Thiazolidinediones and Cardiovascular Disease: Balancing Benefit and Harm

Sonal Singh, MD; Yoon K. Loke, MD


Geriatrics and Aging. 2008;11(3):179-183. 

In This Article

Thiazolidinediones and Heart Failure

The risk of heart failure appears to be a class effect of the thiazolidinediones. Our systematic review of three randomized controlled trials (RCTs) involving 10,731 patients showed that the thiazolidinediones doubled the risk of heart failure (odds ratio [OR] 2.1, 95% CI 1.08 - 4.08; p = .03) compared with controls ( Table 1 ).[8] The median duration for the onset of heart failure with the thiazolidinediones was approximately 24 weeks.[8] We estimate the number needed to harm (NNH) for hospitalization for heart failure with the thiazolidinediones to be 110 per year.[8] The NNH for rosiglitazone among older adults with diabetes (age 63 years without a history of heart failure) is even more unfavourable at 30 per year.[9] Another systematic review of seven RCTs found a similar increase in the risk of heart failure with the thiazolidinediones (nearly 72%), without any deleterious effect on cardiovascular mortality.[11]

Regulatory agencies have provided information about the risk of heart failure with the thiazolidinediones but have given differing recommendations on the severity of heart failure required to restrict the use of these agents. In Europe, these agents have been contraindicated for patients with heart failure and any history of heart failure since approval.[12] Health Canada have also recently updated their recommendation to warn against use in patients with any degree of heart failure.[13] In the U.S., thiazolidinediones have been contraindicated only for persons with NYHA class III and IV heart failure, recently highlighted by a prominent black box warning (added to the labeling of drugs by the Food and Drug Administration [FDA] when serious adverse reactions or special problems occur, particularly those that may lead to death or serious injury).[14] The impact of these restrictions on physician prescribing practices is uncertain as these agents continue to be prescribed for patients with heart failure.

We determined that the thiazolidinediones could cause heart failure even among prediabetic individuals without a history of heart failure, among individuals not assigned to insulin, and among a younger population.[8] Three of the rosiglitazone trials applied stringent criteria to exclude participants with heart failure; despite this careful patient selection process, the meta-analysis still showed a significant increase in the number of patients with heart failure due to rosiglitazone use. There are similar excess rates of heart failure for pioglitazone in the large PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study, (RR 1.43, 95% CI 1.20 - 1.70; p<0.001) even though persons with NYHA class III or IV heart failure were excluded from the study. Careful screening (based on history and clinical examination) by physicians will not be sufficient to prevent new heart failure cases arising as a result of thiazolidinedione therapy. Regulatory authorities also recommend close monitoring of cardiac signs and symptoms, which may be likely to pose a considerable additional burden to physicians and patients.

The mechanism of heart failure due to the thiazolidinediones is via fluid retention (Figure 1). Both these agents act on renal peroxisome proliferator-activated receptor gamma (PPAR gamma) and lead to increased sodium retention, fluid retention, and consequent heart failure among persons with diabetes.[15] Thiazolidinedione-induced heart failure requires immediate discontinuation of the drug and may not respond to loop diuretics such as furosemide. Clinicians should consider the use of potassium-sparing agents such as spironolactone or amiloride.[16]

Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure


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