THIAZOLIDINEDIONES IN TYPE 2 DIABETES
The classes of drugs known as the thiozolidinedionese are widely used as part of antidiabetic treatments (Peters, 2001). These include rosiglitazone, pioglitazone and troglitazone which are used for the treatment of non insulin dependent diabetes mellitus. These agents act by targeting insulin resistance instead of stimulating insulin secretion by interacting with gamma subtype of the peroxisome proliferated activated receptor (PPAR-y2). PPAR-y, a member of the nuclear receptor subfamily, stimulates gene expression of proteins involved in glucose metabolism (Lehman et al, 1998). This results in an increase in insulin sensitivity in skeletal muscle, liver, and adipose tissues (Kumar et al, 1996). The first drug in this class to be approved in the United States was troglitazone in 1997. While troglitazone offered significant clinical benefits to many diabetic patients, it was associated with an elevation of serum alanine aminotransferase in approximately 1-2% of patients and in rare cases, hepatic failures and was therefore withdrawn from the market in 2000. Subsequent to the launch of troglitazone, two other thiozolidinedione replacement drugs entered the market, rosiglitazone and pioglitazone.
Type 2 diabetes
Major characteristics of type 2 diabetes include impaired utilization of glucose and resistance to the ability of insulin to stimulate glucose uptake and disposal in tissue. Glucose intolerance in type 2 diabetes is manifested by defects in glucose transport into muscle and adipose tissue. In adipose tissue from diabetic subjects, defective glucose transport has been shown to result from a reduced complement of insulin-stimulated GLUT4 (insulin-regulated glucose transporter isoform) in intracellular pools. Insulin receptor tyrosine kinase actively is also impaired in adipocytes of obese type 2 diabetic subjects. Both the expression and insulin-stimulated phosphorylation of IRS-1 (insulin receptor substrates-1) are reduced in adipose tissue from diabetic subjects. Events downstream of IRS-1 are also impacted, as insulin stimulation of PI3k (phosphatidylinositol 3 kinase) activity and phosphorylation of Akt are impaired. Thus, adipose tissue insulin resistance in type 2 diabetes involves defects in both insulin signaling pathways and final effector systems, i.e., glucose transporters.
A number of therapeutic approaches have proven useful in controlling hyperglycemia and improving insulin action in type 2 diabetes patients. These include weight loss exercise, sulfonylureas, biguanides such as metaformin, and thiazolidinediones. More recently combination therapies have been used with increasing frequency and effectiveness. The thiazolidinediones are used with diet and exercise to treat people with type 2 diabetes, alone or in combination with other drugs. They lower blood sugar by helping the cells of the body use insulin more efficiently to remove excess sugar from the blood. The effect of combination of thiazolidinediones (TZDs) and metformin has proved maximum tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) achieved. The glucose uptake was significantly high at the combination of lower concentration. Though diet, weight loss, and exercise remain the most imported initial steps in the management of type 2 diabetes, because affected person usually are overweight. Pharmacological therapy is mandatory for patients who are unable to achieve glycemic control with lifestyle modifications or who have significant symptoms at the time of diagnosis.
Thiazolidinediones are the drug presently used in treatment of type2 diabetes. Various studies suggests good side of its effectiveness in controlling hyperglycemia but there are even side effects reported which inhibits many of the physician to fully accept this as drug of today in treatment of non insulin dependent diabetes mellitus. Although majority of the clinician still suggests the treatment with thiazolidinedionese. Only thiazolidinediones (TZDs) have been shown to consistently improve estimates of beta cells function. The TZDs are able to provide durable glycemic control. TZDs have also been found to reduce inflammatory markers, improve vascular function and lipid profiles and decrease blood pressure in patients with type 2 diabetes, which may improve long term cardiovascular outcomes.
Currently two thiazolidinediones, rosiglitazone and pioglitazone are approved in US for treatment of type 2 diabetes. Rosiglitazone is approved for monotherapy and for use in combination therapy with metformin or sulfonylureas. Pioglitazone is approved for monotherapy as well as for use in combination therapy with metformin, insulin or sulfonylureas. But the most serious effect is said to have is hepatotoxicity. Although, rosiglitazone and pioglitazone were not associated with hepatotoxicity in pre-marketing clinical trial. However, post clinical trial and marketing data suggests that a TZD should generally not be used as monotherapy, until evidence is available showing its superiority.
There is growing concern and one of the many suggestion concluded that, thiozolidindiones can cause or exacerbate heart failure and pulmonary oedema and should be avoided in patients with left ventricle dysfunction or chronic renal insufficiency. At present, there is little evidence to suggest such a direct negative effect of TZDs on cardiac performance, and in most patients fluid retention appears to be independent of baseline cardiac function. A recent examining the use of TZDs in patients with diabetes who had established chronic heart failure discovered with fluid retention in 17% ( predominantly peripheral, not central), and there was no direct association between the risk of fluid retention and the severity of heart failure while these patients were taking TZDs.
However there is a growing evidence to suggest that TZDs may have many positive side effects on cardiac functions including diminished vascular resistance, improved cardiac metabolism, positive intropic effect, coronary vasodialation, increased natriuretic peptide production, improved endothelial function, and attenuation of cytokines. All these effects may possibly prevent HF in patients with diabetes, especially if TZDs are used before cardiac dysfunction develops. One of the studies conducted represents the first demonstration of the anti-atherogenic effect of pioglitazone in both nonrespondents and responders and responders with respect to its antidiabetic effect and suggest that pioglitazone can exert its anti-athergenic effect independently of its antidiabetic effect. Rosiglitazone and pioglitazone are also contraindicated in pregnancy and lactation and have not been tested in children. In woman with polycystic ovarian syndrome with insulin resistance, treatment with these drugs may restore ovulation.
The use of conventional medications such as sulfonylureas or insulin to lower HbA1c levels may lead to hypoglycemia. Additionally, the UKPDS showed that these agents do not maintain durable glycemic control when used alone. The potential to achieve target HbA1c levels without producing hypoglycemia makes TZDs offer a variety of benefits that support early use in the management of type 2 diabetes. They effectively lower glucose levels, improve insulin sensitivity, preserve beta cell function, and may exert beneficial cardiovascular effects. The UKPDS showed that the lower the HbA1c level, the lower the risk for long term complication.
The treatment of diabetics has advanced greatly during the past few years with a better understanding of the disease itself and development of new medications. Unfortunately, many patients are still unable to maintain glycemic control because of inappropriate treatment or inability to follow an appropriate diet or pharmacological regimen. This combined with the progression of the disease, leads to development of multiple complications including cardiovascular disease, which is the leading cause of death in patients with diabetes.
Currently there are several classes of drugs that are used to manage type 2 diabetes. However, only thiazolidinediones(TZDs) have been shown to consistently improve estimates of beta cells function, the TZDs are able to provide durable glycemic control The TZDs also been found to reduce inflammatory markers, improve vascular function and lipid profiles and decrease blood pressure in patients with type 2 diabetes, which may improve long term cardiovascular outcomes. The effectiveness of these agents in cardiovascular surrogate markers makes the TZDs particularly appealing as a pivotal treatment option and suggests that they be considered a cornerstone of therapy in the management of type 2 diabetes.
The dramatic increase in the number of classes of oral antidiabetic agents has provided physicians with more tools to help patients manage type 2 diabetes, of course glycemic control must remain paramount when choosing an oral agent. However, the mechanism of action of an agent, its side effect profile, and the potential for various non glycemic benefits may help determine which one is the best drug for an individual patient The evidence and practice though presently indicates that there are more dependence and majority has choice for thiazolidinediones in type 2 diabetes treatment than any other drug. The use of these drugs moreover remains in the hands of physicians whether to go for monotherapy or in combination, based on the evidences and conditions of the patients.