What Is Pioglitazone?

Pioglitazone is a thiazolidinedione antidiabetic drug, which is an insulin sensitizer. Its mechanism of action is related to the presence of insulin, which can reduce insulin resistance in peripheral tissues and the liver, increase insulin-dependent glucose processing, and reduce liver glucose output. Unlike sulfonylureas, this product is not an insulin secretagogue. Its mechanism of action is a highly selective agonist peroxisome body growth factor activation receptor-PPAR- 1. PPAR- activation can regulate the transcription of many insulin-related genes that control glucose and lipid metabolism.

Drug Name: Pioglitazone
Foreign name: Pioglitazone
Main indications: Type 2 diabetes

Dosage: 15 or 30 mg starting dose, taken before breakfast
Adverse reactions: Hypoglycemia, edema, etc.
Pharmacology and toxicology: Reduce insulin resistance, high blood sugar, etc.

Pioglitazone Basic Information

Chinese name: pioglitazone

Chinese alias: ketopiglitazone (M-III); pioglitazone (M-III);

English name: Keto Pioglitazone (M-III)

English alias: 5-[[4- [2- (5-acetylpyridin-2-yl) ethoxy] phenyl] methyl] -1,3-thiazolidine-2,4-dione CAS number: 146062-45-5 Molecular formula: C19H18N2O4S

Molecular weight: 370.42200

Exact mass: 370.09900

PSA: 110.66000

LogP: 3.12860

Physicochemical properties of pioglitazone

Density: 1.315g / cm3

Melting point: 113-115ºC

Boiling point: 623.8ºC at 760 mmHg

Flash point: 331.1ºC

Refractive index: 1.618

Vapor pressure: 1.75E-15mmHg at 25 ° C ^[1]

Information about pioglitazone drugs

Pioglitazone drug classification

Class 1: Class 2 drugs for endocrine system: Class 3 drugs for diabetes and islet diseases:

Pioglitazone and rosiglitazone are currently thiazolidinedione antidiabetic drugs commonly used in clinical treatment of diabetes in China, and are insulin sensitizers. May reduce insulin resistance in peripheral tissues and liver, increase insulin-dependent glucose processing, and reduce liver glucose output. The effect and mechanism are the same as rosiglitazone, which can reduce triglyceride (TG) and increase high density lipoprotein (HDL) during treatment.

Animal experiments show that this product can reduce insulin-resistant hyperglycemia, hyperinsulinemia, and triglyceride. Metabolic changes caused by this product have led to an increase in insulin-dependent tissue responses.

Since this product improves the effect of circulating insulin (ie reduces insulin resistance), it cannot lower blood glucose in animal models lacking endogenous insulin. ^[2]

Pioglitazone pioglitazone indications

It is mainly suitable for the treatment of non-insulin-dependent diabetes mellitus (type II) patients who cannot control blood sugar by diet and exercise alone. Can be treated alone or in combination with sulfonylurea hypoglycemic agents, metformin and insulin.

Pharmacological effects of pioglitazone

Pioglitazone achieves long-lasting blood glucose control by directly reducing insulin resistance and improving -cell function. Pioglitazone is a highly selective and potent peroxisome proliferator-activated receptor gamma (PPAR) agonist. The receptor is a protein found in fat, skeletal muscle, and liver tissues of insulin-sensitive tissues. ^[3]

Pharmacokinetics of pioglitazone

The absolute bioavailability of pioglitazone is 99%. After oral administration, pioglitazone can be detected in the blood within 30 minutes on an empty stomach, reaching a peak concentration in 2 hours. Food will delay the peak concentration time to 3 to 4 hours, and plasma t1 / 2 is 3 to 7 hours. Pioglitazone is mainly bound to serum albumin, and is metabolized by hydroxylation and oxidation. Most of it is excreted into the bile as a prototype or metabolite, and is eliminated from feces. Pioglitazone can increase insulin content in islets without affecting insulin secretion. Pioglitazone prevents the reduction of beta cells by reducing cell death, and this evidence suggests that pioglitazone has a protective effect on beta cells.

Pioglitazone reduces hyperinsulinemia and plasma free fatty acid levels. Decreased plasma insulin levels indicate that pioglitazone can reduce the burden on pancreatic beta cells. Since high levels of free fatty acids have a toxic effect on the pancreas, reducing free fatty acid levels also has a protective effect on pancreatic -cell function. Therefore, the basic physiological link to type 2 diabetes is to reduce insulin resistance and improve -cell function to control blood sugar.

Pioglitazone usage dosage

This product is treated alone. The starting dose is 15 to 30 mg per day. Take it before or after meals. If you miss it, you do not need to increase it. Depending on the patient's blood glucose, the dose can be adjusted, but the maximum recommended daily dose is 45 mg. Combination therapy: 1. Sulfonylureas: Maintain the medicinal amount of the original sulfonylureas for hypoglycemic administration, taking 15-30mg of this product daily. If hypoglycemia occurs, adjust the amount of sulfonylurea hypoglycemic agents. 2. Metformin: Maintain the original metformin dosage and take 15-30mg of this product daily. If hypoglycemia occurs, adjust the amount of metformin. 3. Insulin: Maintain the amount of original insulin, take 15-30mg of this product daily. If hypoglycemia occurs or the blood glucose drops to 100 mg / dl, insulin is reduced by 10% to 25%. This product is used to treat type 2 diabetes. According to the patients' hypoglycemic response, it is recommended to develop an individualized treatment plan. HbAlC levels should be measured every three months for long-term treatment.

Clinical evaluation of pioglitazone

Clinical studies have shown that pioglitazone can improve insulin sensitivity in patients with insulin resistance, increase insulin response to cells, and improve glucose homeostasis in the body. The effect can last for at least 1 year. In a clinical controlled experiment, pioglitazone combined with sulfonylurea, metformin or insulin can improve the efficacy. Domestic multi-center, randomized, double-blind, and parallel control data show that pioglitazone has been used in patients with type 2 diabetes for 12 weeks. The effective rate was 86.24%. After 12 weeks of application, the patient's blood pressure, heart rate, ECG and laboratory indicators were all normal.

Pioglitazone safety

Results of a two-year carcinogenicity test in female and male rats showed that when a pioglitazone was administered orally at a dose of 63 mg / (kg Times), except for the bladder, no tumors caused by drug administration appeared in other organs. When the dosage was 4mg / (kg · d) (converted by body surface area, almost equal to the clinically recommended maximum dose), benign and / or malignant transitional cell tumors were found in male rats. However, the results of a two-year carcinogenicity test in female and male mice showed that the oral dose reached 100 mg / (kg · d) (based on body surface area equivalent to the clinically recommended maximum dose). 11 times), no tumors caused by the administration occurred in any organ.

In epidemiological studies conducted abroad, the risk of bladder cancer associated with pioglitazone use in patients with diabetes has been observed, and long-term use of pioglitazone has a trend of increasing risk.

On June 15, 2011, the FDA issued a statement informing the public that taking pioglitazone for more than one year may be associated with an increased risk of bladder cancer. This warning message is required to be added to the label of pioglitazone-containing medicines, and the patient medication guidelines for these medicines will be modified accordingly.

On June 9, 2011, the French Agency for Health, Safety and Health Products (AFSSAPS) officially announced that it would suspend sales of pioglitazone in France, and also suspended the combination of pioglitazone and metformin.

On June 10, 2011, the German Federal Agency for Research on Medicines and Medical Supplies (BfArM) made the same decision as the French drug regulatory agency, suspending the sale of pioglitazone and requiring doctors not to prescribe the drug for new patients. It is not recommended that patients who are taking medications stop taking medications until they switch to other medications under the guidance of a doctor.

Pioglitazone

Pioglitazone tablets: 15 mg / tablet; 30 mg / tablet. Keep airtight and dry at room temperature to avoid moisture.

Pioglitazone considerations

Patients who are allergic to this product or its ingredients are contraindicated. This product can only play an anti-hyperglycemic effect in the presence of insulin. Therefore, pioglitazone is not suitable for patients with type 1 diabetes or patients with diabetic ketoacidosis. In patients with insulin resistance who have stopped ovulating before menopause, treatment with thiazolidinediones, including pioglitazone, can lead to reovulation.

Combined with contraceptives containing ethinyl estradiol and norethisterone, the plasma concentrations of the two hormones can be reduced by about 30%. This product has no effect on glipizide, digoxin, warfarin, and metformin. CYP3A4 inhibition has a certain effect on the metabolism of this product. Ketoconazole can significantly inhibit the metabolism of this product in vitro. No drug-induced tumors were found in any organ except the bladder. This product can increase the volume of plasma, and be used with caution in patients with grade III or IV cardiac function. Monitor liver and kidney function during medication.

Pioglitazone adverse reactions

1. Anemia can occur in the blood. In clinical experiments, hemoglobin is reduced by an average of 2% to 4% (more obvious at 4 to 12 weeks after starting treatment). When this product was used alone, the incidence of anemia was 1%; when metformin was used in combination, the incidence of anemia was 1.2%. The cause of anemia may be due to increased blood volume. 2. The cardiovascular system can lead to increased blood volume, which in turn can lead to cardiac hypertrophy due to increased preload of the heart. When this product is used alone, the incidence of mild to moderate edema is 4.8%; when combined with insulin, the incidence of edema (15.3%) is higher than that of sulfonylurea antidiabetic drugs or metformin. 3. According to the data of the neuropsychological system, the incidence of headache when using this product alone is 9.1%. In addition, a small-scale controlled experimental study found that 9% of patients developed paresthesia. 4. Metabolic / endocrine system When this product is combined with sulfonylurea antidiabetic drugs, the incidence of hypoglycemia is 2%; when insulin is combined with 15mg and 30mg of this product, the incidence of hypoglycemia is 8%. , 15%. 5. Abdominal discomfort is occasionally seen in the gastrointestinal tract. 6. No liver failure has been reported in the liver. 7. There is a case report in the eye, one patient had worsening retinopathy during treatment (30mg a day), but the relationship with this product is not clear. 8. The respiratory system was found in clinical trials. After treatment with this product, upper respiratory tract infections (13.2%), sinusitis (6.3%) and pharyngitis (5.1%) may occur. 9. There is a case report on the skin. A female patient developed angioedema on the 7th day of treatment (30mg a day). After discontinuing this product and treating with glucocorticoids, the patient's symptoms quickly relieved and no recurrence occurred in the future. 10. A clinical trial of the musculoskeletal system reported that the incidence of myalgia caused by this product was 5.4%. Laboratory inspection found that 7 patients had creatine phosphokinase 10 times higher than the upper limit of the normal value, of which 2 patients stopped treatment. The other 5 patients did not develop clinical sequelae after insisting on treatment.

Pioglitazone drug interactions

1. When combined with grape mannan, it can enhance hypoglycemic effect. 2. When combined with bitter gourd, the risk of hypoglycemia increases due to increased blood glucose utilization and insulin activity in the liver and peripheral tissues. 3. When combined with eucalyptus, fenugreek, and ginseng, it may cause hypoglycemia. 4. Because guar gum can delay gastric emptying, when combined with this product, the risk of hypoglycemia is increased. 5. When combined with plantain and St. John's wort, the risk of hypoglycemia increases. 6. When combined with broad-leaved shrubs, polygrass, Rhododendron plants, Jinbuhua (main ingredient is L-fumarin B), capsaicin, mint, Scutellaria, and valerian, it can cause serum aminotransferase The level rises. 7. Studies in healthy subjects have shown that this product does not change the steady-state pharmacokinetics of digoxin, warfarin, and glipizide. Nor did it affect the pharmacokinetics of a single dose of metformin. 8. When this product is combined with an oral contraceptive containing ethinyl estradiol and norethisterone, the latter's plasma concentration can be reduced by about 30%, which may make the contraceptive effect disappear. 9. Ketoconazole can significantly inhibit the metabolism of this product in vitro. Patients should evaluate blood glucose control more frequently when they are taken together.

/ Pioglitazone restriction / discontinuation

Diabetes drug pioglitazone has carcinogenic risk France has been discontinued

The reporter learned on the 17th from the US Food and Drug Administration (FDA) that taking the diabetic drug pioglitazone (trade name Ertopose, manufactured by Takeda Co., Ltd.) for more than one year, the risk of bladder cancer increased significantly. The drug is currently discontinued in France.

According to the FDA, after five years of trials, data have shown that patients taking high-dose, long-term pioglitazone medications are significantly more likely to develop bladder cancer. Therefore, the FDA requires that this risk information be added to the warnings and cautions on the drug label. The FDA also mentioned that the French Medicines Supervision and Administration Agency's Health Product Health and Safety Agency (AFSSAPS) has suspended the sale of pioglitazone in France.

It is understood that pioglitazone is mainly suitable for patients with type 2 diabetes (non-insulin-dependent diabetes). With the similar drug rosiglitazone, the diabetes drug Avandia produced by the British Glaxo Company is strictly restricted in the United States and banned in Europe. The market for the drug is currently expanding.

It is understood that there are nearly 100 million diabetic patients in China, of which mainly type 2 diabetes patients. Pioglitazone is a very widely used diabetic drug in China. According to the Drug Database of the State Food and Drug Administration, there are as many as 54 domestic medicines based on pioglitazone alone. Some of these drugs can be purchased by prescription in pharmacies.

On April 24, 2012, the State Food and Drug Administration based on the results of the adverse reaction assessment. In order to control the risk of drug use, the State Food and Drug Administration decided to revise the pioglitazone's instructions. The amendments include:

1. Add the following under [Contraindications]: This product is contraindicated in patients with existing or previous bladder cancer history or patients with unexplained gross hematuria.

2. Add the following under [Adverse Reactions]:

Bladder cancer: In epidemiological studies conducted abroad, the risk of bladder cancer associated with the use of pioglitazone in diabetic patients has been observed. Long-term use of pioglitazone has a tendency to increase the risk. An interim analysis of an epidemiological study showed that the overall analysis did not show a significant increase in the risk of bladder cancer (HR 1.2 [95% CI 0.9-1.5], but stratified analysis showed a treatment period of 2 years or more Patients had an increased risk of bladder cancer (HR 1.4 [95% CI 1.03-2.0]). Another epidemiological study showed that pioglitazone was associated with an increased risk of bladder cancer (HR 1.22, [95% CI 1.05- 1.43]), the risk of bladder cancer is further increased in patients with a period of 1 year or longer (HR 1.34 [95% CI 1.02-1.75]). ^[4]

3 Add the following under [Precautions]: (1) Before the treatment is started, the patient or his family should fully explain the risk of bladder cancer. When any symptoms of hematuria, urgency, or pain in urination occur, the patient must consult a doctor immediately. (2) Regular inspections such as urine tests should be performed during pioglitazone. If abnormalities are observed, appropriate measures should be taken. In addition, observation should be continued after stopping pioglitazone.