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). 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). 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). 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. 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 Road map to choices