Issue 212 Item 11 Rosiglitazone Improves Both Endothelium-dependent Vasodilatati

Patients receiving rosiglitazone also experienced significant improvements in insulin sensitivity (+19% vs. baseline, +30% vs. placebo) and ACh dose response. Rosiglitazone, improves both endothelium-dependent vasodilatation and insulin sensitivity in patients with type 2 diabetes.

Endothelial dysfunction, an early step in the development of atherosclerosis, is thought to act as a key component in the excess vascular vulnerability present in diabetic patients. Several studies have shown that the endothelium-dependent reactivity of both conductance vessels and resistance arteries is impaired in type 2 diabetics. Furthermore, studies in both humans and animals have suggested that insulin resistance and endothelial dysfunction may be related to one another in a causal manner.

"If this hypothesis is correct, then treatment of insulin resistance should result in a parallel improvement of endothelial function and, possibly, in a reduction of vascular complications," writes Andrea Natali, MD, of the University of Pisa, Italy. To test the hypothesis, investigators performed a study to determine whether improving metabolic control and peripheral insulin resistance in patients with type 2 diabetes modifies vascular reactivity.

Twenty-eight patients with type 2 diabetes were assigned to receive 1500 mg/day metformin (mean age=58, 22 men), 24 to 8 mg/day rosiglitazone (mean age=59, 22 men) and 22 to placebo (mean age=58, 18 men) for a period of 16 weeks. At baseline and 16 weeks, the researchers measure insulin sensitivity with the euglycemic insulin clamp, and vascular reactivity by forearm blood flow response to intra-arterial acetylcholine (ACh), intra-arterial nitroprusside, the clamp, and blockade of nitric oxide (NO) synthase.

Equipotent doses of rosiglitazone and metformin were used so that metabolic and vascular changes could be compared across treatments with equivalent levels of glucose toxicity. As expected for equivalent doses, metformin and rosiglitazone produced a similar reduction in fasting glucose between (-2.3 ± 0.5 and -2.3 ± 0.5 mmol/L) and glycosylated hemoglobin (-1.2 ± 0.3% and -1.6 ± 0.3%) after 16 weeks of treatment.

Patients receiving rosiglitazone also experienced significant improvements in insulin sensitivity (+19% vs. baseline, +30% vs. placebo) and ACh dose response (+40% vs. baseline, +70% vs. placebo)..

The researchers note that rosiglitazone-induced improvement in Ach response was associated with decreases in circulating free fatty acids and tumour necrosis factor alpha, suggesting that rosiglitazone may influence endothelial function by reducing these factors. "Although the precise mechanisms of rosiglitazone action on endothelial function in vivo remain only suggestive, the potential benefit is of clinical interest," they conclude. Diabetes Care 2004 Jun;27:6:1349-57

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