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

It is the most commonly used TZD.

→ Thiazolidinediones (TZDs)

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.

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

Unique metabolic effect:

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

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

→ Heart Failure Module

Avoid in symptomatic heart failure.

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

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

Use caution in:

• Osteoporosis
• History of bladder cancer

Compared to:

• Metformin
• GLP-1 Receptor Agonists
• 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.

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

• Thiazolidinediones
• Rosiglitazone
• GLP-1 Receptor Agonists
• Heart Failure Module