====== Thiazolidinediones (TZDs) ======

Thiazolidinediones are insulin sensitizers that improve peripheral glucose uptake by activating the PPAR-γ nuclear receptor.

They are antihyperglycemic agents with low intrinsic hypoglycemia risk.

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

TZDs activate:

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

PPAR-γ is a nuclear transcription factor that regulates:

  * Adipocyte differentiation
  * Fat storage
  * Glucose metabolism
  * Insulin sensitivity

Primary effects:

  * Increased peripheral insulin sensitivity
  * Decreased hepatic glucose production
  * Redistribution of fat from visceral to subcutaneous stores

They do NOT increase insulin secretion.

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===== Agents =====

  * [[endocrine:tzds:pioglitazone|Pioglitazone]]
  * [[endocrine:tzds:rosiglitazone|Rosiglitazone]]

Pioglitazone is the most commonly used TZD.

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

  * Moderate HbA1c reduction
  * Improved insulin sensitivity
  * Reduced fasting glucose
  * Improved triglycerides (pioglitazone)

Onset of effect is slow (weeks).

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===== Cardiometabolic Impact =====

TZDs improve:

  * Insulin resistance
  * Fat distribution
  * Inflammatory markers

However, they may:

  * Cause fluid retention
  * Worsen heart failure

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

TZDs are NOT first-line therapy in patients with heart failure.

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

Common:

  * Weight gain
  * Peripheral edema
  * Fluid retention

Serious:

  * Worsening heart failure
  * Increased fracture risk
  * Rare hepatotoxicity

Pioglitazone-specific concern:

  * Possible association with bladder cancer (data mixed)

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===== Contraindications =====

  * Symptomatic heart failure
  * Active liver disease
  * Significant fluid overload

Use caution in:

  * Osteoporosis
  * CKD with volume issues

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===== TZDs vs Other Antihyperglycemics =====

Compared to:

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

TZDs:

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

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

  * Nuclear receptor drug (genomic mechanism)
  * Slow onset
  * Causes edema and weight gain
  * Avoid in symptomatic heart failure
  * Pioglitazone improves triglycerides

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===== Related =====

  * [[endocrine:diabetes:start|Diabetes Pharmacology]]
  * [[endocrine:biguanides:metformin|Metformin]]
  * [[cardio:heart_failure:start|Heart Failure Module]]