Avandia Review Article |
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 Avandia (Generic Name: Rosiglitazone) is a drug that belongs to the classification of oral anti-diabetic drugs termed thiazolidinediones (TZDs) — also known as glitazones— and is anti-hyperglycemic. Members of this class also include Pioglitazone (Actos). On the other hand, another member which is known as Troglitazone or Rezulin was pulled out of the market since it causes liver toxicity. Rosiglitazone combats insulin resistance and is thus used for the treatment of Type 2 Diabetes Mellitus. It works by decreasing the amount of glucose or sugar present in the bloodstream. It is often called an “insulin sensitizer” since it attaches to insulin receptors present in cells all over the body and stimulates the cells to be more sensitive and more responsive to insulin. Consequently, more glucose is eliminated from the blood. However, some insulin must be synthesized by the pancreas so Rosiglitazone can function. Side effects may include eye damage and bone fracture.
Sugar – The Source of Energy
Every day we face a lot of activities – we wake up in the morning, cook breakfast, go to work, do the work, go home etc etc. In each activity that we do, we require a certain amount of energy. In fact, even asleep, we require energy to keep our body functioning well. The energy we spend comes from the food we eat.
Sugar is the main source of energy for our bodies. These sugars or carbohydrates come from foods such as bread, rice, potatoes, beans, pastas and many form. These complex sugars or carbohydrates are metabolized to simpler ones called monosaccharide so that our cells can utilize them as energy source. Glucose, a monosaccharide, is body’s main source of energy. Continue reading...
Glucose levels in the blood vary all throughout the day. Glucose levels rise after a meal because of the sudden intake of carbohydrates, and return to normal levels after two hours of eating. This does not mean that the glucose levels have been used completely. Some of them are stored in the cells as reserve energy source called glycogen. Glucose metabolism into glycogen is done by the hormone insulin. When there is an abnormally high blood glucose (also called hyperglycemia) levels that persist throughout the day, insulin may not be working properly. This condition is called diabetes mellituss.
Diabetes mellitus, or diabetes, is a metabolic disorder in which there is an abnormally high blood glucose levels (WHO). The classic symptoms of diabetes are polyuria (frequent urination), polyphagia (increased hunger) and polydipsia (increased thirst). Blood tests and urinalysis are diagnostic procedures done to determine diabetes. Patients with blood glucose of 200mg/dL and glucosuria (sugar in the urine) may be candidates for diabetes. The following blood tests can confirm a suspected diabetes case (PubMed Health):
• Fasting blood glucose values of >126mg/dL
• Hemoglobin A1c values of 6.5%
• Oral glucose tolerance values of >200mg/dL
• 2 hour blood Glucose of >200mg/dL
• Random blood glucose of >200mg/dL
any complications arise from diabetes. According to the World Health Organization, it is a risk for cardiovascular diseases. In fact, almost 50% of mortality among diabetic patients is caused by heart diseases such as stroke and heart attack. Other complications include blindness from retinopathy, limb amputation from neuropathy and kidney failure.
Diabetes is classified into three: Type 1 or insulin dependent diabetes mellitus (IDDM), wherein the body does not produce enough insulin; Type 2 or non-insulin dependent diabetes mellitus (NIDDM) where the body produces insulin but is not utilized by cells because of resistance to it; and Gestational Diabetes where there is hyperglycemia in pregnant women. Gestational diabetes is very similar to type 2 diabetes, and most women diagnosed with it develop type 2 diabetes later on. Table 1 describes the differences between type 1 and 2 diabetes.
Let us focus on Type 2 Diabetes.
Type 2 Diabetes
Type 2 Diabetes or NIDDM is the most common type of diabetes around the world. 90% of all cases of diabetes are of this type. It occurs most often in adults, but recent studies have shown that more and more diagnoses in children and adolescent are being made. The cause of insulin resistance in type 2 diabetes is not known, however, risk factors have been identified. According to WHO, the increasing rate of obesity due to lack of physical activity and excess food intake is one of the major risk factors for diabetes, along with other risk factors: family history, race or ethnicity, age of greater 45, hypertension, hyperlipidemia, and history of gestational diabetes (women who had gestational diabetes are likely to develop type 2 diabetes later in life). Because there is a delayed onset of symptoms, many people are not aware that they have the disease. It is recommended to have diagnostic tests done once in a while if there are risk factors for a patient. Diagnosis of diabetes is done only upon routine examination.
Exercise, diet, education are important parts of diabetes treatment. Attaining the ideal body weight thru exercise lessens the chances of complication involved with diabetes. Proper nutritional diet is necessary for glucose control, as well as education on the importance of blood glucose monitoring. In addition, several oral hypoglycemic agents (OHAs) are available to lower blood glucose to recommended levels. Insulin secretagogues which increase insulin production and release include sulfonylureas like glyburide and meglitinides like repaglinide. Another class of OHAs would be the insulin sensitizers which increases insulin sensitivity of cells. These include biguanides like metformin and thiazolidinediones like rosiglitazone, or Avandia.
Avandia
Avandia (Rosiglitazone) is an insulin sensitizing agent belonging to the class thiazolidinediones. Its molecular formula is C18H19N3O3S, and its structural formula is
Avandia act by binding to peroxisome proliferator-activated receptors gamma (PPARy) found on the nucleus membrane of skeletal muscle and fat cells. This binding causes an increase in the metabolism and uptake of glucose into cells, resulting to the lowering of blood glucose levels. At higher doses, it can decrease hepatic glucose production, aiding in the reduction of glucose levels.
Avandia For Type 2 Diabetes
Avandia is a well studied antidiabetic agent. Several studies have been published that reports its effectiveness. Balfour and Plosker (1999) reported that rosiglitazone is effective against insulin resistance using animal models. In a study by Mayerson et.al (2002), they found that rosiglitazone increased insulin sensitivity in peripheral adipocytes.
In a study by Lebovitz and colleagues (2001), they found that rosiglitazone is effective as monotherapy for patients not responding well to exercise and diet alone. This was supported by a study made by Kahn et.al (2001) called A Diabetes Outcome Progression Trial (ADOPT). They concluded that rosiglitazone is a good starting drug for diabetes.
Clinical trials have proven its effectiveness for type 2 diabetes at 2 to 12mg/day doses (Balfour & Plosker, 1999). Lebovitz and colleagues (2001) reported that 2mg and 4mg twice a day dose reduced insulin resistance by as much as 16% and 24.6%, respectively.
An exciting result was found in a recent study made by Gerstein et.a.l (2006). They found that rosiglitazone at 8mg/day is an effective drug to prevent Type 2 Diabetes for high risk patients. This is a good sign that the fight against diabetes is going good, as preventive therapies are being discovered.
Combination Therapy With Metformin
Aside from using Avandia as a monotherapy for diabetes, studies have shown that combination therapy is also effective. Unlike other thiazolidnediones (like its predecessor troglitazone), rosiglitazone do no induce cytochrome p4503A4 metabolism. Thus, there is no drug interaction between other drugs such as oral contraceptives, digoxin, ranitidine and other antidiabetic agents metformin and acarbose (Balfour & Plosker, 1999). Because of these findings, rosiglitazone was studied for its effectiveness in combination with metformin, another antidiabetic agent.
Fonseca et.al (2000) found that the combination of rosiglitazone and metformin is better compared to metformin alone. Poorly controlled glucose levels were improved when the combination was used. The combination was also found to be effective as an initial treatment, with better control as compared to rosiglitazone or metformin alone (Rosenstock et.al, 2006).
Obesity and race are two significant factors for type 2 diabetes. Combination therapy was also found to be effective for diabetic patients with high BMI (Jones et.al, 2003) and high risk race/ethnicity whose blood glucose levels that are poorly controlled (Gomez-Perez, et.al, 2002)
Avandia And Anti Inflammation
Rosiglitazone is known to act on PPARy to increase insulin sensitivity. However, aside from insulin resistance, recent studies have found that PPARy play an important role in inflammation. A pilot study was done using animal models to determine whether rosiglitazone can produce anti inflammatory effects, since it acts on these receptors. Cuzzocrea et.al (2003) have found that it indeed it has anti inflammatory properties (as evidenced by reduced edema and inflammation in their study), and have concluded that it may be useful in the treatment of inflammation.
In a much recent study by Lee et.al., they concluded that glucose control produced by rosiglitazone is due to its anti inflammatory properties in peripheral skeletal muscles.
Avandia – Cardiovascular Risks
There has been much concern regarding the cardiovascular effects of Avandia. Studies have shown that among all the different oral hypoglycemic agents, rosiglitazone was found to have the highest risk of myocardial infarction as well as death from cardiovascular diseases (Nissen & Wolski, 2007). An increase of as much as 43% for myocardial risk was reported, causing its withdrawal from several markets.
The Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes, or RECORD study in 2009 confirmed that there is indeed an increase risk for cardiovascular problems. However, the study stated that rosiglitazone does not increase the overall risk when compared to other OHAs. The FDA did not withdraw Avandia despite its adverse effect concerns, but has implemented strict rules on its use starting November of this year.
Bybliography
BALFOUR, J.A., & PLOSKER, G.L. 1999. Rosiglitazone.
CUZZOCREA, S., PISANO, B., IANARO, A., et.al. 2003. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-γ, reduces acute inflammation.
FONSECA, V., ROSENSTOCK, J., PATWARDHAN, R., et.al. 2000. Effect of Metformin and Rosiglitazone Combination Therapy in Patients With Type 2 Diabetes Mellitus.
GERSTEIN, H.C., YUSUF, S., BOSCH, J. 2006. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
GOMEZ-PEREZ, F.J., FANGHANEL-SALMON, G., BARBOSA, J.A., et.al. 2002. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes.
HOME, P.D., POCOCK, S., BECK-NEILSEN, H. 2009. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.
JONES, T.A., SAUTTER, M., VAN GAAL, L.F., JONES, N.P. 2003. Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes.
KAHN, S.E., HAFFNER, S.M., HEIS, M.A., et.al. 2001. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy.
LEBOVITZ, H.E., DOLE, J.F., PATWARDHAN, R., et.al. 2001. Rosiglitazone Monotherapy Is Effective in Patients with Type 2 Diabetes.
LEE, J.W., NAM-GOONG, I.S., KIM, J.G., et.al. 2010. Effects of Rosiglitazone on Inflammation in Otsuka Long-Evans Tokushima Fatty Rats.
MAYERSON, A.B., HUNDAL, R.S., DUFOUR, S., et.al 2002. The Effects of Rosiglitazone on Insulin Sensitivity, Lipolysis, and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes.
MERCK MANUAL. Diabetes mellitus.
PUBMED HEALTH. Diabetes.
ROSENSTOCK, J., ROOD, J., COBITZ, A., et.al. 2006. Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either
rosiglitazone or metformin in patients with uncontrolled type 2 diabetes.
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