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Glitazones - Thiazolidinediones

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Diabetes:  Drug Class Navigation  top of page

Secretagogues

Insulin sensitizers

Alpha-glucosidase inh

Sulfonylureas Biguanides e.g. Metformin Alpha-glucosidase Inhibitors
 Meglitinides (e.g. Prandin) Glitazones -Thiazolidinediones  

Peptide analogs

AMYLIN AGONISTS - Anti-hyperglycemic Synthetic Analogs DPP-4 INHIBITORS -  Dipeptidyl peptidase-4 inhibitor  –    Gliptins Glucagon-like peptide-1 (GLP-1) AGONIST - Incretin Mimetics

Drug Monographs   top of page

Products

pioglitazone (Actos ®) rosiglitazone (Avandia ®)

Combination Products

Avandamet® (Rosiglitazone + Metformin)  

Typical reductions in A1C values - Thiazolidinediones:

 

1.5 - 2.0%.
Background

pioglitazone (Actos ®):   top of page

Mechanism of Action
ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARgamma nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin

INDICATIONS AND USAGE
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


CONTRAINDICATIONS
Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see package insert for BOXED WARNING).

ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components

Dosing (Adults)
Oral:
Monotherapy: Initial: 15 to 30 mg once daily; if response is inadequate, the dosage may be increased in increments up to 45 mg once daily; maximum recommended dose: 45 mg once daily


Combination therapy: Maximum recommended dose: 45 mg/day.
With sulfonylureas: Initial: 15-30 mg once daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia

With metformin: Initial: 15 to 30 mg once daily; it is unlikely that the dose of metformin will need to be reduced due to hypoglycemia.

With insulin: Initial: 15 to 30 mg once daily; dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to <100 mg/dL.


Dosage adjustment in patients with CHF (NYHA Class II) in mono- or combination therapy: Initial: 15 mg once daily; may be increased after several months of treatment, with close attention to heart failure symptoms

Elderly: No dosage adjustment is recommended in elderly patients.

Dosage adjustment in hepatic impairment: Clearance is significantly lower in hepatic impairment. Therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (>2.5 times the upper limit of normal) at baseline.

Supplied
Tablet: 15 mg, 30 mg, 45 mg

rosiglitazone (Avandia ®):  top of page

Mechanism of Action
Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARgamma nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARgamma-responsive genes also participate in the regulation of fatty acid metabolism.

Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.

In animal models, the antidiabetic activity of rosiglitazone was shown to be mediated by increased sensitivity to insulin’s action in the liver, muscle, and adipose tissues. Pharmacological studies in animal models indicate that rosiglitazone inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance


INDICATIONS AND USAGE:
Monotherapy and Combination Therapy:
Rogislitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use:
[1] Due to its mechanism of action, Rosiglitazone maleate is active only in the presence of endogenous insulin. Therefore, Rosiglitazone maleate should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

[2] The coadministration of Rosiglitazone maleate and insulin is not recommended.

[3] The use of Rosiglitazone maleate with nitrates is not recommended.


Dosing (Adults):
Oral:
Monotherapy: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. If response is inadequate after 12 weeks of treatment, the dosage may be increased to 8 mg daily as a single daily dose or in divided doses twice daily. In clinical trials, the 4 mg twice-daily regimen resulted in the greatest reduction in fasting plasma glucose and Hb A1c.

Combination therapy:
With sulfonylureas: Initial: 4 mg daily as a single daily dose or in divided doses twice daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia. Doses of rosiglitazone >4 mg/day are not indicated in combination with sulfonylureas.

With metformin: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. If response is inadequate after 12 weeks of treatment, the dosage may be increased to 8 mg daily as a single daily dose or in divided doses twice daily. It is unlikely that the dose of metformin will need to be reduced due to hypoglycemia

With insulin: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. Dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to <100 mg/dL. Doses of rosiglitazone >4 mg/day are not indicated in combination with insulin.

Elderly: No dosage adjustment is recommended.


Monitoring: Hemoglobin A1c, serum glucose; signs and symptoms of heart failure; liver enzymes (prior to initiation of therapy, then periodically thereafter). Patients with an elevation in ALT >3 times the upper limit of normal should be rechecked as soon as possible. If the ALT levels remain >3 times the upper limit of normal, therapy with rosiglitazone should be discontinued.


Dosage comment in hepatic impairment: Clearance is significantly lower in hepatic impairment. Therapy should not be initiated if the patient exhibits active liver disease of increased transaminases (>2.5 times the upper limit of normal) at baseline.


Supplied
Tablet: 2 mg, 4 mg, 8 mg

Avandamet® (Rosiglitazone + Metformin)  top of page

Management of type 2 diabetes mellitus:
initial:

(previously receiving rosiglitazone 4 mg/day): Avandamet® 2/500mg po bid.
(previously receiving rosiglitazone 8 mg/day): 4/500mg po bid.
(previously receiving metformin 1000 mg/day): 2/500mg po bid.
(previously receiving metformin 2000 mg/day): 2/1000mg po bid.

Titrate in increments of rosiglitazone 4 mg and/or metformin 500 mg po daily.
Maximum: 8 mg/2000 mg daily.


Other:
Take with meals.

When switching from metformin and rosiglitazone therapy given as separate tablets, starting dose of Avandamet is the dose of each drug previously taken.

Dose titration should occur at 1 to 2 week intervals. If the dose of metformin is increased, dose titration should occur at 8 to 12 week intervals. If the dose of rosiglitazone is increased therapeutic response evaluation should be based on fasting plasma glucose values.

Monitoring: renal function, baseline and at least annually.

[Supplied: 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg] .

Background   top of page

Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.

Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARgamma, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on peroxysome proliferator responsive elements (PPRE). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes. The final result is better use of glucose by the cells.

Mode of action
Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARgamma (gamma). The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.

By activating PPARgamma:
1. Insulin resistance is decreased
2. Adipocyte differentiation is modified [1]
3. VEGF-induced angiogenesis is inhibited[2]
4. Leptin levels increase (leading to a decreased appetite)
5. Levels of certain interleukins (e.g. IL-6) fall
6. Adiponectin levels rise

TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.

Some examples are:
• rosiglitazone (Avandia)
• pioglitazone (Actos)
• troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

Multiple retrospective studies have resulted in a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed initial therapy with drugs of this type may prevent the progression of disease, as did the DREAM trial.

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. There have been a significant number of publications since then, and a Food and Drug Administration panel voted, with some controversy, 20:3 that available studies "supported a signal of harm," but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control. Safety studies are continuing.

In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type 2 diabetes who have already had a heart attack.  [source]

References  top of page

Package insert data.

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.
David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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