The withdrawal of
troglitazone has led to concerns of the other thiazolidinediones also increasing the incidence of
hepatitis and potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of
liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones,
rosiglitazone and
pioglitazone have been free of this problem. The main side effect of all thiazolidinediones is water retention, leading to
edema, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized
heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (
NYHA grade III or IV heart failure). Though older studies suggested there may be an increased risk of
coronary heart disease and heart attacks with rosiglitazone,
pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and
plaque progression. These studies led to a period of Food and Drug Administration advisories (2007 – 2013) that, aided by extensive media coverage, led to a substantial decrease in rosiglitazone use. In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease. The new recommendations were largely based on the reasoning that prior meta-analyses leading to the original restrictions were not designed to assess cardiac outcomes and, thus, not uniformly collected or adjudicated. In contrast, one of the largest trials (RECORD trial) that was specifically designed to assess cardiac outcomes found no increased risk of
myocardial infarction with rosiglitazone use, even after independent re-evaluation for FDA review. A 2013
meta-analysis concluded that use of
pioglitazone is associated with a slightly higher risk of
bladder cancer compared to the general population. The authors of the same analysis recommended that other blood sugar lowering agents be considered in people with other risk factors for bladder cancer such as
cigarette smoking, family history, or exposure to certain forms of
chemotherapy. A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal
myocardial infarction, non-fatal
stroke or
end-stage renal disease when comparing
metformin monotherapy to Thiazolidinedione for treatment of
type 2 diabetes. Thiazolidinediones reduce
bone mineral density and increase the risk of fractures in women, possibly as a result of biasing the differentiation of
bone marrow stromal cells away from
osteoblast differentiation and toward
adipocyte formation. == References ==