Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases

• Published in: Nature reviews. Endocrinology 2019-02, Vol.15 (2), p.90-104
• Main Authors: Clemmensen, Christoffer, Finan, Brian, Müller, Timo D., DiMarchi, Richard D., Tschöp, Matthias H., Hofmann, Susanna M.
• Format: Article
• Language: English
• Subjects: 692/163/2743/137/773; 692/163/2743/393; 692/700/565/1436/1437; 692/700/565/1436/2185; Animals; Body Mass Index; Body weight; Body weight loss; Cardiovascular diseases; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - drug therapy; Drug Administration Schedule; Drug therapy; Drug Therapy, Combination; Dyslipidemia; Endocrinology; Energy expenditure; Energy metabolism; Female; Gastrins - therapeutic use; Gastrointestinal Hormones - therapeutic use; Glucagon-Like Peptide 1 - therapeutic use; Glucose metabolism; Hormone therapy; Humans; Insulin; Insulin resistance; Male; Medicine; Medicine & Public Health; Metabolic Diseases - diagnosis; Metabolic Diseases - drug therapy; Metabolic disorders; Metformin - therapeutic use; Methods; Mice; Molecular Targeted Therapy - methods; Obesity; Obesity - diagnosis; Obesity - drug therapy; Pathophysiology; Peptides; Prognosis; Public health; Review Article; Risk Assessment; Signal transduction; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Treatment Outcome; Weight control
• ISSN: 1759-5029; 1759-5037
• DOI: 10.1038/s41574-018-0118-x

Obesity and its comorbidities, such as type 2 diabetes mellitus and cardiovascular disease, constitute growing challenges for public health and economies globally. The available treatment options for these metabolic disorders cannot reverse the disease in most individuals and have not substantially reduced disease prevalence, which underscores the unmet need for more efficacious interventions. Neurobiological resilience to energy homeostatic perturbations, combined with the heterogeneous pathophysiology of human metabolic disorders, has limited the sustainability and efficacy of current pharmacological options. Emerging insights into the molecular origins of eating behaviour, energy expenditure, dyslipidaemia and insulin resistance suggest that coordinated targeting of multiple signalling pathways is probably necessary for sizeable improvements to reverse the progression of these diseases. Accordingly, a broad set of combinatorial approaches targeting feeding circuits, energy expenditure and glucose metabolism in concert are currently being explored and developed. Notably, several classes of peptide-based multi-agonists and peptide–small molecule conjugates with superior preclinical efficacy have emerged and are currently undergoing clinical evaluation. Here, we summarize advances over the past decade in combination pharmacotherapy for the management of obesity and type 2 diabetes mellitus, exclusively focusing on large-molecule formats (notably enteroendocrine peptides and proteins) and discuss the associated therapeutic opportunities and challenges. Therapeutic treatments that target multiple signalling pathways in obesity and type 2 diabetes mellitus (T2DM) could be more effective at reversing the progression of these diseases than current therapies. In this Review, the authors discuss advances in combination pharmacotherapies that target multiple pathways for the treatment of obesity and T2DM. Key points The need for safe and efficacious treatment options to combat metabolic diseases such as obesity and type 2 diabetes mellitus is currently unmet. Coordinated pharmacological targeting of multiple signalling pathways is probably required to obtain sizeable improvements in body weight and glucose metabolism. Several classes of peptide-based multi-agonists and peptide–small molecule conjugates with robust preclinical efficacy are currently emerging. Parallel to advancing interventions that modulate neurocircuits to drive weight loss, attention towards the