Background-Patients

OBJECTIVE -The oral antidiabetic agent pioglitazone improves insulin sensitivity and glycemic control and appears to lower atherogenic dense LDL in type 2 diabetes. Insulin resistance may occur frequently in nondiabetic patients with hypertension. This study is the first to report the effect of pioglitazone on LDL subfractions in normolipidemic, nondiabetic patients with arterial hypertension.RESEARCH DESIGN AND METHODS -We performed a monocentric, double-blind, randomized, parallel-group comparison of 45 mg pioglitazone (n ϭ 26) and a placebo (n ϭ 28), each given once daily for 16 weeks. Fifty-four moderately hypertensive patients (LDL cholesterol, 2.8 Ϯ 0.8 mmol/l; HDL cholesterol, 1.1 Ϯ 0.3 mmol/l; triglycerides, 1.4 mmol/l (median; range 0.5-7.1) were studied at baseline and on treatment.RESULTS -At baseline, dense LDLs were elevated (apolipoprotein [apo]B in LDL-5 plus LDL-6 Ͼ250 mg/l) in 63% of all patients. Sixteen weeks of treatment with pioglitazone did not significantly change triglycerides, total, LDL, and HDL cholesterol. However, pioglitazone reduced dense LDLs by 22% (P ϭ 0.024). The mean diameter of LDL particles increased from 19.83 Ϯ 0.30 to 20.13 Ϯ 0.33 nm (P Ͻ 0.001 vs. placebo), whereas the mean LDL density decreased from 1.0384 Ϯ 0.0024 to 1.0371 Ϯ 0.0024 kg/l (P ϭ 0.005 vs. placebo). The effect of pioglitazone on LDL size and density was independent of fasting triglycerides and HDL cholesterol at baseline and of changes in fasting triglycerides and HDL cholesterol.CONCLUSIONS -The prevalence of atherogenic dense LDL in nondiabetic, hypertensive patients is similar to patients with type 2 diabetes. Pioglitazone significantly reduces dense LDL independent from fasting triglycerides and HDL cholesterol. The antiatherogenic potential of pioglitazone may thus be greater than that expected from its effects on triglycerides, LDL, and HDL cholesterol alone.

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.

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