Rosiglitazone

Mechanism of Action

The molecular mechanism of action behind this drug is the binding of nuclear peroxisome proliferator-activated (PPAR) receptor gamma to the PPRE gene inducing the expression of several genetic networks. It increases insulin-stimulated IRS-1/2 in skeletal muscle and adipose tissue, and subsequently, the expression of GLUT4 glucose transporter. Peroxisome proliferator-activated receptor-gamma agonistic effect potentiates insulin signaling and improves insulin sensitivity at various molecular steps by activating PI3K, PIP3, and serine/ threonine kinases. Peroxisome proliferator-activated-gamma activation in adipocyte tissue induces the expression of genes involved in 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 the production of more insulin sensitive adipocyte tissue.[1][2]

Rosiglitazone and thiazolidinediones affect the vasculature by decreasing the intimal-medial thickness and the development of atherosclerosis in the vascular smooth muscle cells. The protective effect occurs 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]

Administration

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 the drug and following subsequent dose modifications, patients must be observed for rapid weight gain, dyspnea, and/or edema. If symptoms develop, manage the congestive heart failure according to approved care management.[5]

Adverse Effects

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 that have been reported in the literature, as well as cases of ovulation in anovulatory women.[6][7]

Contraindications

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 the associated risk for congenital defects and miscarriage.[7][8]

Monitoring

Monitoring of the liver function test (particularly the ALT) should occur at the beginning of the treatment, then every month for 12 months, and then every three months. 

In the case of renal impairment, no adjustment in the dose is necessary.

If rosiglitazone is being co-administrated with sulfonylureas, dosage adjustments and patient monitoring are recommended to avoid hypoglycemic incidents.[9][10]

Toxicity

For patients with impaired liver function test who reports ALT greater than three times the normal upper limit, it is recommended to stop the treatment. In cases of ALT showing 1.5 to 3 times the upper normal limit, it is recommended to re-test every week until normalization of liver function test.[11][10]

Enhancing Healthcare Team Outcomes

Primary care physicians, nurse practitioners, internists, and endocrinologists can all prescribe rosiglitazone. The drug is useful for the treatment of type 2 diabetes mellitus. However, healthcare workers, including the pharmacists, must warn the patient about the contraindications of this medication in patients with congestive heart failure with New York Heart Association functional class III or IV. Rosiglitazone causes exacerbation of congestive heart failure, and the pharmacist, nurse, and clinician work as a team to monitor patients closely for signs and symptoms of heart failure. Discontinuation is the recommended course if symptoms appear. It is recommended to observe liver function tests in patients using this drug, given its potential hepatic damage.[11][12]

Rosiglitazone requires an interprofessional team approach, including clinicians (MDs, DOs, and mid-level practitioners), specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results and prevent complications. [Level 5]