Heart attack risk from diabetes drug

Behind the Headlines

Wednesday December 12 2007

A picture of a packet of Avandia

Avandia is the brand name for rosiglitazone

“Diabetes drug ‘increases risk of heart attack’”, according to reports in The Times and other newspapers. The reports described a study that has found that rosiglitazone (Avandia) – a drug commonly used by diabetics to control blood glucose – can increase the risk of heart failure by 60% and increase risk of death by 29%. The newspapers report the researchers as saying the results provide more compelling evidence of the health risks associated with this class of drugs.

This study in 159,026 diabetic patients aged 66 or older reinforces findings from previous studies that rosiglitazone is associated with increased risk of heart failure and heart attack. Drug regulators have been keeping rosiglitazone and similar drugs under close review since doubts about their safety became prominent in May this year. It is not clear whether this study on its own will persuade drug regulators to change their recommendations and revise the terms of the licence for rosiglitazone. As these drugs effectively control the blood glucose levels of people with diabetes, there is a balance to be made beween the benefits and potential harms of the treatment.

Rosiglitazone has appeared several times in the news this year. This is the latest of several studies that have reported similar results.

The UK and European drug regulators, the European Medicines Agency and the MHRA, advise that “the benefits of both rosiglitazone and pioglitazone in the treatment of type 2 diabetes continue to outweigh their risks.”


Where did the story come from?

Dr Lorraine Lipscombe and colleagues from the Institute for Clinical Evaluative Sciences in Ontario, Canada, and other medical and academic institutes across Canada carried out this research. The study was funded by Ontario Ministry of Health and Long-Term Care.


The study was published in the peer-reviewed medical journal, Journal of the American Medical Association, or JAMA.

What kind of scientific study was this?

The study was a nested case-control study in diabetics that investigated the use of the drugs rosiglitazone and pioglitazone and the risk of congestive heart failure (CHF) and acute myocardial infarction (AMI).

The researchers were interested what health effects the drugs of this class (called the thiazolidinediones or TZDs), have on people over 65 years old. The researchers were particularly interested in whether these drugs increased the risk of CHF, AMI and death compared to other drugs that control blood glucose levels.

The researchers used data from the Ontario Diabetes database to identify a group of Ontario residents who were all over 66 years old and who had been prescribed at least one treatment, taken in tablet form, to control blood glucose between April 1, 2002 and March 31, 2005.

People who were prescribed insulin by injection in the first year after entry into the study were excluded because insulin because it is usually those with more advanced diabetes who are receive insulin. The researchers believed that including these people in the analysis would have biased the results.

The researchers then identified “cases” for the study, people who had experienced an “event” (CHF, AMI, or death from any cause), between their inclusion in the study and its finish on March 31, 2006.

They compared each “case” with up to five “control” people who did not experience an event during the study. The controls were matched to cases for their age, sex, duration of diabetes, and history of cardiovascular disease.

The researchers were interested in seeing which drugs (TZDs or other drugs) were being used at the time of the event in the cases, and comparing them to the drugs that were being used in the matched controls.

What were the results of the study?

The study found that in comparison to taking other combination oral hypoglycemics, taking TZD monotherapy (rosiglitazone or pioglitazone) were 1.6 times more likely to experience congestive heart failure, 1.4 times more likely to experience acute myocardial infarction and 1.3 times more likely to die during the study.

People who were treated with a TZD in combination with another drug were 1.3 times more likely to experience CHF, equally likely to experience AMI and 1.2 times more likely to die than people taking a combination that did not include a TZD.

When the researchers looked at the particular drug used, i.e. rosiglitazone or pioglitazone, they found that only rosiglitazone increased risk of heart failure, AMI and death.

What interpretations did the researchers draw from these results?

Advice published by the EMA in October says:

  • Doctors should prescribe rosiglitazone- and pioglitazone-containing medicines according to the latest prescribing information.
  • Patients who are taking rosiglitazone or pioglitazone and have questions or concerns should talk to their doctor or pharmacist.

The researchers conclude that treatment with TZDs increases risk of congestive heart failure, acute myocardial infarction, and death compared to “other oral diabetes treatments”.

They say that these increases in risks were independent of other factors that may increase risk of these outcomes, such as cardiovascular risk and how long the parients had diabetes.

The researchers say that the lack of significant effect with pioglitazone alone or in combination with another drug may have been because their study lacked the power to see a real difference (i.e. there were not enough people in their sample who took pioglitazone).

Wphat does the NHS Knowledge Service make of this study?

This study adds to the evidence that there are harms associated with rosiglitazone as a treatment for diabetes. It will put drug regulators under pressure to look again at their recommendations and warnings.

Any interpretation of these findings should take into account the fact that the people in the cohort were a mean age of 75 years old and as such were already at high risk of cardiovascular disease.

Importantly, this was not a randomised study so it cannot be assumed that the cases and controls had the same risk profiles at the beginning of the study (i.e. that the controls were not healthier than the cases). It is possible that the groups were different due to the following:

  • The diabetes patients' drug use was identified through the Ontario Drug Benefit database that records reimbursements for prescriptions. In this Canadian province, people are only reimbursed for TZD use if they have failed treatment with other drugs or if other drugs are contraindicated. This means that the people identified as current users of TZDs are likely to have been at greater risk of adverse outcomes because their disease was probably more severe.
  • In clinical practice, the TZDs can be used differently from other drugs for the same condition (e.g. for people at higher risk). This would again make the results less reliable.

The researchers highlight some potential weaknesses of their study:

  • They relied on records that had been kept about the participants of their study (i.e. the study was retrospective). Incompleteness of the data may have biased their results.
  • The study lacked  “power” (i.e. not enough participants) to make any conclusions about the effects of pioglitazone. However, the researchers say that the trends observed in their results do not support the findings of other studies that suggest that pioglitazone protects against myocardial infarction and death.

Previous research has alerted researchers, drug regulators and practitioners to the harms associated with rosiglitazone and this study supports those findings. However, regulators took the decision not to ban the TZDs because they believe that, in selected groups, benefits outweigh the harms. In drug safety, as in other areas of medical research, the balance of benefits and harms are considered by taking into account all the available evidence and individual patient preferences.

Not withstanding the harms, TZDs are effective drugs in the control of blood glucose for diabetes. The researchers themselves call for  “further studies to better quantify the risk-benefits trade-off associated with thiazolidinedione therapy”.  If these studies can be randomised, the results will be more persuasive.


Sir Muir Gray adds...

Almost all treatments carry the possibility of harm as well as the possibility of benefit.


It is important that patients are given information about both the risks and benefits so they can make a choice based on the chance of each outcome happening and the values they attach to either the benefit or the harm.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Diabetes drug 'increases risk of heart attack'. The Times, December 12 2007

Diabetes drug 'can raise the risk of heart failure by 60pc'. Daily Mail, December 12 2007

Links to the science

Lipscombe LL, Gomes T, Lévesque LE, et al. Thiazolidinediones and Cardiovascular Outcomes in Older Patients With Diabetes. JAMA 2007; 298: 2634-2643.

Further reading

Richter B, Bandeira-Echtler E, Bergerhoff K, et al. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007, Issue 3

Further reading


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