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.

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.

• Pioglitazone
• Rosiglitazone

Pioglitazone is the most commonly used TZD.

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

Onset of effect is slow (weeks).

TZDs improve:

• Insulin resistance
• Fat distribution
• Inflammatory markers

However, they may:

• Cause fluid retention
• Worsen heart failure

→ Heart Failure Module

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

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)

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

Use caution in:

• Osteoporosis
• CKD with volume issues

Compared to:

• Metformin
• GLP-1 Receptor Agonists
• SGLT2 Inhibitors

TZDs:

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

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

• Diabetes Pharmacology
• Metformin
• Heart Failure Module