From the Guidelines
Thiazolidinediones (TZDs) are associated with several notable side effects, including fluid retention, weight gain, bone fracture, and possibly bladder cancer, as reported in the 2018 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1. When considering the use of TZDs, such as pioglitazone and rosiglitazone, it is essential to weigh these potential side effects against their benefits, including increased insulin sensitivity and high glucose-lowering efficacy. Some of the key side effects to consider include:
- Fluid retention and congestive heart failure, which can be mitigated with lower-dose therapy (e.g., pioglitazone 15–30 mg) 1
- Weight gain, which can range from 2-8 pounds and is caused by increased fat storage and fluid retention
- Bone fracture, particularly in postmenopausal women, due to decreased bone density with long-term use
- Possibly bladder cancer, although the absolute risk appears small, as noted in the 2018 ADA and EASD consensus report 1 It is crucial to monitor patients for these side effects and adjust treatment accordingly to minimize risks and maximize benefits, as the 2018 consensus report highlights the importance of balancing the benefits and harms of TZD therapy 1.
From the FDA Drug Label
WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. In all U. S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents ACTOS may cause decreases in hemoglobin and hematocrit. In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.
The typical side effects of thiazolidinediones, such as pioglitazone, include:
- Cardiac effects: fluid retention, heart failure, and edema
- Weight gain: dose-related weight gain due to fluid retention and fat accumulation
- Hematologic effects: decreases in hemoglobin and hematocrit
- Hepatic effects: rare reports of hepatitis and hepatic enzyme elevations 2, 2 These side effects can be serious and may require discontinuation or dose reduction of the medication 2.
From the Research
Typical Side Effects of Thiazolidinediones
- Fluid retention, which can increase the risk of heart failure 3, 4, 5
- Weight gain 4
- Increased risk of leg and forearm fractures 4
- Hepatotoxicity (specifically with troglitazone) 5
- Edema, congestive heart failure, and bone fractures 6
- Cardiovascular disease, with differential effects between pioglitazone and rosiglitazone 4, 7
Comparison of Side Effects between Pioglitazone and Rosiglitazone
- Pioglitazone has a beneficial effect on cardiovascular disease, while rosiglitazone increases cardiovascular risk 4
- Rosiglitazone users have an increased risk of death and hospitalization for heart failure compared to pioglitazone users 7
- The risk of mortality is increased two-fold shortly after starting rosiglitazone, with excess risk of death over 3 years 7