Favorable Effects of Pioglitazone and Metformin Compared With Gliclazide on Lipoprotein Subfractions in Overweight Patients With Early Type 2 Diabetes

Abstract

OBJECTIVE -To compare effects of different oral hypoglycemic drugs as first-line therapy on lipoprotein subfractions in type 2 diabetes.RESEARCH DESIGN AND METHODS -Sixty overweight type 2 diabetic patients not on lipid-lowering therapy were randomized to metformin, pioglitazone, or gliclazide after a 3-month dietary run-in. Drug doses were uptitrated for 3 months to optimize glycemia and were kept fixed for a further 3 months. LDL subfractions (LDL 1 , LDL 2 , and LDL 3 ) were prepared by density gradient ultracentrifugation at randomization and study end. Triglycerides, cholesterol, total protein, and phospholipids were measured and mass of subfractions calculated. HDL subfractions were prepared by precipitation. The primary end point was change in proportion of LDL as LDL 3 .RESULTS -HbA 1c , triglycerides, glucose, and cholesterol were comparable across groups at baseline and over time. LDL 3 mass and the LDL 3 -to-LDL ratio fell with pioglitazone (LDL 3 mass 36.2 to 28.0 mg/dl, P Ͻ 0.01; LDL 3 -to-LDL 19.2:13.3%, P Ͻ 0.01) and metformin (42.7 to 31.5 mg/dl, P Ͻ 0.01; 21.3:16.2%, P Ͻ 0.01, respectively) with no change on gliclazide. LDL 3 reductions were associated with reciprocal LDL 1 increases. Changes were independent of BMI, glycemic control, and triglycerides. Total HDL cholesterol increased on pioglitazone (1.28 to 1.36 mmol/l, P ϭ 0.02) but not gliclazide (1.39 to 1.37 mmol/l, P ϭ NS) or metformin (1.26 to 1.18 mmol/l, P ϭ NS), largely due to an HDL 2 increase (0.3 to 0.4 mmol/l, P Ͻ 0.05). HDL 3 cholesterol fell on metformin (0.9 to 0.85 mmol/l, P Ͻ 0.01). On pioglitazone and metformin, the HDL 2 -to-HDL 3 ratio increased compared with no change on gliclazide.CONCLUSIONS -For the same improvement in glycemic control, pioglitazone and metformin produce favorable changes in HDL and LDL subfractions compared with gliclazide in overweight type 2 diabetic patients. Such changes may be associated with reduced atherosclerosis risk and may inform the choice of initial oral hypoglycemic agent. Diabetes Care 27:41-46, 2004P atients with type 2 diabetes are frequently overweight with associated hypertension and a characteristic dyslipidemia with raised triglycerides and low HDL cholesterol. This cluster of abnormalities partly explains their increased risk of macrovascular disease. Targeting and treating the hypertension and dyslipidemia improves long-term outcomes (1-3). However, despite intervention, these patients remain at increased risk, suggesting that other factors contribute.A proportion of the increased risk may be explained by qualitative changes in lipoprotein subfraction. Although LDL cholesterol may not be elevated in type 2 diabetes, the dyslipidemia is characterized by an increased proportion of LDL as small, dense LDL or LDL 3 (4). Increased LDL 3 has been shown to be associated with increased risk of myocardial infarction (5-7). Risk may also be increased by qualitative changes in HDL subfractions (8), with an increased proportion of HDL occurring as smaller, denser HDL 3 , which is believed t...

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