Feature Obesity

The future of obesity treatment: what can drugs and surgery offer?

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e1011 (Published 14 February 2012) Cite this as: BMJ 2012;344:e1011
  1. Geoff Watts, freelance journalist, London
  1. geoff{at}scileg.freeserve.co.uk

When lifestyle approaches fail, what can drugs and surgery offer in the management of obese patients? Geoff Watts gets expert advice on current and future options

Three fifths of adults in England are either overweight or obese1; so are almost a quarter of 4 to 5 year olds. If present trends continue, three fifths of all men, half of all women, and a quarter of all children will be obese by 2050. Global numbers have more than doubled since 1980.

Unless lifestyle changes prove a lot more effective than they have so far in halting the rise of obesity, we’re looking at drugs and surgery. But which? And which drugs and which surgery? These and other taxing questions were aired at a recent meeting in London, arranged by the Royal Society of Medicine, on the future of obesity treatment. It became clear that attempts to tackle obesity after the event still face daunting hurdles—scientific, practical, or both.

The non-drug medical management of obesity is where it all starts: a package of familiar measures including diet, exercise, behaviour modification, and various forms of psychological support. Studies have shown that single figure percentage weight losses can be achieved and maintained with these measures, but not without commitment on the part of the patient.

Drug treatments can’t completely sidestep that need for commitment, but they can lessen it—at least in theory. Obesity is one area in which pills have so far played little part. “There have been a lot of disappointments,” says Professor Sir Stephen Bloom, head of diabetes and endocrinology, Imperial College. He points out that although the past 25 years have seen 123 products going through clinical trials, only one is currently available on the UK market. This lone survivor is orlistat, which blocks a fat digesting enzyme. Although it is effective, it has a number of well known drawbacks, including the production and occasional leakage of fatty stools.

Professor John Wilding of the department of obesity and endocrinology at Liverpool University identifies a couple of drug combinations as among the current best hopes. One is the appetite suppressant phentermine together with topiramate,2 an anticonvulsant with weight loss effects. The other is a combination of the antidepressant bupropion and the opioid antagonist naltrexone.3 Both combinations have undergone moderately encouraging trials, but their future as marketable remedies is still uncertain. Wilding also picks out glucagon-like peptide-1 (GLP-1) analogues—anti-diabetic agents with weight loss effects—as possible contenders.

GLP-1 is a gut hormone, one of a group of substances that have long been the subject of studies by Bloom, who believes that appetite regulatory systems represent a promising target for anti-obesity pharmacotherapy. Other gut hormones include ghrelin, cholecystokinin, peptide YY, and oxyntomodulin—on which Bloom has done much work.4 Produced in the small intestine after meals, it acts as a satiety signal and has been shown to reduce energy intake in rodents and humans. It too is now undergoing clinical trials.

Bloom dryly remarks that he has a simple touchtone for any new obesity treatment: “Is it better than cyanide? This causes weight loss, but it does have some other effects.” Nevertheless, he still has faith in peptides as anti-obesity treatments, not least because their use mimics the body’s own physiological control system.

Following an initial period of professional suspicion, bariatric surgery found acceptance and is now on the increase. The recent statement on surgery issued by an International Diabetes Federation task force5 should give it a further boost, according to one of the convenors, Professor Sir George Alberti of Newcastle University and Imperial College, London. “And it shouldn’t just be considered as a last resort when all the tissue damage has been done,” he says.

Banding and bypass are the two commonest procedures, but others, including sleeve gastrectomy and bilo-pancreatic diversion, are being investigated, either for their novelty or for particular patient groups. “Lots of new devices and variants of devices keep coming out,” says Alberti. “New techniques should be explored—but in a research setting.”

Nicolas Christou is director of bariatric surgery at the McGill University Health Centre and one of the leading Canadian surgeons working in this field. He quotes the 1991 National Institutes of Health consensus statement,6 which describes bariatric surgery as the only approach providing consistent and permanent weight loss for the morbidly obese. It still is, he maintains. Besides producing a sustained loss of weight there’s good evidence that it’s safe, reduces the risk of obesity associated diseases such as diabetes and cancer, has a low complication rate, and in the long run saves money for the healthcare system. On this last point, McGill data suggest that you get your money back in three to four years. The only weaknesses of surgery, as far as Christou is concerned, are its relative scarcity in relation to the scale of the problem and its perception by a public inclined to think that obesity is a fat person’s own fault, so they don’t merit the expenditure.

Oddly enough, it turns out that we don’t fully understand how all these surgical remedies work. Banding and bypassing appear to be pretty straightforward: you reduce the volume of the available digestive space, or shorten the path from one end of the gut to the other. In the case of banding, says Dr Carel Le Roux of Imperial College, it may actually be an effect of pressure on the vagal nerves at the gastro-oesophageal junction that does the trick. “Restriction may be a side-effect, not why the procedure really works,” he says. And malabsorption from the gut may not be an explanation either. It could be that surgery alters the output of gut hormones. There’s animal evidence for this, and also some preliminary indications that surgery alters patients’ appetites. Some who’ve had a bypass start eating salads for the first time: the “I don’t eat burgers anymore” syndrome. He wonders if bariatric surgery may work by changing a metabolic set point of some kind.

As in other fields of surgery, open procedures have given way to their laparoscopic counterparts—and now, pioneered largely in the States, it’s endoluminal or endoscopic bariatric surgery that’s struggling to establish itself. Gastroenterologist Christopher Thompson of Harvard Medical School is among the pioneers in this field. He compares what he’s doing to arthroscopy and angioplasty: procedures that lie mid-way between non-surgical and fully surgical interventions. With the help of clever engineering by surgical equipment manufacturers, devices have been constructed to perform bariatric suturing, stapling, and sleeving through the endoscope.

So far these techniques are still in the experimental phase, with trials completed on only small numbers of patients. “The long term efficacy and cost-effectiveness are still to be assessed,” says Thompson. He also concedes that some of the techniques do not produce lasting benefits; but he believes they have the potential to do so.

Given the alternative remedies for tackling obesity, and the state of the evidence, you can’t help feeling sorry for NHS commissioners whose duties include buying anti-obesity measures. Mike Lander performs this task for the NHS South East Coast region. He says that the advent of National Institute for Health and Clinical Excellence guidelines on bariatric surgery7 began to make his task slightly easier when commissioning such procedures for patients who have failed on appropriate non-surgical interventions. “The guidance is quite specific in some areas. But it’s still vague in others. Who really are the right patients?” he asks. “What constitutes ‘appropriate non-surgical interventions’?” It’s not altogether surprising that rates of bariatric surgery per head of population vary widely across the country.

The London meeting concluded with a deliberately provocative debate in which each of three participants was asked to champion one of the alternative approaches to obesity: pills, endoscopes, and scalpels. Making the case for surgery, Alberic Fiennes, president of the British Obesity and Metabolic Surgery Society, pointed out that surgery is safe, effective, and cost-effective. He described severe and complex obesity as a permanent biological condition that cannot be modified without permanent measures.

Unless a time limited drug treatment can be devised to effect a permanent resetting of the metabolism, he said, or until there is certainty that drugs administered indefinitely for this purpose are as safe as surgery, pills will not replace the scalpel. The evolution of knowledge may eventually eliminate the need for surgery—as has happened in the treatment of gastric ulcers, for example. But Fiennes saw no likelihood of this happening in the immediate future.

Banging the drum for endoluminal techniques, Harvard’s Christopher Thompson admitted he couldn’t yet claim that any of them was better than existing surgical methods. But on patient numbers alone, even if the cost is overlooked, conventional surgery can’t be the answer to treating an epidemic. Endoluminal methods, he added, are cheaper, less invasive, and potentially suitable for use by a greater number of doctors.

Arguing the case for drugs was Professor Nicholas Finer of University College London, who introduced the most telling reality check. He conceded that the figures for surgical success are impressive, and that this approach could bring about lasting change. “But the future cannot be surgery. We cannot operate on 20 or 30 or 40% of the population,” he argued. “The future must lie in using lesser measures more effectively.” Despite the failure of drugs so far to deal with obesity, he cautioned his audience against giving up on such treatments. Comparisons drawn between drugs and surgery, he claimed, are not always fair. For one thing, the side effects of drugs are held to a higher safety standard than the adverse effects of surgery. He felt certain that the earlier we intervene the better, and that early interventions are most likely to be medical.

At root, of course, the problem of obesity is no more something for doctors alone than were—and still are—lung cancer and emphysema. Physicians and surgeons deal with the consequences, but have only indirect influence over the causes. As Professor Finer put it, “The real answer to the question of obesity has to be to make our environment less obesogenic.”

Biologically speaking, of course, the roots of obesity go deeper still. We’re evolutionarily adapted to live in a different age: an era in which food was scarce and it made sense to grab as much as you could, whenever you could. So we have to face the dismal fact that in this weight reducing enterprise, our own biology will offer us precious little help.

Notes

Cite this as: BMJ 2012;344:e1011

Footnotes

  • Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • bmj.com: Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials (BMJ 2012;344:d7771)

  • Provenance and peer review: Commissioned, externally peer reviewed.

References