New advances in models and strategies for developing anti-obesity drugs

Abstract

Introduction Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events. Areas covered We review the strategies for designing new anti-obesity drugs by describing those currently in development. We describe their target, mechanism of action, and developmental or regulatory status. We also discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy. Expert opinion For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways.

Amylin: Pharmacology, Physiology, and Clinical Potential

“…Monotherapy for obesity, although initially effective, often only yields modest and unsustained weight loss. As with other chronic diseases such 592 as hypertension, cancer, and diabetes, combinatorial approaches have gained significant traction for the potential treatment of obesity (Kim et al, 2013). Analogous to diabetes, monotherapy-based approaches for obesity target only a single aspect of a multihormonal disease state.…”

“…Despite combining different pathways, the weight loss was also modest and the highest dose did elicit the most significant side effects (Gadde et al, 2011). Despite new approvals, the obesity treatment landscape is still very limited due to potential safety concerns (Kim et al, 2013). The recent U.S. Food and Drug Administration approval of the GLP-1 receptor agonist liraglutide for obesity (Saxenda; Novo Nordisk Inc., Plainsboro, NJ) provides a new opportunity for trialling combinations of pramlintide and liraglutide in patients (Ladenheim, 2015).…”

Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives

“…The FDA, in approving an anti-obesity drug, requires a weight reduction of at least 5% for at least one year (difference between the drug and the placebo groups) in the 35% subjects in treatment [47,48]. The newest drug Saxenda ® (liraglutide, rDNA origin) [49,50] is approved by FDA/EMA as “ a treatment option for chronic weight management in addition to a reduced-calorie diet and physical activity to subject who also have one or more complications related to their weight, such as type 2 diabetes, high blood pressure, high cholesterol or obstructive sleep apnea ”.…”

Pharmacotherapy for the management of obesity

“…Pharmacotherapy for the Management of Obesity Patel 9 Although many novel anti-obesity drugs are in development [22], their underutilization may be attributed to safety concerns, perceptions of limited efficacy, and a general unwillingness of patients to view obesity as a disease [19]. In the following section, we review the indications, dosages, safety, and efficacy of FDA-approved anti-obesity pharmacotherapies for short-term and long-term use so that healthcare practitioners may feel more comfortable prescribing these products to their patients and be more equipped to handle the growing obesity epidemic.…”

“…Pharmacotherapy for the Management of Obesity Patel 22 In clinical trials, the most common adverse reactions associated with liraglutide were nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. Liraglutide is contraindicated in pregnancy and in patients with hypersensitivity to liraglutide or any of its product components.…”