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.

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.

Agents

Pioglitazone is the most commonly used TZD.

Clinical Effects

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

Onset of effect is slow (weeks).

Cardiometabolic Impact

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.

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)

Contraindications

Symptomatic heart failure
Active liver disease
Significant fluid overload

Use caution in:

Osteoporosis
CKD with volume issues

TZDs vs Other Antihyperglycemics

Compared to:

TZDs:

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

Clinical Pearls

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