Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease

Abstract

Background Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy. Scope of review In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity. Major conclusions Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.

Nuclear Retention of Leptin/Upd2 Regulates Organismal Resilience to Nutrient Extremes

“…We also showed that during nutrient deprivation, increased circulating levels of the starvation hormone Glucagon impinges on fat cells to inhibit adipokine release via this route, ultimately enabling fat cells to retain adipokines (Rajan et al, 2017). This mechanistic insight is consistent with the idea of using glucagon like peptides (GLPs) to treat obesity and sensitize Leptin signaling (Baggio and Drucker, 2020). While our work (Rajan et al, 2017) provided clues on how systemic signals, including glucagon, impinge on fat cells to regulate adipokine retention, what cell intrinsic mechanisms mediate fasting induced adipokine retention remained an open question, and a central focus of our investigations.…”

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

“…These developments will be the focus of another manuscript on the present supplement volume (Baggio et al. [ 211 ]).…”

Reduction in GLP-1 secretory capacity may be a novel independent risk factor of coronary artery stenosis

“…As “residual risks” underlying cardiovascular events under the condition of control of major risk factors, residual dyslipidemia such as small dense LDL-C and oxidized LDL-cholesterol, proatherogenic inflammatory cytokines such as interleukin-1β, and prothrombotic risk have been characterized 6 – 8 . While GLP-1 plays major roles in the regulation of glucose and lipid metabolism 32 , 33 , GLP-1 secretion does not appear to correlate with most of the classical coronary risk factors (Table 2 ). Change in GLP-1 secretion caused by diabetes mellitus is controversial but results of a meta-analysis argue against a significant effect of diabetes mellitus on GLP-1 secretion 34 .…”