In spite of an inauspicious history, the recognition of future health crises posed by the obesity epidemic, and better understanding of the physiological mechanisms underpinning appetite and energy homeostasis, have driven significant progress in the obesity pharmacotherapy field. The past 4 years have seen approval of a number of new agents. Not all have been met with universal acclaim though; two agents (lorcaserin and phentermine/topiramate) have failed to gain approval for use in Europe. In general, both the FDA and EMA have recognized some uncertainties relating to safety and efficacy with the novel agents; however, the FDA considered the risk to benefit balance acceptable for specific issues to be addressed with post-marketing trials, whereas the EMA demanded that further data be obtained prior to licensing.

Orlistat

The only survivor from the pre-2010 era is orlistat (marketed as Xenical), an intestinally active lipase inhibitor, which reduces absorption of fat by 30 % [45]. Pooled estimates from long-term studies indicate sustained weight loss of 2.9 % over placebo when given at the standard dose of 120 mg three times daily [46]. Reduced progression to diabetes [47] and improved glycaemic control in patients who already have diabetes [48] have also been noted. Fat malabsorption can give rise to side effects, including oily stools, faecal urgency and spotting if patients continue to consume a diet rich in fat, but these can be avoided with appropriate dietary restraint. Indeed, it is hypothesized that the effectiveness of orlistat likely reflects enforced dietary changes rather than a direct reduction in calorie absorption [49].

Lorcaserin

In 2012, lorcaserin (Belviq) was the first new anti-obesity agent to be granted an FDA licence for long-term weight management. Like fenfluramine, lorcaserin stimulates 5-HT (serotonin) receptors on anorectic POMC neurons. However, it was developed as a selective agonist of the 5-HT 2C receptor to avoid 5-HT 2B -mediated valvulopathies, which afflicted the earlier agent. In phase 3 trials, lorcaserin achieved average weight loss of 3.0–3.6 % better than placebo [50, 51], with 2.3 times as many patients losing at least 5 % body weight in the treatment groups. Glycaemic improvements to the tune of a 0.5 % reduction in glycosylated haemoglobin (HbA 1c ) were seen in patients with type 2 diabetes [52]. Lorcaserin is well tolerated by most patients, with few withdrawals during phase 3 trials due to adverse events. It is currently not clear, however, whether long-term use of lorcaserin has the potential to cause valve abnormalities, despite selectivity for 5-HT 2C receptors. Pooled echocardiographic data from 5249 trial participants indicated a non–statistically significant risk ratio of 1.16 (95 % confidence interval [CI] 0.81–1.67) for incident valvulopathy [53]. A post-marketing clinical trial of major adverse cardiac events, including valvular assessment, is intended to answer this question more conclusively. The results of this study might, however, come too late for lorcaserin to be licensed in Europe. The manufacturer withdrew its application in 2013 when it became clear that it would be unable to address the safety concerns expressed by the EMA, which pertained to the potential for psychiatric morbidity, valvulopathy and carcinogenesis.

Phentermine/Topiramate

Soon after lorcaserin was licensed, the FDA approved a second anti-obesity agent for long-term use: a fixed dose combination of phentermine and topiramate extended release (marketed as Qsymia). Individually, these agents were already marketed for different indications and at higher doses, as a short-term adjunct for weight loss (phentermine) and for epilepsy and migraine (topiramate). As a centrally acting appetite suppressant with a mode of action similar to that of amphetamine, phentermine’s short-term-only license reflected concerns regarding the potential for addiction [54]. Weight-lowering properties of topiramate had been noted in its initial trials as an antiseizure agent [55], but dose-limiting neuropsychiatric effects precluded its further development as an obesity monotherapy. The mechanism for topiramate-induced weight loss may involve both inhibition of orexigenic glutamate signalling [56] and increased energy utilization [57]. Combining different weight loss agents with different mechanisms of action is appealing for two reasons: first, it is less likely to be hindered by redundancy and compensation in appetite regulatory pathways; and second, it enables each component to be given at lower dose to reduce side effects. Weight loss data for phentermine/topiramate are impressive, with a placebo-subtracted body weight reduction of 6.6 % at the approved dose of 7.5 mg phentermine/46 mg topiramate [58]. Modest reductions in systolic and diastolic blood pressure of 2.3 and 0.7 mmHg, respectively, were also observed. A higher dose of 15 mg phentermine/92 mg topiramate showed enhanced weight lowering of 9.3 % better than placebo [59], but it is only recommended in selected patients who lose insufficient weight on the standard dose, because of increased adverse effects, including paraesthesia, dizziness, altered taste sensation, insomnia, constipation and xerostomia. In clinical practice, titration from an initial dose of 3.75 mg phentermine/23 mg topiramate is employed to limit side effects. However, safety concerns, particularly with regard to teratogenicity, neuropsychiatric morbidity and cardiovascular effects, have not been addressed to the satisfaction of the EMA, which has refused to grant a license for use of Qsymia in Europe. Some of the safety worries reflected previous experience with higher doses of the individual components of Qsymia rather than direct evidence of harm from trial data, although some signals were present at the 15/92 dose, including elevated heart rate and depression. On the same evidence, the FDA took the view that careful prescribing measures and ongoing patient monitoring were adequate to sway the risk to benefit balance in favour of Qsymia. These include, in particular, a risk evaluation mitigation strategy (REMS) for the teratogenic potential of topiramate, requiring adequate contraception and regular pregnancy testing for ongoing use.

Bupropion/Naltrexone

A second combination therapy, consisting of bupropion and naltrexone (marketed as Contrave in the USA; approved name Mysimba in Europe), gained FDA and EMA approval in 2014 and 2015, respectively. Again, these agents were repurposed from existing indications. Bupropion, an aminoketone which acts as a mixed dopamine/norepinephrine reuptake inhibitor [60], is used as an antidepressant and in smoking cession, and has previously been evaluated as monotherapy in the treatment of obesity [61]. Naltrexone is an opioid receptor antagonist, which is used to treat alcohol dependence, reducing cravings by inhibiting the action of β-endorphins on dopaminergic reward pathways [62]. Combining these two agents leads to enhanced appetite reduction, as bupropion stimulates POMC neurons and naltrexone counteracts the autoinhibitory effects of endogenous opioids they secrete [63]. Data from phase 3 trials have indicated 3.2–5.2 % greater weight loss at 1 year over placebo [64–67], with an associated 0.5 % HbA 1c advantage in patients with type 2 diabetes. Interestingly, despite superior weight loss in the treatment groups, blood pressure reductions were actually better in the placebo groups, suggesting a treatment-related blood pressure increase. Indeed, concerns regarding cardiovascular safety were the primary reason why approval was not granted following the initial application in 2010. However, interim analysis of a subsequent cardiovascular outcomes trial provided reassurance for the regulatory bodies. Hypertension should nonetheless be controlled before treatment is initiated, and blood pressure should be carefully monitored thereafter, particularly in the first 3 months, when an adverse response is most likely to occur. When bupropion is used as monotherapy for depression or smoking cessation, it carries a black box warning stating the potential for increased suicidality. While there was no signal of psychiatric adverse events in the bupropion/naltrexone trials, the same boxed warning is included, and patients should be carefully monitored to ensure these do not develop.

Liraglutide