ADA: Lipid Effects of Diabetes Agents May Protect Arterial Function

CHICAGO, June 25 -- Lipoprotein subfraction changes may be at the root of the dyslipidemia accompanying type 2 diabetes and help explain how thiazolidinediones improve carotid intima-media thickness, researchers said.

High-density and low-density lipoprotein particle size and concentration were significantly improved with pioglitazone (Actos) compared with glimepiride (Amaryl), found Peter M. Meyer, Ph.D., of Rush Medical Center here, and colleagues.

This was revealed in their lipoprotein subfraction subanalysis of the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) trial, which was presented at the American Diabetes Association meeting.

The results were "consistent with a reversal of the pattern of change associated with the transition from insulin sensitivity to insulin resistance or diabetes," they said, and "may explain some of the observed decrease in carotid-intima media thickness progression in the pioglitazone group."

This prospective, double-blind study compared the two drugs in a multiracial and multiethnic population in Chicago. Participants had newly diagnosed type 2 diabetes, which was controlled by diet, or any combination of sulfonylurea, metformin, and insulin.

The 462 patients were randomized to 72 weeks of treatment with pioglitazone at a dose of 15 to 45 mg/d or glimepiride at a dose of 1 to 4 mg/d.

Among the main findings published in the Journal of the American Medical Association in 2006, the researchers reported that pioglitazone significantly slowed progression of carotid-intima media thickness compared with glimepiride (P=0.008).

The subanalysis focused on lipoprotein subfractions measured with NMR spectroscopy done on blood samples taken at baseline and periodically through the study.

"Patients with type 2 diabetes manifest a form of dyslipidemia typified by high LDL particle concentration, small LDL particle size, and high triglyceride and low HDL cholesterol levels," they said.

At 72 weeks there were significant differences favoring pioglitazone in reversing these trends although the baseline lipoprotein parameters were similar between groups.

Total LDL particle concentration was significantly improved by pioglitazone compared with glimepiride (-209.7 versus -109.3 nmol/L, P?0.01).

LDL particle size was likewise improved with pioglitazone (0.59 versus 0.17 nm, P?0.001). This was achieved by increasing large LDL particle concentrations and significantly reducing those of medium-small and small LDL particles (P?0.001 for all).

Very low density lipoprotein (VLDL) particle concentration improved more overall with glimepiride but the difference between groups was not significant (-5.69 versus -1.37 nmol/L).

But, VLDL particle size decreased significantly with pioglitazone compared with glimepiride (-5.01 versus -0.69 nm, P?0.001). This was primarily by increasing small VLDL particle concentration (7.11 versus -1.4 nmol/L, P?0.001) while also modestly decreasing large and medium-intermediate VLDL concentrations.

Total HDL particle concentrations increased slightly with pioglitazone but decreased with glimepiride (0.21 versus -1.05 nmol/L, P?0.001).

HDL particle size followed the same pattern (0.14 versus -0.01 nm, P?0.001). Large and medium HDL particle concentrations increased while that of small particles decreased (all P?0.01).

The researchers noted that the study was underpowered to compare cardiovascular event rates between groups, so it is not known whether the differences seen in carotid intima-media thickness and lipoprotein subfractions would impact outcomes.

However, "in aggregate, the changes in lipoprotein subfraction distribution would be predicted to produce a reduction in cardiovascular disease risk with pioglitazone versus glimepiride," they concluded.