Abstract
Aim
To evaluate the long‐term efficacy and safety data at 104 weeks in tirzepatide‐treated participants with type 2 diabetes who had inadequate glycaemic control on metformin and/or sulfonylurea.
Materials and Methods
This post‐hoc analysis was based on the SURPASS‐4 data (NCT03730662), a multicenter, Phase III trial. Participants were randomised to receive tirzepatide (5, 10, or 15 mg) or insulin glargine. The primary efficacy endpoint was change in HbA1c levels from baseline to 104 weeks. Key secondary endpoints were changes in body weight and the proportion of participants achieving HbA1c <7.0%. Safety endpoints included the incidence of treatment‐emergent adverse events (AEs) and hypoglycaemia.
Results
This post‐hoc analysis included 1,500 participants. At Week 104, participants in the tirzepatide groups had significantly greater mean reduction in HbA1c (5 mg: −2.3%, 10 mg: −2.5%, 15 mg: −2.6%) compared with the insulin glargine group (−1.0%) (p < 0.001). Participants in the tirzepatide groups had significantly greater reduction in body weight (5 mg: −7.6 kg, 10 mg: −10.0 kg, 15 mg: −11.4 kg) compared with the insulin glargine group (2.1 kg) (p < 0.001). Significantly more participants in the tirzepatide group achieved HbA1c <7.0% compared with the insulin glargine group (p < 0.001). The incidence of hypoglycaemia was lower in the tirzepatide groups, and gastrointestinal AEs were mild or moderate in severity.
Conclusions
Tirzepatide significantly improved glycaemic control and body weight reduction compared to insulin glargine over 104 weeks in participants with type 2 diabetes inadequately controlled on metformin and/or sulfonylurea. The safety profile of tirzepatide was acceptable, with a lower incidence of hypoglycaemia than insulin glargine.
Keywords: oral antihyperglycaemic drugs, post‐hoc analysis, SURPASS‐4, tirzepatide, type 2 diabetes
1. INTRODUCTION
Type 2 diabetes is a chronic and complex disease characterised by insulin resistance and impaired insulin secretion. 1 , 2 Around 537 million adults aged 20–79 are living with diabetes. This number is expected to increase to 643 million by 2030 and 783 million by 2045. 3 Effective management of this condition requires a multifactorial approach that includes both behavioural and pharmacological treatments. 1 Current treatment strategies for type 2 diabetes emphasise the aim to achieve intensive glycaemic control, weight goals, as well as overall quality of life. 1 , 2 , 4 Despite treatment with various oral antihyperglycaemic drugs (OADs), a significant proportion of participants (45.2% to 93.0% 5 ) with type 2 diabetes failed to achieve adequate glycaemic control, such as glycated haemoglobin (HbA1c), fasting blood glucose (FBG), and postprandial glucose (PPG), necessitating the need to explore novel therapeutic options in the previous studies. 6 , 7 , 8 Previous findings showed that >64% of the participants from South Asia, Eurasia, Middle East, and Africa with type 2 diabetes who were treated with OADs alone had inadequate glycaemic control. 9 However, achieving optimal glycaemic control with insulin therapy can be challenging, often requiring dose adjustments that lead to increased risk of hypoglycaemia and weight gain. 10 Studies conducted in several countries, such as the United States, China, and India, have revealed that a significant number of patients had poor glycaemic control despite being on insulin therapy. 8 , 11
Tirzepatide, a dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist, is approved in many countries, including the United States, Europe, and China, for the treatment of adults with type 2 diabetes and obesity. 12 , 13 , 14 , 15 Clinical trials have demonstrated that tirzepatide significantly reduces HbA1c levels and body weight compared to other glucose‐lowering agents, without a clinically significant increase in hypoglycaemic events. 16 , 17 , 18 , 19 In the Phase III SURPASS‐3 and SURPASS‐4 trials, participants treated with tirzepatide demonstrated substantial reductions in HbA1c levels and substantial weight reduction compared to insulin degludec and glargine, respectively, at 52 weeks. 20 , 21 Both trials highlight the potential of tirzepatide as an effective add‐on treatment option to multiple OADs in patients with type 2 diabetes. 20 , 21
Metformin and sulfonylureas are commonly used OADs for the management of type 2 diabetes in clinical settings 22 , 23 ; metformin was historically used as first‐line treatment. 24 Tirzepatide or insulin is used as an add‐on therapy to OADs for the management of type 2 diabetes. 24 It is crucial to assess the long‐term efficacy and safety of tirzepatide in patients with inadequate glycaemic control despite multiple OAD treatments. The primary endpoints of SURPASS‐4 were reported till 52 weeks. Meanwhile, this post‐hoc analysis of the SURPASS‐4 study aims to provide insights into the long‐term efficacy (glycaemic control and body weight changes) and safety of tirzepatide at 104 weeks in participants with type 2 diabetes mellitus who had inadequate glycaemic control on metformin and/or sulfonylurea therapy.
2. METHODS
2.1. Study design and participants
This post‐hoc analysis is based on data from the SURPASS‐4 study (NCT03730662), a multicenter, randomised, open‐label, parallel‐group, Phase III trial in which participants were randomised to add tirzepatide or insulin glargine to 1–3 OADs. 21 The SURPASS‐4 study design has been previously published. 21 SURPASS‐4 study included participants with type 2 diabetes who had inadequate glycaemic control while on metformin, sulfonylurea, or sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor therapy and increased cardiovascular risk.
2.2. Inclusion and exclusion criteria
In this post‐hoc analysis, participants were eligible for inclusion if they met the following criteria: aged 18 years or older, diagnosed with type 2 diabetes, glycated haemoglobin (HbA1c) levels between ≥7.5% (≥58 mmol/mol) to ≤10.5% (≤91 mmol/mol) at Visit 1, used metformin and/or sulfonylurea, body mass index (BMI) of 25 kg/m2 or more, and stable weight for the previous 3 months with increased cardiovascular risk, defined as a history of cardiovascular events or the presence of multiple cardiovascular risk factors. Exclusion criteria were the same as the SURPASS‐4 study, that is, the presence of type 1 diabetes, active liver disease, and history of pancreatitis. 21 In addition, we excluded participants receiving SGLT2 inhibitor.
2.3. Randomisation and masking
In SURPASS‐4, participants were randomised to receive either tirzepatide (5, 10, or 15 mg) once weekly or insulin glargine once daily (1:1:1:3). 21 Tirzepatide was initiated at a dose of 2.5 mg, followed by dose escalation by 2.5 mg every 4 weeks to improve tolerability. Glargine (100 U/mL) was titrated to reach FBG of less than 100 mg/dL as previously described. 21 The dose adjustment in insulin glargine is presented in the SURPASS‐4 study. 21 This analysis included participants who had received metformin, sulfonylurea, or a combination of metformin and sulfonylurea. The treatment period lasted for 104 weeks.
2.4. Outcomes
In this post‐hoc analysis of the SURPASS‐4 data, the primary efficacy endpoint was mean change in HbA1c from baseline to 104 weeks. Key secondary efficacy endpoints included mean changes in body weight and the proportion of participants achieving HbA1c <7.0% from baseline to 104 weeks. Other endpoints included the proportion of participants achieving HbA1c levels of 6.5% or less (≤48 mmol/mol) and less than 5.7% (<39 mmol/mol); weight reduction of at least 5%, 10%, or 15% at Week 104; and mean change from baseline to 104 weeks in fasting serum glucose (FSG); BMI, waist circumference, and serum lipids. Self‐reported safety endpoints included the incidence of treatment‐emergent adverse events (TEAEs) and patient‐reported occurrences of clinically significant hypoglycaemia, defined as glucose <54 mg/dL) (<3.0 mmol/L) or severe hypoglycaemia 21 (characterised by altered mental and/or physical status requiring assistance for treatment of hypoglycaemia, irrespective of glucose level. 25 Major adverse cardiovascular events (MACE) were deaths due to cardiovascular cause, myocardial infarction, hospitalisation for unstable angina, hospitalisation for heart failure, coronary interventions (such as coronary artery bypass graft [CABG] or percutaneous coronary intervention [PCI]); and cerebrovascular events, including cerebrovascular accident (stroke) and transient ischaemic attack (TIA), and all cause death.
2.5. Statistical analysis
Efficacy and safety analyses were conducted on the modified intent‐to‐treat (mITT) population, which included all randomly assigned participants who were exposed to at least one dose of study drug. Changes in HbA1c levels and continuous variables were analysed using mixed‐effects models for repeated measures. Categorical variables were assessed using chi‐square tests or Fisher's exact tests. MACE was evaluated using a Cox proportional hazards model. A difference with a p value of <0.05 was considered statistically significant. A summary of hypoglycaemic events was also calculated for participants using metformin alone, sulfonylurea alone, and metformin and sulfonylurea subgroups. The statistical analysis was performed using the statistical analysis system, version 9.4.
2.6. Ethical considerations
The SURPASS‐4 study was conducted in compliance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. 21 Written informed consent was obtained from all participants, and the study protocol was approved by the institutional review boards.
3. RESULTS
3.1. Study population
This post‐hoc analysis included 1,500 participants (75.2%) from the SURPASS‐4 study who were randomised to tirzepatide 5 mg (N = 251), 10 mg (N = 249), and 15 mg (N = 252) groups versus insulin glargine (N = 748) group (1:1:1:3). These participants had insufficient glycaemic control while receiving metformin and/or sulfonylurea. The remaining 25% of the SURPASS‐4 population was excluded from the analysis because they did not receive metformin and/or sulfonylurea. The baseline characteristics were similar across the groups (Table 1). In the overall population of the post‐hoc analysis, the mean age of participants was 63.8 years (standard deviation [SD] 8.5), with a mean duration of diabetes of 11.5 years (SD 7.6). The mean HbA1c was 8.5% (SD 0.9%), the mean BMI was 32.5 kg/m2 (SD 5.5), and the average body weight was 89.9 kg (SD 18.6). A total of 335 participants (22.4%) had an eGFR <60 mL/min per 1.73 m2 (Table 1).
TABLE 1.
Baseline demographics and clinical characteristics in the study population.
| Tirzepatide 5 mg (N = 251) | Tirzepatide 10 mg (N = 249) | Tirzepatide 15 mg (N = 252) | Insulin glargine (N = 748) | Total (N = 1500) | |
|---|---|---|---|---|---|
| Age, years | 63.0 (8.7) | 63.7 (8.8) | 64.0 (8.4) | 64.0 (8.4) | 63.8 (8.5) |
| Sex | |||||
| Female, n (%) | 98 (39.0) | 95 (38.2) | 103 (40.9) | 290 (38.8) | 586 (39.1) |
| Male, n (%) | 153 (61.0) | 154 (61.8) | 149 (59.1) | 458 (61.2) | 914 (60.9) |
| Race | |||||
| Asian | 7 (2.8) | 9 (3.6) | 3 (1.2) | 8 (1.1) | 27 (1.8) |
| Black or African American | 12 (4.8) | 18 (7.2) | 11 (4.4) | 28 (3.7) | 69 (4.6) |
| White | 194 (77.6) | 190 (76.3) | 209 (83.3) | 613 (82.1) | 1206 (80.6) |
| Duration of diabetes, years | 10.9 (7.2) | 11.4 (7.6) | 11.2 (7.5) | 11.8 (7.8) | 11.5 (7.6) |
| HbA1c, % | 8.5 (0.9) | 8.6 (0.9) | 8.5 (1.0) | 8.5 (0.9) | 8.5 (0.9) |
| HbA1c, mmol/mol | 69.4 (9.3) | 70.4 (10.1) | 69.7 (11.2) | 69.6 (9.4) | 69.7 (9.8) |
| Fasting serum glucose, mg/dL | 172.6 (46.9) | 176.2 (53.8) | 174.3 (55.5) | 172.3 (51.4) | 173.3 (51.8) |
| Weight, kg | 89.6 (19.9) | 90.4 (18.2) | 89.8 (16.5) | 89.9 (19.0) | 89.9 (18.6) |
| Body mass index, kg/m2 | 32.5 (5.9) | 32.7 (5.6) | 32.6 (5.0) | 32.5 (5.5) | 32.5 (5.5) |
| eGFR (CKD‐EPI, mL/min/1.73 m2) | 81.1 (22.3) | 81.3 (20.5) | 81.4 (21.4) | 81.1 (20.9) | 81.2 (21.2) |
| eGFR <60 or UACR >300, n (%) | 52 (20.7) | 60 (24.3) | 59 (23.4) | 164 (22.1) | 335 (22.4) |
| Macroalbuminuria (UACR >300 mg/g) | 16 (6.4) | 27 (11.2) | 21 (8.3) | 60 (8.2) | 124 (8.4) |
| Microalbuminuria (UACR 30–300 mg/g) | 62 (24.9) | 69 (28.6) | 81 (32.1) | 199 (27.3) | 411 (27.9) |
| Systolic blood pressure, mm Hg | 134.4 (14.1) | 134.7 (14.9) | 135.7 (14.8) | 135.2 (15.6) | 135.1 (15.1) |
| Diastolic blood pressure, mm Hg | 78.8 (8.9) | 78.4 (9.1) | 78.8 (8.9) | 78.6 (9.6) | 78.6 (9.3) |
| Pulse rate, beats per min | 71.8 (10.6) | 72.6 (10.3) | 72.8 (10.8) | 73.1 (10.5) | 72.7 (10.5) |
| Sulfonylurea use, yes | 152 (60.6) | 141 (56.6) | 140 (55.6) | 424 (56.7) | 857 (57.1) |
| Metformin use, yes | 235 (93.6) | 240 (96.4) | 236 (93.7) | 713 (95.3) | 1424 (94.9) |
| Oral antidiabetic medications use | |||||
| Metformin alone | 99 (39.4) | 108 (43.4) | 112 (44.4) | 324 (43.3) | 643 (42.9) |
| Sulfonylurea alone | 16 (6.4) | 9 (3.6) | 16 (6.3) | 35 (4.7) | 76 (5.1) |
| Metformin + sulfonylurea | 136 (54.2) | 132 (53.0) | 124 (49.2) | 389 (52.0) | 781 (52.1) |
Note: Data are mean (SD) or n (%) unless otherwise indicated.
Abbreviations: CKD‐EPI, chronic kidney disease epidemiology collaboration; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; UACR, urinary albumin‐to‐creatinine ratio.
3.2. Change in HbA1c from baseline
At Week 104, the mean reduction in HbA1c was significantly greater in the tirzepatide groups (5 mg, 10 mg, and 15 mg groups) with reductions of 2.3%, 2.5%, and 2.6%, respectively, compared with the insulin glargine group, who had a reduction of 1.0% (p < 0.001) (Figure 1A, Figure S1A). The estimated treatment differences between tirzepatide groups and the insulin glargine group were −1.3% (95% CI −1.6 to −0.9; p < 0.001) for the tirzepatide 5 mg group, −1.5% (−1.9 to −1.2; p < 0.001) for the tirzepatide 10 mg group, and −1.6% (95% CI −1.9 to −1.2; p < 0.001) for the tirzepatide 15 mg group (Figure S1A). These results are sustained from the mean reduction in HbA1c observed at Week 52 (Figure 1A).
FIGURE 1.
Treatment comparison of tirzepatide 5, 10 and 15 mg versus insulin glargine in study population for change in HbA1c. (A) Mean change in HbA1c from baseline to 104 weeks. (B) Proportion of participants achieving HbA1c targets at 104 weeks. (C) Absolute HbA1c over time from baseline to 104 weeks in the study population. ***p < 0.001 versus insulin glargine; p values shown are for within treatment for HbA1c over time in (1); n in (A) is number of participants at baseline and n in (B) is number of participants at 104 W. Only participants with non‐missing baseline value and at least one non‐missing post‐baseline value of the response variable were included in analysis. HbA1c, glycated haemoglobin; LS mean, least squares mean; SE, standard error.
A significantly higher proportion of participants in the tirzepatide groups achieved target HbA1c levels of <7.0%, ≤6.5%, and <5.7% compared with the insulin glargine group (p < 0.001 for all) (Figure 1B).
Starting from Week 16, the least squares (LS) mean HbA1c levels were ≤6.5% for all 3 tirzepatide groups, while the insulin glargine group maintained >7.0% throughout the study. By Week 104, the LS mean HbA1c was significantly lower in the tirzepatide groups (5, 10, and 15 mg groups) at 6.4%, 6.1%, and 6.0%, respectively, compared to 7.5% in the insulin glargine group (p < 0.001 for all comparisons) (Figure 1C).
3.3. Change in bodyweight from baseline
At Week 104, participants in the tirzepatide groups (5, 10, and 15 mg) showed a significantly greater reduction in body weight from baseline compared to those in the insulin glargine group (−7.6, −10.0, and −11.4 kg vs. +2.1 kg, respectively; p < 0.001 for all comparisons) (Figure 2A,B and Figure S1B). This reduction in body weight was sustained from the decrease observed at Week 52 (Figure 2A). The estimated treatment difference versus insulin glargine was −9.7 kg (95% CI −11.3 to −8.2) for tirzepatide 5 mg, −12.1 kg (−13.7 to −10.5) for tirzepatide 10 mg, and −13.5 kg (95% CI −15.0 to −11.9) for tirzepatide 15 mg; p < 0.001 for all (Figure S1B).
FIGURE 2.
Treatment comparison of tirzepatide 5, 10 and 15 mg versus insulin glargine in participants with diabetes for change in body weight. (A) LS mean change in body weight over time from baseline to 104 weeks. (B) Body weight over time from baseline to 104 weeks in the study population. (C) Proportion of participants achieving weight reduction targets at 104 weeks. ***p < 0.001 versus insulin glargine; p values shown are for within treatment for body weight over time in (B); n indicated in (A) is number of participants at baseline and n in (C) is number of participants at 104 W. Only participants with non‐missing baseline values and at least one non‐missing post‐baseline value of the response variable were included in the analysis. LS mean, least squares mean; SE, standard error.
A significantly greater proportion of participants in the tirzepatide 5, 10, and 15 mg groups achieved the weight reduction targets of ≥5%, ≥10%, or ≥15% compared to those in the insulin glargine group (p < 0.001 for all) (Figure 2C).
A significantly greater proportion of participants in the tirzepatide 5, 10, and 15 mg groups achieved individual or combined HbA1c targets (<7%, ≤6.5%, and <5.7%) and weight reduction targets (≥5% and ≥10%) without experiencing hypoglycaemia, compared to those in the insulin glargine group at Week 104 (p < 0.001 for all) (Table S1).
3.4. Change in FSG from baseline
At Week 104, the LS mean change in FSG from baseline was significantly higher in the tirzepatide groups compared with the insulin glargine group. The changes were −3.0, −3.4, and −3.3 mmol/L (−54.1, −61.3, −59.5 mg/dL) in the tirzepatide 5, 10, and 15 mg groups vs. −2.3 mmol/L (41.4 mg/dL) for insulin glargine; p < 0.001 for all comparisons (Figure S2A). Starting from Week 16, the LS mean FSG remained ≤7.0 mmol/L in the 3 tirzepatide groups and was maintained through Week 104. For the insulin glargine group, it was >7.0 mmol/L at 104 weeks (Figure S2B).
3.5. Change in BMI and waist circumference from baseline
At Week 104, the LS mean change in BMI from baseline was significantly greater in the tirzepatide 5, 10, and 15 mg groups compared with insulin glargine, with changes of −2.8, −3.7, and −4.2 kg/m2 respectively compared to +0.8 kg/m2 for insulin glargine; p < 0.001 for all comparisons (Figure S3A).
The LS mean change in waist circumference was significantly greater in the tirzepatide 5, 10, and 15 mg groups compared with insulin glargine, with changes of −8.2, −10.2, and −9.0 cm versus +1.1 cm for insulin glargine; p < 0.001 for all comparisons (Figure S3B).
3.6. Change in blood pressure and pulse rate from baseline
At Week 104, mean systolic blood pressure (SBP) decreased by −3.6, −8.1, and −2.3 mm Hg, and diastolic blood pressure (DBP) decreased by −2.1, −1.9, and −1.8 mm Hg in the tirzepatide 5, 10, and 15 mg groups, respectively. Mean SBP and DBP increased by 2.5 and 0.2 mm Hg, respectively, in the insulin glargine group (p > 0.05 for all comparisons between tirzepatide groups and insulin glargine).
The mean pulse rate (beats per min [bpm]) (SD) increased by 2.6 (8.8), 4.6 (12.6), and 5.0 (13.0) in tirzepatide 5, 10, and 15 mg groups. The pulse rate decreased by −0.2 (10.9) bpm in the insulin glargine‐treated participants.
3.7. Change in lipid profile from baseline
Participants treated with tirzepatide showed reductions in serum triglycerides, low‐density lipoprotein (LDL) cholesterol, non‐high‐density lipoprotein (non‐HDL) cholesterol, and total cholesterol at both 52 and 104 weeks, compared to minimal changes in those treated with insulin glargine (Figure S4A,B). At 104 weeks, significant differences in LS mean changes were observed in the tirzepatide 5, 10, and 15 mg groups for the percent change in triglycerides (−16.5%, −23.3%, and −28.4%) respectively and percent change in HDL‐C (10.5%, 10.0%, and 11.5%), respectively, compared to the insulin glargine group (0.2%, and −0.5%, respectively) (p < 0.01 for all tirzepatide groups vs. insulin glargine).
3.8. Safety
The overall incidence of TEAEs was higher in the tirzepatide groups compared to the insulin glargine groups (Table 2). Diarrhoea was reported in 14.7% to 22.6% of participants in the tirzepatide group versus 4.7% in the insulin glargine group. Nausea was reported in 13.1% to 21.4% of participants in the tirzepatide group versus 2.6% in the insulin glargine group. Vomiting was reported in 5.6% to 7.9% of those on tirzepatide versus 1.7% of those on insulin glargine.
TABLE 2.
Incidence of adverse events in the study population, safety analysis set.
| Tirzepatide 5 mg (N = 251) | p value | Tirzepatide 10 mg (N = 247) | p value | Tirzepatide 15 mg (N = 252) | p value | Insulin glargine (N = 743) | |
|---|---|---|---|---|---|---|---|
| n (%) | |||||||
| ≥1 TEAE | 185 (73.7) | 0.230 | 185 (74.9) | 0.107 | 190 (75.4) | 0.077 | 516 (69.4) |
| Diarrhoea | 37 (14.7) | <0.001 | 46 (18.6) | <0.001 | 57 (22.6) | <0.001 | 35 (4.7) |
| Nausea | 33 (13.1) | <0.001 | 35 (14.2) | <0.001 | 54 (21.4) | <0.001 | 19 (2.6) |
| Decreased appetite | 25 (10.0) | <0.001 | 34 (13.8) | <0.001 | 29 (11.5) | <0.001 | 3 (0.4) |
| Nasopharyngitis | 9 (3.6) | 0.087 | 15 (6.1) | 0.882 | 15 (6.0) | 0.882 | 49 (6.6) |
| COVID‐19 | 12 (4.8) | 0.441 | 10 (4.0) | 0.209 | 16 (6.3) | >0.999 | 47 (6.3) |
| Dyspepsia | 17 (6.8) | <0.001 | 21 (8.5) | <0.001 | 22 (8.7) | <0.001 | 13 (1.7) |
| Hypertension | 12 (4.8) | 0.869 | 8 (3.2) | 0.229 | 7 (2.8) | 0.120 | 39 (5.2) |
| Influenza | 12 (4.8) | >0.999 | 9 (3.6) | 0.393 | 7 (2.8) | 0.160 | 38 (5.1) |
| Vomiting | 14 (5.6) | 0.003 | 19 (7.7) | <0.001 | 20 (7.9) | <0.001 | 13 (1.7) |
| Lipase increased | 9 (3.6) | 0.075 | 9 (3.6) | 0.072 | 14 (5.6) | 0.002 | 12 (1.6) |
| Abdominal pain | 14 (5.6) | <0.001 | 8 (3.2) | 0.046 | 9 (3.6) | 0.025 | 9 (1.2) |
Note: p values are compared to insulin glargine.
Abbreviations: COVID‐19, coronavirus disease‐19; N, number of participants in the analysis population; TEAEs, treatment‐emergent adverse events.
The incidence of hypoglycaemia was lower among the participants in the tirzepatide 5, 10, and 15 mg groups on metformin alone (2.0%, 0.9%, and 3.6%; p < 0.01), those on sulfonylureas alone (18.8%, 0.0%, and 6.3%), and those on metformin + sulfonylureas (14%, p = 0.02; 7.6%, p < 0.001, and 15.3%, p = 0.08) compared with the insulin glargine groups on metformin alone (16.8%), sulfonylureas alone (20.6%), and metformin + sulfonylureas group (22.7%) (Table S2).
3.9. Major adverse cardiovascular events
MACE occurred in 48 participants (6.4%) in the tirzepatide pooled group and in 62 participants (8.3%) in the glargine group. There was no increased risk of MACE events in the pooled tirzepatide group compared to the glargine group; hazard ratio (HR) 0.75 (95% CI 0.51, 1.1; p = 0.127; Table S3). Twenty deaths (2.7%) in the tirzepatide pooled group and 25 deaths (3.4%) in the glargine group were observed (HR 0.77 [95% CI, 0.43, 1.39], p = 0.39). None of the deaths were related to the study drug.
4. DISCUSSION
In this post‐hoc analysis of the SURPASS‐4 trial, all three doses of tirzepatide were associated with improved glycaemic control and reduced body weight compared to the active comparator insulin glargine over a long‐term period of 104 weeks. A significantly higher proportion of participants in the tirzepatide groups reached the glycaemic targets, with fewer clinically significant hypoglycaemic events compared to participants in the insulin glargine group. Participants treated with tirzepatide had a greater reduction in body weight than those treated with insulin glargine. These findings suggest that tirzepatide may be a valuable therapeutic option for participants with long‐standing type 2 diabetes and inadequately controlled glycaemia with metformin and/or sulfonylurea therapies over a long‐term period of 104 weeks. In this study, we included participants with inadequately controlled glycaemia despite using OADs such as metformin and/or sulfonylureas. Metformin and sulfonylureas are commonly used OADs in clinical settings for managing type 2 diabetes. 22 , 23
Tirzepatide has demonstrated improved glycaemic control and body weight reduction with a lower incidence of hypoglycaemia compared to traditional insulin therapies in clinical trials during 52 weeks of treatment. 20 , 21 In this post‐hoc analysis of the SURPASS‐4 trial, the mean reduction in HbA1c was significantly greater in the tirzepatide groups compared to the insulin glargine group at Week 104. The decrease in mean HbA1c was sustained from Week 52 to Week 104. Starting from Week 16, the LS mean HbA1c levels were ≤6.5% for all three tirzepatide groups, while they were >7.0% for the insulin glargine group throughout the study. By Week 104, the LS mean HbA1c levels were significantly lower in the tirzepatide 5, 10, and 15 mg groups (−2.3%, −2.5%, and −2.6%, respectively) compared to the insulin glargine group (−1.0%). These findings align with previous findings from the SURPASS‐4 trial and a post‐hoc analysis of the SURPASS AP‐Combo study. 19 , 21 The change in HbA1c from baseline to 52 weeks was −2.2%, −2.4%, and −2.6% for tirzepatide 5, 10, and 15 mg, respectively, versus −1.4% with insulin glargine in SURPASS‐4. 21 The decrease in HbA1c levels observed in the tirzepatide groups at 52 weeks was sustained through 78 and 104 weeks of treatment. These results indicate that glycaemic control may be maintained over an extended period with tirzepatide treatment, lasting up to 2 years in this case. At Week 104, participants in the tirzepatide 5, 10, and 15 mg groups showed a significantly greater reduction in body weight compared to those in the insulin glargine group. A significantly greater proportion of participants in the tirzepatide 5, 10, and 15 mg groups achieved weight reduction targets of at least 5%, 10%, and 15% compared to those in the insulin glargine group. These findings were consistent with the overall population in the SURPASS‐4 study. In the SURPASS‐4 trial, tirzepatide showed significant reductions in body weight compared to insulin glargine. The mean bodyweight change with all 3 doses of tirzepatide in the SURPASS‐4 trial was −7.1 to −11.7 kg compared to an average increase of +1.9 kg with insulin glargine. Additionally, a post‐hoc analysis of the SURPASS AP‐Combo trial showed that patients who achieved the HbA1c target while on treatment with tirzepatide had greater improvement in HbA1c levels, body weight, FSG, BMI, waist circumference, blood pressure, and lipid levels. 19 The significant reduction in body weight and waist circumference associated with tirzepatide further supports its potential benefits in managing type 2 diabetes, given the association between obesity and insulin resistance. 26 , 27 Reduction in weight/waist circumference might reduce insulin resistance and hence correlate with better HbA1c control. Better HbA1c control is associated with a better lipid profile. 28 These results may provide evidence for the efficacy of tirzepatide that lasts beyond 52 weeks, without a rebound in body weight during long‐term use.
Furthermore, in this post‐hoc analysis, lipid profile improved in participants treated with all doses of tirzepatide, which was maintained throughout the trial, consistent with the findings from the SURPASS‐4 study. In a substudy of the randomised, open‐label, parallel‐group, Phase III SURPASS‐3 trial, participants with T2D receiving tirzepatide demonstrated a reduction in liver fat content, visceral and subcutaneous adipose tissue, demonstrating the probable reason for the reduction in triglyceride, non‐HDL, and LDL cholesterol levels. 29 Uncontrolled hyperglycaemia impairs lipid metabolism, thus accelerating atherogenesis, leading to cardiovascular complications. 26 HbA1c is a useful biomarker of long‐term glycaemic control and a good predictor of lipid profile, 28 , 30 , 31 thus monitoring HbA1c can have additional benefit to identify patients with diabetes at risk of cardiovascular issues. Our findings with improved HbA1c and lipid profile suggest possible benefits of maintaining tirzepatide treatment over a long‐term period. Participants treated with tirzepatide experienced increased pulse rate (2.6–5 bpm) and decreased SBP (2–8 mmHg), indicating possible improvements in vascular health and a reduced cardiovascular risk. These findings are consistent with the overall population of the SURPASS‐4 study. 21
Although tirzepatide has demonstrated benefits in terms of lower risk of hypoglycaemia and weight reduction compared to insulin and sulfonylureas, it may not be the immediate combination choice for patients inadequately controlled on metformin and/or sulfonylureas who do not exhibit poor glycaemic control. Especially for individuals with existing or potential atherosclerotic cardiovascular disease and/or chronic kidney disease, certain glucose‐lowering agents such as SGLT2 inhibitors or GLP‐1 receptor agonists with proven cardiorenal benefits can be considered as an add‐on therapy in clinical decision‐making. Furthermore, the present analysis used data from the SURPASS‐4 trial, wherein insulin glargine served as the comparator to explore the cardiovascular safety.
Considering the mechanism of action and therapeutic landscape, a GLP‐1 receptor agonist administered at an optimal dose would have served as a more clinically relevant comparator. This is being addressed in the SURPASS‐CVOT trial, 32 the first active‐controlled cardiovascular outcomes trial (CVOT) evaluating a glucose‐lowering therapy in patients with type 2 diabetes. The trial is designed to demonstrate cardiovascular safety of tirzepatide by establishing non‐inferiority to dulaglutide, a GLP‐1 RA with proven cardiovascular benefit. 32 The high proportion of participants treated with SGLT2‐inhibitors at baseline, the large sample and longer study duration are expected to provide insights on the application of incretin‐based medications in mitigating the cardiovascular complications in T2D.
Coskun et al. reported greater weight reduction in obese mice due to the synergistic agonism of the GIP and GLP‐1 receptors compared to the selective GLP‐1 receptor agonism. 33 The mechanism for weight reduction was hypothesised as the synergistic effect of the GIP and GLP‐1 receptors of tirzepatide on modulating energy balance. 33 In GIP receptor knockout mice, tirzepatide demonstrated glycaemic control comparable to that of semaglutide; whereas, in GLP‐1 receptor knockout mice, its glycaemic efficacy mirrored that of a GIP analogue. These findings suggest that tirzepatide exhibited glucose‐lowering activity in the absence of either receptor, underscoring the potential contribution of its dual agonism. 33 To conclusively determine the role of GIP receptor agonism in the efficacy of tirzepatide, a head‐to‐head comparison between tirzepatide and a GLP‐1‐RA with similar GLP‐1 receptor agonistic activity but without GIP receptor agonism would be insightful.
Notably, 25% of participants who were receiving SGLT2 inhibitors were excluded from our analysis. In the SURPASS‐3 and SURPASS‐4 trials, 32% and 25% of participants, respectively, were treated with SGLT2 inhibitors with or without metformin, while the majority were managed with metformin and/or sulfonylureas. 20 , 21 Consequently, the findings of our study provide evidence supporting the efficacy of tirzepatide specifically in participants not receiving SGLT2 inhibitors, thereby addressing a clinically relevant subgroup that may benefit from tirzepatide add‐on therapy. The safety events reported in this post‐hoc analysis were consistent with those observed in the SURPASS‐4 and SURPASS‐AP‐Combo studies. The lower incidence of hypoglycaemia and mild to moderate gastrointestinal adverse events reported with tirzepatide compared with insulin glargine is particularly noteworthy factors in favour of the long‐term tirzepatide treatment, considering that hypoglycaemia and weight gain are major limiting factors in the use of insulin therapy. 34 , 35 , 36 The MACE events and all‐cause death were consistent with those observed in the SURPASS‐4 study with no increased risk for MACE in participants treated with tirzepatide compared to insulin glargine. Cardiovascular risk is an important parameter as cardiovascular diseases are the leading cause of morbidity and mortality in patients with diabetes. 37
The study's strengths include its large sample size and the long duration of 104 weeks. In the SURPASS‐4 trial, a significant proportion of participants were on metformin and/or sulfonylurea, which is relatively common in clinical practice. This study may provide evidence of long‐term efficacy and safety, which may assist physicians in the comprehensive management of type 2 diabetes. The real world data from the Food and Drug Administration Adverse Event Reporting System database reported that tirzepatide could increase the risk of gastrointestinal adverse events. 38 The specific potential contributions of GIP agonism to these events need further investigation. However, the gastrointestinal events were dose‐dependent in a Phase 1, randomised, placebo‐controlled, double‐blind study. 33 While tirzepatide has demonstrated efficacy in improving glycaemic control and reducing body weight in participants with type 2 diabetes, its use may be limited by cost. This study has certain limitations. The variable treatment period beyond 52 weeks was intended to gather longer‐term safety data and to reach a predefined number of MACE‐4 events. As a result, not all participants were treated for the full 104 weeks. Only 150 participants (10.0%) completed the 104‐week follow‐up; hence the long‐term effectiveness should be interpreted with caution. Participants who completed the 104‐week follow‐up would have tolerated tirzepatide well and might have experienced high effectiveness, while those who discontinued the study earlier might have experienced lower effectiveness over time. As this study was a post‐hoc analysis of a randomised controlled trial, statistical and clinical significance should be interpreted with caution. This study exclusively compared tirzepatide with insulin glargine; no direct comparisons were made between different tirzepatide doses. Consequently, we could not determine whether a dose–response relationship exists. Notably, the LS mean changes in FSG and waist circumference were slightly smaller in the 15 mg tirzepatide group compared to the 10 mg group. Hence, these findings should therefore be interpreted with caution.
5. CONCLUSION
In conclusion, in this 104‐week post‐hoc analysis of the SURPASS‐4 trial, tirzepatide‐treated participants were observed to have clinically meaningful and long‐term significant improvement in glycaemic control, body weight, and lipid profile, with acceptable safety and tolerability compared to participants treated with insulin glargine, in a population with type 2 diabetes inadequately controlled by metformin and/or sulfonylurea. These findings suggest that tirzepatide may be a valuable therapeutic option in participants with type 2 diabetes and inadequately controlled glycaemia on metformin and/or sulfonylurea over a long‐term period.
AUTHOR CONTRIBUTIONS
Haixia Guan: Design; conduct; analysis; writing manuscript. Hongwei Jiang: Design; conduct; analysis; writing manuscript. Huijuan Yuan: Design; conduct; writing manuscript. Jie Sun: Design; conduct; analysis; writing manuscript. Jiawei Xu: Design; analysis; writing manuscript. Linong Ji: Design; writing manuscript.
CONFLICT OF INTEREST STATEMENT
JS and JX are the employees and minor stockholders of Eli Lilly and Company.
PEER REVIEW
The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70047.
Supporting information
Data S1. Supporting information.
ACKNOWLEDGEMENTS
The authors thank Li Ying Du and Rui Wang, Eli Lilly and Company, Shanghai, China, for the statistical and medical review support funded by Lilly, and Vedashree S of Eli Lilly Services India Private Limited for medical writing support.
Guan H, Jiang H, Yuan H, Sun J, Xu J, Ji L. Long‐term efficacy and safety of tirzepatide in participants with type 2 diabetes with inadequate glycaemic control on metformin and/or sulfonylurea: Post‐hoc analysis of SURPASS‐4. Diabetes Obes Metab. 2025;27(11):6480‐6490. doi: 10.1111/dom.70047
DATA AVAILABILITY STATEMENT
Lilly provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available upon reasonable request. 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, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting information.
Data Availability Statement
Lilly provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available upon reasonable request. 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, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.