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Saturday, August 2, 2025

Thiazolidinediones


Definition and Therapeutic Role

Thiazolidinediones, also known as “glitazones,” are a class of oral antidiabetic agents used primarily in the management of type 2 diabetes mellitus (T2DM). These drugs function as insulin sensitizers, improving the body’s response to insulin without increasing insulin secretion. They achieve this by activating peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates genes involved in glucose and lipid metabolism.

Thiazolidinediones are used as monotherapy or in combination with other antidiabetic drugs (e.g., metformin, sulfonylureas, insulin) to reduce hyperglycemia and preserve β-cell function in patients with insulin resistance.

Mechanism of Action

  • TZDs bind to and activate PPARγ receptors, which are highly expressed in adipose tissue, skeletal muscle, and the liver.

  • PPARγ activation leads to:

    • Increased insulin sensitivity

    • Enhanced glucose uptake in muscle and adipose tissue

    • Reduced hepatic glucose output

    • Modulation of adipokines such as adiponectin (increased) and resistin (decreased)

  • They do not directly stimulate insulin secretion, so they do not cause hypoglycemia when used alone.

Approved Generic Drugs in this Class

  1. Pioglitazone

    • Brand names: Actos, Glustin

    • Availability: Widely approved and marketed globally

    • Formulations: Oral tablets (15 mg, 30 mg, 45 mg)

  2. Rosiglitazone

    • Brand names: Avandia

    • Availability: Approved in some regions with usage restrictions due to past cardiovascular concerns

    • Formulations: Oral tablets (2 mg, 4 mg, 8 mg)

Pharmacokinetics

  • Absorption: Well absorbed orally; food does not significantly affect absorption

  • Distribution: Highly protein-bound (>99%)

  • Metabolism:

    • Pioglitazone: Metabolized by CYP2C8 and CYP3A4 to active metabolites

    • Rosiglitazone: Metabolized by CYP2C8 (primarily) and CYP2C9

  • Elimination: Predominantly via hepatic metabolism and biliary excretion

  • Half-life: Pioglitazone ~3–7 hours (parent), up to 24 hours (active metabolites)

Indications

  • Type 2 diabetes mellitus, particularly in:

    • Patients with significant insulin resistance

    • Those inadequately controlled with metformin or sulfonylureas

    • Patients requiring triple therapy (e.g., metformin + insulin + TZD)

  • Polycystic ovary syndrome (PCOS) – off-label use for improving insulin resistance

  • Non-alcoholic fatty liver disease (NAFLD) – off-label; particularly pioglitazone

  • Metabolic syndrome – under investigation

Efficacy

  • TZDs reduce HbA1c by 0.5–1.5%

  • Onset of effect is delayed (weeks), but long-lasting

  • Effective in maintaining glycemic control for years, with potential β-cell preservation

  • Pioglitazone may improve lipid profile:

    • ↑ HDL

    • ↓ Triglycerides

    • Minimal LDL effect

Adverse Effects

Adverse EffectDescription
Weight GainDue to fluid retention and increased subcutaneous fat
EdemaPeripheral edema is common, especially with insulin co-administration
Heart FailureRisk of worsening congestive heart failure (black box warning)
Bone FracturesIncreased risk in women, especially postmenopausal (hip, wrist, spine)
Bladder CancerAssociated with pioglitazone in long-term high-dose use (conflicting data)
HepatotoxicityRare; liver enzymes must be monitored
Macular EdemaVisual disturbances reported in some patients
AnemiaMild hemodilution due to plasma expansion



Contraindications

  • Heart failure (NYHA Class III–IV) – absolute contraindication

  • History of bladder cancer (pioglitazone) – use with caution or avoid

  • Active liver disease or ALT > 2.5× ULN

  • Pregnancy and lactation

  • Type 1 diabetes mellitus (not effective)

  • Ketoacidosis

Precautions

  • Monitor weight and signs of fluid retention

  • Monitor liver function tests before initiation and periodically

  • Use caution in elderly and osteoporotic patients

  • Use lowest effective dose to minimize risks

  • Avoid in premenopausal women with anovulatory cycles due to risk of ovulation and pregnancy

Drug Interactions

  • Oral contraceptives: Pioglitazone may reduce efficacy of ethinyl estradiol/norethindrone

  • Gemfibrozil (CYP2C8 inhibitor): Increases pioglitazone and rosiglitazone levels

  • Rifampin (CYP2C8 inducer): Decreases effectiveness of TZDs

  • Insulin: Increased risk of edema and heart failure when combined

  • Other antidiabetics: Can be used additively with metformin, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas

Clinical Use and Dosing

Pioglitazone

  • Starting dose: 15–30 mg once daily

  • Max dose: 45 mg/day

  • Titration: Based on glycemic response over 8–12 weeks

  • Combination therapy: Used with metformin, sulfonylureas, insulin

Rosiglitazone

  • Starting dose: 4 mg daily (once or divided)

  • Max dose: 8 mg/day

  • Usage restrictions: Requires prescriber enrollment in REMS in some regions due to cardiac concerns

Comparative Benefits

FeaturePioglitazoneRosiglitazone
HDL increaseYesMinimal
Triglyceride reductionYesNo (may increase)
Cardiovascular riskPotential reductionHistorical concerns
Bladder cancer signalPossible (dose-dependent)No significant association
REMS requirement (US)NoYes (restricted access program)



Advantages

  • Effective in improving insulin sensitivity

  • Can be used in combination regimens

  • Low risk of hypoglycemia when used alone

  • May improve NAFLD/NASH parameters

  • Durable glycemic control (better than sulfonylureas in long term)

Limitations

  • Weight gain and edema are common

  • Delayed onset (weeks) may frustrate some patients

  • Concerns over safety (cardiac, bone, bladder)

  • Requires liver function monitoring

  • No effect in type 1 diabetes or DKA

Recent Guideline Perspectives

  • ADA/EASD 2024 Consensus: TZDs are not first-line therapy; used as an adjunct when metformin and SGLT2 inhibitors or GLP-1 receptor agonists are inadequate or contraindicated

  • Pioglitazone is sometimes preferred in patients with NAFLD, no heart failure, and low fracture risk

  • Rosiglitazone is largely reserved due to its history of cardiovascular concerns

Monitoring Requirements

  • Baseline and periodic liver function tests

  • Weight and edema assessment

  • Bone health in postmenopausal women

  • HbA1c and fasting glucose (every 3–6 months)

  • Consider urinalysis in patients on long-term high-dose pioglitazone

Ongoing Research and Novel Uses

  • Nonalcoholic steatohepatitis (NASH): Pioglitazone improves liver histology in some clinical trials

  • Polycystic Ovary Syndrome (PCOS): TZDs may reduce insulin resistance and improve ovulation

  • Pre-diabetes/Metabolic Syndrome: Under investigation to delay progression




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