Tesofensine - initial trials of a potential weight-loss drug

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial
Original source: The Lancet Volume 372, Issue 9653
Authors: Arne Astrup (corresponding author), Prof Sten Madsbad, Leif Breum, Thomas J Jensen, Jens Peter Kroustrup, Thomas Meinert Larsen
Publication date: 29 November 2008
DOI (digital document ID): 10.1016/S0140-6736(08)61525-1
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
The investigators are interested in producing a safe, more-effective weight loss drug than those already on the market. They looked at safety and effectiveness of tesofensine, which inhibits the uptake of several hormones. Current weight loss drugs only provide an average of 3-5 kg (7-12 lb) greater weight loss than diet and exercise alone.

The investigators conducted a double-blind, placebo-controlled survey of 203 obese patients over a six-month period, along with diet and exercise. Three strengths of tesofensine were used in the study. The patients who used tesofensine lost more weight than those who did not, and the larger the dose of tesofensine, the more weight they lost. The most common side effects reported in the abstract were relatively minor.

The investigators reported that the two lower strengths of tesofensine did not raise blood pressure or heart rate, and that the middle dosage raised heart rate by an average of 7.4 beats per minute.

Reliability:
This is a Phase II study, conducted by the drug manufacturer. This means it is one of the earlier human-based studies. Based on the small sample and limited time, the investigators believe the drug is safe and effective; however, more complete, Phase III studies are needed to prove this over larger populations, over longer amounts of time.

That the lower strengths of tesofensine "showed no significant increases in systolic or diastolic blood pressure compared with placebo" suggests that the drug does indeed raise blood pressure (they did not state this of the highest strength tested -- suggesting that the higher dosage might indeed cause a significant rise in blood pressure). The increase in heart rate may have other adverse implications.

Update:
Several comments to this article were posted in the 2009 February 28 issue of The Lancet. Concerns addressed included not just the rise in blood pressure -- which apparently was not considered in the context of predicted drops in blood pressure due to weight loss -- and adverse psychological effects of the drug. The authors' response to these concerns was to suggest that drops in blood pressure were due to dietary change rather than weight loss itself, and to note that there were no adverse psychological effects observed in their test population.

Again, this was a Phase II trial, which means that it is one of the earlier human-based trials before a drug can be marketed in the United States.


Practical Applications:
The search for a safe, effective weight loss pill is ongoing. Our understanding of the interrelationship between obesity, insulin resistance, hypertension, and cardiovascular disease is still imperfect, but observation suggests that reducing the degree to which one is obese can reduce or reverse the damage of metabolic syndrome.

Since it will often take more than a year for a determined obese person to lose sufficient weight to move out of the "obese" classification, weight-loss drugs should be proven to be safe and effective over a period of years. Since there is also a potential for impatient patients to want to increase the dose, they should be proven to be safe at greater doses than those intended for prescription.

This synopsis was based on the abstract only.