Introduction
Pioglitazone is an oral antidiabetic medication belonging to the thiazolidinedione class. It is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As an insulin sensitizer, pioglitazone addresses the fundamental pathophysiology of insulin resistance in type 2 diabetes.
Mechanism of Action
Pioglitazone acts as a selective agonist at peroxisome proliferator-activated receptor-gamma (PPAR-γ), nuclear receptors found primarily in adipose tissue, skeletal muscle, and liver. Activation of PPAR-γ receptors regulates the transcription of insulin-responsive genes involved in glucose production, transport, and utilization. This results in increased insulin sensitivity in peripheral tissues, reduced hepatic glucose output, and improved pancreatic beta-cell function.
Indications
- Monotherapy: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- Combination therapy: With metformin, sulfonylureas, insulin, or DPP-4 inhibitors when dual or triple therapy is appropriate
- Off-label uses: Investigationally studied for non-alcoholic steatohepatitis (NASH) and polycystic ovary syndrome (PCOS)
Dosage and Administration
Initial dose: 15-30 mg orally once daily Maximum dose: 45 mg orally once daily Dose adjustments:- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Contraindicated in patients with active liver disease or ALT >2.5× ULN
- Elderly: No dosage adjustment necessary, but monitor for fluid retention and heart failure
Pharmacokinetics
Absorption: Rapidly absorbed, peak plasma concentrations within 2 hours Bioavailability: >80% Distribution: >99% protein-bound, primarily to albumin Metabolism: Extensive hepatic metabolism via CYP2C8 and CYP3A4 Elimination: Half-life 3-7 hours (pioglitazone), 16-24 hours (active metabolites) Excretion: Primarily fecal (15-30% renal excretion)Contraindications
- History of hypersensitivity to pioglitazone or any component of the formulation
- Active liver disease or ALT >2.5× upper limit of normal
- New York Heart Association (NYHA) Class III or IV heart failure
- History of bladder cancer
- Diabetic ketoacidosis
Warnings and Precautions
Boxed Warning:- Congestive heart failure: Thiazolidinediones can cause dose-related fluid retention that may exacerbate or lead to heart failure
- Bladder cancer: Increased risk observed in epidemiologic studies
- Hepatic monitoring: Check liver enzymes before initiation and periodically during treatment
- Macular edema: Reported in some patients
- Fractures: Increased risk of distal upper and lower limb fractures in women
- Ovulation: May restore ovulation in premenopausal anovulatory women with insulin resistance
Drug Interactions
Major interactions:- Strong CYP2C8 inhibitors (gemfibrozil): Significantly increases pioglitazone exposure - avoid combination
- CYP2C8 inducers (rifampin): May decrease pioglitazone concentrations
- Insulin or insulin secretagogues: Increased risk of hypoglycemia - may require dose reduction
- Other medications that cause fluid retention (NSAIDs, corticosteroids): May exacerbate fluid retention
Adverse Effects
Common (≥5%):- Upper respiratory infection
- Headache
- Sinusitis
- Myalgia
- Tooth disorder
- Diabetes mellitus aggravated
- Hypoglycemia (when combined with insulin or secretagogues)
- Congestive heart failure
- Hepatic toxicity
- Macular edema
- Fractures (particularly in women)
- Bladder cancer (potential increased risk)
- Anemia
Monitoring Parameters
- Glycemic control: HbA1c every 3 months until stable, then every 6 months
- Liver function: ALT at baseline, every 3-6 months for first year, then periodically
- Cardiac function: Monitor for signs/symptoms of heart failure (weight gain, edema, dyspnea)
- Renal function: Serum creatinine at baseline and annually
- Hematologic: Hemoglobin/hematocrit at baseline and periodically
- Ophthalmologic: Regular eye exams
- Bladder cancer screening: Monitor for hematuria and other urinary symptoms
Patient Education
- Take medication exactly as prescribed, once daily with or without food
- Notify your healthcare provider immediately if you experience:
- Unexplained weight gain - Swelling in ankles or legs - Shortness of breath - Dark urine or yellowing of skin/eyes - Vision changes - Blood in urine or painful urination
- This medication helps control blood sugar but does not cure diabetes
- Continue following dietary restrictions, exercise program, and regular blood sugar testing
- Inform all healthcare providers you are taking pioglitazone
- Women of childbearing potential should use effective contraception as pioglitazone may restore ovulation
- Report any falls or bone pain, especially in women
References
1. FDA Prescribing Information: Actos (pioglitazone). 2020 2. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S1-S291 3. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471 4. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34(4):916-922 5. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-2443 6. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129-1136 7. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol Endocrinol Metab. 2007;292(3):E871-E883