Long-term Effects of Pioglitazone vs Glimepiride on Lipoproteins and Glyco-oxidation in Patients with Type 2 Diabetes

Background and aim Cardiovascular complications are the first cause of mortality and morbidity in type 2 diabetic patients. Among antidiabetic drugs, those who have shown cardiovascular benefits have ancillary activities that simultaneously control several risk factors. In the PROACTIVE trial, pioglitazone determined a 16% reduction of death for all causes, non-fatal myocardial infarction, non-fatal stroke, compared to placebo. The aim of the study is to investigate the effects of 5 years treatment with pioglitazone/metformin compared to 5 years treatment with glimepiride/metformin on diabetic dyslipidemia, both quantitatively and qualitatively, and on glyco-oxidation processes. Methods 96 diabetic patients, treated with metformin (2g/day) for at least 2 months, were randomized to treatment with pioglitazone or glimepiride. Patients were followed for 5 years: body mass index (BMI), waist circumference (CV), blood pressure, HbA1c; total cholesterol (CT), high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG), advanced glycation end products (AGE), oxidized LDL (oxLDL) were determined at baseline and after 5 years of treatment. Results Treatment with pioglitazone resulted in significant increase in HDL (47.1±11.7 vs 51.3±15.7 mg/dl; p=0.02), non-significant reduction in CT, LDL and TG. Glimepiride treatment resulted in a significant reduction in HDL (48.6±14.1 vs 45.8±12.7 mg/dl; p=0.03), a non-significant reduction in CT, LDL and TG. Only the variation of HDL and oxLDL were significantly different between the two groups (ΔHDLPioglitazone= +4.2±10.5 mg/dl vs ΔHDLGlimepride= -2.9±7.7 mg/dl; p=0.002); (ΔoxLDLPioglitazone= -2.1±9.8 U/l vs ΔoxLDLGlimepride= +3.6±11.4 U/l; p=0.01). AGEs reduction, significant for both treatments, is not significantly different between the two groups. HbA1c reduction was significant only in patients treated with glimepiride (7.7±0.4 vs 7.1±0.8 %; p <0001) and was not correlated with AGEs variation (r=1.22; p=0.59). Conclusions Long-term treatment with pioglitazone significantly improves lipid profile of type 2 diabetic patients, increasing HDL levels and reducing oxLDL levels. In addition, it reduces AGEs formations. The inhibition of glyco-oxidative processes is one of the mechanisms that may explain the drug ability to prevent cardiovascular events.