<p>Dual GIP–GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential</p>

Abstract

The need for efficient and safe therapy to improve such metabolic diseases as obesity and type 2 diabetes mellitus is currently unmet. The development of dual GIPR–GLP1R coagonists that bind to either one or the other receptor (sequence-mixed dual agonists) has emerged as an innovative therapeutic strategy for obesity and type 2 diabetes. Combined activation of both receptors may act synergistically providing additive effects on glucose and body weight in comparison of GLP1 analogues alone. Preclinical studies have confirmed that GIPR–GLP1R coagonists improve several hallmarks of metabolic syndrome, such as obesity, hyperglycemia, and dyslipidemia. These metabolic benefits have been translated from mice to nonhuman primates and humans. Recent clinical trials have shown that coagonists induce significant benefits on body weight, fasting, and postprandial glucose levels, insulin sensitivity, and total cholesterol. Combined GIP- and GLP1R activators have the potential to become a treatment option for patients with type 2 diabetes.

Characterizing Effects of Antidiabetic Drugs on Heart Rate, Systolic and Diastolic Blood Pressure

“…Blocking incretin degradation increases their physiological actions, including stimulation of insulin secretion. 4 More recent treatments focus on the co-stimulation of the GLP1 and GIP receptors 5 and glucagon receptor dual agonists. 6 Preclinical and clinical studies indicate that ADs, especially incretin-based agents, not only control body weight and improve glycemic control but may also exhibit effects on key cardiovascular end points such as heart rate (HR) and blood pressure (BP).…”

“…Blocking incretin degradation increases their physiological actions, including stimulation of insulin secretion 4 . More recent treatments focus on the co‐stimulation of the GLP1 and GIP receptors 5 and glucagon receptor dual agonists 6 …”

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

“…Finally, GIPR, combined with GLP-1R and GCGR, have been intensively studied as targets of dual- or tri- agonists ( 37, 38 ). Combined activation of GLP-1R and GIPR by dual agonists would provide synergistic and improved effects in glycemic and body weight control ( 39 ). The GLP-1R/GIPR dual-agonists LY3298176 (developed by Eli Lilly) and NN9709 (developed by Novo Nordisk/Marcadia) as well as GLP-1R/GCGR/GIPR tri-agonist HM15211 (developed by Hamni Pharmaceuticals) are undergoing phase II or III clinical trials ( 6 ).…”

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

“…The clinical success of GLP-1R agonist peptides has prompted the search for agents that could combine the benefits of GLP-1 with those of other key gut hormones, in order to target multiple signalling pathways with a single molecular entity. Moreover, this emerging dual pharmacological approach may lead to increased metabolic action compared to monotherapies, and a number of these candidates are being evaluated in clinical trials (Bastin et al, 2019).…”