Improved glucose control decreases the interaction of plasma low-density lipoproteins with arterial proteoglycans

The entrapment and retention of plasma low-density lipoproteins (LDL) by arterial proteoglycans (PG) is a process central to atherogenesis. We postulated therefore that accelerated atherosclerosis of diabetic individuals may result from hyperglycemia-associated modifications in LDL that enhance their interaction with arterial PG. To evaluate the role of clinical treatment on this process, LDL-PG binding was evaluated in uncontrolled type 2 diabetic subjects on monotherapy followed by combination therapy. After a 4-week washout (baseline), subjects were randomized to receive glipizide GITS monotherapy (20 mg/d, n = 12) or metformin monotherapy (2.5 g/d, n = 8) for 6 weeks followed by combination treatment with both agents for 12 weeks. Fasting blood glucose and fructosamine were significantly reduced with monotherapy and further reduced with combination therapy P <.01). With combination therapy, glycated hemoglobin (GHb) levels were significantly reduced from baseline for the group initially treated with glipizide GITS (8.5% v 10.5%, P <.0005), or initially with metformin (6.7% v 9.7%, P <.0005). No significant changes in total plasma cholesterol (TPC), LDL, high-density lipoprotein (HDL), or triglycerides (TG) were measured after monotherapy or combination therapy. Plasma LDL was isolated by differential ultracentrifugation. In an in vitro binding assay, LDL from subjects on combination glipizide GITS/metformin demonstrated significantly less binding to arterial PG than LDL obtained after monotherapy with either agent (7.6 +/- 0.5 v 10.7 +/- 0.9 microg LDL cholesterol/microg PG [mean +/- SEM], P <.05). These data demonstrate that combination treatment with glipizide GITS/metformin will further improve glucose control in type 2 diabetic subjects and may favorably improve diabetes-associated modification of LDL-arterial PG binding.