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www.thelancet.com  Vol 372 November 29, 2008 1859

Is new hope on the horizon for obesity?

Obesity is a growing and global problem. The US

Centers for Disease Control and Prevention reported

that the prevalence of obesity, which was established

in a telephone survey of 350 000 Americans, had

increased from 23·2% to 25·7% between 2005 and

2007.1 Although prevention is clearly the first strategy

to deal with this problem, many people will need some

form of treatment. Thus the study on tesofensine

by Arne Astrup and colleagues in The  Lancet today, a

phase II clinical trial with a new agent, is welcome.2 In

a 6-month randomised trial, they compared placebowith three doses of drug, while all patients were also

on an energy-restricted diet. At the end of the trial, the

groups treated with the two highest doses had lost,

on average, 11·3 kg and 12·8 kg of baseline weight

compared with 2·2 kg in the placebo group (the average

proportionate changes from baseline for the drug

compared over that of diet and placebo were –9·2% and

–10·6%, respectively; the change with diet and placebo

was –2·0%). Their trial has many strengths, including a

low drop-out rate of 21% compared with nearly 50% in

other trials,3

documentation that weight loss was bodyfat, demonstration that quality of life improved, and

that no important behavioural changes were noted.

Patients in Astrup and colleagues’ study benefited

from a decrease in plasma triglycerides, a decline in

haemoglobin A1c, a fall in insulin, and an increase

in adiponectin. The table compares the weight-loss

effects of several drugs, including fenfluramine, which

has been withdrawn, and the combination of phen-

termine and fenfluramine.4–7 Clearly, weight loss

with tesofensine is better than with all of the other

monotherapies, and as good as the combination of 

phentermine and fenfluramine when the run-in period

in Astrup’s trial is subtracted.7 This result might indicate

that tesofensine is a form of combination therapy,

because it blocks reuptake of multiple monoamines,

although sibutramine, which has a similar mechanism,

produces a smaller weight loss.

To put these results into perspective we need to

compare them with other studies. First, in Astrup and

colleagues’ trial, the groups treated with the higher

two doses of tesofensine were still losing weight after

6 months, which suggests that clinical weight loss

might be greater than that reported. The plateau for

most drugs occurs between 6 and 9 months,7 except

for topiramate, which takes longer.8 Second, Astrup

used a run-in period, which can generate challenges

for interpretation of metabolic variables, which change

most rapidly at the start of weight loss. The same issue

has been a problem in the interpretation of some trials

with rimonabant. For three reasons, I feel that clinical

trials of drugs should start both drug and diet at the

same time: to avoid distortion of metabolic responses;

because this is how most physicians will use weight-loss

drugs; and to give a clearer picture of overall weightloss. Thus, in Astrup’s trial with tesofensine, actual

weight loss was 1·1 kg more than the change from

baseline because of the 1·1 kg weight loss during the

run-in (table).

Another problem is the placebo group. In Astrup

and colleagues’ trial, the placebo group lost 2·2 kg

(3·3 kg if the run-in is counted). This loss would be an

average placebo effect, which is indicated by the range

of effects shown for other trials (table).8 The size of the

placebo effect affects the net or placebo-subtracted

weight loss. Because the patient will benefit from thecombination of placebo and diet effect, expressing

results of clinical studies as gross weight loss in

addition to placebo-subtracted weight loss makes

sense.

The health-care provider needs to compare risks

versus benefits to enable decisions about obesity

drugs. With tesofensine, the increase in blood

pressure with the highest dose raises the question

Number

of studies

Run-i n period Intervention period (change in

weight [kg])

Length(weeks) Change inweight (kg) Control Controlrange Drug

Tesofensine2* 1 2 –1·1 –2·2 ·· –12·8

Fluoxetine4 11 ·· ·· –0·78 –1·5 to –2·4 –4·10

Orlistat5 14 0–4 0 to –1·5 –2·40 –0·9 to –7·6 –5·70

Sibutramine5 10 ·· ·· –2·22 –0·2 to –8·5 –6·33

Rimonabant5 4 4 –1·9 to 2·1 –1·57 –1·4 to –1·8 –6·23

Phentermine4 9 ·· ·· –2·8 –1·5 to –5·2 –6·3

Fenfluramine4 15 ·· ·· –2·41 –1·2 to –3·2 –5·1

Phentermine+fenfluramine6 1 6 –4·2 –0·7 ·· –9·8

Data for tesofensine and phentermine+fenfluramine are from single studies. Data for tesofensine, fluoxetine,

phentermine, and fenfluramine are unweighted means; data for orlistat, sibutramine, and rimonabant are weighted

means. *Highest daily dose of tesofensine (1·0 mg); weight loss with intermediate dose (0·5 mg) was –11·3 kg.

Table: Comparison of weight loss with different drugs

See Articles page 1906

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1860 www.thelancet.com  Vol 372 November 29, 2008

of whether there will be a similar problem in larger

clinical trials. Sibutramine, another multimonoamine-reuptake inhibitor, substantially increases blood pres-

sure as an undesirable side-effect.5 Although Astrup

and colleagues did a good job of evaluating potential

CNS events, this is an area that needs careful attention

in phase III trials because CNS side-effects have posed a

problem for rimonabant.9,10

Drugs that modulate the functions of monoamines

have been in use since dexamfetamine was shown

to reduce bodyweight more than 70 years ago.11 

Fenfluramine was the first drug to act through sero-

tonergic mechanisms. As monotherapy, fenfluraminehad only modest effects (table). When phentermine

and fenfluramine were combined, weight loss improved

substantially. In Astrup’s and colleagues’ trial, if the run-

in period (1·1 kg) is added to the intervention period,

the overall 6-month weight loss would be 7·8, 12·4, and

13·9 kg for the three doses of tesofensine, respectively.

By contrast, sibutramine produced only modest effects.

The reason for this difference between drugs with a

similar mechanism is unclear.

Weight loss with tesofensine is larger than that with

other single drugs, and approaches that of fenfluraminewith phentermine. The main side-effect was an increase

in pulse rate and a small rise in blood pressure at the

highest dose. Pharmacotherapy for obesity is a rapidly

moving field, but one fraught with diffi culties. On

Oct 23, the European Medicines Agency recommended

the suspension of the marketing authorisation for

rimonabant, because of an approximate doubling

of the risk of pyschiatric disorders, compared with

placebo, in obese or overweight patients who weretaking the drug.12

George A BrayPennington Biomedical Research Center, Baton Rouge,

LA 70808, USA

george.Bray@PBRC.edu

I am a member of the Data and Safety Monitoring Board for this trial.

1 CDC. State-specific prevalence of obesity among adults: United States,2007. MMWR Morb Mortal Wkly Rep 2008; 57: 765–68.

2 Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life inobese patients: a randomised, double-blind, placebo-controlled trial.Lancet 2008; 372: 1906–13.

3 Simons-Morton DG, Obarzanek E, Cutler JA. Obesity research—l imitationsof methods, measurements, and medications.  JAMA 2006; 295: 826–28.

4 Haddock CR, Poston WSC, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapyfor obesity: a quantitative analysis of four decades of publishedrandomized clinical trials. Int J Obes 2002; 26: 262–73.

5 Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapyfor obesity and overweight: updated meta-analysis. BMJ 2007;335: 1194–99.

6 Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight controlstudy I (weeks 0 to 34): the enhancement of behavior modification, caloricrestriction, and exercise by fenfluramine plus phentermine versus placebo.Clin Pharmacol Ther 1992; 51: 586–94.

7 Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev 1999; 20: 805–75.

8 Bray GA, Greenway FL. Pharmacological treatment of the overweightpatients. Pharmacol Rev 2007; 59: 151–73.

9 Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Effi cacy and

safety of the weight-loss drug rimonabant: a meta-analysis of randomisedtrials. Lancet 2007; 370: 1706–13.

10 Nissen SE, Nicholls SJ, Wolski K, et al, for the STRADIVARIUS Investigators.Effect of rimonabant on progression of atherosclerosis in patients withabdominal obesity and coronary artery disease: the STRADIVARIUSrandomized controlled trial. JAMA 2008; 299: 1547–60.

11 Bray GA. The battle of the bulge. Pittsburgh, PA: Dorrance Publishing, 2007.

12 European Medicines Agency. The European Medicines Agency recommendssuspension of the marketing authorisation of Acomplia. Oct 23, 2008.http://www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/53777708en.pdf (accessed Oct 29, 2008).

Chronic wound care

Chronic wounds are defined as wounds that have not

proceeded through an orderly and timely reparation

to produce anatomic and functional integrity after

3 months. All wound types have the potential to become

chronic and, as such, chronic wounds are classified

by cause, identification and treatment of which are

essential.1–3 Venous or arterial insuffi ciency, diabetes,

and local-pressure effects are the most common

pathophysiological causes, whereas systemic factors,

such as compromised nutritional status, infection, and

altered immunological status further contribute to poor

wound healing (table).

General wound-management principles can be applied

to many types of chronic wounds. The Wound Healing

Society has promoted the use of the TIME acronym to

comprehensively define, communicate, and address key

elements of impaired wound healing.4  T  is for tissue:

establishment of the presence of either devitalised or

necrotic tissue, and identification of specific deficits. I is

for the presence of inflammation or infection, or both.

M describes the state of moisture balance, ranging from

desiccation to maceration. E refers to the wound edge,

whether non-advancing or undermined, or the extent of 

re-epithelialisation.4