Evaluating the pharmacotherapy of tirzepatide in patients with type 2 diabetes: The consideration of systemic metabolism.

Seetharaman et al. showed that innovations in pharmacotherapy to ameliorate the symptoms associated with type 2 diabetes promote more insightful developments in medicine. Tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has recently been reported to initiate more beneficial action against type 2 diabetes than other GLP-1 receptor agonists.1 According to an adjusted indirect treatment comparison from SURPASS-2 and SUSTAIN FORTE trials performed by Vadher et al., treatment with tirzepatide in doses of 5, 10 and 15 mg for 40 weeks significantly decreased HbA1c and body weight in patients with type 2 diabetes compared with semaglutide 2 mg.2 However, the issues concerning the metabolic modulation of tirzepatide remain obscure. Therefore, we here present some opinions on the metabolic functions associated with the use of tirzepatide in treating type 2 diabetes. First, compared with semaglutide 2 mg, tirzepatide 10 mg and 15 mg exhibited superior body weight reduction and glucose-lowering activities. Nevertheless, Vadher et al. did not further explore the influence of tirzepatide on appetite, insulin sensitivity and lipid metabolism. The proportions of decreased appetite caused by tirzepatide (7–9%) for body weight loss via the modulation of central GLP-1 receptors should be considered. As for pancreatic islet functions, the administration of tirzepatide 15 mg for 28 weeks significantly improved insulin sensitivity in patients with type 2 diabetes, as evidenced by the clamp disposition index compared with placebo (estimated treatment difference [ETD] 1.92 [95% confidence interval {CI} 1.59–2.24]; P < .0001) or semaglutide 1 mg (ETD 0.84 [95% CI 0.46–1.21]; P < .0001).3 Regarding lipid metabolism, the SURPASS-2 trial indicated that tirzepatide had more beneficial effects on modulating triglycerides, very-low-density lipoprotein and high-density lipoprotein cholesterol levels than semaglutide. Moreover, treatment with tirzepatide for 52 weeks significantly decreased liver fat content, volumes of visceral adipose tissue and abdominal subcutaneous adipose tissue in patients with type 2 diabetes compared with insulin degludec.4 Thus, the application of tirzepatide to alleviate type 2 diabetes through systemic metabolism should be noted. Second, the extraglycaemic and extrapancreatic effects of tirzepatide on hepatic functions linked to type 2 diabetes were not fully investigated in the study by Vadher et al.2 Because the direct histological changes were absent, the liquid biopsy with reliable biomarkers provides an alternative diagnosis for disease outcomes. The 26-week tirzepatide treatment significantly attenuated nonalcoholic steatohepatitis progression to hepatic fibrosis associated with reduced liver enzymes and hepatic fibrosis biomarkers (keratin-18 and procollagen III) compared with the placebo treatment.5 Thus, the effects of tirzepatide on metabolic organ crosstalk in type 2 diabetes should be considered. Third, the effects of tirzepatide on hormonal regulation linked to type 2 diabetes were not thoroughly discussed. Actually, the metabolic dysfunction involved in systemic metabolism was associated with the alteration of metabolic hormones, including insulin, glucagon, adiponectin and leptin. Compared with semaglutide 1 mg, tirzepatide 15 mg treatment for 28 weeks significantly reduced total insulin AUC0–240 min (ETD −12 264.9 [95% CI −20 263.2 to −4266.7]; P = .0030) and total glucagon AUC0–240 min (ETD −552.0 [95% CI −935.8 to −168.2]; P = .0053) from the study by Heise et al.3 Because the prevalence of type 2 diabetes was correlated with lower adiponectin and higher leptin levels,6 the evaluation of tirzepatide in modulating adiponectin and leptin levels in patients with type 2 diabetes was meaningful. The 26-week tirzepatide 5-, 10- and 15-mg treatments significantly improved insulin sensitivity through increasing the circulating levels of adiponectin from 12 to 26%, unlike that with dulaglutide 1.5 mg (11%).7 In contrast, leptin levels were significantly decreased in the tirzepatide 10 mg (−28.2%) and 15 mg (−34.1%) groups compared with those in the dulaglutide 1.5 mg group at 26 weeks, indicating the superiority of tirzepatide in attenuating type 2 diabetes and reducing related cardiovascular risk through the evaluation of several cardiovascular biomarkers targeting inflammation and endothelial dysfunction, including monocyte chemoattractant protein-1, chitinase-3-like protein-1 and intercellular adhesion molecule-1.8 Thus, a comparison of the circulating levels of metabolic hormones is required to clarify the metabolic modulation of tirzepatide. Finally, Seetharaman et al. demonstrated that GIP by itself had no glucose-lowering properties, which was possibly the consequence of GIP-stimulated glucagon secretion. Interestingly, the benefits of tirzepatide are due to the synergistic action of activating both GIP and GLP-1 receptors. This implies that a future pharmacotherapeutic trend that includes the combination of multiple targets may provide a more effective treatment based on the structural basis of functional versatility.9, 10 Collectively, the clinical evaluation of efficacy and safety for tirzepatide in treating patients with systemic metabolism dysfunction linked to type 2 diabetes is promising. Moreover, more clinical investigations in direct head-to-head trials are required to verify the superior disease control and therapy choice. Nothing to report. Lee Yu-Cheng was responsible for revising and editing the whole manuscript. Chung Hsien-Hui was responsible for conceptualization and wrote the whole manuscript.