New Hope For Obesity

Comment

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 placebo with 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 body fat, 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 The table compares the weight-loss effects of several drugs, including fenfluramine, which has been withdrawn, and the combination of phentermine and fenfluramine.4–7 Clearly, weight loss with tesofensine is better than with all of the other monotherapies, and as good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 www.thelancet.com Vol 372 November 29, 2008

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 weight loss. 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 the combination 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 Run-in period of studies

Tesofensine2*

Length (weeks)

Change in weight (kg)

See Articles page 1906

Intervention period (change in weight [kg]) Control

Control range

1

2

–1·1

–2·2

Fluoxetine4

11

··

··

–0·78

–1·5 to –2·4

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

–1·57

–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

1

6

–4·2

–0·7

Phentermine+fenfluramine6

–1·9 to 2·1

··

Drug

··

–12·8 –4·10

–5·1 –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

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Comment

of whether there will be a similar problem in larger clinical trials. Sibutramine, another multimonoaminereuptake inhibitor, substantially increases blood pressure 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 serotonergic mechanisms. As monotherapy, fenfluramine had only modest effects (table). When phentermine and fenfluramine were combined, weight loss improved substantially. In Astrup’s and colleagues’ trial, if the runin 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 fenfluramine with 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 difficulties. 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 were taking the drug.12 George A Bray Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA [email protected] I am a member of the Data and Safety Monitoring Board for this trial. 1 2

3 4

5

6

7 8 9

10

11 12

CDC. State-specific prevalence of obesity among adults: United States, 2007. MMWR Morb Mortal Wkly Rep 2008; 57: 765–68. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1906–13. Simons-Morton DG, Obarzanek E, Cutler JA. Obesity research—limitations of methods, measurements, and medications. JAMA 2006; 295: 826–28. Haddock CR, Poston WSC, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes 2002; 26: 262–73. Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194–99. Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight control study I (weeks 0 to 34): the enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992; 51: 586–94. Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev 1999; 20: 805–75. Bray GA, Greenway FL. Pharmacological treatment of the overweight patients. Pharmacol Rev 2007; 59: 151–73. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007; 370: 1706–13. Nissen SE, Nicholls SJ, Wolski K, et al, for the STRADIVARIUS Investigators. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 2008; 299: 1547–60. Bray GA. The battle of the bulge. Pittsburgh, PA: Dorrance Publishing, 2007. European Medicines Agency. The European Medicines Agency recommends suspension 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 insufficiency, 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). 1860

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 www.thelancet.com Vol 372 November 29, 2008