In this study, we evaluated the effectiveness and safety of tirzepatide for Japanese patients with T2DM in real-world clinical settings. We found that HbA1c and body weight decreased significantly during 24 weeks of tirzepatide treatment in this population. Furthermore, the HbA1c reduction was more pronounced in patients with higher baseline HbA1c levels, but not in those with a high BMI. In our cohort, HbA1c change was significantly correlated with baseline HbA1c (rs = – 0.473), which is commonly observed in glucose-lowering intervention studies and may reflect both regression to the mean and glucose-dependent pharmacological effects. Notably, improvements in glycemic control and reductions in body weight were observed both in patients receiving tirzepatide as add-on therapy and in those switching from other incretin-based therapies, including oral and injectable GLP-1RAs. However, we did not know the reason why basal BMI did not correlate with the observed reduction in body weight. The modest weight reduction observed here may limit the ability to detect the relationships between baseline BMI and the reduction of body weight.

Although the study population in this analysis differed substantially from that of the SURPASS trials, which enrolled patients with inadequately controlled T2DM [10,11,12, 14,15,16], the reductions we observed in HbA1c and body weight were directionally consistent with those previously reported. The reductions in HbA1c and body weight were generally greater in the SURPASS clinical program (including the Japanese phase 3 trials, SURPASS J-mono and J-combo) than those observed here. Additionally, this study did not show any apparent dose-dependent effects of tirzepatide on HbA1c reduction. These differences may be partly explained by differences in baseline characteristics, including a longer diabetes duration and a higher prevalence of concomitant medications in our cohort, with >60% of participants receiving SGLT2 inhibitors or metformin at baseline and the shorter follow-up period of this study compared to the SURPASS trials. Furthermore, tirzepatide in the Japanese phase 3 SURPASS J-mono and J-combo trials was evaluated in fixed maintenance-dose groups of 5, 10, and 15 mg once weekly after stepwise titration from 2.5 mg. In SURPASS J-mono, mean HbA1c reductions at week 52 were – 2.4%, – 2.6%, and – 2.8%, with corresponding body weight reductions of – 5.8, – 8.5, and – 10.7 kg, while in SURPASS J-combo body weight reductions were – 3.8, – 7.5, and – 10.2 kg across the 5-, 10-, and 15-mg groups, respectively [11, 12]. In contrast, 5 mg was the most commonly used dose in our cohort and 78% of patients remained on 2.5–5 mg at week 24 (Table 4). The relatively lower dosage used here may partly explain why the reductions in HbA1c and especially body weight were smaller in this study than those reported in the SURPASS clinical trials. In addition, lower body size and total body weight in Japanese patients may have contributed to more modest dose escalation in routine practice. Clinically meaningful reductions in HbA1c and body weight were observed even with the 5-mg maintenance dose in the Japanese phase 3 SURPASS J-mono and J-combo trials, thus supporting the speculation.

In this study, GLP-1RA-naïve patients with T2DM demonstrated significantly larger reductions in HbA1c and body weight compared to those previously treated with GLP-1RAs [17, 18]. These findings are consistent with previous real-world studies showing that tirzepatide is associated with greater reductions in glycemic measures and body weight in GLP-1RA-naïve patients than in patients switching from GLP-1RAs. Furthermore, Suzuki et al. reported in a small real-world study of Japanese patients with T2DM that tirzepatide improved eating behaviors and metabolic outcomes regardless of prior GLP-1RAs use; however, the improvements were larger in GLP-1RA-naïve patients [19]. These observations suggest that chronic GLP-1 receptor activation may attenuate, but not abolish, the glycemic and metabolic responses to tirzepatide. In contrast, DPP-4 inhibitors increase endogenous GLP-1 to a much smaller extent than pharmacologic GLP-1RAs; therefore, the incremental effect of tirzepatide may be relatively larger in patients switching from DPP-4 inhibitors [20].

Although tirzepatide consistently improved glycemic control and reduced body weight in patients with T2DM regardless of baseline therapy, the beneficial effects on HbA1c and body weight varied among individuals. When exploring clinical predictors of treatment, patients with T2DM who had higher baseline HbA1c levels experienced greater reductions in HbA1c, but no significant association was found between baseline BMI and changes in HbA1c. These results suggest that high baseline HbA1c levels may be a major predictive factor determining the glucose-lowering effect of tirzepatide. This observation could be attributed to the glucose-dependent glucose-lowering effect of incretins [21, 22]. Furthermore, we found that tirzepatide treatment for 24 weeks significantly reduced liver enzyme levels, such as aspartate aminotransferase, alanine aminotransferase, and γ-GTP. Moreover, baseline liver enzyme levels were significantly higher in the responder group, in whom HbA1c levels were significantly reduced. These observations suggest an association between tirzepatide treatment and improved liver function markers in patients with T2DM, suggesting that elevated liver enzyme levels may also be a clinical marker of tirzepatide’s therapeutic effectiveness. The improvements in liver function and metabolic indicators have been reported in previous clinical trials [23, 24] and may reflect the multifaceted metabolic effects of tirzepatide in patients with T2DM. The present findings may also be consistent with those of patients with metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis, in whom tirzepatide may confer greater metabolic benefit, although this interpretation remains speculative in this retrospective analysis. Moreover, in this study, tirzepatide significantly reduced systolic and diastolic blood pressure and improved lipid parameters, including triglycerides and LDL cholesterol levels. Tirzepatide treatment not only improved glycemic profiles but also the metabolic and hemodynamic parameters in patients with T2DM.

In this study, eGFR decreased modestly after 24 weeks of treatment with tirzepatide. This “initial dip” in eGFR may reflect the attenuation of glomerular hyperfiltration, which is associated with improved glycemic control and weight loss. Therefore, it is conceivable that long-term therapy with tirzepatide may exhibit renal protective effects, such as slowing the rate of decline in eGFR and reducing urinary albumin excretion, as has been reported with other GLP-1RAs [25, 26]. Indeed, tirzepatide has been reported to significantly slow the rate of decline in renal function in the SURPASS-4 study. Additionally, a recent prospective study in Japanese patients with chronic kidney disease also confirmed its ability to suppress incrseases in UACR and stabilize renal function [27, 28]. Therefore, the results of our study suggest that tirzepatide may contribute to normalizing renal hemodynamics and providing renal protection in patients with T2DM.

This study has several limitations. First, because this was a retrospective observational, non-comparative pre–post study, the effects of confounding factors, regression to the mean, and selection bias cannot be completely ruled out. Missing data were limited for most variables; however, analyses of changes from baseline to week 24 were performed in patients with available paired measurements (n = 324), excluding those who discontinued treatment and/or their final data could not be obtained at week 24 (n = 49). Therefore, the results may not fully represent patients who discontinued tirzepatide before week 24. Second, the study patients primarily consisted of Japanese patients with T2DM and moderate obesity; therefore, the findings may require careful interpretation when applied to other ethnic populations. In addition, because the study was conducted in a limited number of participating institutions, the findings may not be fully generalizable to all practice settings in Japan. Third, the dose selection and titration of tirzepatide were left to the clinicians’ discretion; thus, the observed outcomes were not obtained under a strict titration protocol. Although label-recommended titration exists, actual dose escalation, de-escalation, or discontinuation was determined by each attending physician based on clinical response, tolerability, and shared decision-making with the patient. As a result, the findings may have limited reproducibility and may not be directly comparable with those of randomized controlled trials. In addition, tirzepatide is covered under Japan’s universal health insurance system; however, higher doses are associated with higher drug costs and may increase patients’ out-of-pocket payments. Since we did not collect information on patients’ out-of-pocket costs, we could not evaluate whether cost considerations could influence the dose escalation decision. Fourth, although data were collected using standardized variable definitions and a prespecified template, residual heterogeneity in documentation and measurement timing across sites is inherent to retrospective real-world data. Fifth, blood samples were collected under both fasting and non-fasting conditions; therefore, the effects of tirzepatide on fasting plasma glucose and lipid parameters require further evaluation under standardized sampling conditions. Sixth, adverse events may have been under-ascertained in retrospective chart reviews. In addition, sex-disaggregated analyses were not prespecified in this study; therefore, potential sex-related differences could not be evaluated, which may limit the generalizability of the findings. Overall, prospective studies with standardized data capture are needed to confirm and extend these findings.