thiazolidinedione

**Drugs:** Pioglitazone, rosiglitazone ("-glitazone"). Troglitazone was withdrawn for hepatotoxicity.

**Mechanism:** Agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor transcription factor highly expressed in adipose tissue. PPAR-γ heterodimerizes with RXR and binds PPAR response elements on DNA. This upregulates genes for glucose and lipid metabolism: increased GLUT4 expression, adiponectin, and lipoprotein lipase, plus adipocyte differentiation. Net effects are increased peripheral (muscle, fat) glucose uptake, decreased hepatic gluconeogenesis, and improved insulin sensitivity. They do NOT increase insulin secretion, so hypoglycemia is rare as monotherapy. Effects are slow in onset (weeks).

**Clinical use:** Type 2 diabetes mellitus, especially with insulin resistance. Used as add-on therapy to metformin, sulfonylureas, or insulin. Pioglitazone also improves NASH (MASH) histology and lowers triglycerides/raises HDL. It reduces A1c by about 1–1.5%.

**Adverse effects (high yield):** - Fluid retention, peripheral edema, and **heart failure exacerbation** (renal sodium and water retention). Contraindicated in NYHA class III–IV HF. Boxed warning. - Weight gain (increased subcutaneous fat, plus fluid). - Increased fracture risk (distal limbs in women) because of decreased osteoblastogenesis. - Hepatotoxicity (mainly troglitazone). Monitor LFTs. - Pioglitazone: possible increased bladder cancer risk (avoid in active bladder cancer). - Rosiglitazone: associated with increased MI risk, so it was restricted in the past. Restrictions were later eased by the FDA in 2013. - Macular edema. - Dilutional anemia.

**Key associations and comparisons:** - Metformin: decreases hepatic gluconeogenesis through AMPK activation. Causes lactic acidosis and weight loss. - Sulfonylureas: close K-ATP channels and increase insulin secretion. Cause hypoglycemia. - TZDs: improve insulin sensitivity. Edema, HF, weight gain, fractures. - Fibrates (e.g., fenofibrate, gemfibrozil) act on PPAR-α, which is a frequently tested distinction. - Pioglitazone is metabolized by CYP2C8 (gemfibrozil, a CYP2C8 inhibitor, increases levels). - Pioglitazone has a role in patients with prior stroke/TIA with insulin resistance (reduced recurrent CV events in the IRIS trial).

**Pearl:** "Glitazones → Gain weight, Goes to heart (HF), Gets bones (fractures), Gene transcription (PPAR-γ)."