Rosiglitazone


Article Author:
Bryan Quintanilla Rodriguez


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Ricardo Correa


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Mayank Singhal


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Sandeep Sekhon


Updated:
6/30/2019 11:09:38 PM

Indications

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]

Mechanism of Action

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]

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, 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]

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

Monitoring

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

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

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

Toxicity

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, cause exacerbation of congestive heart failure. Follow patients closely for signs and symptoms of heart failure. Discontinuation is the recommended course if symptoms appear. It is recommended observing liver function tests in patients using this drug, given its potential hepatic damage.[11][12]

Rosiglitazone requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results and prevent complications.


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Rosiglitazone - Questions

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A 63-year-old male patient with a past medical history of hypertension for the past 5 years presents to the clinician's office. He was diagnosed a couple of months ago with type 2 diabetes. His current medications are metformin 2500mg and lisinopril 20mg. He is compliant with his medication and diet. He has been exercising regularly for the last few months. His vital signs are BP 138/88 mmHg, pulse 80 beats per minute and respiratory rate of 18 per minute, rest of the physical exam is unremarkable. HbA1c is 8.0%. The physician decides to start a new medication given his current glycemic control and explains that the new drug 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. Which of the following is a side effect of the started drug?



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A 75-year-old male patient with a past medical history of hypertension, type II diabetes mellitus, and hypercholesterolemia presents to the emergency department complaining of altered mental status, shortness of breath, bilateral lower limb edema, and cough. Her medications include metformin, losartan, and atorvastatin. He is compliant with his medication and diet. Physical exam reveals BP 139/88 mmHg, pulse 80 beats per minute, and respiratory rate 22 per minute; mucosas are dry, rales are present in both lungs, marked edema in both lower limbs. Labs show an HbA1C of 8.9 %, glucose: 400mg/dl, Creatinine: 1.2 mg/dL, BUN: 28 mg/dL, BNP 350 pg/ml, troponins are positive, Beta-hydroxybutyrate is positive, ABG shows a high anion gap metabolic acidosis, with bicarbonate of 13 mEq/L. Chest x-ray shows cardiomegaly and pulmonary edema signs. Echocardiogram reported an ejection fraction of 20%. He is admitted to the ICU given his condition. After a couple of days, his condition improves and is transferred to the floor. Which of the following conditions is a contraindication to initiate rosiglitazone to address glycemic control in this patient?



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A 70-year-old male patient with a past medical history of hypertension, type 2 diabetes mellitus, congestive heart failure, and hypercholesterolemia, presents to the clinician's office complaining of shortness of breath on minimal exertion despite taking his medications as indicated. Her medications include metformin, furosemide, valsartan, spironolactone, carvedilol, isosorbide dinitrate/hydralazine, and atorvastatin. She is compliant with her medication. Physical exam reveals BP 130/88 mmHg, pulse 80 beats per minute, and respiratory rate 18 per minute, while the rest of the examination is unremarkable. Labs demonstrate an HbA1C of 8.9 %, creatinine: 0.9 mg/dL, BUN: 12 mg/dL. Chest x-ray shows cardiomegaly. Echocardiogram reported an ejection fraction of 20%. The clinician decides to start a medication to improve his glycemic control. Which of the following drugs would be contraindicated to address his glycemic control given his current condition?



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A 60-year-old female patient with a past medical history of hypertension and type II diabetes mellitus presents to the clinician's office complaining of increased urinary frequency, thirst, and increased hunger. Her medications include metformin 2500mg, lisinopril 20mg. She is compliant with her medication. She has been dieting and exercising regularly for the last few months. Physical exam reveals BP 137/82 mmHg, pulse 80 beats per minute, and respiratory rate 17 per minute, while the rest of the examination is unremarkable. Labs demonstrate an HbA1C of 8.5 %. She is started on a new medication to address her hyperglycemia. On a follow-up visit 3 weeks later, she complains of lower limb swelling, putting on more weight, and shortness of breath while exercising. New labs demonstrate an HbA1C of 6.9 %, creatinine: 0.9 mg/dL, and BUN: 12 mg/dL. Her clinician explained that the new medication had caused these problems. What is the mechanism of action of the drug causing this problem?



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A 65-year-old male patient with a past medical history of type II diabetes mellitus presents to the clinic complaining of increased urinary frequency, thirst, hunger, weight loss, and dizziness. His medications include metformin 2500mg. He denies allergies to food and medications. Vital signs are BP 137/89 mmHg, pulse 85 per minute, respiratory rate 18 per minute, temperature 98.6F; rest of the physical examination is unremarkable. Laboratory parameters are: fasting plasma glucose: 180 mg/dL, HbA1C: 7.5%, oral glucose tolerance test: 220 mg/dL, creatinine: 0.9 mg/dL ,BUN: 12 mg/dL. The physician decides to start a new medication to improve his glycemic control. A week later the patient presents to the office complaining of abdominal pain. All labs and imaging tests are normal except for AST: 250U/L, ALT: 260U/L. Which of the following medications is responsible for this patient current condition?



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Rosiglitazone - References

References

Della-Morte D,Palmirotta R,Rehni AK,Pastore D,Capuani B,Pacifici F,De Marchis ML,Dave KR,Bellia A,Fogliame G,Ferroni P,Donadel G,Cacciatore F,Abete P,Dong C,Pileggi A,Roselli M,Ricordi C,Sbraccia P,Guadagni F,Rundek T,Lauro D, Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. Pharmacogenomics. 2014 Dec;     [PubMed]
Hauner H, The mode of action of thiazolidinediones. Diabetes/metabolism research and reviews. 2002 Mar-Apr;     [PubMed]
Dubois M,Vantyghem MC,Schoonjans K,Pattou F, [Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)]. Annales d'endocrinologie. 2002 Dec;     [PubMed]
Lebovitz HE,Dole JF,Patwardhan R,Rappaport EB,Freed MI, Rosiglitazone monotherapy is effective in patients with type 2 diabetes. The Journal of clinical endocrinology and metabolism. 2001 Jan;     [PubMed]
Bundhun PK,Janoo G,Teeluck AR,Huang F, Adverse drug effects observed with vildagliptin versus pioglitazone or rosiglitazone in the treatment of patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. BMC pharmacology     [PubMed]
Millioni R,Puricelli L,Iori E,Arrigoni G,Tessari P, The effects of rosiglitazone and high glucose on protein expression in endothelial cells. Journal of proteome research. 2010 Jan;     [PubMed]
Nissen SE,Wolski K, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. The New England journal of medicine. 2007 Jun 14;     [PubMed]
Winterstein AG, Rosiglitazone and the risk of adverse cardiovascular outcomes. Clinical pharmacology and therapeutics. 2011 Jun;     [PubMed]
Balfour JA,Plosker GL, Rosiglitazone. Drugs. 1999 Jun;     [PubMed]
Werner AL,Travaglini MT, A review of rosiglitazone in type 2 diabetes mellitus. Pharmacotherapy. 2001 Sep;     [PubMed]
Blicklé JF, [Thiazolidinediones: clinical data and perspectives]. Diabetes     [PubMed]
Scheen AJ, [Medication of the month. Rosiglitazone (Avandia)]. Revue medicale de Liege. 2002 Apr;     [PubMed]

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