Drug Management of Obesity

Drugs have a limited role in the management of obesity. Their use is governed by strict criteria which should be met before medication is prescribed.¹ These criteria are laid down by NICE and the licensing requirements of the drug manufacturers.^2,3

Anti-obesity drugs should only be considered after diet, behavioural changes and exercise have been tried and evaluated. If the patient's weight has reached a plateau despite these measures, drug treatment may be considered.

The choice of drug should be made after discussing with the patient the risks and benefits, mode of action, monitoring requirements, and possible impact on the patient's motivation. Information and support on dietary, exercise and behavioural changes should be maintained.

Three drugs are licensed for the treatment of obesity.viz. orlistat, sibutramine and rimonabant. NICE do not recommend combinations of anti-obesity drugs.

• Drug treatment is not usually recommended for children children younger than 12 years. In exceptional cases, (severe life-threatening comorbidities such as sleep apnoea or raised intracranial pressure) it is sometimes prescribed by paediatric specialists.
• NICE recommends treatment with orlistat or sibutramine in children aged 12 and over only if physical comorbidities (such as orthopaedic problems or sleep apnoea) or severe psychological comorbidities are present. Neither orlistat nor sibutramine currently have market authorisation for use in children. Treatment should be initiated in a specialist paediatric setting, by multidisciplinary teams with experience of prescribing in this age group. Regular monitoring of physical parameters, psychological, behaviour, diet and exercise should be part of the treatment package.
• Drug treatment may be continued in primary care if local circumstances and/or licensing allow.

• Drug treatment may be used to maintain weight loss, rather than continue to lose weight.
• Vitamin and mineral supplements should be considered, particularly for vulnerable groups like the elderly and growing adolescents.
• People being withdrawn from drugs should be offered support because it is at this time that their self-confidence and belief in their ability to make changes may be low.
• Regular review of adverse effects and to reinforce lifestyle advice is important.
• Treatment should comply with prevailing guidance concerning withdrawal if the patient does not lose enough weight.
• Type 2 diabetics may lose weight at a slower rate and appropriate allowance should be made.
• If anti-obesity drugs are prescribed for children, a 6-12 month trial is recommended, with regular review to assess effectiveness, adverse effects and adherence.

Orlistat is a lipase inhibitor which acts by reducing the absorption of dietary fat. About 30% of the fat that would otherwise be absorbed passes straight through to the large bowel.²

The manufacturers of orlistat are currently applying to have it made available OTC in the UK at a dose of 60 mg tds. This is being resisted by some members of the medical profession, who feel that the benefits would be minimal at this dose, particularly if ongoing professional support and monitoring was not available. They maintain that patients are likely to become demotivated if they do not see rapid results, and such an initiative would detract from the World Health Organisation's message about eating less and exercising more.⁵ The counter argument is that the drug is safe, OTC does not preclude the option of professional support, and people should be free to spend money as they wish.⁶

Criteria for prescribing²

A BMI of 28 kg/m² or more in the presence of significant co-morbidities (e.g. type 2 diabetes, high blood pressure, hyperlipidaemia) OR a BMI of 30 kg/m² or more with no associated co-morbidities.

Duration of treatment

• Treatment should only be continued beyond three months if a further 5% of body weight has been lost since start of treatment (this target may be made more lenient for type 2 diabetics).
• The use of drug treatment for longer than 12 months (usually for weight maintenance) should be made after discussing potential benefits and limitations with the patient.

Effectiveness^2,7

• Clinical trials suggest a moderate weight loss compared to placebo - about 2-5 kg over a year.
• There is a small but significant reduction in total cholesterol, the ratio of total cholesterol to high-density lipids, and systolic and diastolic blood pressure. This is thought to be due to reduction in body weight and total fat content, as well as redistribution of fat.
• Improvement of self-esteem and self-motivation at least as important as reduction in co-morbidity, based on quality-of-life estimates.
• Most patients gain weight after stopping treatment, but trials suggest it takes three years to gain weight lost in one year on the drug.
• An evaluation conducted in Italy found that orlistat demonstrated a good pharmacoeconomic profile.⁸

Contraindications⁴

• Chronic malabsorption syndrome
• Cholestasis
• Pregnancy - increased incidence of dilated cerebral ventricles in animal studies, no human studies available⁹
• Lactation - not known whether excreted in human milk¹⁰

Cautions

Absorption of fat-soluble vitamins may be impaired. If on long-term therapy monitor A, D, E and beta-carotene levels and prescribe supplementation if appropriate.^2,7,11-12

Interactions^4,13

Orlistat may affect the absorption of many drugs:

• Cyclosporin - orlistat may reduce cyclosporin bioavailability - monitor levels more frequently
• Acarbose - manufacturers advise avoid due to lack of pharmacokinetic data
• Amiodarone - may reduce plasma concentration
• Coumarins - anti-coagulant effect may be enhanced by interference with vitamin K absorption so INR should be monitored

Common problems

• Liquid oily stools, faecal urgency, flatulence
• Less frequently, abdominal and rectal pain, headache, menstrual irregularities, anxiety, fatigue⁷

Initiation²

• Check that patient qualifies according to NICE criteria.
• Check contraindications and interactions.
• Inform patient of benefits and limitations of drug treatment.
• Arrange provision of support for non-drug treatment and lifestyle changes.
• Prescribe one tablet before, during or after each main meal (dose may be missed if meal contains no fat).

Monitoring¹

• Check weight at 3 months and 6 months
• Monitoring of fat-soluble vitamin levels only necessary if patient not having a balanced diet
• Monitor adverse effects, mainly gastro-intestinal
• Monitor interactions

Sibutramine is a centrally-acting serotonin and noradrenaline reuptake inhibitor which has the effect of promoting satiety and increasing energy expenditure.^3,15

Criteria for prescribing³

• A BMI of 27.0 kg/m2 or more and other obesity-related risk factors such as type 2 diabetes or dyslipidaemia OR a BMI of 30.0 kg/m2 or more.
• Ongoing professional support should be available.

Duration of treatment³

• Continue treatment beyond 3 months only if 5% initial body weight or more lost (less stringent targets for type 2 diabetics).
• Not licensed for use beyond 12 months

Effectiveness^15,16

• Clinical trials suggest significant weight loss - 5-10% of initial body weight depending on dose, over a year
• No significant difference in gender or ethnicity

Contraindications^3,16-17

• Major eating disorders
• Psychiatric illness - can induce manic episodes in bipolar patients
• Tourette syndrome
• History of coronary artery disease, congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmias, cerebrovascular disease - can cause increase in blood pressure, tachycardia and sympathetic nervous system stimulation
• Uncontrolled hypertension
• Hyperthyroidism
• Phaeochromocytoma
• Angle-closure glaucoma
• Prostatic hypertrophy with urinary retention
• Drug abuse - listed by manufacturers, but abuse potential low
• Alcoholism
• Pregnancy - animal studies suggest foetal toxicity, however two cases of use in pregnancy reported with healthy outcomes
• Lactation - no human studies available, so manufacturers advise avoid

Cautions

• Hypertension - see monitoring (below)
• Epilepsy- manufacturers recommend caution - reason unclear, evidence-based reports in this group lacking¹⁴
• Sleep apnoea syndrome - take particular care to monitor blood pressure¹⁴
• Hepatic impairment and renal impairment - increased plasma levels of sibutramine reported, use with caution¹⁸
• Family history of motor or verbal tics¹⁴
• Make sure women of child-bearing age are using adequate contraception

Interactions

• Psychoactive drugs - increased risk of CNS toxicity with noradrenaline re-uptake inhibitors, SSRIs, tricyclics, antipsychotics, moclobemide, tryptophan
• Anticoagulants, aspirin, NSAIDs - increased risk of bleeding

Common problems¹⁸

• Very common - constipation, dry mouth, insomnia
• Common - tachycardia, palpitations, raised blood pressure, vasodilatation, nausea, haemorrhoid aggravation, light-headedness, paraesthesiae, anxiety, headache, sweating, taste perversion

Initiation

• Start at 10 mg daily in the morning, increased if weight loss less than 2 kg after 4 weeks to 15 mg daily.
• Discontinue if weight loss less than 2 kg after 4 weeks at higher dose.

Monitoring

• NICE recommends that sibutramine should not be prescribed unless there are adequate arrangements for monitoring both weight loss and adverse effects (specifically pulse and blood pressure). This is consistent with the manufacturer's recommendations.
• Check BP and pulse every 2 weeks for the first 3 months, every month for the next 3 months, and then 3 monthly thereafter. Discontinue treatment if at 2 consecutive visits:
  • BP rises above 145/90 mmHg
  • BP rises by > 10 mmHg from baseline
  • Resting pulse rate rises by > 10 bpm¹
• Advise patients to report chest pain, ankle oedema or dyspnoea (all symptoms of primary pulmonary hypertension). Not reported with sibutramine, but characteristic of anti-obesity drugs as a class.¹⁸

Criteria for prescribing

Rimonabant is a selective cannabinoid 1 (CB1) receptor antagonist. It is licensed as an adjunct to diet and exercise for the treatment of obese adults (BMI 30 kg/m2 or greater) or overweight adults (BMI greater than 27 kg/m2) with associated risk factor(s) such as type 2 diabetes or dyslipidaemia.

At the time of writing, NICE are in the process of consulting on the final appraisal determination of this drug. Their current recommendation is that it should be used as an adjunct to diet and exercise for adults who are obese or overweight and who have had an inadequate response to, are intolerant of, or are contraindicated to orlistat and sibutramine.

Duration of treatment

• Rimonabant treatment should be continued beyond 6 months only if the person has lost at least 5% of their initial body weight since starting rimonabant treatment.
• It should not be continued for longer than 2 years without a formal clinical assessment and discussion of the individual risks and benefits with the person receiving treatment.

Effectiveness

Four randomised controlled trials showed that rimonabant, as an adjunct to diet and exercise, was associated with a statistically significant greater weight loss than placebo with diet and exercise at 1 and 2 years. There were also significant beneficial metabolic effects. At 1 year, rimonabant had a beneficial effect on systolic blood pressure (SBP), high density lipoprotein cholesterol (HDL-C), triglycerides and fasting plasma glucose in the diabetic and non-diabetic groups, and glycosylated haemoglobin (HbA1c) in the diabetic group.

Improvements in associated cardiovascular and diabetes risk factors were also statistically significantly greater with rimonabant treatment compared with those for placebo at 2 years. After rimonabant treatment was stopped at 1 year, there was a gradual increase in weight until there was no statistically significant difference from placebo at 2 years.²⁰

Contraindications

Rimonabant is still a black-triangle drug.¹⁹ The Medicines and Healthcare Regulatory Agency has issued the following guidance:²¹

• Rimonabant is contraindicated in patients with ongoing major depressive illness and/or ongoing antidepressive treatment.
• It should not be used in patients with current suicidal ideation or with a history of suicidal ideation or depressive disorder unless the benefit of the treatment is considered to outweigh the risk in the individual patient.
• Therapy with rimonabant is not recommended in patients with uncontrolled psychiatric illness other than depression.

Other contraindications identified by the manufacturer include severe hepatic impairment, severe renal impairment, lactose intolerance, and patients over 75.

Cautions

• Patients and carers or relatives should be informed about the risk of depression.
• Patients should be encouraged to stop treatment and seek medical advice if symptoms of depression occur. Treatment with rimonabant should be stopped if depression occurs.
• Caution should be exerted in patients with epilepsy, moderate hepatic impairment and moderate renal impairment (mainly due to lack of data).

Interactions

• Rimonabant is metabolised by CYP3A and should be used with caution in patients concomitantly taking potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone).
• CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St John's wort) has not been studied, but it is expected that concomitant administration may result in loss of efficacy.

Common problems

• Common - gastrointestinal symptoms, muscle aches, depression, anxiety, insomnia, dizziness, paraesthesia, hypoaesthesia, sciatica, hot flush, sweating
• Less common - hiccups, anger, aggression, suicidal ideation

Initiation

• As for orlistat.
• Initiating dose is 20 mg daily before breakfast. It should not be exceeded.

Monitoring

Monitor for weight loss, interactions, and side effects.

• Use of anti-obesity drugs in patients younger and older than licensed age group
• Effect of stopping treatment on weight gain
• Benefits on co-morbidities of short-term weight loss vs long-term weight loss
• Use beyond licensed duration
• Should therapy be recommenced if weight regained?
• Any gender, ethnic or social-specific differences in effectiveness?

A meta-analysis of 7 randomised controlled trials suggested that sibutramine was more effective than orlistat. There are however significantly more adverse effects and contraindications with sibutramine. Choice should therefore be tailored to the individual patient. There is no current evidence to support the use of orlistat and sibutramine in combination.²²

There are no head to head large scale trials comparing the effectiveness of rimonabant with the other two drugs, but the current NICE guidance is that it should be used second-line.²⁰