New cholesterol drug tested

A new drug “cuts heart attack and stroke risk without side effects”, according to the Daily Mail. The newspaper says that the eprotirome tablets could rapidly lower cholesterol in people that do not respond to conventional statin drugs.

This is an important and well-conducted trial that gave participants either eprotirome or a placebo alongside their prescribed statin drugs. After 12 weeks of treatment with eprotirome, which is designed to mimic a thyroid hormone, there was a significant reduction in LDL cholesterol. Greater reductions were seen with increasing doses of eprotirome.

While the trial produced good results, newspapers have been premature in predicting the action of the eprotirome - all people in the study still took their prescribed statins so it is unclear how the drug works in isolation. The trial was also limited by size and duration, with only 189 participants and just 12 weeks of treatment.

Overall, the findings of this early trial are promising, but further testing will be needed to establish the drug’s actions in isolation, long-term safety and to see whether it actually cuts heart attack and stroke risk, as newspapers have claimed.

Where did the story come from?

This research was conducted by Dr Paul Ladenson and colleagues from Johns Hopkins University School of Medicine, Baltimore, and other institutions in the US and Sweden. The study was funded by grants from the Swedish Research Council, the Swedish Heart-Lung Foundation, Karolinska Institutet and Stockholm City Council. The study was published in the peer-reviewed The New England Journal of Medicine.

The news reports in the Daily Mail and Daily Express are premature in hailing a ‘new statin’ that cuts cholesterol and disease risk without side effects. All study participants were also taking prescribed courses of statins, but the newspapers have not considered the key fact that this trial has only looked at this drug as an addition to conventional statin treatment, and not as a replacement for it.

There is also a need for longer-term follow-up trials in much larger numbers of people before any firm conclusions can be made on the drug’s safety and efficacy. In particular, no conclusions can be made from this trial about the effect eprotirome has on cardiovascular health or disease risk, as the trial only looked at immediate changes in cholesterol levels.

What kind of research was this?

This was a double-blind randomised controlled trial investigating the cholesterol-lowering effects of a new compound called eprotirome. The drug acts in a similar way to a thyroid hormone, which has been demonstrated to lower levels of low density lipoprotein (LDL), often referred to as ‘bad’ cholesterol. In this trial, people who were already taking a statin were randomised to take either eprotirome or a placebo alongside their existing statin treatment.

Randomised controlled trials are the best way of investigating the safety and efficacy of a new treatment. With this particular ‘thyroid-mimicking’ drug, there is a particular need to ensure that the treatment does not cause adverse effects similar to what would be seen in a person with thyroid disease (either underactive or overactive). Given this potential risk, the safety findings of this small trial would need to be replicated in larger numbers of people using the treatment for a longer duration than 12 weeks.

Importantly, all the people in the trial were already receiving statins and the eprotirome or placebo was added to see whether there was any incremental effect of the new drug. The fact that nobody used eprotirome alone means that at this stage no comparison can be made between eprotirome alone and existing statins with regard to cholesterol-lowering effects, adverse effects, or effects upon risk of cardiovascular disease.

What did the research involve?

People were enrolled in this trial between November 2007 and January 2008. All subjects had to have been stable on statin treatment (atorvastatin or simvastatin) for at least three months, but still have elevated cholesterol (≥116mg per decilitre, equivalent to ≥3.0mmol per litre). The researchers excluded those who had a history of thyroid disease, heart failure, recent heart attack or cardiac surgery, stroke, liver disease, uncontrolled diabetes, severe high blood pressure or drug or alcohol misuse problems.

Those that were eligible and agreed to participate (189 people) then received a four-week dietary education programme before being randomised to receive either eprotirome or placebo for 12 weeks in addition to their prescribed statin. Three different doses of eprotirome were used: 25, 50 or 100 micrograms.

After the 12 weeks the participants discontinued the trial drugs but continued their statin use. They were then reassessed four weeks later, with the main outcome being change in LDL cholesterol from the start of the trial to week 12. Safety assessments documented details of heart rate, blood pressure, body weight, electrocardiogram readings, blood tests (specifically effects on thyroid function) and any adverse effects.

What were the basic results?

Of the 189 participants randomised into the study, 168 (89%) completed the trial, 184 (97.4%) were included in the efficacy analyses and all 189 were included in the safety analysis.

The average LDL cholesterol level was 141mg per decilitre at study start. Supplementing prescribed statin treatment with trial treatments reduced levels to:

  • 127mg per decilitre with placebo (7% reduction)
  • 113mg per decilitre with the 25 microgram dose eprotirome (22% reduction)
  • 99mg per decilitre with the 50 microgram dose eprotirome (28% reduction)
  • 94mg per decilitre with the 100 microgram dose eprotirome (32% reduction)

The proportions of patients who had an LDL cholesterol level of less than 100mg per decilitre (<2.6mmol per litre) at week 12 were:

  • 6% of the group who received placebo
  • 36% of those who received 25 microgram eprotirome
  • 50% of those who received 50 microgram eprotirome
  • 57% of those who received 100 microgram eprotirome

The improvement in LDL cholesterol levels was significantly greater in the eprotirome groups than in the placebo group. Other blood cholesterol and fat levels were also reduced with eprotirome compared with placebo. The four groups showed similar rates of adverse effects, with most effects being of mild or moderate severity.

While eprotirome had no effect upon one of the thyroid hormones measured (triiodothyronine), levels of the other (thyroxine) decreased. However, levels of both hormones remained within the normal range and there were no symptoms of thyroid disease. These effects were reversed on discontinuation of the drug.

How did the researchers interpret the results?

The researchers concluded that 12 weeks of treatment with the thyroid hormone eprotirome, in addition to continued statin treatment, decreased blood cholesterol levels.


This is an important and well-conducted trial, which has demonstrated the potential of a drug, eprotirome, to lower cholesterol levels. However, conclusions about the effects of this drug should not be made too prematurely and much further research is needed:

  • So far, use of the drug alone has not been compared to statin treatment. In this trial eprotirome or inactive placebo was only ever given in addition to people’s long-term statins. Therefore no comparison of cholesterol-lowering effect of each of the treatments alone can be made.
  • Only a small number of people were included in the trial: 47 on the 25microgram dose, 46 on 50micrograms, and 44 on the 100microgram dose of eprotirome. These groups of participants are too small to draw any conclusions on the safety or efficacy of eprotirome. The trial will need replication in much larger groups of participants, particularly when trying to determine the dose of eprotirome that provides the optimal balance between benefits and risks.
  • With both the short, 12-week duration of this trial and the small number of participants, it is not possible to draw firm conclusions about the safety of eprotirome and it is too early to say that this drug is ‘without side effects’ as headlined by the Daily Mail. In particular, the longer-term effects of this drug upon the body’s thyroid function and liver enzymes need to be assessed.
  • As this was only a 12-week trial, it is not possible to tell the longer-term effects that eprotirome could have upon cardiovascular health and mortality risk. Therefore, newspaper claims that eprotirome ‘cuts heart attack and stroke risk’ are currently unfounded.

The findings of this early trial into the use of eprotirome to lower cholesterol in addition to statins are promising, and further research is awaited.

NHS Attribution