Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History - APPROACH — Presented at AHA 2008

Nov 19, 2008
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Trial Sponsor:
GlaxoSmithKline
Date Presented:
01/01/2008
Date Updated:
11/19/2008
Original Posted Date:
11/19/2008
References

Description:

The goal of the trial was to evaluate treatment with rosiglitazone compared with glipizide among patients with diabetes undergoing coronary angiography.

Hypothesis:

Rosiglitazone may reduce the progression of coronary atherosclerosis.

Study Design

Study Design:

Patients Enrolled: 692
Mean Follow Up: 18 months
Mean Patient Age: 61 years
Female: 32

Patient Populations:

  • Patients with type 2 diabetes undergoing coronary angiography with a 10-50% stenosis in a nonintervened segment

Exclusions:

  • Prior CABG
  • Valvular heart disease
  • Left ventricular systolic dysfunction (ejection fraction <40%)
  • Congestive heart failure
  • Renal or liver dysfunction
  • Uncontrolled hypertension

Primary Endpoints:

  • Change in percent atheroma volume

Secondary Endpoints:

  • Change in normalized total atheroma volume
  • Change in atheroma volume in the most diseased 10 mm segment

Drug/Procedures Used:

Patients were randomized to rosiglitazone titrated to 8 mg daily (n = 333) vs. glipizide titrated to 15 mg daily (n = 339). Metformin or insulin could be added after 3 months to achieve a glycated hemoglobin of <7.0%. Patients had baseline and repeat intravascular ultrasound (IVUS) at 18 months.

Concomitant Medications:

At baseline, in the rosiglitazone group, the use of aspirin was 84%, beta-blocker was 72%, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker was 71%, statin was 75%, and fibrate or another lipid-lowering agent was 10%. There was no difference in baseline medications between the groups.

Principal Findings:

Overall, 692 patients were randomized. The mean age of participants was 61 years and 32% were women. The median duration of diabetes was 4.8 years. The mean glycated hemoglobin was 7.2% and the mean low-density lipoprotein (LDL) cholesterol was 90 mg/dl.

The primary endpoint, change in percent atheroma volume, was -0.21% in the rosiglitazone group vs. 0.43% in the glipizide group (p = 0.12 between groups). The change in total atheroma volume was -3.9 mm3 vs. 1.2 mm3 (p = 0.04), and the change in atheroma volume in the most diseased 10 mm segment was -5.3 mm3 vs. -3.6 mm3 (p = 0.13), respectively, for rosiglitazone vs. glipizide.

For cardiovascular outcomes, death was 2.4% vs. 2.1%, myocardial infarction was 2.1% vs. 1.8%, stroke was 1.5% vs. 0.3%, congestive heart failure was 2.4% vs. 0.9%, and coronary revascularization was 7.8% vs. 8.0%, respectively, for rosiglitazone vs. glipizide. There was no difference between the groups.

For adverse events, bone fracture was 2% vs. <1% (p = 0.17), mean weight gain was 2.6 kg vs. 1.4 kg (p = 0.02), hemoglobin decrease >3 g/dl was 8% vs. 3% (p = 0.01), hypoglycemia was 8% vs. 28% (p < 0.0001), and alanine aminotransferase >3x normal was <1% vs. <1% (p = 1.0), respectively, for rosiglitazone vs. glipizide.

The percent change in glycated hemoglobin was -0.3% vs. -0.2% (p = 0.44), change in systolic blood pressure was 2.4 mm Hg vs. 2.6 mm Hg (p = 0.90), percent change in high-sensitivity C-reactive protein was -68% vs. -54% (p < 0.001), percent change in HDL was 14.6% vs. 6.1% (p < 0.001), and percent change in LDL was 3.1% vs. -8.4% (p = 0.002), respectively, for rosiglitazone vs. glipizide.

Interpretation:

Among type 2 diabetic patients, the use of rosiglitazone did not reduce percent atheroma volume compared with glipizide. However, there was a reduction in total atheroma volume in the rosiglitazone group. Cardiovascular outcomes were similar between the groups. In the rosiglitazone group, there was more weight gain and more decline in hemoglobin; however, there was less hypoglycemia.

The design of this trial is similar to the PERISCOPE trial, which showed that pioglitazone slightly reduced percent atheroma volume compared with glimepiride, which increased percent atheroma volume. Future trials powered to examine clinical endpoints with the use of these medications are warranted.

References:

Presented by Dr. Richard Nesto at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Keywords: Coronary Artery Disease, Myocardial Infarction, Insulin, Stroke, Plaque, Atherosclerotic, Diabetes Mellitus, Type 2, Fractures, Bone, Blood Pressure, Constriction, Pathologic, Weight Gain, Hypoglycemia, Glycated Hemoglobin A, Glipizide, Sulfonylurea Compounds, Cholesterol, C-Reactive Protein, Coronary Angiography, Metformin, Heart Failure, Hypoglycemic Agents, Thiazolidinediones


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