Rosiglitazone

Abstract

Rosiglitazone, a thiazolidinedione with a different side chain from those of troglitazone and pioglitazone, reduces plasma glucose levels and glucose production and increases glucose clearance in patients with type 2 diabetes mellitus. Insulin sensitivity, pancreatic β-cell function and surrogate markers of cardiovascular risk factors are significantly improved by rosiglitazone. Double-blind trials of 8 to 26 weeks of rosiglitazone 4 or 8 mg/day monotherapy indicate significant decreases in fasting plasma glucose (−2 to −3 mmol/L with 8 mg/day) and glycosylated haemoglobin levels [HbA_1c; −0.6 to −0.7% (−0.8 to −1.1% in drug-naive patients) with 8 mg/day]. Significant decreases in hyperglycaemic markers occurred when rosiglitazone was combined with metformin (HbA_1c −0.8 to −1.0%), a sulphonylurea (−1.4%) or insulin (−1.2%) for 26 weeks versus little change with active comparator monotherapy. Efficacy was maintained in trials of ≤2 years, and was also apparent in various ethnic subgroups, elderly patients, and both obese and nonobese patients. Rosiglitazone is currently not indicated in combination with injected insulin. It should be administered in conjunction with diet and exercise regimens. Rosiglitazone is generally well tolerated. Despite rare individual reports of liver function abnormalities in rosiglitazone recipients, the incidence of these in clinical trials (≤2 years’ duration) was similar to that in placebo and active comparator groups. Fluid retention associated with rosiglitazone may be the cause of the increased incidence of anaemia in clinical trials, and also means that patients should be monitored for signs of heart failure during therapy. Although bodyweight is increased overall with rosiglitazone therapy, increases are in subcutaneous, not visceral, fat; hepatic fat is decreased. The pharmacokinetic profile of rosiglitazone is not substantially altered by age or renal impairment, nor are there important drug interactions. Rosiglitazone is not indicated in patients with active liver disease or increased liver enzymes. Conclusions: Oral rosiglitazone 4 or 8 mg/day provides significant antihyperglycaemic efficacy and is generally well tolerated, both as monotherapy and in combination with other antihyperglycaemic agents, in patients with type 2 diabetes mellitus who do not have active liver disease. Long-term data are required before conclusions can be drawn about the clinical significance of positive changes to surrogate markers of cardiovascular disease risk and improvements to pancreatic β-cell function. Rosiglitazone significantly improves insulin sensitivity and, as such, is a welcome addition to the treatment options for patients with type 2 diabetes mellitus. Rosiglitazone is a thiazolidinedione drug used for the treatment of type 2 diabetes mellitus. The side chain of this oral antihyperglycaemic agent differs markedly from those of the related troglitazone and pioglitazone. Binding of rosiglitazone to the peroxisome proliferator-activated receptor-γ results in reduced plasma glucose levels and endogenous glucose production, and increased glucose clearance in patients with type 2 diabetes mellitus. Rosiglitazone has several pharmacodynamic effects that could ameliorate the increased risk of cardiovascular disease in patients with type 2 diabetes mellitus. Insulin resistance is decreased, as are plasma levels of small dense atherogenic low-density lipoprotein-cholesterol (LDL-C) particles, despite an initial overall increase in total LDL-C. Levels of the atheroprotective large high-density lipoprotein particles are increased. Changes in triglyceride levels are small and often not clinically significant. Diastolic blood pressure (DBP) is significantly decreased and systolic blood pressure (SBP) is slightly decreased in rosiglitazone recipients, compared to no change in DBP and a significant increase in SBP in patients receiving glibenclamide. Myocardial blood flow is increased, levels of plasminogen-activator inhibitor-1 are decreased and endothelial function appears to be improved. Rosiglitazone also reduces the excretion of urinary albumin to a greater extent than seen with glibenclamide in patients with type 2 diabetes mellitus. While an increase in bodyweight has been associated with rosiglitazone, the increase is seen in subcutaneous fat depots rather than in visceral fat. Hepatic fat depots are decreased. Rosiglitazone appears to have little propensity for damage to hepatic cells, unlike the now withdrawn troglitazone. The incidence of liver function abnormalities in clinical trials of up to 2 years’ duration was similar in rosiglitazone, placebo and active comparator groups. Rosiglitazone has beneficial effects on pancreatic β-cell function in obese and nonobese patients with type 2 diabetes mellitus, suggesting possible positive effects on disease progression. The concentration of rosiglitazone in plasma increases with the dose. Oral bioavailability is 99%. Clearance after oral administration is rapid; the elimination half-life is 3 to 4 hours. Excretion occurs mostly via the urine. Rosiglitazone is fully metabolised, mainly by N-demethylation and hydroxylation by cytochrome P450 (CYP) [primarily CYP2C8] enzymes. Renal impairment or age did not result in clinically significant changes to the pharmacokinetics of rosiglitazone. Rosiglitazone did not interact with several other drugs metabolised by CYP enzymes (paclitaxel, warfarin, nifedipine, ethinylestradiol, norethindrone) nor with drugs commonly used in patients with type 2 diabetes mellitus (metformin, acarbose, atorvastatin, fibrates). The efficacy of rosiglitazone in double-blind trials in patients with type 2 diabetes mellitus has been assessed using fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA_1c) levels. FPG and HbA_1c levels decreased significantly in patients receiving monotherapy for 8 to 26 weeks with once- or twice-daily administration of rosiglitazone 4 mg/day (by 0.9 to 2.1 mmol/L and up to 0.3%, respectively) or 8 mg/day (by 2 to 3 mmol/L and 0.6 to 0.7%, respectively); increases of 0.3 to 1.1 mmol/L and 0.3 to 1.0%, respectively, were observed in patients receiving placebo. Sixty-two to 75% of these patients had received prior oral antihyperglycaemic therapy; response tended to be greater in drug-naive patients (decreases in HbA_1c of 0.9% with 4 mg/day and 0.8 to 1.1% with 8 mg/day). FPG levels began to decrease after 2 to 4 weeks of therapy, and HbA_1c levels began to decrease after 8 weeks. The efficacy of rosiglitazone monotherapy was retained with continued therapy in trials of up to 1 year in duration. Monotherapy with rosiglitazone 8 mg/day for 12 months resulted in significantly greater reductions in FPG (2.3 mmol/L) than were seen in patients receiving glibenclamide (1.7 mmol/L). The differences were significant for both the full cohort and the drug-treatment naive subgroup. Changes in HbA_1c were not significantly different between treatments. The concomitant administration of rosiglitazone (for 26 weeks) to patients with type 2 diabetes mellitus inadequately controlled by monotherapy with metformin, a sulphonylurea or insulin resulted in significant decreases in FPG and HbA_1c levels. FPG fell by 3.5 mmol/L with rosiglitazone 8 mg/day plus glibenclamide 20 mg/day, by 2.7 to 3.0 mmol/L with rosiglitazone 8 mg/day plus metformin 2.5 g/day and by 2.5 mmol/L with rosiglitazone 8 mg/day plus insulin (baseline 73 U/day). HbA_1c fell by 1.4% with rosiglitazone plus glibenclamide, by 0.8 to 1.0% with rosiglitazone plus metformin and by 1.2% with rosiglitazone plus insulin at these same dosages. Continued monotherapy with a sulphonylurea, metformin or insulin had little effect on these parameters. There are indications that the concomitant administration of rosiglitazone and repaglinide may also be more beneficial than monotherapy with either agent. Rosiglitazone appears to be effective in patients from differing ethnic groups (Indo-Asian, Mexican, African American and Chinese), in elderly patients, in patients with concomitant cardiovascular or renal disease, and in obese and non-obese patients. Rosiglitazone is generally well tolerated in patients with type 2 diabetes mellitus. The percentage of patients reporting one or more adverse event in clinical trials was similar in rosiglitazone, placebo and active comparator groups. The tolerability of rosiglitazone in combination with other oral antihyperglycaemic drugs appears to be similar to that of rosiglitazone monotherapy. Rosiglitazone is well tolerated in older patients and in patients with renal impairment. Oedema and congestive heart failure occurred more often in patients receiving rosiglitazone plus insulin than in those receiving insulin alone. This fluid retention may also be responsible for the anaemia seen in some patients. Case reports of liver function abnormalities that may be associated with rosiglitazone are rare. Bodyweight gains of 2 to 3kg with 26 to 52 weeks of rosiglitazone therapy are common. Rosiglitazone monotherapy is indicated in North America and in other countries, but not in Europe, for the treatment of adult patients with type 2 diabetes mellitus. Combination therapy with a sulphonylurea drug or metformin is indicated when monotherapy is inadequate. Rosiglitazone is not currently indicated for concomitant use with injected insulin. Rosiglitazone should be given orally once or twice daily at a starting dosage of 4 mg/day (monotherapy and combination therapy), increased as required to 8 mg/day, with or without food, in combination with diet and exercise regimens. The dosage of the concomitant antihyperglycaemic agent should be reduced if hypoglycaemia occurs on addition of rosiglitazone. Dosage adjustments of rosiglitazone are not required for elderly patients or those with renal impairment. Patients with active liver disease or increased liver enzymes (ALT ≥2.5 times the upper limit of normal) should not receive rosiglitazone. Hepatic monitoring is required for all patients during therapy. Rosiglitazone is not approved for use in patients with New York Heart Association Class III and IV cardiac status and, because of the possibility of fluid retention, all patients should be monitored for signs of heart failure during therapy.