Lorcaserin, phentermine topiramate combination, and naltrexone bupropion combination for weight loss: the 15-min challenge to sort these agents out
Obesity is a substantial and increasing contributor to morbidity and mortality worldwide. Somatic and psychiatric complications allied to obesity are common. Diet, lifestyle and psychological interventions are recommended treatments, but often fail. Consequently medication interventions, and increasingly bariatric surgery, are viewed as supplementary mechanisms to manage the problem 1. Numerous pharmaceutical interventions have been devised to treat obesity 2. However, the history of orexigenic drugs has been plagued with problems. A bevy of weight loss drugs have exited the marketplace because of safety concerns – usually as a result of cardiovascular and/or psychiatric adverse events – and include fenfluramine phentermine combination (‘fen-phen’), rimonabant, and sibutramine 3. Replacing them are three new prescription agents available for oral administration for long-term use: lorcaserin 4, phentermine topiramate combination 5, and naltrexone bupropion combination 6. Are they effective? Are they safe? Let's take the 15-min challenge to sort some of these issues out.
Step 1. Obtain the prescribing information from the web 4-6. Construct a table of pertinent information regarding indications, contraindications, bolded boxed warnings, dosage recommendations, drug interactions, and most commonly encountered adverse effects (incidence ≥ 5%) (Table 1).
| Generic name | Lorcaserin | Phentermine and topiramate | Naltrexone and bupropion |
|---|---|---|---|
| US brand name | Belviq | Qsymia | Contrave |
| Initial US approval | 2012 | 2012 | 2014 |
| DEA schedule* | IV | IV | NA |
| Classification | Serotonin 2C receptor agonist | Combination of phentermine, a sympathomimetic amine anorectic, and topiramate extended-release, an antiepileptic drug | Combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant |
| Indications | Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of ≥ 30 kg/m2 (obese), or ≥ 27 kg/m2 (overweight) in the presence of ≥ 1 weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes) | Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of ≥ 30 kg/m2 (obese), or ≥ 27 kg/m2 (overweight) in the presence of ≥ 1 weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia | Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass i index of ≥ 30 kg/m2 (obese), or ≥ 27 kg/m2 (overweight) in the presence of ≥ 1 weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia) |
| Contraindications | Pregnancy | Pregnancy; glaucoma; hyperthyroidism; during or within 14 days of taking monoamine oxidase inhibitors; known hypersensitivity or idiosyncrasy to sympathomimetic amines | Uncontrolled hypertension; seizure disorders, anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; use of other bupropion-containing products; chronic opioid use; during or within 14 days of taking monoamine oxidase inhibitors; known allergy to any of the ingredients in the product; pregnancy |
| Bolded boxed warnings | None | None | Suicidal thoughts and behaviours; neuropsychiatric reactions |
| Dosage | One tablet of 10 mg twice daily; discontinue if 5% weight loss is not achieved by week 12 | Four dosage strengths of extended-release capsules: 3.75 mg/23 mg (phentermine 3.75 mg and topiramate 23 mg), 7.5 mg/46 mg (phentermine 7.5 mg and topiramate 46 mg), 11.25 mg/69 mg (phentermine 11.25 mg and topiramate 69 mg), and 15 mg/92 mg (phentermine 15 mg and topiramate 92 mg). Take once daily in morning. Avoid evening dose to prevent insomnia. Titration schedule: 3.75 mg/23 mg daily for 14 days, then increase to 7.5 mg/46 mg daily. Discontinue or escalate dose (as described) if 3% weight loss is not achieved after 12 weeks on 7.5 mg/46 mg dose. Discontinue if 5% weight loss is not achieved after 12 weeks on maximum daily dose of 15 mg/92 mg. Discontinue 15 mg/92 mg dose gradually to prevent possible seizure. Do not exceed 7.5 mg/46 mg dose for patients with moderate or severe renal impairment or patients with moderate hepatic impairment | Extended-release tablets of 8 mg/90 mg (naltrexone HCl 8 mg and bupropion HCl 90 mg). Titration schedule: week 1 – one tablet in morning, none in evening; week 2 – one tablet in morning and 1 in evening; week 3 – two tablets in morning and 1 tablet in evening; week 4 and onwards – two tablets in morning and two tablets in evening |
| Drug interactions | Serotonergic drugs (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, triptans, bupropion, dextromethorphan, St. John's Wort): use with extreme caution because of the risk of serotonin syndrome | Oral contraceptives: altered exposure may cause irregular bleeding but not increased risk of pregnancy – advise patients not to discontinue oral contraceptives if spotting occurs; CNS depressants including alcohol: potentiate CNS depressant effects – avoid concomitant use of alcohol; non-potassium sparing diuretics: may potentiate hypokalemia – measure potassium before/during treatment | Monoamine oxidase inhibitors: increased risk of hypertensive reactions can occur when used concomitantly; drugs metabolised by CYP2D6: bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., selective serotonin reuptake inhibitors and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide) – consider dose reduction when using with this product; concomitant treatment with CYP2B6 Inhibitors (e.g., ticlopidine or clopidogrel) can increase bupropion exposure – do not exceed one tablet twice daily when taken with CYP2B6 inhibitors; CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure – avoid concomitant use; drugs that lower seizure threshold – dose product with caution; dopaminergic drugs (levodopa and amantadine) – CNS toxicity can occur when used concomitantly with product; drug-laboratory test interactions – product can cause false positive urine test results for amphetamines |
| Most commonly encountered adverse effects (incidence ≥ 5%) | Non-diabetic patients: headache, dizziness, fatigue, nausea, dry mouth, and constipation; diabetic patients: hypoglycaemia, headache, back pain, cough, and fatigue | Rate at least 1.5 times placebo: paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth | Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhoea |
- NA, not applicable. *Schedule IV of the Controlled Substances Act, as determined by the US Drug Enforcement Agency.
Although all of the interventions have essentially the same indication (adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults), they differ in mechanism of action, and for the combination medication products, represent the re-purposing of agents that have already been available for quite some time. Two of the products are classified as Category IV by the US Drug Enforcement Agency because of a potential of abuse, however, naltrexone bupropion combination is not (other examples of Category IV medications include benzodiazepines). All three products are contraindicated in pregnant women. The combination products have longer lists of additional contraindications, and naltrexone bupropion combination has an additional bolded boxed warning regarding suicidality (a warning that is found in the product labels of all agents that have been approved as antidepressants). Lorcaserin does not require titration but is taken twice daily. Phentermine and topiramate combination is taken once daily but requires titration. Naltrexone and bupropion combination requires both titration and twice daily dosing. Drug interactions can occur with any of these agents, with a longer list present for the combination products, especially for naltrexone bupropion combination. All of the agents have their own distinct adverse event profile.
Step 2. Extract the efficacy information regarding the achievement of a ≥ 5% or 10% reduction from baseline body weight and calculate the number needed to treat (NNT) vs. placebo (Table 2).
| % of patients losing ≥ 5% body weight | NNT (95% CI) | % of patients losing ≥ 10% body weight | NNT (95% CI) | |||
|---|---|---|---|---|---|---|
| Active medication | Placebo | Active medication | Placebo | |||
| Lorcaserin 10 mg bid* | 46.4 | 22.1 | 5 (4–5) | 21.9 | 8.4 | 8 (7–9) |
| Phentermine and topiramate 15 mg/92 mg qAM† | 69.0 | 19.7 | 2 (2–3) | 47.7 | 7.0 | 3 (3–3) |
| Naltrexone and bupropion 16 mg/180 mg bid‡ | 46.6 | 22.9 | 5 (4–5) | 25.2 | 9.7 | 7 (6–8) |
- CI, confidence interval; NNT, number needed to treat. *Studies 1, 2, and 3 as listed in product labelling (lorcaserin n = 3349, placebo n = 3286). †Studies 1 and 2 as listed in product labelling (phentermine and topiramate combination 15 mg/92 mg qAM n = 1479, placebo n = 1477). ‡Studies COR-I, COR-BMOD, and COR-Diabetes as listed in product labelling (naltrexone and bupropion combination 16 mg/180 mg bid n = 1424, placebo n = 898).
The most robust effect sizes are observed with phentermine topiramate combination, with the 95% confidence intervals of the NNT free of any overlap with those for the other products.
Step 3. Extract the safety and tolerability information regarding the proportion of patients who discontinued the clinical trial(s) because of an adverse event and calculate the number needed to harm (NNH) vs. placebo. Do the same for the incidence of the most common adverse event (Table 3).
| % of patients discontinuing because of an adverse event | NNH (95% CI) | % of patients with the most commonly encountered adverse event | NNH (95% CI) | ||||
|---|---|---|---|---|---|---|---|
| Active medication | Placebo | Adverse event | Active medication | Placebo | |||
| Lorcaserin 10 mg bid | 8.6 | 6.7 | 53 (32–161) | Headache* | 16.8 | 10.1 | 15 (12–20) |
| Phentermine and topiramate 15 mg/92 mg qAM | 17.4 | 8.4 | 12 (9–15) | Paraesthesia | 19.9 | 1.9 | 6 (5–7) |
| Naltrexone and bupropion 16 mg/180 mg bid | 24.0 | 12.0 | 9 (7–11) | Nausea | 32.5 | 6.7 | 4 (4–5) |
- CI, confidence interval; NNH, number needed to harm. *Headache was the most commonly encountered adverse event in non-diabetic patients (Table 2 in product labelling); hypoglycaemia was the most commonly encountered adverse event in diabetic patients, with incidence of 29.3% vs. 21.0% for placebo, resulting in a NNH of 12 (95% CI 7–127) (Table 3 in product labelling).
Lorcaserin appears to be the best tolerated based on the NNH vs. placebo for patients discontinuing because of an adverse event, and in terms of the NNH for the adverse event most commonly observed with that agent (headache).
Step 4. Compare and contrast. The concept of likelihood to be helped or harmed (LHH) can be helpful here, provided that you select a relevant harm to contrast with the anticipated benefit 7. Table 4 provides the NNT for response, NNH for discontinuation because of an adverse event, and the resultant LHH.
| NNT vs. placebo for losing ≥ 5% body weight | NNH vs. placebo for discontinuing because of an adverse event | LHH | NNT vs. placebo for losing ≥ 10% body weight | NNH vs. placebo for discontinuing because of an adverse event | LHH | |
|---|---|---|---|---|---|---|
| Lorcaserin 10 mg bid | 5 | 53 | 10.6 | 8 | 53 | 6.6 |
| Phentermine and topiramate 15 mg/92 mg qAM | 2 | 12 | 6 | 3 | 12 | 4 |
| Naltrexone and bupropion 16 mg/180 mg bid | 5 | 9 | 1.8 | 7 | 9 | 1.3 |
- LHH, likelihood to be helped or harmed; NNH, number needed to harm; NNT, number needed to treat.
Lorcaserin is almost 11 times more likely to result in ≥ 5% weight loss than a discontinuation because of an adverse event. LHH for these outcomes for phentermine and topiramate combination is 6, and for naltrexone and bupropion combination, almost 2. LHH values are lower (less favourable) when the bar for weight loss rises to a 10% threshold. LHH values are also lower when the calculation is made using the NNH for the most commonly encountered adverse event (Table 5). For naltrexone and bupropion combination the LHH in this instance is less than 1. Thus, one would expect to encounter the adverse event (nausea) more often than weight loss. However, this does not necessarily eliminate naltrexone and bupropion combination from further consideration if the nausea is mild, temporary, and easily managed.
| Adverse event | NNT vs. placebo for losing ≥ 5% body weight | NNH vs. placebo for the most commonly encountered adverse event | LHH | NNT vs. placebo for losing ≥ 10% body weight | NNH vs. placebo for the most commonly encountered adverse event | LHH | |
|---|---|---|---|---|---|---|---|
| Lorcaserin 10 mg bid | Headache* | 5 | 15 | 3 | 8 | 15 | 1.9 |
| Phentermine and topiramate 15 mg/92 mg qAM | Paraesthesia | 2 | 6 | 3 | 3 | 6 | 2 |
| Naltrexone and bupropion 16 mg/180 mg bid | Nausea | 5 | 4 | 0.8 | 7 | 4 | 0.6 |
- LHH, likelihood to be helped or harmed; NNH, number needed to harm; NNT, number needed to treat. *Headache was the most commonly encountered adverse event in non-diabetic patients; hypoglycaemia was the most commonly encountered adverse event in diabetic patients, with a NNH of 12.
There are several important caveats. The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from persons encountered in routine clinical practice. Thus pragmatic clinical trials that are more generalizable will help place these weight loss agents into clinical perspective for their use in the ‘real world’. In addition, the data presented are regarding the highest approved dose for each product. Not mentioned in this mini-review is orlistat 8, a reversible inhibitor of gastrointestinal lipases, also approved for obesity management with a similar indication as for the products discussed here, and available by prescription since 1999, and now also over-the counter in lower dose strengths.
The threshold of a 5% reduction in body weight is arbitrary and just a start. To achieve desired reductions in blood pressure, plasma lipids, and improvements in insulin resistance, greater weight loss will likely be important. Prior to prescribing any of these agents, attention should be paid to potential drug–drug interactions that can impact on safety and tolerability. Adoption of healthier lifestyles that include regular exercise and more wholesome diets will also be necessary to optimise the management of obesity.
References
Acknowledgements
The author thanks Anthony Wierzbicki, Associate Editor for Cardiovascular Disease Prevention and Metabolic Diseases for the International Journal of Clinical Practice, for his helpful review and suggestions.
Disclosures
No external funding or writing assistance was utilised in the production of this editorial. Although the average clinician may take 15 min to read the editorial and accompanying tables, the creation of this mini-review took well in excess of 15 h. In the past 36 months, Leslie Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Forest, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant.
