FormalPara Key Summary Points

Why carry out this study?

The prevalence of type 2 diabetes (T2D) and obesity has steadily increased in Japan over recent decades, with the presence of visceral obesity associated with multiple metabolic abnormalities that comprise metabolic syndrome, including hypertension, insulin resistance, hyperglycemia, and dyslipidemia.

As patients with T2D with multiple metabolic abnormalities have an increased risk of cardiovascular disease and other comorbidities compared to patients with T2D without metabolic abnormalities, it is of interest to examine the effects of new T2D therapies on metabolic abnormalities, as a reduction in their prevalence may have a beneficial impact on cardiovascular risk in this patient population.

This analysis used data from the phase 3 SURPASS J-mono trial to compare the effects of tirzepatide and dulaglutide on the prevalence of metabolic abnormalities, as defined by the thresholds in the Japanese criteria for metabolic syndrome.

What was learned from the study?

At week 52, the percentage of patients meeting a composite endpoint (comprising the thresholds for metabolic abnormalities in the Japanese criteria of metabolic syndrome) decreased from approximately 70% to 31.7%, 23.0%, and 14.2% following tirzepatide 5 mg, 10 mg, and 15 mg, respectively, and to 56.5% following dulaglutide 0.75 mg.

The prevalence of multiple metabolic abnormalities was reduced following tirzepatide treatment, indicating a potential broad metabolic effect of tirzepatide in Japanese patients with T2D. 

Introduction

Based on data collected via the National Health and Nutrition Survey, mean body mass index (BMI) has significantly increased over the past two decades in Japan, and the prevalence of both type 2 diabetes (T2D) and obesity has steadily increased within the same time frame, particularly among males [1]. In Japan and other East Asian countries, patients with T2D have a lower mean BMI than patients from non-East Asian countries and a higher percentage of body fat, particularly visceral body fat, at any given BMI [2]. Accordingly, the Japanese definition of obesity uses a lower cutoff point for BMI than that of the World Health Organization (≥ 25 kg/m2 instead of ≥ 30 kg/m2) and includes a cutoff in waist circumference of 85 cm and 90 cm in men and women, respectively, which is considered equivalent to 100 cm2 visceral body fat accumulation [3].

Visceral obesity is strongly associated with metabolic abnormalities such as hypertension, insulin resistance, hyperglycemia, and dyslipidemia [4,5,6,7]. The clustering of visceral obesity with these metabolic abnormalities is termed the “metabolic syndrome”—a syndrome that conveys a higher risk of both cardiovascular disease and T2D in Japanese patients [8, 9]. Considering the strong association of multiple metabolic abnormalities with cardiovascular disease risk, as well as the risk for other comorbidities, it is of interest to examine the effects of new T2D therapies on metabolic abnormalities, as a reduction in their prevalence may have a broader impact on cardiovascular risk reduction in this patient population.

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of T2D in the United States, Europe, and Japan [10,11,12] and under development as a potential treatment for obesity [13]. In the global phase 3 SURPASS clinical trials, tirzepatide (5, 10, and 15 mg) demonstrated clinically meaningful improvements in glycemic control and bodyweight reduction in patients with T2D as either a monotherapy [14] or as an add-on therapy to other antihyperglycemic medications [15,16,17,18].

In addition to the global studies, two phase 3 clinical trials were conducted to assess tirzepatide treatment outcomes in Japanese patients with T2D, the SURPASS J-mono and SURPASS J-combo studies [19, 20]. The SURPASS J-mono study compared the efficacy and safety of once-weekly tirzepatide monotherapy with that of dulaglutide 0.75 mg, a once-weekly GLP-1 receptor agonist [19]. In this study, tirzepatide demonstrated statistically significant, dose-dependent reductions in glycated hemoglobin (HbA1c; reduced by − 2.4% to − 2.8% from a mean of 8.2%) and bodyweight (− 7.8% to − 13.9%) over 52 weeks of treatment [19]. Tirzepatide was generally well tolerated in Japanese patients with T2D, with the safety profile consistent with that of the GLP-1 receptor agonist class [19]. In light of the significant weight loss associated with tirzepatide treatment, we hypothesized that the prevalence of the metabolic parameters that comprise metabolic syndrome would be reduced with tirzepatide treatment. The objective of this analysis was to examine this hypothesis in Japanese patients with T2D using data from the SURPASS J-mono study.

Methods

Study Design and Participants

This was a post hoc analysis using data from the SURPASS J-mono clinical trial. A full description of the study design, eligibility criteria, and main outcomes of the trial has been published [19]. In brief, SURPASS J-mono was a multicenter, randomized, double-blind, active-controlled, parallel-group, phase 3 trial that assessed the efficacy and safety of tirzepatide 5, 10, and 15 mg compared to dulaglutide 0.75 mg in Japanese participants with T2D (ClinicalTrials.gov identifier: NCT03861052). Dulaglutide was used at 0.75 mg, the only approved dose in Japan [21] and, at the time of study initiation, was the most commonly prescribed GLP-1 receptor agonist in Japan [22].

Participants were Japanese adults (aged ≥ 20 years) with T2D (World Health Organization classification) who were naïve to oral antihyperglycemic medication (OAM; diet and exercise only) or were receiving OAM monotherapy except for thiazolidinediones and willing to discontinue the OAM during an 8-week washout period; had stable bodyweight (± 5% for ≥ 3 months prior to visit 1), a BMI ≥ 23 kg/m2 at visit 1, and an HbA1c ≥ 53 to ≤ 86 mmol/mol (≥ 7.0 to ≤ 10.0%) at both visits 1 and 2 (for OAM-naïve participants) or ≥ 48 to ≤ 75 mmol/mol (≥ 6.5 to ≤ 9.0%) at visit 1 and ≥ 53 to ≤ 86 mmol/mol (≥ 7.0% to ≤ 10.0%) at visit 2 (for participants discontinuing OAM). Key exclusion criteria included a type 1 diabetes diagnosis, history of any injectable therapy use for T2D (pramlintide, GLP-1 receptor agonists, and insulin) except for the use of insulin for treatment of gestational diabetes or short-term use (≤ 14 days) for acute conditions, and history of pancreatitis or hepatitis [19].

The study protocol was approved by independent ethical review boards at each participating site (protocol and list of ethical review boards were previously published in the primary manuscript [19]). The study was conducted in accordance with the Declaration of Helsinki in 1995 (as revised in Fortaleza, Brazil, October 2013) and the Council for International Organizations of Medical Sciences International Ethical Guidelines. All participants provided written informed consent prior to participating in the trial.

Procedures

Participants were randomly assigned by computer-generated sequence in a 1:1:1:1 ratio to receive tirzepatide 5, 10, or 15 mg or dulaglutide 0.75 mg. Following a 4-week (OAM-naïve participants) or 10-week (≥ 8-week washout for participants discontinuing OAM) screening/lead-in period, participants underwent a 52-week treatment period and 4-week safety follow-up period. During the treatment period, tirzepatide or dulaglutide was administered once weekly by subcutaneous injection. For tirzepatide, a dose-escalation strategy was followed in which the dose was initiated at 2.5 mg, increased by 2.5 mg every 4 weeks until the assigned dose was reached, and then maintained for the remainder of treatment.

Statistical Analyses

Analyses were performed on the modified intention-to-treat population, which comprised all randomized participants who received at least one dose of the study drug. This analysis used the efficacy analysis set, obtained during treatment of the modified intention-to-treat population, which excluded data after rescue therapy was initiated or treatment was discontinued.

For baseline demographic and clinical characteristics, descriptive statistics are presented as n and mean (standard deviation [SD]) for continuous measures and as frequency (percentage) for categorical measures. Metabolic abnormalities were identified based on the thresholds for abnormal metabolic parameters used in the Japanese Committee for the Diagnostic Criteria of Metabolic Syndrome (2005) [23]. These criteria include waist circumference at the umbilical level ≥ 85 cm in men and ≥ 90 cm in women (considered equivalent to visceral fat ≥ 100 cm2) plus two or more of the following: (1) triglycerides ≥ 150 mg/dl and/or high-density lipoprotein cholesterol < 40 mg/dl; (2) systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg; and (3) fasting serum glucose ≥ 110 mg/dl. The full Japanese definition of metabolic syndrome includes the consideration of concomitant medication use for hypertension and/or dyslipidemia, which was not assessed herein. Metabolic abnormalities were examined in each treatment group at baseline and 52 weeks. For metabolic abnormality status, data were assessed based on non-missing (observed) values at 52 weeks using the efficacy analysis set. The composite endpoint was the proportion of participants who met the thresholds for the Japanese criteria of metabolic syndrome (i.e., elevated waist circumference plus two or more of dyslipidemia, hypertension, or hyperglycemia, as noted above). Additional endpoints included the proportion of participants who met the thresholds for each component of the criteria. The proportion of participants who met the composite endpoint was also calculated at baseline and week 52 by baseline BMI category (< 25, 25 to < 30, and ≥ 30 kg/m2).

The effect of treatment on the status of metabolic abnormalities (individual or composite) was explored using a logistic regression model with “metabolic abnormality” status (yes/no) at week 52 as the response variable, with the randomized treatment as a fixed explanatory effect. In this model, “metabolic abnormality” was assessed as “yes” if the participant met the thresholds for the composite or individual endpoints and “no” if thresholds were not met. Response was defined as improvement (i.e., metabolic abnormality status of “no” for composite and component endpoints). This analysis was based on on-treatment data at week 52. Odds ratios with 95% confidence intervals and p values are presented, with analyses conducted at a two-sided alpha level of 0.05. To describe the effect of the potential interaction between treatment and the baseline metabolic abnormality status on the metabolic abnormality status at 52 weeks, individual and composite metabolic abnormalities at 52 weeks were tabulated by treatment and metabolic abnormality at baseline. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) or R Statistical Software, version 4.1.2 (R Core Team) [24].

Results

Baseline Demographics and Characteristics

The flow diagram of participants in SURPASS J-mono is shown in Fig. S1. In total, 560 participants in the SURPASS J-mono study had on-treatment data at week 52, 11 of whom were excluded from the efficacy analyses due to initiation of rescue therapy or missing data.

Overall, participants were mostly men (75.6%) and had a mean (SD) age of 56.6 (10.3) years. The proportions of participants in the BMI < 25 kg/m2, 25 to < 30 kg/m2, and ≥ 30 kg/m2 subgroups were 25.3%, 48.1%, and 26.6%, respectively, which were similar across treatment arms (Table 1). Baseline metabolic parameters, including waist circumference, BMI, fasting serum glucose, blood pressure, and lipid profile, were well balanced across the treatment arms (Table 1). Across all participants, mean (SD) baseline values were 96.2 (10.1) cm for waist circumference, 28.1 (4.4) kg/m2 for BMI, and 167.0 (38.6) mg/dl for fasting serum glucose (Table 1). Mean (SD) systolic and diastolic blood pressure at baseline was 130.8 (14.4) mmHg and 82.8 (9.9) mmHg, respectively. Mean (SD) baseline lipid levels were 174.8 (150.1) mg/dl for triglycerides and 52.0 (13.6) mg/dl for high-density lipoprotein cholesterol (Table 1).

Table 1 Demographics and baseline characteristics
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In SURPASS J-mono, 409 (64.3%) participants had dyslipidemia at baseline, and 239 (37.6%) used lipid-lowering drugs. Additionally, 333 (52.4%) participants had hypertension at baseline, and 262 (41.2%) used antihypertensive therapy. Use of antihypertensive and lipid-lowering therapy at baseline and postbaseline is summarized in Table S1.

Prevalence of Metabolic Abnormalities

Of the 636 randomized participants, 431 (67.8%) participants (men: 70.7%; women: 58.7%) met the thresholds for the composite endpoint at baseline, with similar percentages observed across treatment arms (Fig. 1). Among participants who completed study treatment, the proportion that met the composite endpoint decreased in all tirzepatide arms at week 52 (31.7%, 23.0%, and 14.2% in the tirzepatide 5-mg, 10-mg, and 15-mg arms, respectively), with the greatest reduction observed in the 15-mg arm. In comparison, the proportion of participants that met the composite endpoint in the dulaglutide 0.75-mg arm was similar at baseline (61.0%) and week 52 (56.5%) (Fig. 1). A logistic regression analysis of the effect of treatment on the improvement of metabolic abnormalities at week 52 indicated that the proportion of participants with improvement in metabolic abnormalities was significantly higher in the tirzepatide 5-mg, 10-mg, and 15-mg arms than in the dulaglutide arm (composite endpoint: odds ratio [95% confidence interval] 3.11 [1.71–5.77], 4.61 [2.48–8.78], and 9.91 [5.12–20.0], respectively; p < 0.001 for all comparisons; Table 2). Individual components are shown in Table S2.

Fig. 1
figure 1

Proportion of participants meeting the composite endpoint of metabolic abnormalities in the SURPASS J-mono study. Data are from the modified intention-to-treat population (efficacy analysis set). Dula dulaglutide, TZP tirzepatide

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Table 2 Cross tabulation of the composite endpoint of metabolic abnormalities by baseline metabolic abnormality statusa
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Overall, the composite endpoint was met in 45.3% of participants with a BMI < 25 kg/m2 at baseline, with a higher proportion of participants meeting this endpoint in both the BMI 25 to < 30 kg/m2 and ≥ 30 kg/m2 subgroups at baseline (73.2 and 79.3%, respectively). Across treatment arms, the proportion of participants that met the thresholds for the composite endpoint in the BMI subgroups was slightly imbalanced at baseline (Fig. 2), with a numerically higher percentage of dulaglutide-treated participants (52.5%) than tirzepatide-treated participants (42.9–43.2%) in the BMI < 25 kg/m2 subgroup and a lower percentage of dulaglutide-treated participants (63.0–65.8%) than tirzepatide-treated participants (71.2–86.7%) in the BMI 25 to < 30 and ≥ 30 kg/m2 subgroups.

Fig. 2
figure 2

Proportion of participants meeting the composite endpoint of metabolic abnormalities in the SURPASS J-mono study by baseline BMI subgroup. Data are from the modified intention-to-treat population (efficacy analysis set). BMI body mass index, Dula dulaglutide, TZP tirzepatide

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In the BMI < 25 kg/m2 subgroup, the proportion of participants that met the composite endpoint decreased from 43.2% at baseline to 13.3% at week 52 in the tirzepatide 5-mg arm and from 42.9% at baseline to 12.9% and 0.0% at week 52 in the 10-mg and 15-mg arms, respectively (Fig. 2). In comparison, a higher proportion met the composite endpoint in both the BMI 25 to < 30 kg/m2 (≥ 71.2%) and ≥ 30 kg/m2 subgroups (≥ 81.4%) at baseline, with greater reductions observed in the tirzepatide 15-mg treatment arm at week 52 (Fig. 2). In the highest BMI (≥ 30 kg/m2) subgroup, the proportion of participants that met the composite endpoint decreased from 86.7% at baseline to 57.1% at week 52 in the tirzepatide 5-mg arm, with larger reductions observed in the 10-mg and 15-mg arms (from 81.4% at baseline to 42.5% and 28.2%, respectively; Fig. 2). In comparison, the proportion of participants in the dulaglutide 0.75-mg arm that met the composite endpoint was reduced at week 52 in the BMI < 25 kg/m2 (baseline: 52.5%; week 52: 37.1%) and ≥ 30 kg/m2 subgroups (baseline: 65.8%; week 52: 58.8%; Fig. 2).

In all three tirzepatide treatment arms, the proportion of participants with each of the individual components of metabolic syndrome (i.e., elevated waist circumference, abnormal blood lipid profile, elevated blood pressure, and elevated fasting serum glucose) was reduced from baseline at week 52 (Fig. 3). Greater reductions were observed in the 10- and 15-mg treatment arms for all parameters except for the percentage of participants with an abnormal lipid profile, which showed a similar reduction (from approximately 50% at baseline to approximately 25% at week 52) across all three tirzepatide treatment arms. In contrast, the dulaglutide 0.75-mg arm showed a reduction only in the proportion of participants that met the elevated fasting serum glucose criterion at week 52 (98.7–81.2%; Fig. 3).

Fig. 3
figure 3

Prevalence of metabolic abnormalities in the SURPASS J-mono study. Proportion of participants with metabolic abnormalities in a waist circumference, b lipids, c blood pressure, and d FSG at baseline and following 52 weeks of treatment. Data are from the modified intention-to-treat population (efficacy analysis set). DBP diastolic blood pressure, Dula dulaglutide, FSG fasting serum glucose, HDL-C high-density lipoprotein cholesterol, SBP systolic blood pressure, TG triglycerides, TZP tirzepatide

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Discussion

The current analysis found that the prevalence of metabolic abnormalities was high at baseline in Japanese patients with T2D from the SURPASS J-mono study. In accordance with the clinical definition of obesity in Japan, which has a BMI cutoff of ≥ 25 kg/m2, the baseline prevalence of metabolic abnormalities was higher in both the BMI 25 to < 30 kg/m2 and ≥ 30 kg/m2 subgroups (73.2 and 79.3%, respectively) than in the BMI < 25 kg/m2 subgroup (45.3%) [3]. In the overall population, all doses of tirzepatide were shown to reduce the proportion of participants meeting the combined thresholds for abnormal metabolic parameters used in the Japanese diagnostic criteria for metabolic syndrome at week 52, as well as the proportion meeting each criterion of the definition.

The current data are in agreement with prior findings on tirzepatide in patients with T2D. Tirzepatide resulted in statistically significant and clinically meaningful improvements in several metabolic parameters across the SURPASS clinical program, with tirzepatide 10 mg and 15 mg associated with greater metabolic improvement than tirzepatide 5 mg [14,15,16,17,18,19,20]. In a 48-participant subset from the SURPASS J-mono study, tirzepatide treatment resulted in changes in body composition at week 52, with statistically significant percent reductions from baseline in bodyweight, mainly due to significant reductions in body fat mass, which were not observed in the dulaglutide 0.75-mg arm [25]. Additionally, in a post hoc assessment of participants from East Asian countries in the SURPASS-1, -3, -4, -5, J-mono, and J-combo phase 3 clinical trials, Kiyosue et al. (2023) [26] reported that tirzepatide induced dose-dependent reductions at week 52 in mean HbA1c, waist circumference, and BMI across BMI (< 25 and ≥ 25 kg/m2) and age (< 65 and ≥ 65 years) subgroups, which were accompanied by improvements in insulin resistance, lipid profiles, and blood pressure. Visceral body fat was directly assessed in a substudy of 296 participants with T2D from the SURPASS-3 clinical trial, which reported significant reductions in liver fat content and in the volume of visceral and abdominal subcutaneous adipose tissue in a pooled tirzepatide 10-mg and 15-mg treatment group compared with insulin degludec [27]. The reduction in visceral body fat is of particular clinical relevance, as visceral fat is a well-established pathogenic factor for insulin resistance, and a reduction of visceral fat likely contributes to the improvements in insulin sensitivity observed with tirzepatide treatment [26, 28]. Visceral fat accumulation is also associated with an increased risk of metabolic disorders [4,5,6] and cardiovascular disease in Japanese patients [9].

The primary study report for SURPASS J-mono reported mean bodyweight reductions across tirzepatide treatment arms (− 5.8, − 8.5, and − 10.7 kg in the tirzepatide 5-mg, 10-mg, and 15-mg arms, respectively) at week 52, representing bodyweight reductions of − 7.8% to − 13.9% [19]. This weight reduction is smaller than that observed following bariatric surgery in patients with obesity and T2D (20–25%) [29, 30]; however, it should be noted that no drug has yet reported achieving an equivalent reduction in bodyweight to that achieved by surgery. A study on the impact of lifestyle modifications over 6 months showed that a relatively modest reduction in bodyweight of ≥ 3% was sufficient to improve several obesity-related metabolic parameters in Japanese patients [4]. Herein, we show that the previously reported bodyweight reduction in tirzepatide-treated participants from the SURPASS J-mono study was associated with substantial reductions in the proportion of participants with multiple metabolic abnormalities, indicating that tirzepatide improved the metabolic profile in Japanese patients with T2D. As metabolic abnormalities are associated with a higher risk of cardiovascular disease and other comorbidities in Japanese patients [8, 9] and most participants in the SURPASS J-mono study experienced a reduction in metabolic abnormalities, tirzepatide treatment may be associated with lower cardiovascular risk. This is consistent with a post hoc analysis of a phase 2b study, which showed that 26 weeks of tirzepatide treatment reduced circulating levels of cardiovascular risk biomarkers compared with both placebo and dulaglutide [31]. The effects of tirzepatide on cardiovascular risk are being examined more fully in the ongoing SURPASS CVOT trial (ClinicalTrials.gov identifier: NCT04255433).

This analysis had limitations, including the limitations inherent to post host analyses. Additionally, concomitant use of and changes in antihypertensive medications and/or lipid-lowering treatment were not evaluated, so our assessments cannot be considered an estimate of metabolic syndrome prevalence. Additional factors potentially affecting the analysis results include the lack of consideration of concomitant treatment changes during the study and the exclusion of patients who discontinued treatment. Finally, an imbalance was noted across treatment arms in the proportion of participants that met the composite endpoint at baseline when examined by BMI subgroup, which should be considered when interpreting the current results.

Conclusions

This post hoc analysis showed that once-weekly tirzepatide 5 mg, 10 mg, and 15 mg reduced the prevalence of metabolic abnormalities in waist circumference, serum lipids, blood pressure, and blood glucose in Japanese patients with T2D. These data, as well as those from the primary report [19], indicate that 52 weeks of tirzepatide treatment may have metabolic benefit in Japanese patients with T2D.