Obesity Pharmacotherapy: Current Perspectives and Future Directions

Abstract

The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis

Tumour necrosis factor‐α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice

“…With the marked increase in the prevalence of obesity in adults, adolescents and children, it has become more important to identify and characterize novel therapeutic targets to preserve organ function in the face of obesity. Nonetheless, the currently available therapeutic regimens for obesity and diabetes, such as pharmacological treatment, caloric restriction and exercise, have had somewhat limited success . Thus, it is necessary to identify novel effective drugs to better manage multiple organ damage in uncorrected obesity.…”

Binge eating in pre-clinical models

“…Throughout the years, several drugs have been widely used in obesity treatment (see Table 1). Unfortunately, extensive research and substantial funds spent on development of new medications were largely limited by their numerous notorious side effects and restricted effectiveness [17]. Orlistat (sold as Xenical or sold over-the-counter under the trade name Alli) is the most often prescribed anti-obesity drug.…”

“…The drug acts peripherally by inhibiting gastric and pancreatic lipases, thus blocking the hydrolysis of triglycerides into absorbable free fatty acids. Consequently, undigested fats are eliminated from the diet through the feces [17,18]. At commonly prescribed doses (120 mg/3 times a day), the drug can decrease fat absorption up to 30% [16].…”

“…It has a minor influence on weight loss (on average 2-3 kg per year compared to control group), but it demonstrates preventive effects to diseases, such as type 2 diabetes. On the other hand, orlistat users often experience various adverse effects, with steatorrhea (oily stools) being the most common [17]. Orlistat can lead to impairment of liver and can impair kidneys functioning, most likely as a result of the excessive oxalate absorption and its deposition into these organs [20].…”

For a Step Change to Curb the Obesity Epidemic

“…The complex etiology of obesity (i.e., genetic, environmental, and psychological factors) makes the development of pharmacotherapies and other interventions particularly susceptible to regulatory and reimbursement barriers [2]. In general, pharmacotherapies for obesity can be directed at the following pathways: (1) decreasing energy intake (e.g., appetite suppressants and lipase inhibitors), (2) increasing energy expenditure, (3) modulating fat storage or adipocyte differentiation, or (4) mimicking caloric restriction [54]. However, existing therapies mostly work as appetite suppressants [55] and so does much of the late-stage pipeline of future innovations, despite a number of early-stage options investigating all four pathways [56].…”