Intended for healthcare professionals

Practice Therapeutics

Pharmacotherapy for weight loss

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3526 (Published 06 June 2014) Cite this as: BMJ 2014;348:g3526
  1. Christian F Rueda-Clausen, postdoctorate fellow,
  2. Raj S Padwal, associate professor
  1. 1Department of Medicine, University of Alberta, Edmonton, AB, Canada, T6G 2G3
  1. Correspondence to: R S Padwal rpadwal{at}ualberta.ca
  • Accepted 7 April 2014

A severely obese 28 year old woman (body mass index (BMI) 37.9) with type 2 diabetes, controlled hypertension, and sleep apnoea is seeking your advice about weight loss. She has lost 6 kg over the past year by reducing portion sizes, but her weight has recently plateaued. She does not want to consider bariatric surgery and asks instead about drug treatments.

What are antiobesity drugs?

Current treatment for obesity consists primarily of health behaviour modification (diet, exercise, and behavioural therapy) for all patients and bariatric surgery for a minority of selected severely obese people.1 Because health behaviour modification is unsuccessful in many patients, and the availability of bariatric surgery is limited, additional adjunctive, effective, and safe obesity treatments are needed.

To date, antiobesity drugs have not adequately filled this therapeutic void. The serotonergic agents fenfluramine and dexfenfluramine were withdrawn in 1997 because of associations with cardiac valvulopathy and pulmonary hypertension.2 After the withdrawals of rimonabant (Acomplia) in 2009 for depression and suicidal ideation, and sibutramine (Meridia, Reductil) in 2010 because of increased cardiovascular risk, orlistat became the only agent available for long term weight management.

In 2012, two new oral agents—phentermine and extended release (ER) topiramate (Qsymia) and lorcaserin (Belviq)—were approved by the US Food and Drug Administration as adjuvants to health behaviour modification in patients with a BMI of greater than 30 or greater than 27 if they also had an obesity related comorbidity, such as hypertension, dyslipidaemia, or type 2 diabetes. As discussed elsewhere, the European Medicines Agency did not approve either agent, citing toxicity concerns and a lack of morbidity and mortality data.3 Here, we provide a clinically focused summary to guide GPs in the use of these drugs.

What are the currently available pharmacological options for obesity?

Orlistat

This inhibitor of gastric and pancreatic lipase prevents intestinal fat metabolism and absorption.4 Prescription orlistat (Xenical) has been available since 1999 and over the counter orlistat (Alli) since 2007.

Phentermine-ER topiramate

Phentermine is an amphetamine analogue that enhances satiety by increasing hypothalamic noradrenaline (norepinephrine) levels.5 Phentermine monotherapy for obesity was approved in 1959 for short term use only; it is currently the most commonly prescribed antiobesity drug in the US. Topiramate, which is approved for epilepsy and migraine prophylaxis, putatively reduces weight by decreasing food intake, decreasing lipogenesis, increasing thermogenesis, improving insulin sensitivity, and increasing secretion of adiponectin.6

Lorcaserin

This is a selective agonist of serotonin (5-hydroxytryptamine or 5-HT) 2c receptors that stimulates pro-opiomelanocortin (POMC) producing neurones in the hypothalamus, resulting in generation of α-melanocortin stimulating hormone, which acts on melanocortin receptors to decrease food intake and enhance satiety.7

How well do they work?

Orlistat

In a meta-analysis of 16 randomised controlled trials (RCTs; 10 631 patients), orlistat (120 mg three times a day) reduced weight by 2.9 kg (95% confidence interval 2.5 to 3.2) more than placebo after one year.8 Compared with placebo, 21% (19% to 24%) more patients in the orlistat group achieved at least 5% weight loss (number needed to treat (NNT) 5) and 12% (8% to 16%) more achieved at least 10% weight loss (NNT 8).8 Orlistat improved systolic blood pressure (−1.5 mm Hg, −0.9 to −2.2) and low density lipoprotein-cholesterol (−0.26 mmol/L, −0.22 to −0.30 mmol/L) more than placebo. Orlistat also improved glycosylated haemoglobin (HbA1c) in patients with diabetes to a greater extent than placebo (−0.39%, −0.18% to −0.59 %) and, in one trial, reduced the four year incidence of type 2 diabetes from 9.0% to 6.2% (hazard ratio 0.63, 0.46 to 0.86).9

Overall, orlistat leads to small amounts of weight loss and modest improvements in cardiovascular risk profiles. Long term adherence to treatment is poor (<2% at two years).10 Current evidence is limited by high study attrition rates (averaging 30%), and the lack of data on cardiovascular morbidity and mortality makes it difficult to draw definitive conclusions about the overall benefits of this agent.

Phentermine-ER topiramate

Two large, 56 week, phase III RCTs (EQUIP11 and CONQUER12) compared phentermine-ER topiramate with placebo (table 1). All patients received advice on health behaviour modification. Those receiving phentermine-ER topiramate (15 and 92 mg/d, respectively) lost 8.8-10.8 kg more weight than those receiving placebo (P<0.05) and were significantly (P<0.05) more likely to lose at least 5% (NNT 2) and 10% (NNT 3) of initial body weight. Other cardiovascular risk factors were improved, including systolic blood pressure (−3.8 mm Hg, −2.8 to −4.7), total cholesterol (−0.15 mmol/L, −0.2 to 0.15), and HbA1c (−0.2%, −0.16% to −0.24%). In a 52 week blinded extension of the CONQUER study, annualised rates of progression to overt diabetes in 475 people with prediabetes, with or without the metabolic syndrome, were 1.3% with phentermine-ER topiramate (15 and 92 mg/d, respectively) and 6.1% with placebo (NNT 21; P<0.05).13

Table 1

 Effect of phentermine-extended release topiramate on anthropometric indices*†

View this table:

These studies were limited by high attrition rates (40% in EQUIP and 31% in CONQUER) and a lack of endpoint data on cardiovascular morbidity and mortality. Overall, weight reductions with phentermine-ER topiramate are relatively high (compared with other agents), but improvements in cardiovascular risk factors are modest and, as with orlistat, “hard” endpoint data are needed to verify that these benefits are clinically important.

Lorcaserin

In three one year phase III RCTs, weight reductions were 2.9-3.6 kg higher in people receiving lorcaserin (10 mg orally twice daily) compared with placebo (table 2).14 15 16 All patients received advice on health behaviour modification. Subjects receiving lorcaserin were also more likely to lose at least 5% (NNT 4) or 10% (NNT 7) of their initial body weight (P<0.05). Patients receiving lorcaserin also showed greater improvements in systolic blood pressure (−0.6 mm Hg, −0.4 to −1.1), high density lipoprotein-cholesterol (0.09 mmol/L, 0.03 to 0.16), and, in those with diabetes, HbA1c (−0.5%, −0.65% to −0.33%).

Table 2

  Effect of lorcaserin on anthropometric indices*

View this table:

The limitations of the studies on orlistat and phentermine-ER topiramate also apply to lorcaserin—namely, high attrition rates (36-50% in lorcaserin trials) and lack of data on cardiovascular morbidity and mortality.

What are the safety issues and precautions?

Orlistat

Orlistat is minimally absorbed and faecally excreted, so doses do not need to be reduced in patients with liver or kidney impairment. Gastrointestinal adverse effects (including steatorrhoea and abdominal distension) occur in about 25% of patients (number needed to harm (NNH) 4) and faecal incontinence in 2-8% (NNH 16).8

Orlistat should be avoided in patients with chronic malabsorption or cholestasis and in pregnancy. Isolated cases of liver failure and calcium oxalate nephrolithiasis have been reported.4 Orlistat may decrease the absorption of fat soluble vitamins (A, D, E, and K) and drugs (including ciclosporin, amiodarone, anticonvulsants, and levothyroxine). These drugs should be taken two to four hours after the ingestion of orlistat.

Phentermine-ER topiramate

Common adverse effects of phentermine-ER topiramate include paraesthesias (21% of patients, NNH 5), nausea (7%, 33) dizziness (10%, 14), dysgeusia (10%, 11), constipation (17%, 11), and dry mouth (21%, 5).12 Neuropsychiatric related adverse events were also more common, including depression (7%, 33), anxiety (4%, 50), irritability (3%, 50), insomnia (10%, 20), and disturbances in attention (4%, 33).12

Although phentermine-ER topiramate (15 and 92 mg/d, respectively) increases heart rate by about 2 beats/min, the FDA judged that the potential increase in cardiovascular risk was balanced by improvements in blood pressure and other cardiovascular risk factors.17

The drug is contraindicated in pregnancy because topiramate has been associated with teratogenicity, mainly in the form of orofacial clefts.18

Because this agent is renally excreted, reduce the dose in patients with a creatinine clearance less than 50 mL/min (maximum of phentermine 7.5 mg and ER topiramate 46 mg daily). Avoid in patients with nephrolithiasis or renal tubular acidosis or use lower doses and monitor renal function closely because topiramate can also promote acidaemia by inhibiting renal carbonic anhydrase.19

Because the drug is not recommended in severe liver disease owing to the lack of safety data in this population, use lower doses (maximum of phentermine 7.5 mg and ER topiramate 46 mg daily) in moderate hepatic failure (Child-Pugh class B) and avoid the drug in severe liver disease (Child-Pugh class C).

Other contraindications to phentermine-ER topiramate include severe vascular disease, moderate-severe hypertension, hyperthyroidism (owing to the risk of increased heart rate), and glaucoma (owing to the risk of angle-closure glaucoma). Severe anxiety or agitation (phentermine may aggravate symptoms); history of drug misuse (because of the risk of dependence, although this risk seems more theoretical than real20); and current or recent use of monoamine oxidase inhibitors, which can enhance amphetamine related increases in blood pressure, are also contraindications.

Lorcaserin

Lorcaserin is metabolised in the liver to multiple inactive metabolites that are renally excreted.16 It is not recommended in patients with a creatinine clearance less than 30 mL/min. Periodically monitor liver enzymes or avoid use in patients with severe hepatic impairment.

Do not co-prescribe with other agents that may increase the risk of serotonin syndrome.

Common adverse effects of lorcaserin include headache (18% of patients, NNH 14), upper respiratory tract infection (15%, 13), dizziness (8%, 25), nausea (8%, 33), constipation (7%, 33), and dry mouth (5%, 33).16 Hypoglycaemia is slightly more common in patients taking oral hypoglycaemic drugs (8.3% for lorcaserin v 6.3% for placebo; P=0.4).15 Priapism is a rare adverse effect.

Lorcaserin treatment has not been associated with depression or suicidal ideation,15 and the potential for recreational misuse is low.21 Although studies in rats raised concerns of mammary and brain tumours, these findings have not been replicated in other animal models, and risk has been judged to be low in humans.17 Clinical trials to date do not indicate an increased risk of cardiac valvulopathy; however, studies are underpowered and further postmarketing surveillance is needed.

How are these agents taken and monitored (table 3)?

Table 3

 Details of the use of antiobesity drugs and contraindications

View this table:

Orlistat

The dose is 60-120 mg three times daily, taken with meals. Doses can be skipped if the meal is small or has a low fat content.

Phentermine-ER topiramate

The recommended initial dose of 3.75 mg and 23 mg, respectively, as a single daily dose in the morning to avoid insomnia, is prescribed for two weeks and then doubled to 7.5 and 46 mg once daily for 12 weeks. If 3% weight loss has not been achieved, either discontinue the drug or increase the dose to 11.25 mg and 69 mg daily for two weeks and then to 15 mg and 92 mg daily. If 5% weight loss is not achieved after 12 weeks, the drug should be tapered over one to two weeks, to avoid withdrawal, and then discontinued.

A risk evaluation and mitigation strategy for teratogenicity that includes clinician training, patient education, and restricted dispensing (limited to certified pharmacies) has been developed to minimise risk. In women of childbearing age, a negative pregnancy test should be documented before starting treatment. Thereafter, monthly pregnancy testing and effective contraceptive precautions are recommended.

Lorcaserin

The recommended oral dose is 10 mg twice daily. Discontinue after 12 weeks if at least 5% weight reduction has not been achieved.

How cost effective are these new agents?

One month of orlistat therapy costs $120 (£71.5; €88) to $140. The two newer agents cost $240 a month. Cost effectiveness analyses are available only for orlistat; a National Institute for Health and Care Excellence health technology assessment reported a cost per quality adjusted life year of £19 000 in the United Kingdom.1

Case outcome

You discuss average weight loss that studies show with these drugs, possible side effects, and the costs for each agent. You also mention that the drugs have not been proved to lower risk of heart disease or stroke. In this patient, because no absolute contraindications exist, any one of the three agents can be used. You both agree that, if her weight has not dropped by at least 5% (and preferably 10%) after 12-24 weeks the drug should be stopped and another one tried. Because the patient is of childbearing age, the need for contraception and monthly pregnancy testing should be discussed if phentermine-ER topiramate is prescribed.

Tips for patients

  • Phentermine-extended release topiramate (Qsymia) and lorcaserin (Belviq) are two new drugs for obesity. They are currently approved for use in the United States (but not the European Union) for the long term treatment of obesity. Orlistat (Xenical and Alli) is an existing drug approved worldwide. All should be used in combination with diet and exercise

  • Phentermine-topiramate lowers weight by about 9-11 kg, lorcaserin by about 3-4 kg, and orlistat by about 2-3 kg after six to 12 months of treatment. Treatment is continued indefinitely in those who respond and stopped after three to six months in those who do not

  • Phentermine-topiramate carries a potential risk of birth defects, and women of childbearing age should avoid becoming pregnant while using this drug. Lorcaserin and orlistat are also not recommended in pregnant women

  • Data examining the effect of these agents on death and cardiovascular events are not currently available and are needed before the benefits of these drugs can be properly judged. Large, long term studies of phentermine-topiramate and lorcaserin are currently ongoing

Notes

Cite this as: BMJ 2014;348:g3526

Footnotes

  • This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Albert Ferro, professor of cardiovascular clinical pharmacology, King’s College London. To suggest a topic, please email us at practice{at}bmj.com.

  • Contributors: Both authors wrote the first draft of the paper and revised subsequent versions of the manuscript. RSP is guarantor.

  • Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: CFR-C has none. RSP: Antiobesity drug related clinical trial site investigator for Novo Nordisk (2011-2014); epidemiological consulting for Vivus (2011).

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

  • Patient consent not required: Patient dead, anonymised, or hypothetical.

References

View Abstract

Log in

Log in through your institution

Subscribe

* For online subscription