Favorable Impact on LDL Particle Size in Response to Treatment With Pioglitazone is Associated With Less Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes

Mani P, Uno K, St John J et al.,
J Am Coll Cardiol. 2015 Jul 21;66(3):328-9

Background

Even when LDL-c levels seem well-controlled, a preponderance of small dense LDL particles may promote the accelerated plaque progression seen on intravascular ultrasound (IVUS) imaging in patients with diabetes [1]. In the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary obstruction Prospective Evaluation) trial, pioglitazone stopped atheroma progression in patients with diabetes type 2, which appeared independently associated to lowering the triglyceride/HDL cholesterol ratio [2]. LDL-c levels did not change, thus changes in LDL particle measures were now analysed. The PERISCOPE trial included 543 patients with type 2 diabetes and angiographic coronary artery disease, who were treated by either pioglitazone or glimepiride.

Main results

• Pioglitazone-treated patients showed greater increases in HDL-c (15.1+1.2% vs. 2.8+1.2%, P<0.001), mean LDL particle size (3.8+0.21% vs. 0.74+0.20%, P<0.001) and large LDL concentration (66.5%+4.3% vs. 16.6+4.2%, P<0.001).
  Greater decreases were seen with pioglitazone in triglycerides (-16.9+2.6% vs. 1.0+2.6%, P<0.001), total LDL particles (-15.9+1.7% vs. -1.3+1.6%, P<0.001) and small LDL concentration (-39.0+3.7% vs. -3.4+3.6%, P<0.001).
• Changes in percent atheroma volume (PAV)  were associated with increases in small (r=0.19, P<0.001) and total LDL (r=0.12, P=0.02) particle concentrations, as well as with decreases in large LDL particle concentration (r=-0.14, P=0.008) and mean LDL particle size (r=0.21, P<0.001).
• Less PAV progression was associated with changes in mean LDL particle size more than the median in the context of LDL<70mg/dL (-0.89+0.48% vs. 1.01+0.44% , P=0.004) and LDL-c 70-100 mg/dl (-0.21+0.30% vs. 0.56+0.32%, P=0.08), but not when LDL-c was >100 mg/dL (P=0.83).
• Multivariable analyses (adjusting for baseline PAV and treatment) showed that the percent change in mean LDL particle size, large LDL concentration and small LDL concentration were significantly associated with changes in PAV.

Conclusion

This analysis revealed that pioglitazone had a favourable impact on LDL particle measures, by increasing particle size and decreasing particle concentration, and that it was associated with less plaque progression. At higher LDL-c levels, particle-based measures were less reliable, presumably because of the established CV risk.
Even after correcting for the favourable effects of pioglitazone on insulin resistance, hyperglycaemia, hypertriglyceridaemia and systemic inflammation, increasing LDL particle size was associated with less disease progression.

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References

1. Nicholls SJ, Tuzcu EM, Kalidindi S, et al. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling: a pooled analysis of 5 intravascular ultrasound trials. J Am Coll Cardiol 2008;52:255–62.
2. Nicholls SJ, Tuzcu EM, Wolski K, et al. 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 study. J Am Coll Cardiol 2011;
57:153–9.