Raghu G. Mirmira, MD, PhD

Type 2 diabetes (T2D), frequently associated with obesity, results from a mismatch between insulin resistance and insulin secretion by islet β cells. Normally, as tissue resistance to insulin increases, β cells increase insulin output in an effort to maintain normal glucose and lipid homeostasis;¹ however, when insulin resistance increases beyond the capacity of β cells to compensate – and/or if β cell insulin secretion fails prematurely – hyperglycemia and eventual T2D ensues. Most oral therapies for T2D target either insulin resistance (e.g., metformin, thiazolidinediones) or insulin secretion (e.g., sulfonylureas). 

In the past decade, a mostly injectable class of drugs that stimulates the glucagon-like peptide-1 (GLP-1) receptor has been shown to target both insulin secretion and insulin resistance, the latter largely through weight loss. Recently, there has been focus in the pharmaceutical industry on the development of yet a newer class of drug that stimulates both GLP-1 receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor.² In this class, tirzepatide is a synthetic 39-amino acid peptide that is being developed for the treatment of T2D. Tirzepatide has been shown to have effects on both glycemic control and weight loss that are significantly superior to GLP-1 receptor agonists.³ 

The study by Thomas et al. is a post-hoc analysis comparing tirzepatide to dulaglutide (a GLP-1 receptor agonist), in which the authors focused on the effects of these drugs on biomarkers of insulin resistance and β cell function. As markers of β cell function, the authors analyzed HOMA-2B, proinsulin/insulin ratio, and proinsulin/C-peptide ratios, all of which were significantly improved in subjects given tirzepatide compared to dulaglutide. HOMA2-IR (a marker of insulin resistance), adiponectin, IGFBP-1, and IGFBP-2 (all markers of insulin sensitivity) were also significantly improved in the tirzepatide group. Perhaps more strikingly, the authors performed a regression analysis that controlled for multiple variables to show that the improvement in insulin sensitivity in the tirzepatide group was only partially (13–21%) attributable to weight loss, implying that tirzepatide may have weight-loss-independent effects on insulin sensitivity. A limitation in this study is that the authors relied primarily on biomarkers of insulin resistance and β cell function from a post-hoc analysis, rather than upon more traditional dynamic testing in a dedicated cohort of subjects. Moreover, it remains unclear if a dual receptor-targeting approach has added benefit for diabetes complications beyond just the lowering of HbA1c. Nevertheless, this study emphasizes that this new class of dual receptor agonist represents a new approach in the treatment of T2D – wherein targeting weight loss, insulin resistance, and β cell function collaborates to achieve greater reductions in HbA1c than seen previously with compounds that have single receptor specificity.

 

References

1. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function. Diabetes 1993;42(11):1663–72. 
2. Samms RJ, Coghlan MP, Sloop KW. How May GIP Enhance the Therapeutic Efficacy of GLP-1? Trends Endocrinol Metab TEM 2020;31(6):410–21. 
3. Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018;392(10160):2180–93.