Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases.
Christoffer ClemmensenBrian FinanTimo D MüllerRichard D DiMarchiMatthias H TschöpSusanna M HofmannPublished in: Nature reviews. Endocrinology (2019)
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.
Keyphrases
- insulin resistance
- public health
- weight loss
- type diabetes
- small molecule
- metabolic syndrome
- cardiovascular disease
- glycemic control
- high fat diet induced
- clinical evaluation
- polycystic ovary syndrome
- cancer therapy
- high fat diet
- adipose tissue
- physical activity
- skeletal muscle
- endothelial cells
- weight gain
- cardiovascular risk factors
- risk factors
- stem cells
- climate change
- cell therapy
- body mass index
- drug delivery
- bone marrow
- social support
- cardiovascular events
- induced pluripotent stem cells
- mesenchymal stem cells