Rosiglitazone Monotherapy Is Effective in Patients with Type 2 Diabetes

Abstract

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A 1c ; other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A 1c relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ␤-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions. (J Clin Endocrinol Metab 86: 280 -288, 2001) I NSULIN RESISTANCE contributes to the pathophysiology of several major chronic diseases. Insulin resistance precedes the development of type 2 diabetes mellitus and contributes to the hyperglycemic state in about 80 -85% of patients with this disorder (1, 2). In addition, evidence suggests that insulin resistance and hyperinsulinemia are also associated with other disease states, such as polycystic ovarian syndrome, an insulin-resistant state that leads to hyperinsulinemia, thus stimulating excessive ovarian androgen production in genetically susceptible individuals (3, 4). Insulin resistance and hyperinsulinemia have also been associated with increased risks of atherosclerosis and hyperten-

Thiazolidinediones Block Fatty Acid Release by Inducing Glyceroneogenesis in Fat Cells

“…In adipose tissue, the resulting increase of fatty acid re-esterification would be facilitated by the concomitant increase of proteins that allow their uptake and acyl-CoA activation, as expected from the reported increase in the corresponding mRNAs by PPAR␥ agonists (10,24). Furthermore, it was observed that a 6-month rosiglitazone monotherapy in patients with type 2 diabetes enhances the body weight, although moderately (25).…”

Involvement of Inducible 6-Phosphofructo-2-kinase in the Anti-diabetic Effect of Peroxisome Proliferator-activated Receptor γ Activation in Mice

“…Peroxisome proliferator-activated receptor ␥ (PPAR␥) 5 is a nuclear receptor whose activation by thiazolidinediones (TZDs) effectively improves systemic insulin sensitivity and lowers plasma glucose levels in both human patients and rodent models of type 2 diabetes (1)(2)(3)(4)(5)(6)(7)(8). Because TZDs are effective in liver-or muscle-specific PPAR␥-deficient mice (9, 10) but not in adipose tissue-deleted mice (11) and adipose-specific PPAR␥-deficient mice (12), adipose tissue has been considered as the primary target site for the anti-diabetic effect of PPAR␥ activation (13,14).…”

Improvement of Solubility and Oral Bioavailability of 2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine (FPFS-410) with Antidiabetic and Lipid-Lowering Activities in Dogs by 2-Hydroxypropyl-.BETA.-cyclodextrin

“…5,6) TZDs are reported to influence several processes that increase cell sensitivity to insulin, 7,8) including activation of peroxisome proliferator-activated receptor g (PPARg), 9,10) although their mechanism has not been fully elucidated. TZDs are widely used in clinical practice, but in some cases they cause weight gain, plasma volume expansion, edema or hepatotoxicity.…”