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Cardiovascular update on TZDs

Questions remain about whether drug dose, meta-analyses data affect the results.

Issue: March 2008

ByPeter W.F. Wilson, MD

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The favorable effects of thiazolidinediones on metabolism are well appreciated. The general action is via PPAR gamma and seemingly salutary metabolic changes include lowering of plasma glucose, improved insulin sensitivity, higher HDL cholesterol, lower triglycerides, reduction in microalbuminuria, and improved blood levels of inflammatory markers. On the other hand, safety has been a concern with these medications since they were first used in the Primary Prevention of Diabetes trial. In that study it was noted that troglitazone was associated with the development of severe liver toxicity in the rare patient. Case reports followed up, the troglitazone arm of the trial was discontinued, and eventually the medication was withdrawn from the market.

A variety of cardiovascular and metabolic observational studies have been undertaken with TZDs over the last few years. The PROactive study investigated the use of pioglitazone in the secondary prevention of CVD in adults with diabetes. During this trial, it was noted that pioglitazone users were more likely to gain weight and develop leg edema. As reported in 2005, pioglitazone users in this trial experienced a 40% greater risk of heart failure (5.7% pioglitazone vs. 4.1% non-users).

Recent studies have placed greater emphasis on assessing cardiovascular benefits and adverse events for TZD users. For example, the DREAM study was a clinical trial designed to assess the prevention of type 2 diabetes in people with impaired fasting glucose or impaired glucose tolerance. The researchers reported three-year cumulative rates of heart failure that were 0.5% in the rosiglitazone users and 0.1% in the non-users, a result that was statistically significant. On the other hand, the ADOPT study, which investigated glycemic control in rosiglitazone users vs. other oral hypoglycemic agents, reported heart failure risks of 1.5% in TZD users vs. 1.4% in non-users, which was not statistically significant.

A review and meta-analysis of the effects of rosiglitazone were reported by Nissen, et al and it described a 43% greater risk for myocardial infarction (P=.03), and 64% increased risk for cardiovascular death (P=.06) across 42 trials. Usually one meta-analysis on a topic is relatively definitive, but TZDs and cardiovascular safety are of considerable interest. Last September, Singh et al published a review and meta-analysis of long-term risk of CVD in people taking rosiglitazone. They reported a 42% greater risk of MI (P=.02), a 109% greater risk for heart failure (P<.001), and 10% lower risk of cardiovascular mortality (P=.53).

Correspondingly, more than one meta-analysis of the cardiovascular effects of pioglitazone were published in 2007. Lincoff et al reviewed 19 trials and reported a 41% greater risk of heart failure in people with diabetes taking pioglitazone (P=.002) and a 10% lower risk of a composite CVD endpoint [death, MI or stroke] (P=.005). Within the same month, Lago et al reported a 32% greater risk of heart failure in pioglitazone users (P=.02) and 118% greater risk of heart failure in rosiglitazone users (P=.0003). For the outcome cardiovascular death Lago et al reported a 1% lower risk in pioglitazone users (P=.99) and 11% lower risk in rosiglitazone users (P=.89).

A nested case-control study of TZD use in Ontario, Canada showed that TZD monotherapy imparted a 60% greater risk for MI (P<.001), a 40% greater risk of MI and a 29% greater risk of death (P=.03) compared with other oral hypoglycemic regimens.

Unanswered questions linger for use of TZDs in the outpatient setting. Does drug dose affect the results, do the results vary for comparisons with different oral hypoglycemic agents, and do meta-analyses with raw data, not summary data, provide different interpretations? The most recent analyses try to incorporate these issues into their studies and we can expect to read more about them in the future.

To summarize, both pioglitazone and rosiglitazone appear to increase the risk for heart failure, risks for cardiovascular morbidity and composite events are generally greater for rosiglitazone than for pioglitazone, and the effects of TZDs on the risk for death are generally smaller and in some reports not statistically evident.

Prudence and vigilance for TZD users and prescribers now are the cautionary words, especially considering that most of the candidates for TZDs are older and usually obese. These potential TZD users are at intermediate-to-high risk for the development of heart disease, and they may have already been diagnosed with heart disease. More safety data will be forthcoming when the ongoing trials using TZDs report their final results.

We may even have some more meta-analyses to read after these new studies report their results.

Peter W. F. Wilson, MD, is a Professor of Medicine at Emory University and is a member of the Endocrine Today Editorial Board.

For more information:

• Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet. 2005;366:1279-1289.
• Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
• Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials. Lancet. 2007; 370:1129-1136.
• Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007; 298:1180-1188.
• Lipscombe LL, Gomes T, Levesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA. 2007;298:2634-2643.
• Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; 356:2457-2471.
• Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189-1195.