 to -0.7, p = 0.048) with 50 µg to -1.35% (-0.99 to -1.70, p < 0.0001) with 600 µg. A similar dose-response relationship was noted for fasting plasma glucose. Although the study was not powered to study differences between pioglitazone and aleglitazar, the 150 µg dose of aleglitazar seemed to have similar efficacy as that recorded for pioglitazone compared with placebo.

Given that aleglitazar is a PPAR-α agonist as well, significant changes in lipid parameters were also noted. There seemed to be a dose-dependent decrease in baseline triglycerides (p < 0.001), and increase in high-density lipoprotein (p < 0.05). A significant reduction in low-density lipoprotein cholesterol was also noted at doses ≥150 µg compared with placebo (p < 0.05).

The highest dose of aleglitazar was associated with the highest rate of withdrawal from the study. Peripheral edema seemed to increase in a dose-dependent fashion, with the highest incidence in the 300-600 µg arms. Similarly, other side effects such as increased blood creatine phosphokinase, anemia, and decreased white blood cell count were all noted with higher doses of aleglitazar. Weight gain also seemed to occur in a dose-dependent fashion (-0.24 kg for 50 µg to 2.72 kg for 600 µg). Similarly, a dose-dependent decrease in estimated glomerular filtration rate was noted with aleglitazar. Two patients (300 and 600 µg arms) developed congestive heart failure. No myocardial infarctions or coronary revascularizations were recorded.

Interpretation:

Aleglitazar was associated with a dose-dependent improvement in HbA1c, fasting plasma glucose, and an improvement in lipid parameters at 16 weeks, compared with placebo. Weight gain, anemia, and some impairment of renal function were noted with all doses of aleglitazar, but seemed to be maximum with higher doses. The efficacy of the 150 µg dose seemed to be equivalent to that of 45 mg daily of pioglitazone.

The results of this trial indicate a good safety and efficacy profile for 150 µg of aleglitazar, and should prompt phase III clinical trials to further study this agent.

References:

Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009;374:126-35.

Keywords: Myocardial Infarction, Creatine Kinase, Cholesterol, LDL, PPAR alpha, Thiophenes, Leukocyte Count, Diabetes Mellitus, Type 2, Edema, Capsules, Weight Gain, Glycated Hemoglobin A, Blood Glucose, Oxazoles, Heart Failure, Glomerular Filtration Rate, Hypoglycemic Agents, Diet, Confidence Intervals, Triglycerides, Lipoproteins, HDL, Thiazolidinediones, Fasting


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