Thiazolidinediones and Cardiovascular Disease: Balancing Benefit and Harm

Sonal Singh, MD; Yoon K. Loke, MD

Disclosures

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

In This Article

Thiazolidinediones and Myocardial Infarction

The currently available thiazolidinediones differ in their ischemic risk profile. In a meta-analysis of 42 short- and long-term trials in patients with heterogeneous conditions (diabetes and Alzheimer's disease, as well as psoriasis), Nissen and Wolski showed that rosiglitazone increased the risk of myocardial infarction (MI) (OR 1.43, 95% CI 1.03 - 1.98; p = .03) and nonsignificantly increased the risk of cardiovascular death (OR 1.64, 95% CI 0.98 - 2.64; p = .06).[7] In contrast, our meta-analysis of four long-term trials with rosiglitazone among individuals with diabetes in which the cardiovascular events were monitored showed that rosiglitazone increased the risk of MI by 42% (relative risk [RR] 1.42, 95% CI 1.06 - 1.91) compared with other oral hypoglycemic agents without an increase in the risk of cardiovascular death (RR 0.90, 95% CI 0.63 - 1.26; p = .53) ( Table 2 ).[9] The improved glucose control seen with rosiglitazone does not appear to confer cardiovascular benefits. Persons taking rosiglitazone in ADOPT (A Diabetes Outcome Progression Trial) had a mean glycosylated hemoglobin (HbA1C) after 4 years that was 0.42% lower than those in the glyburide arm, but the rate of MIs was higher in the rosiglitazone arm—1.8% as opposed to 1.2% with glyburide.[17] The RCTs were inadequately powered to detect mortality outcomes; hence, this increased risk of MI with rosiglitazone is not reflected in an increase in cardiovascular mortality. An internal review by the U.S. FDA using patient-level data confirmed this increased ischemic risk with rosiglitazone.[18] The combination of rosiglitazone and insulin accentuates this ischemic risk even further. The FDA panel voted overwhelmingly that rosiglitazone increased the ischemic risk but allowed it to remain on the market.

On the other hand, pioglitazone does not increase the risk of MI. The claim of any cardiovascular benefit of pioglitazone in the systematic review by Lincoff et al.[10] on an artificial composite of MI, stroke, and death will require corroboration from adequately powered long-term trials as pioglitazone failed to meet its primary end point in the only large clinical trial measuring cardiovascular outcomes—PROactive (Hazard Ratio 0.90, 95% CI 0.80 - 1.02; p=.100).[19] The differences in ischemic risk may be explained by the thiazolidinediones' varying effects on lipid levels—pioglitazone lowers low-density lipoprotein cholesterol while rosiglitazone raises it.[20]

Accumulating evidence from long-term trials has demonstrated the negative effects of the thiazolidinediones on cardiovascular disease among individuals with type II diabetes. The risk of heart failure is a class effect of the thiazolidinediones, whereas the ischemic cardiovascular risk is confined to rosiglitazone. The public health impact of the use of the thiazolidinediones among older adults with type II diabetes is substantial. According to an FDA review, more than 205,000 cardiovascular ischemic events may have occurred among rosiglitazone users from its approval in 1999 until 2006.[18] Their benefit on a surrogate measure such as HbA1C should be balanced against their complex actions elsewhere in the body, including a doubling of the risk of bone fractures among women, which may negate any potential gain.

A recent systematic review highlighted that older agents (metformin and sulfonylureas) are less expensive and more effective for the treatment of type II diabetes and do not carry the negative cardiovascular risks of the thiazolidinediones.[21] In another recent systematic review, metformin was the only antidiabetic agent not associated with harm among individuals with heart failure and diabetes.[22]

Health Canada issued a safety update in November 2007 based on a review of these studies.[13] According to the update, rosiglitazone is not approved for use alone, or with a sulfonylurea drug, except when metformin is contraindicated. Rosiglitazone is also not indicated in combination with Insulin or as triple therapy for patients with type II diabetes mellitus. Rosiglitazone is not indicated for patients with heart failure or a history of heart failure.

A recent American Diabetes Association/European Association for the Study of Diabetes update considers that thiazolidinediones should still be a possible second step option in the algorithm for management of patients with type II diabetes who are not well controlled on diet/lifestyle/metformin, as an alternative to insulin (most effective) and sulfonylureas (cheapest).[23] However, "the weight of the new information should prompt clinicians to consider more carefully whether to use this class of drugs." They also urge "greater caution in using thiazolidinediones in people with or at risk for congestive heart failure."[23]

A recent case-control study highlights the specific dangers of thiazolidinedione use in older people (age above 66 years) with diabetes.[24] This health care database study from Ontario, Canada found that that current thiazolidinedione therapy was associated with a significantly increased risk of heart failure (RR, 1.60, 95% CI, 1.21 - 2.10; p<0.001), acute myocardial infarction (RR 1.40, 95% CI 1.05 - 1.86;p=0.02) and death (RR 1.29, 95% CI, 1.02 - 1.62; p=0.03) compared with oral hypoglycemic agents. The increased risk with thiazolidinedione use seemed to be mainly with rosiglitazone.

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