Thiazolidinedione Side effects and contraindications

The discontinuation of troglitazone has raised concerns that other thiazolidinediones also increase the incidence of hepatitis and potentially liver failure which occurs in approximately 1 in 20,000 troglitazone patients.Therefore, the FDA recommends a two- to three-month check of liver enzymes during the first year of thiazolidinedione therapy to check for this rare but potentially disastrous complication.So far, in 2008,the newer thiazolidinediones, rosiglitazone and pioglitazone, do not have this problem.The main side effect of all thiazolidinediones is water retention, leading to edema, usually this is a problem in less than 5% of people, but it is a big problem for some people and can be severe water retention leading to Decompensation of heart failure that may not have been previously recognized.Therefore, thiazolidinediones should be prescribed with caution and patients warned of the possibility of water retention/weight gain, especially with decreased ventricular function (NYHA class III or IV heart failure ) patients).

Although earlier studies suggested that rosiglitazone may increase the risk of coronary artery disease and heart attack,in contrast, pioglitazone treatment has shown significant protection against microvascular and macrovascular cardiovascular events and plaque progression.These studies led to FDA recommendations for a period of time (2007-2013), which, aided by widespread media coverage, resulted in a dramatic reduction in the use of rosiglitazone.In November 2013, the FDA announced that it would lift restrictions on the use of rosiglitazone in patients with coronary artery disease.The new recommendations are largely based on the reasoning that the previous meta-analyses that led to the initial limitations were not designed to assess cardiac outcomes and were therefore not uniformly collected or adjudicated.In contrast, one of the largest trials designed to assess cardiac outcomes (the RECORD trial) found no increased risk of myocardial infarction with rosiglitazone, even after an independent reassessment for FDA review.

A 2013 meta-analysis concluded that use of pioglitazone was associated with a slightly higher risk of bladder cancer compared with the general population.The authors of the same analysis recommend that other hypoglycemic agents should be considered in people with other risk factors for bladder cancer, such as smoking, family history, or exposure to certain forms of chemotherapy.

A 2020 Cochrane systematic review comparing metformin monotherapy with thiazolidinediones in type 2 diabetes.Thiazolidinediones reduce bone mineral density and increase fracture risk in women, possibly by biasing the differentiation of bone marrow stromal cells away from osteoblastic differentiation in favor of adipocyte formation.Thiazolidinediones increase the expression of angiotensin-converting enzyme 2 (ACE2).Presumably, this increases the chance of severe infection with the SARS-CoV-2 virus, which causes COVID-19.