Approaches to the Pharmacological Treatment of Obesity

Victoria Salem; Stephen R Bloom

Disclosures

Expert Rev Clin Pharmacol. 2010;3(1):73-88. 

In This Article

Other Pharmaceutical Strategies for the Treatment of Obesity

The shortcomings of presently available therapies has led to massive interest in finding new therapeutic approaches. Table 1 summarizes the major therapeutic advances so far, and the following sections highlight some of the more promising future candidates.

Peripherally Acting Approaches

Pharmacological approaches to the treatment of obesity can broadly be classified into peripherally and centrally acting drugs. The company Alizyme has moved into Phase III clinical trials of its lipase inhibitor, cetilistat, which had comparable efficacy to orlistat at inducing weight loss but with a more favorable gastrointestinal side effect profile at Phase II testing.[37] There are few other imminent developments in obesity pharmacotherapy utilizing peripheral mechanisms, such as the inhibition of nutrient absorption or the regulation of fatty acid metabolism. However, this is the focus of early-stage research at present and may hold promise for the future.[38,39] One such example is fatostatin, a recently discovered molecule that inhibits sterol regulatory element-binding proteins (SREBPs), which are major transcription factors regulating genes encoding enzymes required for lipogenesis. Pharmacological studies in genetically obese ob/ob strains revealed a reduction of bodyweight, visceral adiposity and blood glucose in fatostatin-treated mice.[40]

Centrally Acting Approaches

There are many more anti-obesity agents currently unergoing late-stage clinical trials which are centrally-acting drugs that interact with appetite-regulatory neurotransmission. Intensive monitoring for side effects with these types of drugs has gained even greater importance with the lessons learned from cannabinoid receptor antagonists. Endocannabinoids are endogenous lipid-based neurotransmitters synthesized from arachidonic acid which activate cannabinoid receptors (CBs). In the CNS, CB1 receptor activation alters the release of a variety of neurotransmitters, including dopamine in the mesolimbic system, and affects appetite and energy expenditure in the hypothalamus by changing the relative expression of orexigenic and anorexigenic neuropeptides to increase appetite.[41] The CB1 receptor antagonist rimonabant, developed by Sanofi-Aventis, received European approval as an anti-obesity agent following the results of the four Phase III studies that comprised the Rimonabant in Overweight/Obesity (RIO) program. Subjects taking the drug lost an average of 4.5 kg relative to placebo in 1 year, with concomitant significant improvements in visceral fat, abdominal circumference and all other measures of the metabolic syndrome.[42] However, postmarketing surveillance unveiled serious concerns regarding the association between rimonabant and psychiatric side effects, including depression and suicide, and neurological side effects, such as the risk of convulsions. In June 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that the safety of rimonabant had not been adequately demonstrated by the manufacturer Sanofi-Aventis and the full application for approval was subsequently withdrawn. Later that year, the European Medicines Agency (EMEA) concurred that the benefits of rimonabant no longer outweighed its risks and marketing authorization was suspended across the EU. All drug manufacturers have since ceased further development of centrally acting CB1 receptor antagonists.

5-HT2C Agonists

The serotonin 5-HT2 family of receptors mediate a wide range of physiological functions including appetitive behavior, mood and smooth muscle function.[43] Early, less selective serotoninergic appetite suppressants such as fenfluramine and dexfenfluramine, were removed from the market in the 1990s after a link was established with the development of valvular heart disease, found to be mediated via the 5-HT2B subtype.[44] Lorcaserin is a serotonin receptor agonist with 104-fold selectivity for the 5-HT2C over the 5-HT2B receptor[45] and which therefore holds promise as an appetite suppressant with a safer side-effect profile. 5-HT2C receptors are widely distributed throughout the CNS, including higher centers involved in reward and mood, as well as areas involved in the homeostatic regulation of appetite such as the hypothalamus and NTS.[43] The 5-HT2C knockout mouse is obese and hyperphagic and resistant to the weight-lowering effects of other serotonin agonists.[46] Chronic daily treatment with lorcaserin in diet induced obese rats produce dose-dependent reductions in food intake and bodyweight.[44] Lorcaserin has since made its way through to Phase III human testing in the Behavioral modification and lorcaserin for Overweight and Obesity Management (BLOOM) trial. First-stage results report a 5.77-kg weight loss in the Lorcaserin group over 1 year compared with 2.14-kg weight loss in the placebo group. It was also revealed that 47.5% of patients on the drug lost at least 5% of their bodyweight, compared with 20.3% of those on placebo, and that 22.6% lost at least 10% of their bodyweight compared with 7.7% on placebo.[205] Notably, no excess valvular cardiac disease has been reported during 2 years of its use. The BLOOM trial discontinuation rates owing to adverse events in the lorcaserin and placebo groups were similar, with 7.1 versus 6.7% for year 1 and 3.0 versus 3.0% for year 2, respectively.

Qnexa

The pharmaceutical company Vivus is developing Qnexa, a combination of low-dose phentermine and the anticonvulsant agent topiramate, for the long-term treatment of obesity. Topiramate is a sulphamate-substituted fructose approved for the treatment of refractory seizures and for migraines. It inhibits excitatory neurotransmission by blocking voltage-gated sodium channels and other actions on GABA and glutamate systems. The exact mechanism by which it promotes weight loss remains unclear, although dose-ranging studies reveal that it does so in a dose-dependent fashion.[47] The Phase III EQUATE trial evaluated Qnexa versus placebo in 756 obese subjects over 28 weeks. Patients taking full-dose and mid-dose Qnexa achieved an average weight loss of 9.2 and 8.5% respectively, as compared with 1.7% reported for the placebo group.[206] There were also significant improvements in HbA1c in the group taking Qnexa mediated via its weight-loss effects. In the high-dose group, 20% reported paraesthesia, 18% dry mouth and 15% altered taste versus 3, 0, and 0%, respectively, in the placebo group, but there was no difference in reports of mood disturbance.

Contrave

Contrave is a combination of bupropion, a dopamine and noradrenaline reuptake inhibitor, with naltrexone, an opioid antagonist used to treat various addictive disorders. These two agents are reported to synergistically block b-endorphin-mediated inhibition of POMC neurones, leading to increased hypothalamic anorexigenic neuronal activity. They have each on their own been shown to reduce appetite and bodyweight in humans.[48,49] Contrave's developers, Orexigen, have published results from the NB-302 trial, a 56-week, double-blind, placebo-controlled trial, conducted in 793 patients also receiving intensive dietary and exercise advice. It revealed that over the course of the study, the Contrave group lost 9.2–11.4 kg compared with 7.3 kg in the placebo group and that 41.5% lost at least 10% of their weight in the treatment arm compared with 20.2% on placebo.[207] The overall discontinuation rate owing to adverse events was 25.9% for patients taking Contrave versus 13.0% for those taking placebo, but the drug was not associated with an increased incidence of depressive symptoms. Overall, 4.6 % discontinued the drug owing to nausea – an effect that is attenuated with adequate dose titration.

Reuptake Inhibitors

Tesofensine is an inhibitor of presynaptic noradrenaline, dopamine and serotonin uptake under development by NeuroSearch who have completed a 24 week Phase II, randomized, double-blind, placebo-controlled trial, testing it in 203 obese patients.[50] Patients receiving tesofensine lost 6.7–12.8 kg of weight compared with a 2.2-kg loss in the placebo group. A total of 74% of patients receiving high-dose tesofensine and 35% receiving medium dose lost more than 10% of their bodyweight, compared with 7% in the placebo group. However, 20% of patients withdrew from the trial due to adverse events in the high dose group, compared with 8% in both the medium-dose and placebo groups. Dose-dependent reports of nausea, dry mouth and insomnia were reported and there were increased reports of agitation and mood disturbance, which are a cause for concern following the market withdrawal of cannabinoid receptor antagonists for similar reasons. These side effects will be carefully monitored in future planned Phase III studies.

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