Heart study questions diabetes drugs
Published online 22 June 2009
nature.com doi:10.1038/news.2009.588
News
A molecular pathway could explain how a class of drugs leads to heart failure.
Charlotte Schubert
Researchers who study how tumours balloon in size have discovered one way that enlargement of the heart can lead to heart failure. The work, although mostly done in mice, could help explain why a class of diabetes drugs called thiazolidinediones (TZDs) increase the risk of heart failure.
These drugs have been controversial since a 2007 analysis1 of Avandia (rosiglitazone), a TZD made by GlaxoSmithKline, suggested that patients taking it are at increased risk of heart attack. Less controversial are data linking TZDs with heart failure, a distinct condition in which the heart cannot pump enough blood through the body.
"We already knew if you had heart failure you probably should not be taking these drugs, but this paper provides an additional explanation why," says Clay Semenkovich, an endocrinologist at the Washington University School of Medicine in St Louis, Missouri.
The work suggests that a molecule activated by TZDs, called PPAR-[gamma], underlies one aspect of heart failure.
Serendipity
When Wilhelm Krek, a cancer biologist at the Swiss Federal Institute of Technology in Zurich, and his colleagues began the study, they were not thinking about diabetes drugs. They wanted to know what happens when tissues enlarge.
"If a cancer grows, it outstrips its nutrient and oxygen supply," says Krek. Something similar may happen when the heart enlarges, as it often does after a heart attack or during chronic high blood pressure. The increased size enables the heart initially to pump more blood but can ultimately weaken the organ.
Enlarged hearts labour to get oxygen, and they switch from burning fat to glucose, which can provide energy without oxygen but is less efficient. Heart cells can then weaken, accumulate fat and eventually commit suicide. Krek and his colleagues found that PPAR-[gamma] may usher in this downfall.
The researchers found high levels of PPAR-[gamma] in heart tissue from people with heart failure, as well as in hearts of mice experimentally manipulated to model the condition. When they knocked PPAR-[gamma] out in mouse heart cells, the cells did not accumulate fat and did not die.
In the failing heart, PPAR-[gamma] works together with a protein found in many tumours that coordinates the body's response to low oxygen. The study is published in the June issue of Cell Metabolism.2
New treatments
The findings open the door to new ways of counteracting heart failure, which afflicts between 1% and 2% of adults in developed countries. But they also raise the possibility that activation of PPAR-[gamma] by TZDs could bump up fat accumulation and cell suicide in the heart.
David Moller — a researcher at Eli Lilly, the Indianapolis, Indiana-based maker of the TZD Actos (pioglitazone) — points out that the drugs may also promote heart failure by causing the accumulation of fluids in the body, forcing the heart to work harder. The new study, he says, "provides one additional hypothesis".
The clinical effect of TZDs on heart failure is more clear-cut. In the 20 June issue of The Lancet, researchers funded by GlaxoSmithKline published a study3 examining whether Avandia raised the risk of cardiovascular events such as stroke and heart attack compared with conventional diabetes drugs. The study shows that Avandia doubles the risk of heart failure, in sync with previous findings on TZDs.
Avandia's role in heart attacks is far more in dispute. The Lancet paper is the full publication of a trial involving 4,447 people and confirms an earlier, interim analysis that Avandia does not increase deaths from cardiovascular events.
But in an editorial accompanying the study, endocrinologists Ravi Retnakaran and Bernard Zinman of Mount Sinai Hospital in Toronto, Ontario, in Canada, said: "Definitive conclusions about the relation between [Avandia] and cardiovascular disease remain elusive." For instance, people in the study who took Avandia also had increased use of statins, drugs that may have reduced cardiovascular events. And people taking Avandia did have a slightly higher risk of heart attack, although the increase was not statistically significant.
Diabetes researchers note that not all TZDs are the same. Actos, for instance, raises fewer concerns about heart attack in clinical studies and may be beneficial. It's possible that new agents under development which target PPAR-[gamma] in a slightly different way might carry fewer risks.
References
1. Nissen, S. E. & Wolski, K. N. Engl. J. Med. 356, 2457–2471 (2007).
2. Krishnan, J. et al. Cell Metab. 9, 512–524 (2009).
3. Home, P. D. et al. Lancet 373, 2125 - 2135 (2009). |
