In population pharmacokinetic analyses from three large clinical trials, including 642 men and 405 women with type-2 diabetes (35 to 80 years of age), the pharmacokinetic properties of rosiglitazone tablet were not influenced by age, race, smoking, or alcohol consumption. Both oral clearance (CL/F) and the oral steady-state volume of distribution (Vss/F) rose with increases in body weight. Over the weight range observed in these analyses (50 to 150 kg), the range of predicted CL/F varied by less than 1.7-fold; that of Vss/F varied by less than 2.3-fold. Rosiglitazone’s CL/F was also influenced by both weight and sex, being lower by approximately 15% in women.
SUPPORTING CLINICAL DATA:THE CASE FOR TZD THERAPY IN DIABETES
Efficacy and Spectrum of Action
TZDs are approved for the treatment of hyperglycemia in patients with type-2 diabetes, even though their effects have varied. According to placebo-controlled studies, both pio-glitazone and rosiglitazone canadian decrease HbA1c values by 1% to 1.5%. In some analyses, however, clinical chart reviews showed no significant differences in HbA1c reductions between the two agents.
Seems to increase both TC and LDL-C concentrations. Pioglitazone canadian decreases TC and triglycerides and increases HDL-C levels. It is interesting to note that experimental studies have suggested that the TZDs might be used in treating insulin-resistant conditions such as non-alcoholic fatty liver disease, polycystic ovary syndrome, and lipo-dystrophies.
It is well accepted that TZDs may cause volume expansion and peripheral edema. The edema that sometimes accompanies the use of a TZD can be worrisome, because it may be a harbinger of congestive heart failure (CHF). There is a growing concern that the use of TZDs is associated with CHF, although this relationship is unclear. The American Heart Association and the American Diabetes Association have issued an official statement on the use of TZDs and have developed guidelines to minimize the risk of heart failure.
The possible association of TZDs with the risk of CHF has been documented in several studies, although no prospective controlled clinical trials have been completed. Tang et al., at the Cleveland Clinic, reported that despite the association of TZDs with an increased risk of edema, the additional risk of cardiovascular disease attributable to TZDs is relatively small. On the other hand, a published longitudinal observational study by Delea et al. reported that the initiation of TZDs was associated with an increased risk of incident CHF (hazard ratio 1.7; P < .001). If TZDs do confer an increased risk for CHF, one might expect a dose-response effect; however, no such evidence was reported in the Delea study.
Researchers are conducting a long-term study, funded by the American Diabetes Association, of TZD use and CHF in the Kaiser Permanente Northern California Diabetes Registry. Preliminary analyses have noted a substantially elevated prevalence of several markers of disease severity, including poor glycemic control (HbA1c above 9.5%), among patients initiating new diabetes medications compared with patients who were not starting new therapies. Moreover, compared with those initiating other therapies, the TZD initiators had more CHF risk factors, including the greatest prevalence of ischemic heart disease, hypertension, elevated urinary albumin excretion, elevated serum creatinine, microalbuminuria, and obesity; the poorest glycemic control; and the lowest mean HDL-C levels. These patients were also those most likely to need medications for dyslipidemia and hypertension, and they had the highest utilization of outpatient and inpatient services.
In an observational study by Masoudi et al., the use of a TZD combined with was not associated with increased mortality in older patients with diabetes and heart failure. The authors also noted that patients in their study sample might have better outcomes with the use of either TZDs or metformin canadian.
Thus, TZDs were initiated more frequently in diabetic patients with more advanced disease. Because there are no generic TZDs at present, these expensive therapies will probably be reserved for more severe or advanced cases of diabetes.