Baseline Characteristics

A total of 687 patients were included for this subgroup analysis, who received tirzepatide 5 mg (n = 230), tirzepatide 10 mg (n = 228) or tirzepatide 15 mg (n = 229). A greater proportion of patients were male versus female across the tirzepatide treatment subgroups (5, 10 and 15 mg) (Table 1). The mean (SD) overall age of patients across the tirzepatide treatment groups ranged from 53.1 (11.2) to 54.3 (11.6) years. The mean (SD) BMI of patients across the tirzepatide treatment groups ranged from 27.7 (3.8) to 28.1 (3.9) kg/m2. Overall, baseline characteristics were generally well balanced across the tirzepatide treatment groups (Table 1).

Table 1 Summary of baseline characteristicsEfficacyChanges from Baseline in HbA1c

All doses of tirzepatide (5, 10 and 15 mg) resulted in a reduction in HbA1c from baseline to week 40 across each subgroup, irrespective of age, sex, baseline HbA1c, BMI, body weight, duration of diabetes and concomitant OAM use (Fig. 1). For the individual analyses by subgroup, LS mean (standard error [SE]) reductions in HbA1c from baseline to 40 weeks were significantly greater in patients with a higher baseline HbA1c (≤ 8.5 vs. > 8.5%) with all tirzepatide doses: tirzepatide 5 mg – 2.52% (0.093) vs. – 1.76% (0.105) P < 0.001; tirzepatide 10 mg – 2.95% (0.099) vs. – 1.78% (0.103), P < 0.001; tirzepatide 15 mg – 3.01% (0.100) vs. – 1.86% (0.102), P < 0.001 (Fig. 1). LS mean (SE) reductions in HbA1c were significantly greater in younger patients (< 65 vs. ≥ 65 years) with tirzepatide 15 mg: – 2.53% (0.087) vs. – 2.08% (0.160), respectively, P = 0.011 (Fig. 1). Furthermore, a numerically greater LS mean (SE) reduction in HbA1c was observed in patients with a higher baseline body weight (≥ 75 vs. < 75 kg) with tirzepatide 10 and 15 mg, and the difference reached statistical significance for tirzepatide 10 mg: – 2.56% (0.111) vs. – 2.26% (0.105), respectively, P = 0.040 (Fig. 1). Comparatively small and non-statistically significant differences in the reduction in HbA1c from baseline to week 40 were observed between the remaining subgroups across the tirzepatide treatment groups (P ≥ 0.05).

Fig. 1

Changes from baseline to week 40 in HbA1c (%) stratified by potential influential factors. P-value from MMRM model. BMI body mass index; HbA1c hemoglobin A1c; LS mean least-square mean; MMRM mixed-model for repeated measures; n number of patients who were randomized and received at least one dose of study drug; OAM oral antihyperglycemic medication; TZP tirzepatide

Change from Baseline in Body Weight

Across all subgroups, tirzepatide was associated with a reduction in mean body weight from baseline to week 40, irrespective of age, sex, baseline HbA1c, BMI, body weight, duration of diabetes and use of concomitant OAMs (Fig. 2). LS mean (SE) reductions in body weight from baseline to 40 weeks were significantly greater in patients with a higher baseline body weight (≥ 75 vs. < 75 kg) across all tirzepatide doses: tirzepatide 5 mg – 5.83 kg (0.460) vs. – 4.13 kg (0.493), respectively, P = 0.010; tirzepatide 10 mg – 7.89 kg (0.511) vs. – 6.34 kg (0.473), respectively, P = 0.022; tirzepatide 15 mg – 8.09 kg (0.491) vs. – 6.31 kg (0.485), respectively, P = 0.008 (Fig. 2). Similarly, patients with a higher baseline BMI (≥ 25 vs. < 25 kg/m2) receiving tirzepatide 10 and 15 mg also experienced a numerically greater LS mean (SE) reduction in body weight, and this was statistically significant in the 5 mg treatment group: – 5.42 kg (0.385) vs. – 3.66 kg (0.714), P = 0.026 (Fig. 2). A lower baseline HbA1c (≤ 8.5% vs. > 8.5%) was associated with a significantly greater LS mean (SE) reduction in body weight from baseline to week 40 with tirzepatide 5 mg: – 5.85 kg (0.509) vs. – 4.41 kg (0.447), respectively, P = 0.029 (Fig. 2). In addition, LS mean (SE) reductions in body weight were numerically greater in younger patients (< 65 vs. ≥ 65 years) across all tirzepatide treatment groups, and the difference reached significance for patients receiving tirzepatide 15 mg: – 7.90 kg (0.393) vs. – 4.67 kg (0.728), respectively, P < 0.001 (Fig. 2). No statistically significant differences in reduction in body weight were observed in the remaining subgroups across the tirzepatide treatment groups (P ≥ 0.05).

Fig. 2

Changes from baseline to week 40 in body weight (kg) stratified by potential influential factors. P-value from MMRM. BMI body mass index; HbA1c hemoglobin A1c; LS mean least-square mean; MMRM mixed-model for repeated measures; n number of patients who were randomized and received at least one dose of study drug; OAM oral antihyperglycemic medication; TZP tirzepatide

Change from Baseline in FSG

Tirzepatide (5, 10 and 15 mg) was associated with a reduction in mean FSG from baseline to week 40, irrespective of age, sex, baseline HbA1c, BMI, body weight, duration of diabetes or use of concomitant OAMs (Fig. 3). A greater LS mean (SE) reduction in FSG from baseline to week 40 was observed in patients with a lower baseline HbA1c (≤ 8.5% vs. > 8.5%) receiving tirzepatide 5 mg: – 63.16 mg/dl (3.678) vs. – 53.82 mg/dl (3.376), respectively, P = 0.033 (Fig. 3). Similar reductions in FSG from baseline to week 40 were observed in the remaining subgroups, across the tirzepatide treatment groups (P ≥ 0.05) (Fig. 3).

Fig. 3

Changes from baseline to week 40 in FSG (mmol/l) stratified by potential influential factors. P-value from MMRM. BMI body mass index; FSG fasting serum glucose; HbA1c hemoglobin A1c; LS mean least-square mean; MMRM mixed-model for repeated measures; n number of patients who were randomized and received at least one dose of study drug; OAM oral antihyperglycemic medication; TZP tirzepatide

Reduction in Daily Glucose Average of SMBG Profiles

At week 40, all doses of tirzepatide were associated with reductions from baseline in the daily glucose average from SMBG profiles, irrespective of age, sex, baseline HbA1c, BMI, body weight, duration of diabetes and use of concomitant OAMs (Supplementary Fig. 2). A significantly greater LS mean (SE) reduction in daily glucose average from SMBG profiles was observed in younger patients (< 65 vs. ≥ 65 years) receiving tirzepatide 15 mg: – 5.04 mmol/l (0.180) vs. –4.18 mmol/l (0.288), respectively, P = 0.003 (Supplementary Fig. 2). Among patients receiving tirzepatide 5 mg, a lower baseline HbA1c (≤ 8.5% vs. > 8.5%) was associated with a significantly greater LS mean (SE) reduction in daily glucose average from SMBG profile: – 4.75 mmol/l (0.214) vs. – 4.15 mmol/l (0.198), respectively, P = 0.014 (Supplementary Fig. 2). Conversely, in the tirzepatide 10 and 15 mg treatment groups, a numerically greater reduction in SMBG profiles was observed in patients with a higher baseline HbA1c, but the difference did not reach statistical significance (Supplementary Fig. 2). In the remaining subgroups, similar reductions in SMBG profiles from baseline to week 40 were observed across the tirzepatide treatment groups (P ≥ 0.05) (Supplementary Fig. 2).

SafetyGastrointestinal AEs and Hypoglycemia Incidence

The proportion of patients reporting treatment-emergent gastrointestinal AEs was generally similar across each subgroup (Table 2). Across all tirzepatide doses, the total incidence of hypoglycemia was broadly comparable among the patient subgroups (Table 3). Patients with a BMI of < 25 vs. ≥ 25 kg/m2 and a body weight of < 75 vs. ≥ 75 kg experienced a higher incidence of hypoglycemia with tirzepatide 10 mg (Table 3). Notably, across all tirzepatide doses, patients using metformin plus sulfonylurea versus metformin alone experienced a higher incidence of hypoglycemia (Table 3).

Table 2 Incidence of treatment-emergent gastrointestinal AEs at 40 weeks stratified by potential influential factorsTable 3 Incidence of hypoglycemia at 40 weeks stratified by potential influential factors