Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with Type II diabetes

Abstract

Because insulin resistance plays a prominent part in the development of Type II diabetes [1,2], therapeutic interventions to improve insulin action are likely to be of considerable benefit in the management of the condition. The thiazolidinediones (or glitazones) are a new class of orally active drugs that reduce insulin resistance [3] and hence increase glucose uptake in skeletal muscle and adipose tissue, as well as decrease hepatic glucose production. These effects are thought to be mediated through interactions of these drugs with the gamma subtype of the peroxisome proliferator-activated receptor gamma (PPARg) [4,5].The thiazolidinediones currently marketed, or in late-phase clinical trials, include troglitazone, rosiglitazone and pioglitazone. Although these compounds share a common thiazolidine-2±4-dione structure, Diabetologia (2000) Abstract Aims/hypothesis. The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study. Methods. After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. Results. All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA 1 c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, nonesterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity. Conclusion/interpretation. Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose. [Diabetologia (2000) 43: 278±284]

Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

“…Treatment with thiazolidinediones has resulted in either no significant reduction or, at best, a modest lowering of plasma TGs in clinical trials in humans with insulin resistance and Type 2 diabetes (31), despite their documented insulin sensitizing effects (21,32,33). This is consistent with our observation that treatment with rosiglitazone resulted in a non-significant reduction in fasting plasma TG levels in the fructose-fed hamster, an animal model of mild hypertriglyceridemia associated with VLDL oversecretion.…”

“…This is consistent with the demonstration of increased whole-body glucose disposal rate with treatment of fructose-fed hamsters in the present study. Rosiglitazone treatment has also resulted in insulin sensitization of adipose tissue (20) and has often led to a reduction of plasma FFA levels and flux (21,22). Although rosiglitazone treatment did not result in a significant reduction in fasting plasma FFA in the present study, we cannot rule out that rosiglitazone treatment in this model may have resulted in lower postprandial FFA levels and lower overall FFA flux to the liver.…”

Effects of Troglitazone in Young First-Degree Relatives of Patients With Type 2 Diabetes

“…Several clinical studies have suggested that glitazones may improve glycemic control, insulin sensitivity, and circulating lipid levels in type 2 diabetic patients (17)(18)(19). Troglitazone has also been shown to increase insulin sensitivity in subjects with impaired glucose tolerance (IGT) (20 -22) and women with polycystic ovary syndrome (23).…”

Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes

“…These findings suggest that the effect of TZDs on biomarkers of cardiovascular risk may be independent of their antidiabetic actions. 129 Previous data indicate that throughout the spectrum of insulin resistance, from the metabolic syndrome to type 2 diabetes, PAI-1 levels are increased. 130 Because PAI-1 promotes clot formation in plasma and various studies demonstrated an association between circulating PAI-1 levels and cardiovascular events, 131 a TZD-mediated decrease in PAI-1 might play an important role in reducing the incidence of CAD and its complications in this population.…”