Thiazolidinediones, including pioglitazone, can cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of pioglitazone, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, manage the heart failure according to the current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered.
Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.
Note: May require a dose reduction of insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia; consider discontinuation or dose reduction of insulin (AACE/ACE [Garber 2020]; ADA/EASD [Davies 2018]; manufacturer's labeling).
Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin; may be preferred when avoidance of hypoglycemia is desirable. Use has been associated with an increased risk of heart failure, and risk is increased with concomitant insulin use (AACE/ACE [Garber 2020]; ADA 2021). Avoid use in patients with preexisting heart failure (ADA/EASD [Davies 2018]; Inzucchi 2021).
Oral: Initial: 15 to 30 mg once daily.
Dosage adjustment: May increase in 15 mg/day increments every 4 to 12 weeks if needed to achieve glycemic goals (maximum: 45 mg/day) (AACE/ACE [Garber 2020]; Dormandy 2005; Inzucchi 2021). Discontinue use if signs or symptoms of heart failure develop (Nesto 2004; manufacturer’s labeling).
Nonalcoholic steatohepatitis (off-label use):
Note: May consider use in patients with biopsy-confirmed nonalcoholic steatohepatitis who also have type 2 diabetes mellitus; treatment may also be considered in patients with prediabetes, though risks may more closely match benefits (AASLD [Chalasani 2018]; Belfort 2006; Bril 2018; Cusi 2016; EASL/EASD/EASO 2016).
Oral: 30 mg once daily for 2 months, then increase dose to 45 mg once daily (Belfort 2006; Bril 2018; Cusi 2016). Consider limiting dose to ≤30 mg/day if worsening heart failure is a concern (AACE/ACE [Garber 2020]); patients with cardiovascular disease were excluded from clinical trials (Belfort 2006; Bril 2018; Cusi 2016).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (Budde 2003; manufacturer's labeling).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed; no supplemental dose or dosage adjustment necessary (Eckland 2000).
Peritoneal dialysis: Unlikely to be dialyzed due to high protein binding (expert opinion); no dosage adjustment necessary (expert opinion).
CRRT: No dosage adjustment necessary (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (expert opinion).
Hepatic impairment prior to initiation: No dosage adjustment necessary; use with caution if baseline liver tests are abnormal
Hepatic impairment during therapy: If liver injury is suspected (eg, fatigue, jaundice, dark urine): Interrupt therapy, measure serum liver tests, and investigate possible etiologies:
If an alternative etiology is not identified and ALT >3 x ULN: Do not reinitiate therapy.
If an alternative etiology is identified and ALT elevated (but <3 x ULN) or total bilirubin elevated (but <2 x ULN): May reinitiate with caution.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Actos: 15 mg, 30 mg, 45 mg
Generic: 15 mg, 30 mg, 45 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Actos: 15 mg [DSC], 30 mg [DSC], 45 mg [DSC]
Generic: 15 mg, 30 mg, 45 mg
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021073s049lbl.pdf#page=35, must be dispensed with this medication.
Oral: May be administered without regard to meals
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus
Nonalcoholic steatohepatitis
Actos may be confused with Actidose, Actonel
Tiazac: Brand name for pioglitazone [Chile], but also the brand name for dilTIAZem [U.S, Canada]
Pioglitazone may increase the risk of bladder carcinoma. A meta-analysis of randomized controlled trials and observational data support this association (Ref). Older data suggest the risk may be as high as 40% with duration >24 months and cumulative doses >28,000 mg (Ref).
Mechanism: Dose- and time-related; not clearly established but thought to be associated with activation of peroxisome proliferator activated receptor gamma (PPAR γ), which may alter tumor growth and progression in non-adipose cells (Ref).
Onset: Delayed; cases and risk generally occur with long-term use and high-dose exposure; however, there have been cases diagnosed within the first year of use (Ref).
Risk factors:
• Cumulative doses (>28,000 mg) (Ref)
• Duration of therapy (>24 months) (Ref)
• European ethnicity (Ref)
• Caucasian race (Ref)
• Prior history of bladder cancer
Thiazolidinediones (TZDs) may increase the risk of bone fractures, but the risk associated with pioglitazone is conflicting. Analysis of safety data after 5 years of pioglitazone therapy in patients without diabetes from the Insulin Resistance Intervention after Stroke Trial (IRIS) showed an absolute risk increase of 1.6% to 4.9% and relative risk increase of 47% to 60%. Fractures were typically low energy, not related to stress or pathology, and not serious (ie, not requiring surgery or hospitalization) (Ref). Fractures were in the spine, rib, foot, fibula, radius, tibia, humerus, and hip with no one skeletal region more affected (Ref). In contrast, a meta-analysis of patients with type 2 diabetes mellitus found the risk of fracture comparable to other hyperglycemic agents (Ref). Cited explanations for a correlation from prior evidence include the study populations (ie, mostly older adults and post-menopausal females), as well as older TZDs used (Ref). Discontinuation of TZDs may attenuate adverse bone effects (Ref).
Mechanism: Time-related; TZDs activate peroxisome proliferator activated receptor gamma (PPAR γ) which is expressed in bone as well as various other tissues (Ref). Activation creates an imbalance of bone remolding, including changes in bone marrow structure and function (Ref). Additionally, TZDs have been associated with a decrease in estrogen synthesis, which may exacerbate the effects on bone metabolism (Ref).
Onset: Delayed; IRIS data indicates an increased risk after 2 years of pioglitazone therapy (Ref).
Risk factors:
• Duration of drug therapy (>2 years) (Ref)
• Older adults (Ref)
• Prior stroke (Ref)
• Retinopathy (Ref)
Pioglitazone has been with associated with an increased risk of cardiac failure/worsening of cardiac failure and dose-dependent edema but has not been shown to have adverse effects on cardiac function structure (Ref). Symptoms are reversible with discontinuation (Ref).
Mechanism: Plasma volume increase appears to be the underlying etiology. Reduction in renal excretion of sodium and increase in sodium and free water retention is consistently thought of as the primary contributor to this plasma volume increase (Ref). Other exacerbating mechanisms could be increased sympathetic nervous system activity, alteration in endothelial permeability, and peroxisome proliferator activated receptor gamma (PPAR γ) mediated expression of vascular permeability growth factor (Ref).
Onset: Intermediate; within the first few weeks of initiation (Ref)
Risk factors:
• Presence of pedal edema or treatment with loop diuretics (Ref)
• Cardiovascular disease/significant aortic or mitral valve heart disease (Ref)
• Hypertension (Ref)
• Concurrent administration of drugs associated with fluid retention or pedal edema (Ref)
• Use with other glucose lowering therapies (especially insulin) (Ref)
• Older adults (>70 years) (Ref)
• Left ventricular hypertrophy (Ref)
• History of heart failure (Ref)
• Diabetes for >10 years (Ref)
• Chronic kidney failure (creatinine >2 mg/dL) (Ref)
Older thiazolidinediones (TZDs) seem to have stronger evidence of liver injury and liver function test increases than pioglitazone. Acute hepatic failure has been reported with pioglitazone (Ref). Resolution of symptoms may occur within 6 weeks of discontinuation (Ref). It is rare for the outcome to be fatal (Ref). Pioglitazone (in combination with lifestyle modifications) has been shown to improve hepatic fat in patients with diabetes and liver histology, steatosis, and resolution of nonalcoholic fatty liver disease (NAFLD) in patients without diabetes (Ref).
Mechanism: Time-related; exact mechanism is unknown (Ref). All patterns of serum enzyme elevations have been described (hepatocellular, cholestatic, and mixed); however, the pattern and course seem to be different from other TZDs (Ref). Moreover, excess free fatty acids in the insulin resistant state may be directly toxic to hepatocytes (Ref), which may support the positive finding in NAFLD studies with pioglitazone (Ref).
Onset: Delayed; occurs 1 to 6 months after therapy initiation (Ref)
Risk factors:
• Prior hepatic changes with other TZDs (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions and incidences reported are associated with monotherapy unless otherwise stated.
>10%:
Cardiovascular: Edema (3% to 27%; including exacerbation of edema) (table 1)
Drug (Pioglitazone) |
Placebo |
Dose |
Number of Patients (Pioglitazone) |
Number of Patients (Placebo) |
---|---|---|---|---|
27% |
15% |
N/A |
2,605 |
2,633 |
7% |
1% |
45 mg/day |
169 |
259 |
5% |
1% |
30 mg/day |
275 |
259 |
3% |
1% |
15 mg/day |
81 |
259 |
Endocrine and metabolic: Hypoglycemia (27%)
Respiratory: Upper respiratory tract infection (13%)
1% to 10%:
Cardiovascular: Cardiac failure (8%; including worsening of heart failure) (table 2)
Drug (Pioglitazone) |
Placebo |
Number of Patients (Pioglitazone) |
Number of Patients (Placebo) |
---|---|---|---|
8% |
6% |
2,605 |
2,633 |
Nervous system: Headache (9%)
Neuromuscular & skeletal: Back pain (6%), bone fracture (females: 5%; males: 2%) (table 3) , myalgia (5%)
Drug (Pioglitazone) |
Placebo |
Population |
Number of Patients (Pioglitazone) |
Number of Patients (Placebo) |
---|---|---|---|---|
5% |
3% |
Females |
870 |
905 |
2% |
2% |
Males |
N/A |
N/A |
Respiratory: Pharyngitis (5%), sinusitis (6%)
<1%:
Hematologic & oncologic: Bladder carcinoma (table 4)
Drug (Pioglitazone) |
Placebo |
Number of Patients (Pioglitazone) |
Number of Patients (Placebo) |
---|---|---|---|
0.5% |
0.2% |
2,605 |
2,633 |
Hepatic: Increased serum alanine aminotransferase
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen
Frequency not defined:
Endocrine & metabolic: Decreased serum triglycerides, increased HDL cholesterol, weight gain
Hematologic & oncologic: Decreased hemoglobin
Postmarketing:
Hepatic: Hepatic failure (LiverTox 2018)
Ophthalmic: Decreased visual acuity, macular edema (new-onset or worsening) (Oshitari 2008)
Hypersensitivity to pioglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy)
Canadian labeling: Additional contraindications (not is U.S. labeling): Any stage of heart failure (eg, NYHA Class I, II, III, IV); serious hepatic impairment; active bladder cancer; history of bladder cancer; uninvestigated macroscopic hematuria; pregnancy
Concerns related to adverse effects:
• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume.
• Hypoglycemia: The risk of hypoglycemia is increased when pioglitazone is combined with insulin or other diabetic medications; dosage adjustment of concomitant hypoglycemic agents may be necessary.
• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams.
• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).
– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).
• Diabetes, type 1: Mechanism requires the presence of insulin; therefore, use in type 1 diabetes or diabetic ketoacidosis is not recommended.
Substrate of CYP2C8 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Abiraterone Acetate: May enhance the hyperglycemic effect of Thiazolidinediones. Risk C: Monitor therapy
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
CYP2C8 Inducers (Moderate): May decrease the serum concentration of Pioglitazone. Risk C: Monitor therapy
CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Pioglitazone. Risk C: Monitor therapy
CYP2C8 Inhibitors (Strong): May increase the serum concentration of Pioglitazone. Management: Limit the pioglitazone dose to 15 mg daily and monitor for increased pioglitazone toxicities (eg, hypoglycemia) when used in combination with strong CYP2C8 inhibitors. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Pioglitazone may enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, consider insulin dose reductions to avoid hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure, and consider pioglitazone dose reduction or discontinuation if heart failure occurs Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pregabalin: May enhance the fluid-retaining effect of Thiazolidinediones. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sulfonylureas: Thiazolidinediones may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Topiramate: May decrease the serum concentration of Pioglitazone. Risk C: Monitor therapy
Thiazolidinediones may cause ovulation in anovulatory premenopausal patients, increasing the risk of unintended pregnancy.
Thiazolidinediones are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)
Information related to the use of pioglitazone in pregnancy is limited (Glueck 2003; Ortega-Gonzalez 2005; Ota 2008).
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).
Agents other than pioglitazone are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if pioglitazone is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Individualized medical nutrition therapy (MNT) based on American Diabetes Association recommendations is an integral part of therapy
Closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases or in NYHA class I or II (systolic) heart failure.
Type 2 diabetes mellitus, treatment:
Serum glucose.
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Chronic therapy:
Liver enzymes (ALT, AST, alkaline phosphatase, and total bilirubin) prior to initiation in all patients (with or without liver disease); continue routine periodic monitoring during treatment only in patients with liver disease or suspected liver disease; monitor for signs/symptoms of liver injury closely.
Signs and symptoms of fluid retention or heart failure; weight gain; signs/symptoms of bladder cancer (dysuria, macroscopic hematuria, dysuria, urinary urgency); ophthalmic exams.
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (ADA 2021):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2021): Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Classification of hypoglycemia (ADA 2021):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.
Onset of action: Delayed
Peak effect: Glucose control: Several weeks
Distribution: Vd (apparent): 0.63 ± 0.41 L/kg
Protein binding: Pioglitazone >99% and active metabolites >98%; primarily to albumin
Metabolism: Hepatic (99%) via CYP2C8 and 3A4 to active and inactive metabolites; M-III and M-IV are major circulating active metabolites
Half-life elimination: Parent drug: 3 to 7 hours; M-III and M-IV metabolites: 16 to 24 hours
Time to peak: ~2 hours; delayed with food
Excretion: Urine (15% to 30%) and feces as metabolites
Tablets (Actos Oral)
15 mg (per each): $15.54
30 mg (per each): $23.75
45 mg (per each): $25.76
Tablets (Pioglitazone HCl Oral)
15 mg (per each): $0.07 - $7.01
30 mg (per each): $0.10 - $10.72
45 mg (per each): $0.11 - $11.63
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