Monday April 11 2011
Further issues need examination before the drug can be approved
Scientists have developed a “wonder pill to fight the flab”, the Daily Express has today reported. The newspaper says that scientists have developed a fat-busting wonder drug that has more than double the slimming power of an over-the-counter pill.
The drug, called Qnexa, has recently been trialled against a placebo (dummy) pill in overweight and obese individuals with at least two common associated illnesses, such as diabetes or high blood pressure. Compared with a placebo the new drug increased weight loss and also offered greater improvements in the other outcomes measured, including blood pressure.
This study will form part of the manufacturer’s submission to have the drug approved by the US Food and Drug Administration, and the drug company may then submit a similar application for marketing authorisation of this treatment in Europe. Both organisations will also look at the adverse effects of the drug, particularly the psychiatric side effects that are reported to be more common with this amphetamine-like drug. Until then the drug should be considered to be under investigation. A full review of its safety and efficacy is needed before people can start taking it.
Where did the story come from?
The study was carried out by researchers from Duke University Medical Center, the University of Alabama, Pennington Biomedical Research Center, the Medpace research organisation and the Vivus pharmaceutical company, all of which are in the USA. The research was funded by Vivus, which manufactures the drug. The study was published in the peer-reviewed medical journal The Lancet.
Many news sources claim that the drug leads to double the weight loss of orlistat, which is one of the drugs approved to treat obesity. However, this study compared Qnexa with a placebo rather than orlistat. The research paper only says that Qnexa “compares favourably” with orlistat.
What kind of research was this?
This randomised controlled trial investigated the effects of a newly developed weight loss drug called Qnexa in overweight and obese adults who also had two or more comorbidities (other health problems) including high blood pressure, disruption of blood lipids (dyslipidemia), abdominal obesity or diabetes or prediabetes. The study compared this drug in two different doses to a placebo. All drugs were administered orally.
Qnexa contains a combination of two drugs called phentermine and topiramate. Phentermine has similar pharmacological properties to amphetamines and acts by reducing appetite, while topiramate was originally marketed as an anti-epilepsy drug.
A randomised controlled trial is the best way to determine the effectiveness of a new treatment. This large randomised trial is one of three conducted by the drug manufacturer to test this treatment, and its results will be taken into account by the US Food and Drug Administration, which has asked for more research into the drug before it grants it approval. If the FDA approves Qnexa, it is likely that the manufacturer will then submit an application to the European Medicines Authority to make it available across EU member states.
What did the research involve?
In this trial 2,487 patients were randomly assigned either a placebo, a pill combining phentermine (7.5mg) and topiramate (46.0mg), or a pill combining phentermine (15.0mg) and topiramate (92.0mg). The patients were recruited from 93 centres in the US and the majority were white women. Their average age was 51 years and they were overweight or obese, with an average body mass index (BMI) of 36.6kg/m2. Each also had two or more pre-specified comorbidities. The majority of the sample had a large waist circumference (abdominal obesity) and a large proportion (68%) had impaired glucose metabolism including type 2 diabetes. Just over half the sample had high blood pressure.
The treatments (placebo and the study drug at different doses) were once-daily oral medications that were intended to be taken for 56 weeks alongside standardised counselling for diet and lifestyle modification. The participants had their weight and various aspects of health assessed before the study started, at two and four weeks after treatment began and then every four weeks thereafter. Among the factors measured were blood pressure, heart rate and waist circumference, as well as levels of substances such as inflammatory markers and blood lipids. Participants were also asked about the use of any other drugs, adverse events and how compliant they had been with their treatments.
The researchers were mainly interested in the average percentage change in bodyweight in each group during the study and also how many people achieved at least 5% weight loss. There were also secondary outcomes of interest, including changes in body mass index, blood pressure, blood fats and effects on diabetes. When they analysed these outcomes, they used an estimation method that allowed them to include the majority of randomised patients in analyses, even if those patients did not actually take part in the whole study. There are several statistical ways to do this and all essentially involve filling in the missing data with plausible values.
What were the basic results?
Both doses of the study drug were more effective than the placebo, resulting in greater weight loss: 6.5kg and 8.8kg more than placebo for the low and high dose treatments, respectively. Patients in the low-dose treatment group were more than six times more likely than those treated with placebo to achieve a weight loss of at least 5% (OR 6.3, 95% CI 4.9 to 8.0). The effect was greater with the higher dose of the treatment (OR 9.0, 95% CI 7.3 to 11.1). The drug also improved other outcomes measured, including blood pressure, waist circumference, blood fats and inflammatory markers.
Several side effects were greater with treatment than placebo, including dry mouth, taste problems, constipation, insomnia, depression, and irritability and anxiety with the high dose. The researchers note that the psychiatric adverse events were mainly during the early phase of treatment and they disappeared when the drug was discontinued.
How did the researchers interpret the results?
The researchers conclude that their drug combining topiramate and phentermine, when given along with lifestyle interventions, could be “added to the limited number of available treatments for obesity”.
This large randomised controlled trial describes a study assessing the effects of a new treatment for weight loss in overweight and obese individuals. It is well described and the authors raise the major limitation of their study: the fact that 31% of enrolled people had dropped out of the study by the time of the final assessment at week 56. This is a large dropout rate and it essentially means that the final analyses are based on imputed (inferred) results rather than actual results for many participants.
Imputation methods are not necessarily inaccurate, but they are by definition estimates of the true end points for participants. The researchers have not given much focus to this limitation and say that they addressed it by analysing their available data in three different ways, which did not produce greatly differing results. They note that dropout is usually a problem in these trials, although theirs was worse than seen in recent studies of two other weight loss drugs for obesity.
Dropouts during the study do not necessarily have anything to do with treatment effects or side effects. In this trial 38% of the total participants stopped taking their assigned treatment, but the dropout rate was highest in the placebo group, with 43% dropping out compared with 31% of the low-dose group and 36% in the high-dose group.
The authors raise several other important points that help to put this treatment in context:
- The study excluded people with clinically significant depression and the researchers say that caution is warranted when considering these treatments for people with mood disorders. The higher dose of treatment investigated here increased depression and anxiety.
- They say that continued treatment should be limited to people who have weight loss while using the drug. Not all participants taking these treatments lost weight.
- Certain side effects may lead to discontinuation of the drug, including neuropsychiatric problems.
Overall, there are limited pharmacological treatments for obesity. Orlistat is probably the most common alternative. The manufacturer’s website for this new drug, Qnexa, says that there are three large studies investigating its effects and that together they demonstrate that the drug is effective. It remains to be seen whether the FDA in the US approves it for use in America. The FDA has singled out the need to confirm that the drug does not increase adverse cardiovascular events and the need for suitable evidence and planning to ensure the drug does not pose a risk to foetuses if pregnant women take it.
If the drug is approved for use in the US, an application to the EU may then follow for consideration of the treatment under European regulations and systems. Until these full reviews of Qnexa’s efficacy and safety, the drug should be considered to be at an investigational stage.