Association Between Early Weight Loss and Metabolic Outcomes with Tirzepatide in Japanese Patients with Type 2 Diabetes: A SURPASS J Post Hoc Analysis

Abstract

Introduction

This study assessed whether early weight loss following tirzepatide treatment was associated with clinical characteristics and outcomes at 52 weeks in Japanese patients with type 2 diabetes (T2D).

Methods

Post hoc analyses used pooled data from the phase 3 SURPASS J-mono and J-combo studies, which examined tirzepatide 5, 10, and 15 mg as monotherapy or combination therapy in Japanese participants over 52 weeks. Subgroup analyses of clinical characteristics and metabolic outcomes at 52 weeks were conducted based on early weight loss achievement of < 5% or ≥ 5% after 8 weeks of tirzepatide (comprising 4 weeks each at 2.5 mg and 5 mg, per dose-escalation scheme). Selected safety outcomes were evaluated by weight-loss subgroups.

Results

The analysis included 893 participants (< 5% subgroup: n = 683 [76.5%]; ≥ 5% subgroup: n = 210 [23.5%]). Multivariate regression analysis showed that participant clinical characteristics, including lower baseline weight, concomitant alpha-glucosidase inhibitor use, and lack of concomitant sulfonylurea use, were independently predictive of achieving ≥ 5% weight loss at 8 weeks. Clinically significant reductions with tirzepatide were observed in body mass parameters over 52 weeks in both subgroups, with greater weight reductions observed at week 52 in the ≥ 5% subgroup versus the < 5% subgroup (5 mg: − 13.8% vs. − 4.1%; 10 mg: − 16.5% vs. − 8.8%; 15 mg: − 20.0% vs. − 11.5% [p < 0.001, all comparisons]). Blood pressure and lipid level improvements were also significantly greater in the ≥ 5% subgroup. Improvements in glycated hemoglobin were similar between subgroups; however, the ≥ 5% subgroup had a higher proportion of participants who achieved normoglycemia at week 52 with a shorter time to reach normoglycemia. Tirzepatide was generally well tolerated across the weight-loss subgroups.

Conclusions

These findings suggest early weight loss following tirzepatide may be predictive of metabolic outcomes at 52 weeks in Japanese patients with T2D. These data may inform clinical management of tirzepatide-treated patients.

ClinicalTrials.gov

NCT03861052, NCT03861039.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13300-025-01775-y.

Key Summary Points

Why carry out this study?

Limited information is currently available on the factors that influence response to tirzepatide treatment among Japanese patients with type 2 diabetes (T2D).

This post hoc analysis assessed whether early weight loss (< 5% or ≥ 5% weight loss following 8 weeks of tirzepatide treatment) was associated with clinical characteristics and outcomes at 52 weeks in Japanese participants with T2D, using pooled data from the phase 3 SURPASS J-mono and J-combo studies.

What was learned from the study?

The results suggest that achievement of ≥ 5% weight loss after 8 weeks of tirzepatide treatment was associated with a subset of clinical characteristics (lower baseline body weight, concomitant alpha-glucosidase inhibitor use, and lack of concomitant sulfonylurea use) and with improvements in body mass and metabolic parameters after 52 weeks of tirzepatide treatment.

Tirzepatide was generally well tolerated, regardless of early weight-loss subgroup.

These findings are anticipated to be of interest and utility for managing treatment of Japanese patients with T2D.

Introduction

East Asian populations, including Japanese populations, develop type 2 diabetes (T2D) at a lower body mass index (BMI) compared with non-East Asian populations, which has been attributed to increased visceral adiposity and insulin resistance coupled with an inadequate beta-cell response in East Asian patients [1–3]. Given these differences in the pathophysiology of T2D, it is of interest to examine the factors that influence treatment outcomes in East Asian patient populations as these may inform treatment decisions in clinical practice and help improve the clinical management of T2D in these patients. Additionally, T2D is recognized as a heterogeneous disease, with variable clinical characteristics and risks of comorbidities, requiring an individualized and personalized approach for optimal disease management [4].

Tirzepatide is a glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide 1 receptor agonist that has been approved in Japan for the treatment of T2D and obesity disease. In the global phase 3 SURPASS clinical program, participants with T2D had clinically meaningful improvements in body weight and in several metabolic parameters concurrent with improvements in glycated hemoglobin (HbA_1c) following up to 52 weeks of treatment with tirzepatide 5, 10, and 15 mg, as monotherapy or in combination with other antihyperglycemic medications [5–9]. Subsequent post hoc analyses of the SURPASS-1–4 studies showed that the clinical response to tirzepatide at 40–42 weeks varied among participants, with the achievement of normoglycemia more likely in younger participants and in those who had a shorter duration of disease or lower baseline HbA_1c levels [10] and achievement of ≥ 15% body weight loss more likely in female participants and those who were of white or Asian race or of younger age [11].

The SURPASS J-mono and SURPASS J-combo clinical studies confirmed the efficacy and safety findings of the global studies in Japanese participants with T2D [12, 13]. However, limited information is currently available on the factors that influence the response to tirzepatide treatment among Japanese patients with T2D. The objectives of this post hoc analysis were to investigate the clinical characteristics associated with early body weight loss with tirzepatide treatment in Japanese participants from the SURPASS J studies and to assess whether early body weight loss was associated with better outcomes at 52 weeks. It is anticipated that the findings of this analysis may lead to a deeper understanding of the treatment response to tirzepatide in Japanese patients with T2D and may enable improvements in individualized patient care.

Methods

Study Design and Participants

This was a post hoc analysis of pooled data from the phase 3 SURPASS J-mono and J-combo studies (ClinicalTrials.gov identifiers NCT03861052 and NCT03861039, respectively), which examined the safety and efficacy of tirzepatide in Japanese participants with T2D. The study design, eligibility criteria, and outcomes of the SURPASS J studies have been previously described in detail [12, 13]. In brief, SURPASS J-mono was a multicenter, randomized, double-blind, active-controlled study that compared tirzepatide 5, 10, and 15 mg with dulaglutide 0.75 mg over 52 weeks. SURPASS J-combo was a randomized, open-label, parallel-group study that assessed tirzepatide 5, 10, and 15 mg as an add-on treatment to oral antihyperglycemic medication (OAM) over 52 weeks.

Both studies enrolled Japanese adults (≥ 20 years of age) with T2D, with a BMI of ≥ 23 kg/m² and stable body weight (± 5%). Participants in SURPASS J-mono were OAM-naïve or were on OAM monotherapy except thiazolidinediones and willing to discontinue OAM with an 8-week washout period [12]. Participants in SURPASS J-combo had T2D inadequately controlled with OAM monotherapy, including alpha-glucosidase inhibitors, biguanides, glinides, sodium-glucose cotransporter 2 inhibitors, sulfonylureas, and thiazolidinediones [13]. Participants in SURPASS J-combo had received OAM monotherapy for ≥ 3 months at baseline and continued their usual background OAM regimen throughout the treatment period [13].

In both studies, the initial dose of tirzepatide was 2.5 mg, administered subcutaneously once a week. The dose was increased by 2.5 mg every 4 weeks until the randomly assigned dose was reached and then maintained until week 52. Participants were allowed to initiate, modify, or discontinue use of other required concomitant medications (excluding antihyperglycemic medications other than background OAMs [SURPASS J-combo only], any weight-loss-promoting medication, and chronic systemic glucocorticoid therapy). In the current analysis, an early clinical response was defined as achieving a ≥ 5% reduction in body weight after 8 weeks of tirzepatide treatment, comprising 4 weeks of tirzepatide 2.5 mg followed by 4 weeks of tirzepatide 5 mg for all dose groups. This analysis evaluated the associations between the early clinical response and participant clinical characteristics, metabolic outcomes, and safety over 52 weeks of treatment with tirzepatide.

The SURPASS J study protocols were approved by independent ethical review boards at each study site (published in the primary manuscripts [12, 13]). The studies were conducted in accordance with the Declaration of Helsinki of 1964 (and its later amendments) and the Council for International Organizations of Medical Sciences International Ethical Guidelines. All participants provided written informed consent prior to study participation.

Statistical Analysis

In the SURPASS J studies, efficacy and safety assessments were conducted using the modified intention-to-treat population, which comprised all randomly assigned participants who received ≥ 1 dose of the study drug. Using data pooled from the SURPASS J-mono and J-combo studies, subgroup analyses by the percent weight reduction achieved at week 8 (< 5% or ≥ 5%) were conducted. Analyses included participants randomly assigned to receive tirzepatide 5, 10, or 15 mg who were on treatment at week 8 and had body weight data available at week 8. Efficacy analyses were conducted on the efficacy analysis set, which excluded data collected after a participant started rescue therapy or discontinued study treatment.

Descriptive statistics are shown for baseline patient characteristics as mean (standard deviation [SD]) or median (interquartile range) for continuous variables and as frequency (percentage) for categorical variables. Univariate and multivariate logistic regression analyses were performed to assess the association between participant clinical characteristics and the achievement of ≥ 5% weight loss after 8 weeks of tirzepatide treatment. Odds ratios (ORs), 95% confidence intervals (CIs), and p values were estimated using logistic regression models.

Percent change from baseline in body weight and change from baseline in other body mass and metabolic parameters were assessed by achievement of a < 5% or ≥ 5% reduction in body weight at week 8. Least-squares mean (LSM) change from baseline (standard error [SE]) over 52 weeks was calculated for each tirzepatide dose. For body weight, BMI, waist circumference, and HbA_1c, postbaseline data were analyzed using a mixed model for repeated measures (MMRM) with study (SURPASS J-mono or J-combo), baseline body weight, baseline HbA_1c, weight-loss subgroup (< 5% or ≥ 5% at week 8), visit, and weight-loss subgroup-by-visit interaction as fixed effects. For blood pressure and lipid parameters, postbaseline data were analyzed with an MMRM, adding the baseline parameter value (systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, or triglycerides) to the base model.

The proportion of participants achieving HbA_1c < 5.7% at 52 weeks was analyzed by achievement of a < 5% or ≥ 5% reduction in body weight at week 8. Data collected after a participant initiated rescue medication or discontinued the study drug were considered missing. Postbaseline data were analyzed using an MMRM with baseline HbA_1c, stratification factor, treatment, visit, and treatment-by-visit interaction as factors, which were then dichotomized. ORs, 95% CIs, and p values for postbaseline measures were calculated with a logistic regression model using imputed data for HbA_1c < 5.7% at 52 weeks with study (SURPASS J-mono or J-combo), baseline HbA_1c, baseline body weight, and weight-loss subgroup (< 5% or ≥ 5% at week 8) as factors. Median (95% CI) time to achieve HbA_1c < 5.7% in weight-loss subgroups was estimated using the Kaplan–Meier method [14] for each tirzepatide dose group and weight-loss subgroup.

Safety assessments were performed using the safety analysis set, which included data collected from the start of treatment to the end of safety follow-up. Only participants with available body weight data from week 8 were included in the safety analysis. Safety data were summarized descriptively for weight-loss subgroups, including the incident proportion of treatment-emergent adverse events (TEAEs), gastrointestinal TEAEs, and study drug discontinuations due to adverse events and gastrointestinal adverse events. The severity of TEAEs was also summarized.

P values < 0.05 were considered statistically significant. Analyses were performed using R Statistical Software, version 4.3.2 (R Core Team, 2023 [15]).

Results

A total of 893 participants were included in the analysis from the SURPASS J-mono and J-combo studies (n = 296, n = 299, and n = 298 randomized to the tirzepatide 5-, 10-, and 15-mg, groups, respectively). At week 8, 683 participants (76.5%) had achieved a < 5% reduction in body weight from baseline and 210 (23.5%) had achieved a ≥ 5% reduction in body weight from baseline.

In the ≥ 5% weight-loss subgroup, there was a lower proportion of male participants (70.5%), compared with the < 5% weight-loss subgroup (77.7%), and participants had a slightly higher mean (SD) age (57.9 [9.9] years vs. 56.1 [10.7] years in the < 5% weight-loss subgroup) (Table 1). The mean (SD) duration of diabetes was shorter in the ≥ 5% weight-loss subgroup (7.2 [6.1] years) compared with the < 5% weight-loss subgroup (7.9 [5.9] years). At baseline, participants in the ≥ 5% weight-loss subgroup, compared with those in the < 5% weight-loss subgroup, had a lower mean (SD) body weight (72.9 [11.4] vs. 80.0 [16.2] kg), BMI (26.7 [3.2] vs. 28.6 [5.0] kg/m²), waist circumference (92.7 [8.4] vs. 97.4 [11.1] cm), fasting serum glucose (158.7 [35.3] vs. 175.3 [44.1] mg/dL), and HbA_1c (8.1% [0.9] vs. 8.5% [1.0]). No major differences were observed in blood pressure, triglycerides, or high-density lipoprotein cholesterol levels between the weight-loss subgroups at baseline. There were no major differences in OAM use between the subgroups, except that the ≥ 5% weight-loss subgroup had a higher proportion of participants who used alpha-glucosidase inhibitors (24 [11.4%] vs. 39 [5.7%]) and a lower proportion who used sulfonylureas (17 [8.1%] vs. 109 [16.0%]) compared with the < 5% weight-loss subgroup (Table 1).

Table 1.

Baseline demographics and clinical characteristics by 8-week body weight-loss achievement subgroups

Variable	Weight loss ≥ 5% (N = 210)	Weight loss < 5% (N = 683)
Age, years	57.9 (9.9)	56.1 (10.7)
Sex, n (%)
Female	62 (29.5%)	152 (22.3%)
Male	148 (70.5%)	531 (77.7%)
Diabetes duration, years	7.2 (6.1)	7.9 (5.9)
HbA1c, %	8.1 (0.9)	8.5 (1.0)
FSG, mg/dL	158.7 (35.3)	175.3 (44.1)
Weight, kg	72.9 (11.4)	80.0 (16.2)
BMI, kg/m2	26.7 (3.2)	28.6 (5.0)
Waist circumference, cm	92.7 (8.4)	97.4 (11.1)
eGFR (CKD-EPI), mL/min/1.73 m2	76.9 (11.4)	79.0 (12.7)
SBP, mmHg	130.2 (14.0)	130.3 (13.9)
DBP, mmHg	80.5 (10.3)	81.8 (10.0)
HDL-C, mg/dL	52.5 (15.4)	52.3 (12.6)
Median (IQR)	50.0 (43.0, 59.8)	51.0 (43.0, 61.0)
Triglycerides, mg/dL	166.6 (125.1)	172.2 (146.9)
Median (IQR)	134.5 (95.0, 188.3)	135.0 (99.0, 190.0)
Study, n (%)
SURPASS J-mono	115 (54.8%)	346 (50.7%)
SURPASS J-combo	95 (45.2%)	337 (49.3%)
Treatment group, n (%)
Tirzepatide 5 mg	71 (33.8%)	225 (32.9%)
Tirzepatide 10 mg	67 (31.9%)	232 (34.0%)
Tirzepatide 15 mg	72 (34.3%)	226 (33.1%)
OAM use, n (%)
Alpha-glucosidase inhibitors	24 (11.4%)	39 (5.7%)
Biguanides	14 (6.7%)	45 (6.6%)
Glinides	11 (5.2%)	50 (7.3%)
SGLT2is	16 (7.6%)	47 (6.9%)
Sulfonylureas	17 (8.1%)	109 (16.0%)
Thiazolidinediones	13 (6.2%)	47 (6.9%)
None	115 (54.8%)	346 (50.7%)

Data are mean (standard deviation), unless otherwise specified

BMI body mass index, CKD-EPI Chronic Kidney Disease-Epidemiology Collaboration, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, FSG fasting serum glucose, HbA_1c glycated hemoglobin, HDL-C high-density lipoprotein cholesterol, IQR interquartile range, N total number of participants in the analysis, n number of participants in the specified category, OAM oral antihyperglycemic medication, SBP systolic blood pressure, SGLT2is sodium-glucose cotransporter 2 inhibitors

Univariate logistic regression analysis of baseline factors showed that sex, age, HbA_1c, fasting serum glucose, body weight, BMI, waist circumference, estimated glomerular filtration rate, alpha-glucosidase inhibitor use, and sulfonylurea use were statistically significantly associated with achievement of ≥ 5% weight loss at 8 weeks (Table S1). Factors identified as statistically significant in the univariate analysis were included in the multivariate analysis. Body weight, BMI, and waist circumference were found to be closely correlated with each other (Pearson correlation > 0.8); therefore, only body weight was included in the multivariate regression model to prevent collinearity. Multiple regression analysis showed that lower baseline body weight and concomitant alpha-glucosidase inhibitor use were statistically significantly associated with higher rates of ≥ 5% weight loss achievement at 8 weeks, whereas concomitant sulfonylurea use was associated with lower odds of achieving ≥ 5% weight loss at 8 weeks (Fig. 1).

Fig. 1.

Multivariate regression analysis of baseline parameters associated with achievement of ≥ 5% weight loss at 8 weeks. ORs (95% CI) of baseline factors associated with ≥ 5% weight loss achievement after 8 weeks of tirzepatide treatment were calculated using a multivariate logistic regression model incorporating variables that were found to be statistically significant in the univariate analysis. Only participants with weight data available at week 8 were included in the analysis. Participants in SURPASS J-combo had received OAM monotherapy for ≥ 3 months at baseline and continued their background OAM regimen throughout treatment. CI confidence interval, eGFR estimated glomerular filtration rate, FSG fasting serum glucose, HbA_1c glycated hemoglobin, OAM oral antihyperglycemic medication, OR odds ratio

Decreases were observed in body mass parameters across the 52-week treatment period in both < 5% and ≥ 5% weight-loss subgroups (Fig. 2). Statistically significant differences were observed between weight-loss subgroups starting from 4 weeks (Table S2). At week 52, the LSM (SE) percent change from baseline in body weight was significantly higher in the ≥ 5% weight-loss group compared with the < 5% weight-loss group for all tirzepatide doses (5 mg: − 13.8% [0.7] vs. − 4.1% [0.4], LSM difference − 9.6; 10 mg: − 16.5% [0.8] vs. − 8.8% [0.4], LSM difference − 7.7; 15 mg: − 20.0% [0.9] vs. − 11.5% [0.5], LSM difference − 8.5 [p < 0.001 for all comparisons]) (Fig. 2; Table S2).

Fig. 2.

Effect of tirzepatide on body mass parameters over 52 weeks by 8-week weight-loss subgroups. Data were pooled from the modified intention-to-treat populations in the SURPASS J-mono and J-combo trials. Subgroup analyses were conducted based on the achievement of < 5% or ≥ 5% body weight loss at week 8 for a percent change from baseline in body weight and change from baseline in b BMI and c waist circumference over 52 weeks. Postbaseline data are from a mixed model for repeated measures analysis and are shown as least-squares mean (standard error). ***p < 0.001 for within-treatment comparison between 8-week weight loss achievement subgroups (< 5% and ≥ 5%) at 52 weeks. BMI body mass index

Similarly, participants who achieved ≥ 5% weight loss at week 8 had greater LSM (SE) reductions in BMI (5 mg: − 3.7 [0.2] vs. − 1.1 [0.1] kg/m², LSM difference − 2.6 kg/m²; 10 mg: − 4.5 [0.2] vs. − 2.5 [0.1] kg/m², LSM difference − 2.0 kg/m²; 15 mg: − 5.3 [0.3] vs. − 3.3 [0.1] kg/m², LSM difference − 2.1 kg/m² [p < 0.001 for all comparisons]) and waist circumference (5 mg: − 9.3 [0.7] vs. − 2.9 [0.4] cm, LSM difference − 6.3 cm; 10 mg: − 11.3 [0.7] vs. − 5.8 [0.4] cm, LSM difference − 5.5 cm; 15 mg: − 14.4 [0.8] vs. − 7.8 [0.4] cm, LSM difference − 6.7 cm [p < 0.001 for all comparisons]) at week 52 compared with those who achieved < 5% weight loss (Fig. 2; Table S2).

Improvements from baseline in high-density lipoprotein cholesterol and triglycerides at week 52 were also significantly greater in the ≥ 5% weight-loss subgroup than in the < 5% weight-loss subgroup for all tirzepatide doses and for systolic blood pressure and diastolic blood pressure in the 5-mg and 15-mg tirzepatide groups (Fig. 3). Concomitant antihypertensive and lipid-lowering medication usage at baseline and at 52 weeks was generally balanced between the weight-loss subgroups, and there were no major changes in the proportion of participants using antihypertensive and lipid-lowering medications between baseline and week 52 (Table S3). Mean improvement in HbA_1c at week 52 did not significantly differ between the weight-loss subgroups (Fig. 3). However, statistically significantly lower proportions of participants in the < 5% weight-loss subgroup achieved HbA_1c < 5.7% at week 52 compared with those in the ≥ 5% weight-loss subgroup for the 5-mg (34.7% vs. 71.8%; OR, 4.1 [95% CI 2.2, 7.7]; p < 0.001) and 10-mg tirzepatide doses (56.5% vs. 83.6%; OR, 3.5 [95% CI 1.7, 7.5]; p < 0.001), with a similar trend observed for the 15-mg dose (70.8% vs. 87.5%; OR, 2.1 [95% CI 1.0, 4.9]; p = 0.063) (Fig. 4). Examination of the time to achieve normoglycemia (HbA_1c < 5.7%) indicated that more participants in the ≥ 5% weight-loss subgroup had achieved HbA_1c < 5.7% compared to those in the < 5% weight-loss subgroup in each tirzepatide arm across the treatment period (Fig. 5).

Fig. 3.

Effect of tirzepatide on metabolic parameters at week 52 by 8-week weight-loss subgroups. Week 52 data are shown as least-squares mean (standard error) change from baseline in a SBP, b DBP, c HDL-C, d triglycerides, and e HbA_1c. Data were pooled from the modified intention-to-treat populations in the SURPASS J-mono and J-combo trials. Subgroup analyses were conducted based on the achievement of < 5% or ≥ 5% body weight loss at week 8. *p < 0.05, **p < 0.01, and ***p < 0.001 for comparison between weight-loss subgroups within treatment groups at week 52 by a mixed model for repeated measures. DBP diastolic blood pressure, HbA_1c glycated hemoglobin, HDL-C high-density lipoprotein cholesterol, SBP systolic blood pressure

Fig. 4.

Proportion of participants achieving HbA_1c < 5.7% at week 52 by 8-week weight-loss subgroups. Data were pooled from the modified intention-to-treat populations in the SURPASS J-mono and J-combo trials. Subgroup analyses were conducted based on the achievement of < 5% or ≥ 5% body weight loss at week 8. Postbaseline data were analyzed using a mixed model for repeated measures and then dichotomized. ORs (95% CIs) and p values were calculated with a logistic regression model using imputed data for HbA_1c < 5.7%. CI confidence interval, HbA_1c glycated hemoglobin, N total number of participants, n number of participants in the specified category, OR odds ratio

Fig. 5.

Time to initial achievement of HbA_1c < 5.7% by 8-week body weight-loss subgroups. Data were pooled from the modified intention-to-treat populations in the SURPASS J-mono and J-combo trials and were categorized by the percent weight reduction achieved at week 8 (< 5% or ≥ 5%) and the tirzepatide maintenance dose. Analyses included participants randomly assigned to receive tirzepatide 5, 10, or 15 mg who were on treatment at week 8 and had body weight data available at week 8. Median (95% CI) time to HbA_1c < 5.7% was estimated using the Kaplan–Meier method. CI confidence interval, HbA_1c glycated hemoglobin, N total number

As originally reported in the SURPASS J studies [12, 13], TEAEs were more frequent in the tirzepatide 10-mg and 15-mg groups, compared with the 5-mg group, and were most commonly gastrointestinal symptoms of mild severity (Table 2). The proportion of participants reporting any TEAE (82.1–91.7% vs. 73.3–81.9%) and any gastrointestinal TEAE (58.2–59.2% vs. 40.9–54.0%) trended slightly higher in the ≥ 5% weight-loss subgroup compared to the < 5% weight-loss subgroup. Nausea, diarrhea, and vomiting were the most frequent TEAEs reported across the SURPASS clinical program [5–9, 12, 13]. Of these, the incidence proportion of nausea and vomiting were slightly higher in the ≥ 5% weight-loss subgroup, whereas diarrhea events occurred at a similar frequency across the weight-loss subgroups (Table 2). Study drug discontinuations due to adverse events were numerically higher in the ≥ 5% weight-loss subgroup (7.0–16.7%) compared with the < 5% weight-loss subgroup (3.1–6.2%) (Table 2).

Table 2.

Proportion of participants with AEs in SURPASS J-mono and J-combo by 8-week body weight-loss achievement subgroups

	Weight loss ≥ 5%			Weight loss < 5%
	Tirzepatide 5 mg (N = 71)	Tirzepatide 10 mg (N = 67)	Tirzepatide 15 mg (N = 72)	Tirzepatide 5 mg (N = 225)	Tirzepatide 10 mg (N = 232)	Tirzepatide 15 mg (N = 226)
	n (%) [E]	n (%) [E]	n (%) [E]	n (%) [E]	n (%) [E]	n (%) [E]
Any TEAE	59 (83.1%) [378]	55 (82.1%) [236]	66 (91.7%) [401]	170 (75.6%) [625]	170 (73.3%) [836]	185 (81.9%) [1081]
Discontinuation of study drug due to AEs	5 (7.0%) [5]	8 (11.9%) [8]	12 (16.7%) [12]	7 (3.1%) [7]	14 (6.0%) [14]	14 (6.2%) [14]
Discontinuation of study drug due to GI AEs	3 (4.2%) [3]	3 (4.5%) [3]	6 (8.3%) [6]	3 (1.3%) [3]	4 (1.7%) [4]	8 (3.5%) [8]
GI AEs, any	42 (59.2%) [137]	39 (58.2%) [105]	42 (58.3%) [155]	92 (40.9%) [257]	101 (43.5%) [279]	122 (54.0%) [387]
Nausea	12 (16.9%) [68]	16 (23.9%) [34]	23 (31.9%) [45]	17 (7.6%) [62]	35 (15.1%) [71]	48 (21.2%) [107]
Vomiting	4 (5.6%) [5]	9 (13.4%) [15]	15 (20.8%) [33]	11 (4.9%) [14]	10 (4.3%) [15]	18 (8.0%) [29]
Diarrhea	7 (9.9%) [13]	10 (14.9%) [15]	8 (11.1%) [11]	31 (13.8%) [56]	24 (10.3%) [52]	28 (12.4%) [52]

AEs were coded using the Medical Dictionary for Regulatory Activities version 23.1

Data were pooled from tirzepatide-treated participants in the modified intention-to-treat populations (safety analysis sets) of the SURPASS J-mono and J-combo trials. Only participants with available body weight data from week 8 were included in the analysis

AE adverse event, E number of events, GI gastrointestinal, N number of participants in the analysis population, n number of participants with AEs, TEAE treatment-emergent adverse event

Discussion

This post hoc analysis of the SURPASS J studies identified participant clinical characteristics associated with tirzepatide-mediated early weight loss and further determined the association of early weight loss with better metabolic outcomes at 52 weeks in Japanese participants with T2D. This analysis found that participants who achieved ≥ 5% weight loss at week 8 had greater improvements in body mass parameters, blood pressure, and lipid levels at 52 weeks compared to those who had < 5% weight loss at 8 weeks. The proportion of participants who achieved normoglycemia was also higher for all tirzepatide doses in the ≥ 5% weight-loss subgroup at all time points, corresponding to a shorter time to reach normoglycemia, although the magnitude of HbA_1c improvement at 52 weeks was similar between the weight-loss subgroups. The safety profile of tirzepatide in this analysis was consistent with the known safety reported for the glucagon-like peptide 1 receptor agonist class and prior global SURPASS studies [5–9], with tirzepatide generally well tolerated across the weight-loss subgroups. Collectively, these data suggest that early body weight loss of ≥ 5% with tirzepatide in Japanese participants with T2D may be indicative of better clinical outcomes at 52 weeks with tirzepatide treatment. This information may aid in identifying those patients who will have a better response to tirzepatide and, conversely, those who might benefit from alternative or more intensive therapeutic interventions.

In this study, early response was defined as the achievement of ≥ 5% body weight loss at 8 weeks of treatment. Week 8 marks the completion of the administration of the lowest maintenance dose of 5 mg and is the last time point in the SURPASS J studies where all participants received the same dosage. The ≥ 5% threshold represents a clinically relevant amount of body weight loss for patients with T2D or obesity. The consensus guidelines from the American Diabetes Association and the European Association for the Study of Diabetes recommend a weight loss target of 5–15% for patients with T2D to achieve meaningful improvements in glycemic and metabolic parameters, with greater benefit observed with greater weight loss [4]. Additionally, the Japanese Society for the Study of Obesity recommends a ≥ 3% body weight reduction for Japanese patients with obesity disease (defined as obesity [i.e., BMI ≥ 25 kg/m² associated with excessive fat storage] accompanied by ≥ 1 obesity-related health disorder or ≥ 100 cm² visceral fat accumulation) and 5–10% for those with high-degree obesity disease (BMI ≥ 35 kg/m² accompanied by ≥ 1 obesity-related health disorder or ≥ 100 cm² visceral fat accumulation) [16]. As the initial 8 weeks of treatment correspond to the lower end of the tirzepatide dose-escalation scheme (i.e., 2.5 mg to 5 mg), it is notable that approximately a quarter of the SURPASS J participants achieved this early response threshold in this post hoc analysis.

Factors found to be independently predictive of achieving ≥ 5% weight loss at week 8 in regression analyses were lower baseline body weight, concomitant alpha-glucosidase inhibitor use, and lack of concomitant sulfonylurea use, suggesting that these parameters may aid in predicting the early weight loss response to tirzepatide in Japanese patients with T2D. As alpha-glucosidase inhibitor use has been associated with mild weight loss and sulfonylurea use has been associated with significant weight gain [17–19], it is reasonable that participants receiving alpha-glucosidase inhibitors had higher odds of achieving ≥ 5% weight loss whereas those receiving concomitant sulfonylureas had lower odds of ≥ 5% weight loss. It should be noted that use of other OAMs that have been previously associated with weight loss (e.g., sodium-glucose cotransporter 2 inhibitors) was not significantly associated with early weight loss in the univariate analysis and therefore was not included in the multivariate model in this analysis. Although prior studies investigated the clinical features associated with better outcomes in tirzepatide-treated participants in the global SURPASS studies at 40–52 weeks of treatment [10, 11, 20], comparison of the current results to the prior studies at 40–52 weeks are precluded by the experimental differences between the studies (e.g., differences in statistical models, study populations, outcomes, and time points).

The current findings are consistent with a substantial body of literature indicating that early weight loss is predictive of longer-term weight loss in patients with T2D or obesity following lifestyle and behavioral interventions [21–23], pharmacological treatment [24, 25], or bariatric surgery [26, 27]. In a secondary analysis of the SCALE Obesity and Prediabetes and SCALE Diabetes studies of liraglutide 3.0 mg, ≥ 4% weight loss at week 16 was shown to be a strong predictor of ≥ 5% weight loss at 56 weeks in participants with and without T2D, with the early responders showing greater improvements in weight and cardiometabolic risk factors at 56 weeks [25]. The data are also consistent with prior reports that substantial weight loss is associated with improvements in metabolic outcomes and cardiovascular risk factors in patients with T2D and obesity [11, 28]. The findings of greater weight loss and larger reductions in BMI and waist circumference across the treatment period in early responders are of particular interest, as the existing literature suggests such improvements in these parameters in Japanese patients with T2D are directly correlated to better metabolic health outcomes. Recent real-world prevalence estimates of metabolic abnormalities in Japanese patients with T2D show that prevalence increases with increasing BMI, with prevalence at 17.3% in patients with BMI < 25 kg/m² and increasing to 54.6% and 66.1% for patients with a BMI of 25 to < 30 kg/m² and ≥ 30 kg/m², respectively [29]. Additionally, prior post hoc analyses of SURPASS J-mono showed that the prevalence of multiple metabolic abnormalities comprising the Japanese criteria of metabolic syndrome (waist circumference of ≥ 85 cm in men and ≥ 90 cm in women plus at least two of the following: 1. elevated triglycerides and/or reduced high-density lipoprotein cholesterol; 2. elevated blood pressure; and 3. elevated fasting plasma glucose [30]) was reduced from approximately 70% to 31.7%, 23.0%, and 14.2% following treatment with tirzepatide 5, 10, and 15 mg in Japanese participants with T2D [31], and the level of tirzepatide-mediated weight loss directly correlated with improvements in blood lipid levels and blood pressure [32].

A strength of the current study is that it pooled data from two phase 3 studies to enhance the robustness of the findings. This study also had limitations. The study included participants with relatively early-stage T2D, and therefore the findings may not be generalizable to participants with later-stage disease. We also acknowledge that there may be predictors or confounders of weight loss that were not identified herein. In addition, further long-term studies in real-world clinical settings are warranted to evaluate the impact of early clinical response on the effectiveness and safety of tirzepatide beyond 52 weeks.

Conclusion

The results of this post hoc analysis of SURPASS J study data from Japanese participants with T2D identified clinical characteristics associated with tirzepatide-mediated weight loss at 8 weeks, including lower baseline body weight, concomitant alpha-glucosidase inhibitor use, and lack of concomitant sulfonylurea use. The current data further support an association between early weight loss and clinical improvements at 52 weeks of tirzepatide treatment in Japanese patients with T2D, suggesting that weight loss of ≥ 5% by week 8 may be associated with better metabolic outcomes at 52 weeks. These results provide a greater understanding of the response to tirzepatide in Japanese patients with T2D. The current data suggest that increasing the dose level for participants receiving treatment with tirzepatide 5 mg who have an inadequate weight loss response at 8 weeks may have long-term benefits for weight loss and metabolic parameters. This information is anticipated to be of use for predicting which patients are likely to benefit from treatment with tirzepatide based on their individual clinical profiles and thus may assist health care providers when devising individualized treatment plans for their Japanese patients with T2D.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Hanaka Mimura contributed to the study conception and design. Data analysis was performed by Hanaka Mimura and Tomonori Oura. Hanaka Mimura, Tomonori Oura, Rina Chin, Tetsuaki Hirase, and Dai Shimono contributed to data collection and interpretation, participated sufficiently in the work to agree to be accountable for all aspects of the work, and contributed to the writing and critical revision of the manuscript. All authors read and approved the final manuscript.

Funding

This study was sponsored by Eli Lilly and Company, and the manuscript was funded by Eli Lilly Japan and Mitsubishi Tanabe Pharma Corporation.

Data Availability

For trial data, Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data-sharing environment. The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. For details on submitting a request, see the instructions provided at www.vivli.org.

Declarations

Conflict of Interest

All authors declare funding support for this study and manuscript from Eli Lilly Japan K.K. and Mitsubishi Tanabe Pharma Corporation. Dai Shimono reports grants from Novo Nordisk Pharma and honoraria from Eli Lilly and Company and Mitsubishi Tanabe Pharma Corporation. Hanaka Mimura, Tomonori Oura, Rina Chin, and Tetsuaki Hirase are employees of Eli Lilly Japan and minor shareholders of Eli Lilly and Company.

Ethical Approval

The SURPASS J study protocols were approved by independent ethical review boards at each study site (published in the primary manuscripts [12, 13]). The studies were conducted in accordance with the Declaration of Helsinki of 1964 (and its later amendments) and the Council for International Organizations of Medical Sciences International Ethical Guidelines. All participants provided written informed consent prior to study participation.