What are possible adverse effects of thiazolidinediones (TZDs) to treat type 2 diabetes mellitus (DM)?

Updated: Jul 13, 2021
  • Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
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While TZDs have many desirable effects on inflammation and the vasculature, edema (including macular edema) and weight gain may be problematic adverse effects, especially when TZDs are administered with insulin or insulin secretagogues. [193] These effects may induce or worsen heart failure in patients with left ventricular compromise and occasionally in patients with normal left ventricular function. TZDs have not been tested in patients with New York Heart Association class III or IV heart failure.

Fluid retention from TZDs has been considered resistant to treatment with loop diuretics, because of upregulation of renal epithelial sodium channels. However, a randomized, double-blind, placebo-controlled, crossover study by Rennings et al found that response to the loop diuretics furosemide and amiloride were preserved in rosiglitazone-treated subjects with insulin resistance. [194]

The use of pioglitazone for more than 2 years is weakly associated with an increased bladder cancer risk, with the highest risk among patients who took pioglitazone the longest and at the highest cumulative doses. [195, 196, 197] Constant surveillance and vigilance is needed. Ninety-five percent of these cases were detected in early stage. The US Food and Drug Administration (FDA) currently recommends not prescribing pioglitazone for patients with active bladder cancer and using it with caution in patients with a history of bladder cancer.

A meta-analysis indicated that in women with type 2 diabetes, long-term (ie, 1 y or longer) use of TZDs doubles the risk of fracture. [198] Although in this study, TZDs were not found to have significantly increased fracture risk among men with type 2 diabetes, risk of fracture in males has since been reported.

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