GLIZONE 15

Indications

• Type 2 diabetes mellitus as monotherapy
• Type 2 diabetes mellitus in combination with other antidiabetic drugs including insulin

Dosage

Adults: Initially 15–30 mg once daily, adjusted according to response to a maximum of 45 mg once daily. Review treatment after 3–6 months.

Mechanism of action

Pioglitazone selectively activates PPARγ, a nuclear receptor that regulates gene transcription associated with insulin sensitivity. This activation enhances glucose uptake in insulin-sensitive tissues, reduces hepatic glucose production, and improves lipid metabolism, leading to better glycaemic control in type 2 diabetes mellitus. Additionally, pioglitazone may have rapid nongenomic effects that can alleviate hyperalgesia.

Pharmacodynamics

Pioglitazone improves cellular response to insulin, increases glucose disposal, and enhances glucose homeostasis. In clinical settings, it leads to reduced plasma glucose, lower insulin levels, and improved HbA1c measurements. Care must be taken due to associated risks such as fluid retention, potential heart failure, and increased incidence of bladder cancer, particularly in patients with pre-existing conditions.

Pharmacokinetics

Pioglitazone is well-absorbed after oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. It has a long half-life allowing for once-daily dosing. The drug undergoes extensive hepatic metabolism, primarily by CYP2C8, and is excreted mainly in urine and feces. Liver function should be monitored, as the drug is contraindicated in patients with hepatic impairment.

Contra-indications

• Active bladder cancer
• Severe heart failure
• History of heart failure

Adverse effects

• Bone fracture
• Increased risk of infection
• Bladder cancer
• Macular oedema
• Liver dysfunction
• Fluid retention leading to heart failure

Interactions

• Opicapone: Severe (increases exposure)
• Clopidogrel: Moderate (increases exposure)
• Gemfibrozil: Moderate (increases exposure)
• Antifungals (azoles): Moderate (decreases exposure)
• Isavuconazole: Moderate (decreases exposure)
• Rifampicin: Moderate (decreases exposure)
• Deferasirox: Unknown (increases exposure)
• Leflunomide: Unknown (increases exposure)
• Mifepristone: Unknown (increases exposure)
• St John's Wort: Unknown (decreases exposure)

Precautions

• Monitor liver function before and during treatment
• Assess for risk factors for bladder cancer
• Careful monitoring for signs of heart failure
• Adjust concomitant sulfonylurea or insulin doses if used together

Pregnancy

Avoid-toxicity in animal studies.

Breast-feeding

Avoid-present in milk in animal studies.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Pioglitazone 15 mg tablets
• Pioglitazone 30 mg tablets
• Pioglitazone 45 mg tablets

Mechanism of action

Pioglitazone is a selective agonist at peroxisome proliferator-activated receptor-gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose and lipid production, transport, and utilization. Through this mechanism, pioglitazone both enhances tissue sensitivity to insulin and reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta cells. Repeated administration of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARgamma is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal (i.t.) injection of pioglitazone, a PPARgamma agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid antihyperalgesic actions of PPARgamma activation, we administered pioglitazone to rats with spared nerve injury and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 minutes of injection, consistent with a nongenomic mechanism. Systemic or i.t. administration of GW9662, a PPARgamma antagonist, inhibited the antihyperalgesic actions of intraperitoneal or i.t. pioglitazone, suggesting a spinal PPAR?-dependent mechanism. To further address the contribution of nongenomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When coadministered intrathecally, anisomycin did not change pioglitazone antihyperalgesia at an early 7.5-minute time point, further supporting a rapid nongenomic mechanism. At later time points, anisomycin reduced pioglitazone antihyperalgesia, suggesting delayed recruitment of genomic mechanisms. Pioglitazone reduction of spared nerve injury-induced increases in GFAP expression occurred more rapidly than expected, within 60 minutes. We are the first to show that activation of spinal PPARgamma rapidly reduces neuropathic pain independent of canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation and through both genomic and nongenomic PPARgamma mechanisms. Pioglitazone hydrochloride is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone hydrochloride decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an 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. ... Thiazolidinediones reduce insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity. The mechanism of action involves binding to the peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also in other tissues. It is likely that thiazolidinediones primarily act in adipose tissue where PPARgamma is predominantly expressed. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g. free fatty acids, adipocytokines such as tumor necrosis fact

Pharmacodynamics

Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves impaired glucose homeostasis. In patients with type 2 diabetes mellitus, these effects result in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. Significant fluid retention leading to the development/exacerbation of congestive heart failure has been reported with pioglitazone - avoid its use in patients in heart failure or at risk of developing heart failure. There is some evidence that pioglitazone may be associated with an increased risk of developing bladder cancer. Pioglitazone should not be used in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer.