Diet pill needs more research

“A weight loss drug that helps users shed two stones in six months will give new hope to the obese” the_ Daily Express_ reports. The newspaper adds that treatment is “twice as effective as current treatments and can see overweight patients lose up to 10 per cent of their body weight quickly”.

The story is based on a Danish study of a drug – tesofensine – which was used in obese patients who also on a restrictive diet. It found that dieting patients taking the highest doses lost up to 12.8kg (28.2lbs) in six months. However, the drug was compared with placebo not with other currently used weight-loss drugs. There were some short-term side effects, but the trial was not large enough or long enough to look for any other side effects, particularly long-term effects on the heart. More trials are needed before this drug is likely to become available for people to use.

Where did the story come from?

Professor Arne Astrup from the Department of Human Nutrition, Faculty of Life at the University of Copenhagen and colleagues from other hospitals in Denmark carried out this research. The study was funded by Neurosearch A/S, a pharmaceutical company in Denmark, and supported by grants from the European Union and the Center for Pharmacogenomics in Denmark. It was published in the peer-reviewed medical journal, The Lancet.

What kind of scientific study was this?

This was a phase 2 randomised controlled trial in which the researchers wanted to test the efficacy (how well a drug works in trial situations) and safety of the new drug tesofensine in obese patients. Tesofensine was developed to increase the levels of certain chemicals in the brain – noradrenaline, dopamine and serotonin – as the levels of these chemicals are known to be lower in people with Alzheimer’s and Parkinson’s disease. Early trials with the drug showed unintended weight loss in Parkinson’s patients, and it is thought that increased concentrations of these chemicals act to reduce appetite.

The researchers recruited patients from five Danish obesity management centres from September 2006 to August 2007. They recruited men and women aged 18 to 65 years by advertisement or by taking people who were on waiting lists for obesity treatment. Pregnant women were excluded, and all women participating in the study had to be using safe contraceptive methods (contraceptive pills, intrauterine device or have been surgically sterilised). Smokers were allowed to take part if their smoking habits hadn’t changed for at least two months. There were several other exclusions designed to ensure a relatively healthy population, and, importantly, patients with a previous history of anxiety or depression were not excluded if they had fully recovered. However, the researchers did exclude those requiring treatment for a psychiatric disorder. This is because the chemicals in the brain that the drug affects are linked to depression.

At the start of the trial, the participants had a two-week ‘run-in period’. During this time, they started an energy-restricted diet on the instruction of dieticians. This diet provided a daily energy deficit of 300 kcal, and ensured 20–25% of energy from fat, 20–25% from Protein, and 50–60% from carbohydrate. After two weeks, the researchers split the 203 obese patients into four groups: one placebo group and three groups that took different doses of the active drug (0.25mg, 0.5mg or 1mg), taken daily. Everyone was given instructions to increase their levels of physical activity gradually, up to 30–60 min per day. Every week for the first four weeks, and then every second week, patients attended group sessions at the centre where they were trained by skilled dieticians in basic nutritional education and behavioural change for weight control. They all received information reinforcing the diet.

After six months, all the participants had their weight re-measured. Throughout the period, they were asked to record any side effects that they noticed. Although all groups were blinded and therefore unaware of whether they were receiving the active or dummy pills, the researchers did not ask the groups whether they knew which group they were allocated to – this could have been a measure of the success of the blinding.

What were the results of the study?

The treatment groups had similar characteristics at the start of the trial. Out of the 203 patients, 143 (70%) were women. In all, 161 (79%) completed the treatment, although 42 (21%) participants withdrew during the 24 weeks, with fewer patients withdrawing in the tesofensine 0.5mg group than in the tesofensine 1.0mg group.

The average weight loss produced by diet and placebo was 2.0%. Diet and 0.25mg tesofensine induced a average weight loss of 4.5%, whereas the stronger doses 0.5mg and 1.0mg (along with diet) induced losses of 9.2% and 10.6%, respectively. Compared with diet and placebo alone, all reported differences were statistically significant.

The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea and insomnia. After 24 weeks, tesofensine 0.25mg and 0.5mg caused no significant increases in blood pressure compared with placebo, but heart rate was increased by 7.4 beats per min in the tesofensine 0.5mg group.

What interpretations did the researchers draw from these results?

The authors concluded that their results suggest that tesofensine 0.5mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase 3 trials.

What does the NHS Knowledge Service make of this study?

Phase 2 trials are an important part of the evaluation of new drugs. As they are not designed to recruit large numbers of patients, or to run for a long period of time, they cannot provide information on long-term outcomes (weight loss or side effects), and they cannot detect rare, uncommon adverse effects that might later prove to be important. Several features of this trial are worth noting:

• There was no direct comparison with existing weight loss drugs, and therefore the claim in the Daily Express that the drug is “twice as effective” comes from an indirect comparison of the results of this trial with the results of other trials. As these other trials may have been conducted in different populations or groups of people with different starting weights, this might not be a fair comparison.
• The significant increase in heart rate shown in this research suggests that the drug has an effect on the heart. Any increases in heart attack or stroke (not measured in this small trial) will need careful evaluation. Any drug that is used to treat obesity and has demonstrated these side effects will need to show that it does not adversely affect cardiovascular risk.
• The researchers also say that the adverse event profile of tesofensine 0.5mg is promising, and the haemodynamic effects are similar to or slightly weaker than those of another commonly used weight-loss drug, sibutramine. The authors say that the 0.5mg dose of tesofensine has the potential to produce twice the weight loss as currently approved drugs.

The researchers rightly warn that larger phase 3 studies are needed to substantiate their findings.