Rosiglitazone is a drug FDA approved for the treatment of type 2 diabetes mellitus. It belongs to the family called thiazolidinediones. It is capable of lowering the glucose levels by improving target cell response to insulin, without increasing the stimulation and release of insulin by the pancreatic beta cells. This drug acts by activating the nuclear peroxisome proliferator-activated (PPAR) receptor gamma, the primary role of this intracellular receptor appears to be regulating adipogenesis along with glucose and metabolism. Rosiglitazone use can be as monotherapy or in combination with other oral hypoglycemic drugs, such as metformin or sulfonylureas. Rosiglitazone is a very potent thiazolidinedione; it has a binding affinity for PPAR-gamma 30-fold higher than pioglitazone.[1]

Currently, there are two thiazolidinediones available: rosiglitazone and pioglitazone. Rosiglitazone carries a low risk of causing hypoglycemia and improve significantly insulin resistance; it has been incorporated into clinical practice and is prescribed by many physicians in selected patients.

There are reports that thiazolidinediones, including rosiglitazone, typically reduce hemoglobin A1c by 1 to 2% when compared to placebo. Its potency to decrease glycemic levels is similar to the hypoglycemic effect of metformin and sulfonylureas. Its effect is mainly by increasing skeletal muscle glucose uptake. It is also considered to preserve pancreatic beta-cell function.

Thiazolidinediones first appeared for the treatment of type 2 diabetes mellitus in 1996. The first approved drug by FDA was troglitazone. This drug got pulled from the market because of its idiosyncratic hepatotoxicity. Rosiglitazone was patented in 1987 and approved for medical use in 1999. In 2011 rosiglitazone was restricted given its apparent relationship with increased heart attack risk. In 2013, the FDA removed the restrictions of this drug after a clinical trial failed to show increased heart risk in patients using rosiglitazone.[2]

The molecular mechanism of action behind this drug is the binding of nuclear peroxisome proliferator-activated (PPAR) receptor gamma to PPRE gene inducing the expression of several genetic networks. It increases insulin-stimulated IRS-1/2 in skeletal muscle and adipose tissue, and subsequently, expression of GLUT4 glucose transporter. Peroxisome proliferator-activated receptor-gamma agonistic effect potentiate insulin signaling and improve insulin sensitivity at various molecular steps, by activation of PI3K, PIP3, and serine/ threonine kinases. Peroxisome proliferator-activated-gamma activation in adipocyte tissue induces the expression of genes involved in the insulin signaling such as GLUT4 glucose transporter and CAP, thereby improving insulin sensitivity. Finally, PPAR-gamma improves insulin sensitivity by three apparent mechanisms: 1) increases expression of GLUT4 glucose transporter, 2) regulates signaling factors in adipocyte tissue that affect insulin sensitivity in muscle tissue, and 3) inducing production of more insulin sensitive adipocyte tissue.[1][2]

Rosiglitazone and thiazolidinediones affect the vasculature by decreasing the intimal-medial thickness and development of atherosclerosis in the vascular smooth muscle cells. The protective effect is by inhibiting the gene expression of AT1R, TXS, and TXR, involved with intimal medial thickness and atherosclerosis.[1][2][3][4]

Rosiglitazone bioavailability is high (99%). The onset of action initially is delayed; the maximum effect is achieved up to 12 weeks. It is mostly protein bound (99%). It is subject to hepatic metabolism and excreted by urine (64%) and feces (22%).[2][3]

Rosiglitazone administration is via the oral route. It is available in 2 mg and 4 mg tablets. Its indication is the treatment of type 2 diabetes mellitus. The initial dose is 4 mg orally each day or divided every 12 hours. If the glycemic response is inadequate after 8 to 12 weeks, dosing can increase to 8 mg by mouth each day or divided every 12 hours.[5]

After beginning, and with subsequent dose modifications, observe patients for rapid weight gain, dyspnea, and/or edema. If symptoms develop, manage the congestive heart failure according to approved care management.[5]

The most common adverse effects reported are increased LDL-cholesterol, increased HDL-cholesterol, increased total cholesterol. Less common adverse effects are edema, hypertension, heart failure/congestive heart failure, myocardial ischemia, diarrhea, upper respiratory tract infection. Uncommon adverse effects reported include anemia, back pain, fatigue, headache, hypoglycemia, myalgia, sinusitis, weight gain.

Reports exist an increased risk of fractures of the upper arm, hand or foot in women.

There are case reports of macular edema have been reported in the literature, as well as cases of ovulation in anovulatory women.[6][7]

Contraindications to rosiglitazone include patients with active liver disease, hypersensitivity, Type 1 diabetes mellitus, diabetic ketoacidosis, and hyperosmolar hyperglycemic state. 

Strict contraindications to the administration of rosiglitazone include patients with congestive heart failure with New York Heart Association functional class III or IV. Thiazolidinediones, including rosiglitazone, can exacerbate congestive heart failure. After starting this drug, and adjusting the dose, observe patients for signs and symptoms of heart failure (weight gain, edema, dyspnea), which would indicate discontinuation of therapy. Combination with insulin in patients with congestive heart failure functional class I and II may increase the risk of other cardiovascular effects. Peroxisome proliferator-activated (PPAR) gamma agonists can cause fluid retention when used in combination with insulin.

It has been reported not sufficient data in pregnant women to determine associated risk for congenital defects and miscarriage.[7][8]