Thiazolidinediones (often shortened to TZDs) are a class of oral medication used to treat type 2 diabetes. They work by making your body more sensitive to insulin, the hormone that moves sugar from your blood into your cells. Two TZDs are currently approved by the FDA: pioglitazone (brand name Actos) and rosiglitazone (brand name Avandia). Used alone, they typically lower HbA1c (a measure of average blood sugar over three months) by 1 to 1.5 percentage points.
How TZDs Lower Blood Sugar
TZDs work differently from most diabetes medications. Instead of increasing insulin production or blocking sugar absorption, they activate a receptor inside cells called PPAR-gamma. This receptor acts like a switch for genes involved in how your body processes sugar and fat. The primary target is fat tissue, where PPAR-gamma is most abundant.
When TZDs activate this receptor, several things happen. Fat cells become better at storing lipids, which pulls fatty acids out of places they don’t belong, like your muscles and liver. Excess fat in those tissues is one of the main drivers of insulin resistance, so clearing it out helps those organs respond to insulin again. TZDs also shift the balance of signaling molecules released by fat tissue: they reduce inflammation-promoting signals and increase adiponectin, a hormone that improves insulin sensitivity throughout the body.
The net result is threefold: your muscles take up more sugar from the blood, your liver produces less sugar on its own, and your pancreas doesn’t have to work as hard to produce insulin. This makes TZDs unique among diabetes drugs because they address insulin resistance at multiple sites simultaneously.
How TZDs Compare to Metformin
Metformin, the most widely prescribed diabetes drug, also improves insulin sensitivity, but the overlap isn’t complete. Both drugs help the liver respond better to insulin and reduce the amount of sugar it dumps into the bloodstream. However, TZDs go a step further by improving how well your muscles absorb sugar under insulin’s direction, something metformin does not do. In practice, this means TZDs and metformin can complement each other. When added to metformin or other diabetes medications, TZDs lower HbA1c by roughly an additional 1 percentage point.
Effects on Cholesterol and Triglycerides
Both pioglitazone and rosiglitazone raise HDL (“good”) cholesterol. Beyond that, their lipid effects diverge. Pioglitazone tends to lower triglycerides and leaves LDL (“bad”) cholesterol unchanged. Rosiglitazone, on the other hand, raises LDL cholesterol, and its effect on triglycerides is inconsistent, ranging from a slight increase to a modest decrease across studies. This difference in lipid profiles is one reason pioglitazone is prescribed far more often than rosiglitazone today.
Cardiovascular Risk With Rosiglitazone
Rosiglitazone’s history with the FDA has been turbulent. In 2010, the FDA significantly restricted its use after data suggested an elevated risk of heart attacks. Updated labeling now states that rosiglitazone should only be used in patients already taking it or in those whose blood sugar can’t be controlled with other medications and who, after discussion with their doctor, choose not to use pioglitazone. While those restrictions were later loosened somewhat, the cardiovascular concerns remain on the drug’s label, and in practice, rosiglitazone is rarely the first choice.
Bone Fracture Risk
TZDs increase the risk of bone fractures, particularly in women and with long-term use. A meta-analysis of ten randomized controlled trials found that TZD users had a 45% higher odds of fracture compared to non-users. The risk is not evenly distributed across the skeleton. Fractures of the foot, ankle, and lower leg (tibia and fibula) show the sharpest increases, with risk roughly 50 to 70% higher in TZD users compared to people on other diabetes medications.
Duration matters considerably. Patients who had filled 30 or more TZD prescriptions over their lifetime had a threefold increased risk of osteoporotic fracture compared to those using other diabetes drugs. This makes bone health a particularly important consideration for anyone on long-term TZD therapy, especially postmenopausal women who already face elevated fracture risk.
Pioglitazone and Bladder Cancer
The FDA has concluded that pioglitazone may be linked to an increased risk of bladder cancer, though the evidence is mixed. A large 10-year study of nearly 200,000 patients found no statistically significant overall increase in bladder cancer risk. However, a separate study found a 63% higher risk, and there were suggestions of a trend toward greater risk with longer use and higher cumulative doses. A randomized controlled trial showed a roughly threefold increase in bladder cancer during the active treatment period, but this elevated risk disappeared when patients were followed for nearly 13 years total.
Because the findings conflict, the FDA’s current position is cautious rather than definitive. Pioglitazone should not be used in patients with active bladder cancer, and the decision to prescribe it to someone with a history of bladder cancer requires careful weighing of benefits and risks.
Other Common Side Effects
The most noticeable side effects of TZDs are weight gain and fluid retention. TZDs promote fat storage (part of how they work), so some weight gain is expected. Fluid retention can cause swelling in the ankles and legs and, in more serious cases, can worsen or trigger heart failure. Both TZDs carry a warning about heart failure risk, and they are not recommended for people with moderate to severe heart failure.
Because TZDs work by changing gene expression rather than directly lowering blood sugar in the moment, they take several weeks to reach full effect. They also carry a low risk of causing dangerously low blood sugar on their own, though combining them with insulin or drugs that stimulate insulin production can increase that risk.
Where TZDs Fit in Diabetes Treatment
TZDs are not first-line therapy for type 2 diabetes. Metformin holds that role due to its longer track record, lower cost, and weight-neutral profile. TZDs are typically considered when metformin alone isn’t enough, or when a patient can’t tolerate metformin. They can be used as a single drug or combined with metformin, sulfonylureas, or insulin. Pioglitazone is the more commonly prescribed of the two, given rosiglitazone’s cardiovascular concerns and less favorable cholesterol profile.
Their ability to directly improve insulin sensitivity across multiple tissues gives TZDs a distinct role that newer drug classes, like GLP-1 receptor agonists and SGLT2 inhibitors, don’t replicate in quite the same way. For patients whose core problem is severe insulin resistance, TZDs remain a relevant option, provided the risks around fractures, fluid retention, and (for pioglitazone) bladder cancer are factored into the decision.