Common name in Nepal: Pioz, Piostad, Piocris
What Are Thiazolidinediones?
Thiazolidinediones (TZDs), commonly called "glitazones," are a class of oral diabetes medications. Pioglitazone is the only TZD in wide clinical use today, after an earlier member of the class (rosiglitazone) fell out of favor due to cardiovascular safety concerns, and another (troglitazone) was withdrawn due to liver toxicity. Pioglitazone works differently from most other diabetes drugs — it improves how the body's own tissues respond to insulin, rather than increasing insulin supply.
Mechanism of Action
Pioglitazone binds to and activates a nuclear receptor called PPAR-gamma, found mainly in fat cells but also in muscle and liver tissue. Activating PPAR-gamma changes the expression of many genes involved in fat and glucose handling, ultimately making fat, muscle, and liver tissue more responsive to insulin — this is why TZDs are called "insulin sensitizers." Because the drug works through changes in gene expression, its effects build up slowly, often taking several weeks to months to reach full effect. Pioglitazone only works in the presence of the body's own or injected insulin, so it is not useful in situations where insulin is completely absent (such as untreated type 1 diabetes).
Benefits
Pioglitazone can lower HbA1c by around 1 to 1.5 percentage points, an effect that tends to be durable over time compared with some other oral agents. It also modestly raises HDL ("good") cholesterol and lowers triglycerides, and does not cause hypoglycemia when used alone. It may have benefit in patients with fatty liver disease (metabolic dysfunction-associated steatotic liver disease).
Side Effects
Fluid retention and edema are common, caused by increased sodium and water reabsorption in the kidney. This can present as swelling in the legs/ankles and mild weight gain from fluid rather than fat.
Heart failure risk — because of the fluid retention effect, pioglitazone can precipitate or worsen heart failure in susceptible patients. This carries a boxed warning in many countries, and the drug should not be used in patients with moderate-to-severe heart failure (NYHA class III–IV).
Bone fractures — long-term use has been associated with an increased risk of fractures, particularly in women, likely related to reduced bone formation. Regular weight-bearing exercise and adequate calcium/vitamin D intake are commonly advised.
Bladder cancer — some studies have found a modest increase in bladder cancer risk with long-term, high-cumulative-dose use, though the data are mixed across studies. Pioglitazone is generally avoided in patients with active bladder cancer or a history of it, and patients are advised to report blood in the urine or urinary symptoms promptly.
Weight gain and, less commonly, liver enzyme elevation can also occur; liver function is monitored periodically as a precaution, given the history of liver toxicity with an earlier drug in this class.
Precautions
Pioglitazone should be avoided or used with great caution in anyone with a history of heart failure or significant fluid retention, and is not recommended in active or prior bladder cancer. Women should be counseled about the fracture risk and encouraged toward bone-protective lifestyle measures. Because effects build up slowly, dose changes should not be judged too early, but patients should be watched for swelling, rapid weight gain, or breathlessness at each visit, especially in the first few months.
Required Tests: Before and After Starting
Before starting, it is reasonable to check liver function tests and assess for a history of heart failure or bladder cancer. During treatment, patients should be monitored clinically for signs of fluid retention or heart failure (weight, swelling, breathlessness) at follow-up visits, and liver function is often rechecked periodically, particularly if there are symptoms suggestive of liver problems (unusual fatigue, jaundice, dark urine). HbA1c is checked every 3 to 6 months as with other oral agents.
Sources
Kung J, Henry RR. "Thiazolidinedione safety." Expert Opinion on Drug Safety, 2012;11(4):565-579.
Bełtowski J, Rachańczyk J, Włodarczyk M. "Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms." PPAR Research, 2013. DOI: 10.1155/2013/628628
Azoulay L, et al. "The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study." BMJ, 2012;344:e3645.
Tulane University PharmWiki. "Pioglitazone." tmedweb.tulane.edu/pharmwiki