Both pioglitazone and rosiglitazone have been shown to increase HDL levels, and pioglitazone has also been shown to decrease triglyceride levels. Data indicate that pioglitazone raises HDL levels by up to 19% and decreases triglyceride levels by up to 15% relative to baseline. Data on rosiglitazone from a 52-week study indicate mean significant increases in HDL of 19% from baseline, with variable, insignificant changes in triglycerides. Increases in LDL levels are associated with both agents as well. Pioglitazone has shown small, insignificant increases in LDL cholesterol (identical to placebo), while each of the rosiglitazone studies referenced in this article has demonstrated statistically significant increases of 10%-25% in mean LDL cholesterol from baseline.
Recently, a small observational study compared the lipid-lowering efficacy of both pioglitazone and rosiglitazone. This study reported that both pioglitazone and rosiglitazone increased HDL levels, but pioglitazone demonstrated a greater increase overall. Pioglitazone decreased triglycerides, and increased LDL to a lesser extent than rosiglitazone. These results are consistent with previously published data. To date, this represents the only reported comparative study between the two agents, although a randomized long-term study evaluating this issue is currently in progress.
Adverse Effects: The two available thiazolidinediones are generally well-tolerated and show similar safety profiles. They can produce several mild class effects which occur at similar rates with the different agents. The incidence of edema with pioglitazone or rosiglitazone was greater than that for placebo in clinical trials. The incidence of edema is particularly high in combination therapy with insulin in both clinical trial sets. The mechanism underlying this effect is unclear, but has been postulated to be a result of the loss of the osmotic diuresis associated with hyperglycemia as well as enhanced insulin sensitivity in the kidney tubule, resulting in greater renal tubular absorption of sodium and in peripheral vasculature.
Mild anemia occurs with both drugs, resulting in clinically insignificant hemoglobin reductions of approximately 2%-4%. This generally occurs during the first 4-12 weeks of therapy and remains constant thereafter. The mechanism has been attributed to hemodilution (increased plasma volume).
Weight gain of a moderate extent has been reported with both agents (1.2-3.5 kg with rosiglitazone monotherapy over 26 weeks, 0.5-2.8 kg with pioglitazone monotherapy). Weight gain is somewhat greater when pioglitazone is used in combination with sulfonylurea and when pioglitazone is combined with insulin. The mechanisms contributing to the weight gain have included improved glycemic control and diminished urinary caloric losses, fluid retention, and potentially through stimulation of adipocyte differentation via effects on PPAR.
Relevant to this issue are data reported with troglitazone, in which underwater weighing was used to measure total body fat content, and MRI assessed body fat distribution in 21 subjects before and after 12 weeks of troglitazone monotherapy. Intriguingly, in that study, while the body weight did not change significantly, there was a redistribution to a more favorable pattern, with a significant reduction of intra-abdominal fat content.
Blood Pressure: Troglitazone has been shown to decrease systolic and diastolic blood pressure to a modest but significant extent in several clinical trials. This property is attributed to its effects on insulin resistance, since an association between hypertension and insulin resistance has been previously demonstrated. Rosiglitazone and pioglitazone have been shown to improve hypertension in animal models.
Vascular Reactivity: In addition to having tendencies for essential hypertension, insulin-resistant patients are also prone to having altered vascular reactivity, which may be due to defective production or activation of nitric oxide by vascular endothelial cells. In a few small clinical studies with troglitazone, impaired brachial artery vasoactivity was normalized with troglitazone, and response to acetylcholine in the coronary arteries was improved in troglitazone-treated patients but not in those treated with diet or a sulfonylurea.
Atherosclerosis: Substantial in vitro data show various thiazolidinediones affect vascular smooth muscle proliferation. Pioglitazone has been shown to inhibit the effects of insulin, epidermal growth factor, and serum-induced growth of cultured arterial vascular smooth muscle cells, and troglitazone has also been shown to inhibit DNA synthesis induced by various growth factors implicated in atherosclerosis. Recent in vivo data now corroborate these experimental findings. Troglitazone was shown to reduce carotid intimal and medial thickness, a marker of early atherosclerosis, in a placebo-controlled, 6-month study involving 135 Japanese subjects with type 2 diabetes.Similarly, subjects with type 2 diabetes who had undergone coronary stenting for atherosclerosis were studied at baseline and after a 6-month trial period during which they received troglitazone 400 mg/day. Luminal area increased and intimal area decreased significantly in troglitazone-treated vs. control subjects, implying that troglitazone reduces neointimal proliferation after stent implantation and could potentially reduce the risk of restenosis following this procedure.