Are peptide conjugates the golden therapy against obesity?

Abstract

Obesity is a worldwide pandemic, which can be fatal for the most extremely affected individuals. Lifestyle interventions such as diet and exercise are largely ineffective and current anti-obesity medications offer little in the way of significant or sustained weight loss. Bariatric surgery is effective, but largely restricted to only a small subset of extremely obese patients. While the hormonal factors mediating sustained weight loss and remission of diabetes by bariatric surgery remain elusive, a new class of polypharmacological drugs shows potential to shrink the gap in efficacy between a surgery and pharmacology. In essence, this new class of drugs combines the beneficial effects of several independent hormones into a single entity, thereby combining their metabolic efficacy to improve systems metabolism. Such unimolecular drugs include single molecules with agonism at the receptors for glucagon, glucagon-like peptide 1 and the glucose-dependent insulinotropic polypeptide. In preclinical studies, these specially tailored multiagonists outperform both their mono-agonist components and current best in class anti-obesity medications. While clinical trials and vigorous safety analyses are ongoing, these drugs are poised to have a transformative effect in anti-obesity therapy and might hopefully lead the way to a new era in weight-loss pharmacology.

Keywords: diabetes; metabolism; obesity; peptides.

Figure 1

Schematic demonstrating the qualitative metabolic effects of GLP-1 (red arrows), glucagon (blue arrows) and GIP (green arrows) on systems metabolism, including key metabolic tissues. Arrows pointing upwards indicate an increase or improvement, while arrows pointing downwards indicate a decrease.

Figure 2

Schematic demonstrating the working principle, metabolic effects and key target tissues of the GLP-1/glucagon dual agonist, with the size of the text weighted to indicate the magnitude of the observed effect. Arrows pointing upwards indicate an increase or improvement, while arrows pointing downwards indicate a decrease. This dual agonist most prominently affects body weight.

Figure 3

Schematic demonstrating the working principle, metabolic effects and key target tissues of the GLP-1/GIP dual agonist. Arrows pointing upwards indicate an increase or improvement, while arrows pointing downwards indicate a decrease. The emphasis on glycemic control indicates the relative magnitude of the effect.

Figure 4

Schematic demonstrating the working principle, metabolic effects and key target tissues of the GLP-1/GIP/glucagon triple agonist, with the size of the text weighted to indicate the magnitude of the observed effect. Arrows pointing upwards indicate an increase or improvement, while arrows pointing downwards indicate a decrease. The triagonist most predominately affects body weight, glycemic control and liver cholesterol and hepatosteatosis.