====== Pioglitazone ======

Pioglitazone is a thiazolidinedione (TZD) that improves insulin sensitivity through activation of the PPAR-γ nuclear receptor.

It is the most commonly used TZD.

→ [[endocrine:tzds:start|Thiazolidinediones (TZDs)]]

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===== Mechanism of Action =====

Pioglitazone activates:

  * Peroxisome proliferator-activated receptor gamma (PPAR-γ)

This results in:

  * Increased peripheral insulin sensitivity
  * Reduced hepatic glucose production
  * Increased glucose uptake in muscle and adipose tissue
  * Redistribution of visceral fat to subcutaneous stores

It does NOT stimulate insulin secretion.

Hypoglycemia risk is low unless combined with insulin or secretagogues.

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===== Clinical Effects =====

  * Moderate HbA1c reduction
  * Improved insulin resistance
  * Slow onset of action (weeks)

Unique metabolic effect:

  * Decreases triglycerides
  * Increases HDL
  * Neutral to slight LDL increase

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===== Cardiometabolic Considerations =====

Potential benefits:

  * Improves insulin resistance
  * May reduce progression of prediabetes
  * Some data suggest stroke risk reduction in select populations

Major limitation:

  * Fluid retention
  * Worsening heart failure

→ [[cardio:heart_failure:start|Heart Failure Module]]

Avoid in symptomatic heart failure.

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===== Adverse Effects =====

Common:

  * Weight gain
  * Peripheral edema
  * Fluid retention

Serious:

  * Worsening heart failure
  * Increased fracture risk (especially in women)
  * Possible association with bladder cancer (data mixed)

Monitor:

  * Liver enzymes
  * Weight
  * Edema

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===== Contraindications =====

  * NYHA Class III or IV heart failure
  * Active liver disease
  * Significant fluid overload

Use caution in:

  * Osteoporosis
  * History of bladder cancer

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===== Pioglitazone vs Other Antihyperglycemics =====

Compared to:

  * [[endocrine:biguanides:metformin|Metformin]]
  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[endocrine:sglt2:start|SGLT2 Inhibitors]]

Pioglitazone:

  * Improves insulin sensitivity directly
  * Causes weight gain (vs weight loss with GLP-1/SGLT2)
  * May worsen heart failure
  * Low hypoglycemia risk
  * Improves triglycerides

Due to edema risk, it is not preferred in patients with heart failure or volume overload.

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===== Clinical Pearls =====

  * Nuclear receptor drug (genomic effect)
  * Slow onset
  * Improves triglycerides
  * Causes edema and weight gain
  * Avoid in symptomatic heart failure
  * Rare bladder cancer signal (controversial)

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===== Related =====

  * [[endocrine:tzds:start|Thiazolidinediones]]
  * [[endocrine:tzds:rosiglitazone|Rosiglitazone]]
  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[cardio:heart_failure:start|Heart Failure Module]]