Lowering the Triglyceride/High-Density Lipoprotein Cholesterol Ratio Is Associated With the Beneficial Impact of Pioglitazone on Progression of Coronary Atherosclerosis in Diabetic Patients: Insights From the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) Study

Study Questions:

What factors are associated with the favorable effect of pioglitazone on atheroma progression?

Methods:

A total of 360 diabetic patients with coronary artery disease were treated with pioglitazone or glimepiride for 18 months in the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study. All patients had a clinical indication for coronary arteriography. Coronary atheroma progression was evaluated by serial intravascular ultrasound at 18 months of follow-up. The relationship between changes in biochemical parameters, percent atheroma volume (PAV), and total atheroma volume (TAV) was investigated. Progression and regression of PAC was considered as a gain or loss of 5%, respectively.

Results:

Mean age was 60 years, 69% were male, and mean body mass index was 32 kg/m2. Nearly 90% were on statins and >30% were on high-dose statins. Pioglitazone-treated patients demonstrated slightly greater reductions in glycated hemoglobin, and greater relative reductions in triglycerides (-15.3% vs. +0.6%, p < 0.001), triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio (-26.4% vs. -2.6, p < 0.001), apolipoprotein B (apoB) (-5.0% vs. +1.7%, p = 0.003), apoB/A-I ratio (-11.0% vs. -4.2%, p = 0.005), and C-reactive protein (-44.9% vs. -18.0%, p < 0.001). A greater relative increase in HDL-C (+16.1% vs. 4.2%, p < 0.001) was also observed with pioglitazone with no differential effect on apoA-I. Pioglitazone had a favorable effect on progression of PAV (-0.16 % vs. +0.73%, p = 0.002) and TAV (-5.5 mm3 vs. -1.5mm3, p = 0.06) compared with glimepiride. Significant correlations were observed between changes in PAV and triglycerides (r = 0.15, p = 0.04), triglyceride/HDL-C ratio (r = 0.16, p = 0.03), and glycated hemoglobin (r = 0.16, p = 0.03) with pioglitazone, and changes in low-density lipoprotein cholesterol (r = -0.15, p = 0.05), apoB (r = -0.16, p = 0.04), and apoA-I (r = -0.20, p = 0.01) with glimepiride. Substantial atheroma regression, compared to progression, was associated with greater relative increases in HDL-C (14.2% vs. 7.8%, p = 0.04), relative decreases in triglycerides (-13.3% vs. -1.9%, p = 0.045), triglyceride/HDL-C ratio (-22.5 vs. -9.9%, p = 0.05), and decrease in glycated hemoglobin (-0.6% vs. -0.3%, p = 0.01). Multivariable analysis revealed that pioglitazone-induced effects on triglyceride/HDL-C were associated with changes in PAV (p = 0.03) and TAV (p = 0.02).

Conclusions:

Favorable effects of pioglitazone on the triglyceride/HDL-C ratio correlated with delayed atheroma progression in diabetic patients. This finding highlights the potential importance of targeting atherogenic dyslipidemia in diabetic patients with coronary artery disease.

Perspective:

The atherosclerosis regression associated with pioglitazone is impressive, particularly in light of the aggressive treatment with statins and the 18-month time period of the study. It is not surprising that improvement in the components of the atherogenic lipid phenotype (increased triglycerides and decrease in HDL-C, which is associated with excessive small LDL particles) can be associated with plaque regression, particularly in light of the findings associated with niacin. This study adds to the clinical and angiographic data supporting the role of decreasing the triglyceride/HDL-C and apoB/apoA-I ratios in the management of coronary heart disease.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins

Keywords: Coronary Artery Disease, Atherosclerosis, Plaque, Atherosclerotic, Follow-Up Studies, Cholesterol, LDL, Apolipoprotein A-I, Lipoproteins, LDL, Sulfonylurea Compounds, Cholesterol, HDL, Hypoglycemic Agents, Lipoproteins, HDL, Triglycerides, Diabetes Mellitus, Thiazolidinediones


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