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Management: Part II—Drugs
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Management: Part II—Drugs
Mike Lean, Nick Finer
Despite the availability of evaluated and approved obesity Diet and exercise play a central role in preventing
drugs—and even though some patients will have failed to lose obesity and are the first line treatment for the
weight after non-drug treatment—doctors have been reluctant condition. But many patients also need drugs to help
to prescribe drugs. The reasons for this may include memories them lose weight, and to maintain the loss, however that
of the adverse events with amphetamine, and amphetamine-like was achieved
drugs, and the serious complications from combiningphentermine and fenfluramine. Current drugs recommendedfor treating obesity have all been evaluated and approved byregulatory standards that apply to all drug treatments. The useof obesity drugs should follow the principles of any other Clinical targets from which to evaluate drug efficacy in
therapeutic area—that is, they may be prescribed after interventions for weight management
assessment of the potential benefits and risks (both clinical andeconomic), with appropriately informed patients, and with Physical
Clinical end
medical monitoring of the results of treatment.
Risk factor
severity
Many people, including doctors, still believe that a short course of drug treatment might “cure” obesity or that efficacy is measured only by ever-continuing weight loss. These misconceptions are at odds with biology: people who become obese have a lifelong tendency both to defend their excess weight and to continue to gain extra body fat. Effective management, including drugs when needed, must be life long and focused on weight loss maintenance in a similar fashion to the effective treatment for hypertension or diabetes. Drug efficacy can be considered in terms of the impact on measures such as body mass index or fat distribution, risk factors, disease improvement, or reduction in clinical end points. Starting drug *Derived from computed tomography or magnetic resonance imaging.
treatment should always be regarded as a therapeutic trial and †Predicted from cross sectional computed tomography, magnetic resonance stopped if weight loss is not apparent after one to two months.
imaging, or (more weakly) dual emission x ray absorptiometry (DEXA)—which Drug treatment of the consequences
of obesity
Current approaches to obesity management largely involvetrying to treat all the additional symptoms, risk factors forfuture disease, and existing comorbidity without necessarilytackling the primary problem. The excess polypharmacyadministered to obese patients was highlighted in a recent auditof primary care (the UK Counterweight programme).
Obese patients often take five or more different drugs, all for components of metabolic syndrome, plus symptomatictreatments such as use of bronchodilators, analgesics, and drugsfor arthritis and angina. Insulin sensitising agents (such asmetformin) are sometimes used to try to improve severalobesity related risk factors simultaneously, but they rarelyadequately improve the hazards and symptoms of obesity, sopolypharmacy may still be necessary.
Obese patients are at increased risk from cardiovascular
disease: it is imperative that risk factors are treated early
and optimally. Effective treatment to prevent the
Treating obesity itself
underlying cause (body fat accumulation) would make
better clinical and economic sense and is now accepted
as a reasonable target for drug development
If the many diseases associated with obesity are causally related,then they will be modified by treatments that can generateweight loss (that is, loss of body fat) and prevent the regain ofexcess body fat. Inherent in this is a need to establish energy Liposuction removes only subcutaneous fat, which
balance at a lower body weight. Temporary weight loss by carries little metabolic risk, and energy intake is
liposuction does not do this, nor does it affect metabolic risk.
unaffected; thus body weight will rise again to achieve
An effective drug against obesity must reduce energy energy balance
assimilation from food (without compensatory reduction in BMJ VOLUME 333 14 OCTOBER 2006
energy expenditure) or stimulate energy expenditure (without compensatory increase in food consumption), or both. Current drugs act mainly on energy intake; for maximal effectiveness, Sibutramine plus brief lifestyle modification they depend on patients adopting a well designed diet and lifestyle programme. In a recent one year study, intensive lifestyle intervention produced weight loss (6.7 (standard deviation 7.9) kg) similar to that achieved with the drugsibutramine alone (5.0 (7.4) kg); combining lifestyle interventionwith the drug doubled the weight loss (12.1 (9.8) kg).
Principles of drug therapy
Weight loss—The benefit of obesity drugs depends on effects on body fat and body weight. Two thirds of patients can achieve Effects on weight loss of sibutramine with or without some degree of
a 5-10% loss in three to six months with lifestyle modification lifestyle modification (adapted from Wadden et al. N Engl J Med
2005;353:2111-20)
and drug treatment. A weight loss of less than 1-2 kg after sixweeks indicates an inadequate response, except in patients whohave already lost weight with diet and exercise and patients withtype 2 diabetes.
Weight maintenance—Most patients who lose weight regain it.
Drugs are a logical treatment not just for weight loss inductionbut for long term weight loss maintenance. A reasonable longterm target is to restrict regain—for example, to below theaverage rate of weight gain (1-2 kg a year for obese people).
What current obesity drugs can do
Symptoms and risk factors—Patients should show long term improvements as a consequence of the weight control or x Increase weight loss by about 4-6 kg beyond what can be achieved through separate mechanisms of the drug.
x Maintain weight loss (however achieved) 12-15 kg below baseline Duration of treatment—It is logical to continue the drug for as x Improve most cardiovascular risks in direct relation to weight loss long as it is effective; if the drug is effective, withdrawal will leadto weight regain. Current licensing criteria still limit treatmentduration to one to two years, although for some drugs, trialsshow continuing benefit. Treatment beyond this limit, however,must still be recognised as “off licence,” and patients should becounselled and supervised accordingly.
Side effects and safety—Overall risk to benefit of existing drugs has been favourably shown in terms of symptoms, risk factors, Combining drugs with different mechanisms is a logical
and diabetes prevention. As for any other disease, patients have way to increase efficacy. However, the limited evidence
to be seen regularly for benefit to be assessed and unwanted does not support combining orlistat and sibutramine
effects identified. Limited information on safety and efficacyexists for elderly people, children, and adolescents. Pregnantand breast feeding women should not take obesity drugs.
Drugs licensed for obesity
management
Orlistat
Orlistat is an intestinal lipase inhibitor taken three times daily
with meals. It generates malabsorption of 30% of dietary fat. Itleads to 5-10% weight loss in 50-60% of patients, and in clinical trials the loss (and related clinical benefit) is largely maintainedup to at least four years.
In a recent review by Finer et al (see Further Reading box), when orlistat was compared with placebo, all risk factors forcoronary heart disease improved and 37% fewer patients (52% Proportion of study participants (%) of those with impaired glucose tolerance) developed diabetes over four years. Reduced intestinal fat absorption may havedirect effects on improving lipids and insulin sensitivity.
Outcome improved with a structured diet and exercise programme. (A good action plan (known as MAP) is provided, Proportion of study participants achieving 5-10% weight loss in one year,
via the makers of orlistat, to patients prescribed the drug.) according to drug taken (data from combined datasets of 1 year phase 3
Patients who do not follow advice to eat a low fat diet (in trials of three obesity drugs including rimonabant (adapted from Finer N,
general < 60 g fat a day) will have steatorrhoea. Gastrointestinal see Further Reading box)
side effects are not necessary for effective weight loss becausemalabsorption of 20 g of fat is usually asymptomatic andproduces an energy deficit of 180 kcal a day.
BMJ VOLUME 333 14 OCTOBER 2006
Sibutramine
Sibutramine inhibits the reuptake of noradrenaline and
serotonin, promoting and prolonging satiety; it is taken once
Sibutramine’s main side effects include a dry mouth,
constipation, headaches, and dizziness; all may be
daily. It produces 5-10% weight loss in 60-70% of patients, and improved by drinking more water when losing weight.
in clinical trials it is well maintained for at least two years. If Poor sleep and agitation may occur early in treatment
weight loss is less than 2 kg at four weeks, the dose can be and are usually self limiting. Several potential drug
interactions (for example, with selective serotonin
High density lipoprotein cholesterol concentrations increase reuptake inhibitors) may limit usage
by 25%, partly independently of weight loss. The noradrenergicaction increases heart rate by 1-2 beats/min and attenuates thefall in blood pressure expected with weight loss. Some patients,especially if they fail to lose weight, may record a rise in theirblood pressure; it is therefore essential to monitor blood Drugs that are not recommended
pressure during the first 12 weeks of treatment. Controlledhypertension is not a contraindication for prescribing x Methyl cellulose is still licensed in the UK as an adjunct in obesity, but no evidence exists for its efficacy or safety x Phentermine is a catecholamine releasing agent that stimulates the Rimonabant
central nervous system, producing appetite suppression. Efficacyand safety have not been sufficiently established Rimonabant is the first cannabinoid-1 receptor antagonist to belicensed for obesity treatment. Stimulation of cannabinoid-1receptors in the brain promotes eating and in peripheral tissuescardiovascular risk factors such as low concentration of highdensity lipoprotein cholesterol, insulin resistance, andinflammation. Blockade with rimonabant produces weight loss Drugs licensed for non-obesity indications
and weight-independent improvements of some cardiovascular x Any drug that produces anorexia or nausea as a side effect will produce weight loss but would be inappropriate as an obesitytreatment.
Rimonabant produces 5-10% weight loss in 60-70% of x Metformin produces minor effects on body weight but improves subjects, maintained for up to two years in clinical trials. Side insulin sensitivity, preventing progression from impaired glucose effects reported were mild and infrequent. Clinical trials tolerance to diabetes. It improves fertility in women with polycsytic excluded depressed patients; effects on mood and depression ovarian syndrome. Gastrointestinal side effects, however, may limit should be assessed during routine clinical care.
x In epileptic patients, topiramate (atypical anticonvulsant) produces less weight gain than other anticonvulsants and often strikingweight loss. It was withdrawn during clinical trials for use in obesity The three licensed obesity drugs (orlistat, sibutramine,
because of cognitive side effects at effective doses in non-epileptic rimonabant) can all significantly improve glycaemic
control in overweight patients with diabetes
Incidence of side effects expressed as ratio of active
treatment to placebo from clinical trials of orlistat,
sibutramine and rimonabant. Adapted from Greenway and
Caruso (see Further Reading box)
Rimonabant
Orlistat Sibutramine
Weight loss over first year of treatment with rimonabant (combined with
lifestyle modification) is maintained in year 2 if drug is continued. Weight
regain occurs if drug is withdrawn even if lifestyle modification is continued
(adapted from Pi-Sunyer et al. JAMA 2006;295:761-75)
*These effects occur only if excess fats are eaten.
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New drugs in development
Clinical trials are now well advanced for several drugs withdifferent modes of action.
Many of the hormones and hormone receptors that contribute to regulation of appetite or satiety are targets fordrug treatment and under active development in preclinical and early clinical trials. Newer agents primarily designed to treat diabetes, such as the synthetic amylin pramlintide and GLP-1analogue exenatide, are licensed in the US and unlike most other hypoglycaemic drugs lead to clinically important weight For the very rare cases of leptin deficiency, daily injections are curative. Most obese people, however, have highconcentrations of leptin, and trials of hyperaugmentation were Recombinant leptin given once or twice daily in addition to lifestyle advice
disappointing. Rosenbaum et al found that after 10% weight on weight loss over 12 weeks in obese subjects with normal plasma leptin
concentration shows no benefit over placebo. (Adapted from Zelissen et al.
loss induced by a low energy liquid diet, recombinant leptin Diabetes Obes Metab 2005;7:755-61)
restored circulating leptin concentrations, energy expenditure,the work efficiency of skeletal muscle, sympathetic nervoussystem tone, and circulating concentrations of thyroxine andtriiodothyronine to levels present before the weight loss (Journalof Clinical Investigation 2005;115:3579-86).
Obesity is associated both directly and indirectly
Pharmacoeconomics
(through its comorbidities and excess prescribing) with
excess health costs. Effective early treatment with long
term weight maintenance may be cost effective
Drug treatment is considered effective (in terms of numbers
needed to treat) and cost effective by the National Institute for
Health and Clinical Excellence, with an overall cost per quality
adjusted life year of £19 000 (€27 500; $35 000) to £55 000,
which can be further improved by targeting patients with
comorbidities.
Cost effectiveness is estimated to vary between €3462 per Key references and further reading
life year gained for obese diabetic patients with hypertension x Finer N. Does pharmacologically-induced weight loss improve and hypercholesterolaemia and €19 986 per life year gained for cardiovascular outcome? Impact of anti-obesity agents on obese diabetic patients without other risk factors (Diabetes Care cardiovascular risk. Eur Heart J Supplements 2005;7(suppl):L32-8.
x Greenway FL, Caruso MK. Safety of obesity drugs. Expert Opin Drug Evaluation of drug treatment in routine clinical practice, x Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system including cost effectiveness studies, is confounded when data and the treatment of obesity. Ann Med 2005;37:270-5.
from randomised controlled trials are used because patients x Small CJ, Parkinson JR, Bloom SR. Novel therapeutic targets for who fail to respond to treatment continue to be included. In appetite regulation. Curr Opinion Invest Drugs 2005;6:369-72.
routine practice, such patients’ treatment would be stopped at x Curran MP, Scott LJ. Orlistat: a review of its use in the management of patients with obesity. Drugs 2004;64:2845-64.
an early stage. Long term randomised controlled trials of x Rissanen A, Lean M, Rossner S, Segal KR, Sjostrom L. Predictive obesity drugs thus tend to exaggerate costs of effective value of early weight loss in obesity management with orlistat: an evidence-based assessment of prescribing guidelines. Int J Obes RelatMetab Disord 2003 Jan;27:103-9.
Useful websites
The photograph at the start of this article is published with permissionfrom Rex.
x www.counterweight.org (multicentre obesity management project led by practice nurses, conducted in seven UK regions) Nick Finer is director of the Wellcome Clinical Research Facility, x www.changeforlifeonline.com (week by week plan for lifestyle Addenbrooke’s Hospital, Cambridge.
x www.itswhatyougain.co.uk (support site for patients taking The ABC of Obesity is edited by Naveed Sattar (nsattar@clinmed.gla.ac.uk), professor of metabolic medicine, and x www.rcplondon.ac.uk/pubs/wp_antiobesitydrugs.htm (Royal Mike Lean, professor of nutrition, University of Glasgow.
College of Physicians’ guidelines) (accessed 10 Jul 2006) The series will be published as a book by Blackwell Publishing in early x www.nice.org.uk (National Institute for Health and Clinical Excellence is an independent organisation responsible forproviding national guidance on promoting good health and Competing interests: Nick Finer has received research grants and consultancy fees from, and served on advisory boards to, many x www.cochrane.org (for Cochrane reviews) pharmaceutical companies involved in the development of treatments for x www.jr2.ox.ac.uk/bandolier/band100/b100-4.html (for research obesity and diabetes, including Roche, Abbott, Sanofi-Aventis, Merck, Shionogi, Pfizer and GlaxoSmithKline. For series editors’ competing x www.obesity-news.com (for research information about obesity interests, see the first article in this series.
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