Recent achievements and future directions of anti-obesity medications

Abstract

Pharmacological management of obesity long suffered from a reputation of a 'Mission Impossible,' with inefficient weight loss and/or unacceptable tolerability. However, the tide has turned with recent progress in biochemical engineering and the development of long-acting agonists at the receptor for glucagon-like peptide-1 (GLP-1), and with unimolecular peptides that simultaneously possess activity at the receptors for GLP-1, the glucose-dependent insulinotropic polypeptide (GIP) and glucagon. Some of these novel therapeutics not only improve body weight and glycemic control in individuals with obesity and type 2 diabetes with hitherto unmet efficacy and tolerable safety, but also exhibit potential therapeutic value in diverse areas such as neurodegenerative diseases, fatty liver disease, dyslipidemia, atherosclerosis, and cardiovascular diseases. In this review, we highlight recent advances in incretin-based therapies and discuss their pharmacological potential within and beyond the treatment of obesity and diabetes, as well as their limitations in use, side effects, and underlying molecular mechanisms.

Keywords: Anti-obesity medication (AOM); Diabetes; GIP; GLP-1; Obesity.

Fig. 1

Weight loss efficacy of selected AOMs in clinical studies. Placebo-corrected weight loss (% to baseline) of semaglutide 2.4 mg QW (red), tirzepatide 15 mg QW (blue), retatrutide 8 mg QW (black), and AMG133 420 mg QM (red) were selected from Ref., , , , , , , Effects in individuals with overweight/obesity without T2D are indicated as solid lines, whereas effects in subjects with overweight/obesity with T2D are indicated as dashed lines. QW: once-weekly; QM: once-monthly.

Fig. 2

Schematic time-line on the approval of incretin-based drugs for treatment of T2D and obesity by the FDA and EMA.