This parallel-design double-blind trial includes a post hoc analysis of data for patients with type 2 diabetes and cardiovascular disease to compare the incidence of an expanded range of cardiorenal adverse events for tirzepatide vs dulaglutide.
Key Points
Question
In patients with diabetes and cardiovascular disease, is tirzepatide associated with reduced cardiorenal adverse events compared with dulaglutide?
Findings
In this post hoc analysis of a parallel-design double-blind trial involving 13 165 patients, treatment with tirzepatide up to 15 mg weekly, compared with dulaglutide, 1.5 mg, was associated with a lower rate of cardiorenal adverse events.
Meaning
Compared with the GLP-1 agonist dulaglutide, the dual GLP-1/GIP agonist tirzepatide was associated with a lower incidence of major cardiorenal adverse events in patients with diabetes and cardiovascular disease.
Abstract
Importance
The dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide was noninferior to a GLP-1 agonist, dulaglutide, for effects on the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke. However, comparison for a comprehensive range of major adverse cardiovascular and kidney outcomes has not been reported.
Objective
To perform a post hoc analysis for an expanded range of adverse outcomes in a completed randomized clinical trial comparing the effects of tirzepatide and dulaglutide in patients with type 2 diabetes and cardiovascular disease.
Design, Setting, and Participants
This parallel-design double-blind trial enrolled patients with diabetes and preexisting cardiovascular disease (from May 29, 2020, to June 27, 2022) at 640 centers in North and South America, Europe, Asia, and Oceania. Data were analyzed from July 2025 to February 2026.
Interventions
Participants were randomized to receive subcutaneous tirzepatide up to 15 mg (n = 6586) or a fixed dose of dulaglutide, 1.5 mg (n = 6579), administered weekly.
Main Outcomes and Measures
The primary efficacy measure was time from randomization to first occurrence of a 6-component composite of cardiorenal adverse outcomes, including all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and a composite of adverse kidney outcomes.
Results
Among the 13 165 patients enrolled, the mean (SD) age was 64 (8.8) years; 9348 patients (71.0%) were male and 3817 were female (29.0%). The mean (SD) hemoglobin A1c was 8.4% (0.93). After a median (IQR) treatment duration of 46.9 (34.6-50.6) months, the primary cardiorenal end point occurred in 1559 tirzepatide-treated patients (23.7%) and 1803 dulaglutide-treated patients (27.4%; hazard ratio [HR], 0.84; 95% CI, 0.79-0.90; P < .001). Sensitivity analyses showed similar hazard ratios for a narrower 5-component end point (without the kidney composite outcomes: HR, 0.86; 95% CI, 0.80-0.93) and the 4-component composite (without either kidney or heart failure end points: HR, 0.86; 95% CI, 0.80-0.93). Gastrointestinal adverse events were more common with tirzepatide (2827 patients [42.5%]) than dulaglutide (2387 patients [35.9%]) treatment. Other adverse events were similar.
Conclusions
In this post hoc analysis, the dual GLP-1 and GIP agonist tirzepatide, compared with the GLP-1 agonist dulaglutide, was associated with a lower incidence of a broad 6-component composite cardiovascular and kidney end point in patients with diabetes and established cardiovascular disease.
Trial Registration
ClinicalTrials.gov Identifier: NCT04255433
Introduction
Incretin-based therapies, initially glucagon-like peptide 1 (GLP-1) receptor agonists, were first introduced in 2005 and have evolved into important therapeutic options in the treatment of patients with type 2 diabetes, obesity, or both disorders. GLP-1 agonists improve glycemic control in patients with diabetes, reduce body weight in obese individuals with and without diabetes, decrease the progression of kidney disease, lower blood pressure, improve levels of atherogenic lipoproteins, and reduce the risk of heart failure adverse events. Clinical trials have established that several drugs in this class reduce the risk of major adverse cardiovascular and kidney outcomes in patients with atherosclerotic cardiovascular disease and diabetes, obesity, or chronic kidney disease. Tirzepatide, introduced in 2022, is a dual agonist that targets both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors and has shown added benefits compared with GLP-1 agonists on body weight, glycemic control, and several biomarkers associated with adverse cardiorenal outcomes.
The Study of Tirzepatide Compared With Dulaglutide on MACE in Participants With Type 2 Diabetes (SURPASS-CVOT) was the first cardiovascular outcome trial with an active incretin-based comparator. SURPASS-CVOT demonstrated that tirzepatide was noninferior to the GLP-1 agonist dulaglutide for the 3-component composite end point of cardiovascular death, myocardial infarction (MI), or stroke. This end point was selected because dulaglutide had previously received a regulatory indication to reduce major adverse cardiovascular events (MACE) based on the 3-component end point. Regulatory authorities required the trial to study this end point to consider whether to award tirzepatide a noninferiority or superiority claim in comparison with dulaglutide. However, given the established effects of incretin-based therapies on a broader range of adverse outcomes, the narrow 3-component end point may not fully reflect the effects of these drugs on major sources of morbidity and mortality. The current post hoc analysis was undertaken to evaluate the association of tirzepatide and dulaglutide with outcomes for an expanded 6-component composite cardiorenal end point that included all-cause mortality, MI, stroke, coronary revascularization, heart failure, and serious adverse kidney outcomes.
Methods
Trial Organization and Oversight
The rationale, design, methods, and primary results of the SURPASS CVOT trial have been previously reported. Briefly, the trial was an active comparator, randomized double-blind global trial conducted at 640 sites in North America, Europe, Asia, South America, and Oceania. The trial was designed by Eli Lilly and Company in collaboration with an academic Executive Committee. The study protocol and statistical analysis plan are available in Supplement 1 and Supplement 2, respectively. Enrollment was from May 29, 2020, to June 27, 2022.
The protocol and all amendments were approved by ethics committees at participating sites, and all participants provided written informed consent. An independent data monitoring committee monitored the trial. The sponsor collected the data and performed the initial statistical analysis. The trial database was transferred to Monash University (Melbourne, Australia) for independent statistical analysis for the primary article. The analyses in the current article were performed by the sponsor from July 2025 to February 2026. The study was conducted in accordance with ethical principles derived from the Declaration of Helsinki and international ethical guidelines from the Council for International Organizations of Medical Sciences.
Trial Population
The protocol specified enrollment of patients at least 40 years of age with type 2 diabetes and established atherosclerotic cardiovascular disease, which could include coronary, cerebrovascular, or peripheral arterial disease. Definitions of established cardiovascular disease are provided in the protocol (Supplement 1). Participants were required to have a body mass index greater than 25 (calculated as weight in kilograms divided by height in meters squared) and a hemoglobin A1c level between 7.0% and 10.5%. Patients who had experienced a cardiovascular event within the past 6 months were excluded. Patients with type 1 diabetes and those with hospitalization for heart failure within the previous 2 months were also excluded. Other inclusion and exclusion criteria are reported in the protocol (Supplement 1).
Study Procedures
Tirzepatide and matching dulaglutide were randomly assigned in a 1:1 ratio for weekly subcutaneous self-administration using a single-dose pen. The injection device for dulaglutide was indistinguishable from the tirzepatide injector. At the time of randomization, the protocol recommended discontinuing dipeptidyl peptidase 4 inhibitors, reducing the dose of or discontinuing sulfonylureas, and consideration of temporary insulin dose reduction. After randomization, patients followed a double-blinded dose escalation schedule over 24 weeks. A fixed dose of dulagutide, 1.5 mg, was supplied. The starting dose of tirzepatide was 2.5 mg weekly, which was escalated every 4 weeks to a maximum of 15 mg weekly or to the highest maintenance dose tolerated by the patient. If intolerable adverse effects occurred with tirzepatide, patients could have their dose de-escalated. For patients who did not reach the maximum dose or had their dose de-escalated, 2 more attempts for dose escalation were offered. Sham dose escalation of dulaglutide was performed according to the same schedule as the tirzepatide dose titration. If adverse effects occurred for patients randomized to receive dulaglutide, sham dose de-escalation was performed, but the 1.5 mg dose of dulaglutide was maintained. Other details regarding dosing escalation and de-escalation are described in the protocol (Supplement 1).
Study End Points
The primary end point for the current analysis was first occurrence of a 6-component composite of cardiorenal adverse outcomes, including all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and a composite of adverse kidney outcomes. All-cause mortality, revascularization, hospitalization for heart failure, and adverse kidney outcomes were secondary efficacy assessments. All end points except the composite kidney outcome were centrally adjudicated by a blinded independent committee at the Cleveland Clinic. The composite kidney end point was defined as persistent macroalbuminuria or persistent doubling of serum creatinine level with estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m2, need for continuous kidney replacement therapy, or death due to kidney disease. The CKD-EPI creatinine-cystatin C equation 2021 was used to calculate eGFR. Persistent was defined in participants with at least 2 postbaseline measurements as meeting criteria at either 2 consecutive measures at least 30 days apart or only at the final visit. For all end points, the time-to-event data were analyzed using a Cox proportional hazard model stratified by use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Sensitivity analyses were performed for a narrower 5-component end point (without the kidney composite end point) and a 4-component composite (without either kidney or heart failure end points) and the 6-component end point using cardiovascular death rather than all-cause mortality.
In the current analysis, baseline characteristics of patients in both treatment groups were assessed in patents who did and did not experience a subsequent 6-component cardiorenal adverse event. Treatment-emergent adverse events were also assessed for patients who did and did not have a cardiorenal event.
Statistical Analysis
The primary trial was designed to assess noninferiority of tirzepatide compared with dulaglutide based on an upper 95.3% CI of less than 1.05 for the primary 3-component end point of cardiovascular death, MI, or stroke. A sample size of 12 500 patients followed up for an average of 4 years would lead to the accrual of at least 1615 primary end points, which provided 90% power to demonstrate superiority with a 15% reduction for hazard of tirzepatide compared with dulaglutide, at a 2-sided α of .0472 adjusted for an interim analysis.
In the current post hoc analysis of the broader 6-component cardiorenal end point, no power calculations were performed. The time-to-event data were analyzed using a Cox proportional hazard model stratified by SGLT-2 inhibitor use with observed significance level for treatment comparison based on the Wald test. The sensitivity analyses were not adjusted for multiplicity and are reported without P values.
Results
Study Population
A total of 13 165 patients were enrolled at 640 centers in North and South America, Europe, Asia, and Oceania. The mean (SD) age was 64 (8.8) years; 9348 patients (71.0%) were male and 3817 were female (29.0%). The mean (SD) hemoglobin A1c was 8.4% (0.93).
Table 1 reports baseline characteristics for each treatment group for patients who did and did not experience any of the composite cardiorenal end points. For both the tirzepatide and dulaglutide treatment groups, trial participants who experienced an event were approximately 4 years older, more likely to be male, had a lower eGFR, and were more likely to have had a prior MI, stroke, revascularization, prior heart failure event, or peripheral arterial disease. Tobacco use, a higher urinary albumin to creatinine ratio, and macroalbuminuria or microalbuminuria were also associated with a higher event rate. No clinically meaningful differences were observed in body mass index or hemoglobin A1c levels in patients with cardiorenal events compared with those without an event.
Table 1. Baseline Characteristics of Participants Who Experienced a Cardiorenal End Point and Those Who Did Not.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Tirzepatide group (n = 6586) | Dulaglutide group (n = 6579) | |||
| Had end point (n = 1559) | No end point (n = 5027) | Had end point (n = 1803) | No end point (n = 4776) | |
| Sex | ||||
| Male | 1232 (79.0) | 3463 (68.9) | 1387 (76.9) | 3266 (68.4) |
| Female | 327 (21.0) | 1564 (31.1) | 416 (23.1) | 1510 (31.6) |
| Age, mean (SD), y | 66.0 (8.6) | 63.4 (8.8) | 65.8 (8.7) | 63.5 (8.7) |
| Racea | ||||
| American Indian or Alaska Native | 87 (5.7) | 400 (8.1) | 89 (5.0) | 390 (8.3) |
| Asian | 124 (8.1) | 449 (9.0) | 144 (8.1) | 445 (9.5) |
| Black or African American | 26 (1.7) | 85 (1.7) | 33 (1.8) | 74 (1.6) |
| Native Hawaiian or Other Pacific Islander | 3 (0.2) | 6 (0.1) | 3 (0.2) | 6 (0.1) |
| White | 1290 (84.0) | 4009 (80.7) | 1510 (84.5) | 3772 (80.2) |
| Multiple races | 6 (0.4) | 16 (0.3) | 7 (0.4) | 19 (0.4) |
| Missing, No. | 23 | 62 | 17 | 70 |
| Ethnicitya | ||||
| Hispanic or Latino | 449 (28.8) | 1539 (30.6) | 526 (29.2) | 1455 (30.5) |
| Not Hispanic or Latino | 1031 (66.1) | 3255 (64.8) | 1201 (66.6) | 3067 (64.2) |
| Weight, mean (SD), kg | 93.4 (19.2) | 92.4 (18.7) | 93.8 (18.8) | 92.0 (18.8) |
| BMI, mean (SD)b | 32.6 (5.4) | 32.6 (5.5) | 32.8 (5.6) | 32.5 (5.4) |
| Hemoglobin A1c, mean (SD), % | 8.5 (1.0) | 8.4 (0.9) | 8.4 (1.0) | 8.4 (0.9) |
| Duration of diabetes, mean (SD), y | 16.0 (9.0) | 14.4 (8.7) | 15.7 (8.7) | 14.3 (8.7) |
| Hypertension | 1442 (92.5) | 4499 (89.5) | 1708 (94.7) | 4224 (88.5) |
| LDL cholesterol, mean (SD), mg/dL | 81.5 (37.7) | 80.2 (36.6) | 82.5 (38.6) | 80.1 (37.7) |
| Triglycerides, median (IQR), mg/dL | 162.5 (120.5-233.8.2) | 158.6 (115.2-224.1) | 161.2 (116.0-226.8) | 158.6 (116.0-222.3) |
| Estimated GFR, mean (SD), mL/min/1.73 m2 | 69.7 (25.5) | 81.2 (23.0) | 71.7 (24.7) | 82.1 (22.4) |
| UACR, median (IQR), mg/g | 46 (14-199) | 19 (8-63) | 46 (13-189) | 18 (8-56) |
| Microalbuminuriac | 616 (40.4) | 1456 (29.4) | 752 (42.5) | 1318 (28.0) |
| Macroalbuminuriad | 287 (18.8) | 467 (9.4) | 301 (17.0) | 436 (9.3) |
| Current tobacco use | 245 (15.7) | 718 (14.3) | 307 (17.0) | 689 (14.4) |
| Systolic BP, mean (SD), mm Hg | 136.7 (16.5) | 134.6 (15.2) | 137.0 (16.8) | 135.0 (15.4) |
| Diastolic BP, mean (SD), mm Hg | 77.6 (10.2) | 77.9 (9.5) | 77.9 (10.2) | 78.2 (9.6) |
| Prior myocardial infarction | 816 (52.3) | 2281 (45.4) | 897 (49.8) | 2222 (46.5) |
| Prior revascularization | 990 (63.5) | 2766 (55.0) | 1141 (63.3) | 2632 (55.1) |
| Prior heart failure | 421 (27.0) | 889 (17.7) | 515 (28.6) | 853 (17.9) |
| Prior stroke | 315 (20.2) | 938 (18.7) | 396 (22.0) | 876 (18.3) |
| Peripheral arterial disease | 443 (28.4) | 1217 (24.2) | 521 (28.9) | 1153 (24.1) |
Abbreviations: BMI, body mass index; BP, blood pressure; LDL, low-density lipoprotein; GFR, glomerular filtration rate; UACR, urinary albumin to creatinine ratio.
SI conversion factors: To convert LDL cholesterol to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113.
Race and ethnicity were self-reported.
Calculated as weight in kilograms divided by square of height in meters.
Defined as UACR 30-300 mg/g.
Defined as UACR >300 mg/g.
Clinical End Points
After a median (IQR) treatment duration of 46.9 (34.6-50.6) months, the 6-component primary cardiorenal end point occurred in 1559 (23.7%) tirzepatide-treated patients and 1803 (27.4%) dulaglutide-treated patients (hazard ratio [HR], 0.84; 95% CI, 0.79-0.90; P < .001) (Table 2). Figure 1 shows Kaplan-Meier curves for time to first incidence of a 6-component composite cardiorenal event. Table 2 shows the event rates for each of the individual components of the composite outcome for both treatment groups. Each component contributed to the benefit observed for the composite outcome. All-cause mortality occurred in 566 (8.6%) tirzepatide-treated patients and 669 (10.2%) dulaglutide-treated patients (HR, 0.84; 95% CI, 0.75-0.94). MI occurred in 311 (4.7%) tirzepatide-treated patients and 357 (5.4%) dualglutide-treated patients (HR, 0.86; 95% CI, 0.74-1.00). Stroke occurred in 229 (3.5%) tirzepatide-treated patients and 249 (3.8%) dulaglutide-treated patients (HR, 0.91; 95% CI, 0.76-1.09). Coronary revascularization occurred in 527 (8.0%) tirzepatide-treated patients and 617 (9.4%) dulaglutide-treated patients (HR, 0.84; 95% CI, 0.75-0.95). Hospitalization or urgent visit for heart failure occurred in 198 (3.0%) tirzepatide-treated patients and 204 (3.1%) dualglutide-treated patients (HR, 0.96; 95% CI, 0.79-1.17). The composite kidney end point occurred in 326 (4.9%) tirzepatide-treated patients and 404 (6.1%) dulaglutide-treated patients (HR, 0.79; 95% CI, 0.68-0.91).
Table 2. Time-to-Event Efficacy End Points for the Tirzepatide Treatment Group Compared With the Dulaglutide Group.
| End point | No. (%) | HR (95% CI) | P value | |
|---|---|---|---|---|
| Tirzepatide group | Dulaglutide group | |||
| Follow-up, median, y | 4.0 | 4.0 | NA | |
| 6-Component efficacy end pointa | 1559 (23.7) | 1803 (27.4) | 0.84 (0.79-0.90) | <.001 |
| End point components | ||||
| All-cause mortality | 566 (8.6) | 669 (10.2) | 0.84 (0.75-0.94) | NA |
| Myocardial infarction | 311(4.7) | 357 (5.4) | 0.86 (0.74-1.00) | NA |
| Stroke | 229 (3.5) | 249 (3.8) | 0.91 (0.76-1.09) | NA |
| Coronary revascularization | 527 (8.0) | 617 (9.4) | 0.84 (0.75-0.95) | NA |
| Heart failure hospitalization | 198 (3.0) | 204 (3.1) | 0.96 (0.79-1.17) | NA |
| Composite renal end point | 326 (4.9) | 404 (6.1) | 0.79 (0.68-0.91) | NA |
| Sensitivity analyses | ||||
| 5-Component efficacy end pointb | 1330 (20.2) | 1514 (23.0) | 0.86 (0.80-0.93) | NA |
| 4-Component efficacy end pointc | 1259 (19.1) | 1435 (21.8) | 0.86 (0.80-0.93) | NA |
| 6-Component efficacy end point with CV death rather than all-cause mortalityd | 1361 (20.6) | 1559 (23.7) | 0.85 (0.79-0.92) | NA |
Abbreviations: HR, hazard ratio; NA, not applicable; CV, cardiovascular.
Time to first occurrence of all-cause mortality, myocardial infarction, stroke, coronary revascularization, heart failure hospitalization, and a composite of adverse kidney outcomes. P value was calculated using the Wald test.
Time to first occurrence of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure.
Time to first occurrence of all-cause mortality, myocardial infarction, stroke, or coronary revascularization.
Time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, or a composite of adverse kidney outcomes.
Figure 1. Kaplan-Meier Curves for Time to First Incidence of a 6-Component Cardiorenal Event.
The 6-component major cardiorenal events included a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, or a composite of adverse kidney events. The time-to-event data were analyzed using a Cox proportional hazard model stratified by sodium-glucose cotransporter 2 (SGLT-2) inhibitor use with observed significance level for treatment comparison based on Wald test. The median follow-up time was 4.0 years. HR indicates hazard ratio.
Sensitivity analyses for a narrower 5-component end point (without inclusion of the kidney composite outcome) showed 1330 events (20.2%) in the group randomized to receive tirzepatide and 1514 events (23.0%) in the group randomized to receive dulaglutide (HR, 0.86; 95% CI, 0.80-0.93). Results for a 4-component composite (without inclusion of either kidney or heart failure end points) showed 1259 events (19.1%) in the tirzepatide treatment group and 1435 events (21.8%) in the dulaglutide treatment group (HR, 0.86; 95% CI, 0.80-0.93). Results for the 6-component end point substituting cardiovascular death for all-cause mortality showed 1361 events (20.7%) in the tirzepatide treatment group and 1559 events (23.7%) in the dulaglutide treatment group (HR, 0.85; 95% CI, 0.79-0.92). Kaplan-Meier curves showing time to first occurrence of an end point for the 5-component and 4-component outcomes are shown in Figure 2A and B, respectively. Results for the 6-component end point for prespecified subgroups (not multiplicity adjusted) are shown in eFigures 1 and 2 in Supplement 3. There was a marginally significant interaction for BMI category (<27, 27-30, and >30), but no interaction for sex, age (<65 or ≥65 years), region of enrollment, race, ethnicity, hemoglobin A1c level (≤8.5% or >8.5%), duration of diabetes (<10 years or ≥10 years), history of MI, history of congestive heart failure, impaired kidney function, or baseline SGLT-2 inhibitor use.
Figure 2. Kaplan-Meier Curves Showing Time to First Incidence of 5-Component and 4-Component Cardiovascular Events.
A, The 5-component major cardiovascular events included a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure. The median follow-up time was 4.0 years. B, The 4-component major cardiovascular events included a composite of all-cause mortality, myocardial infarction, stroke, or coronary revascularization. The median follow-up time was 4.0 years. HR indicates hazard ratio.
Adverse Events
Adverse effects of the study regimens were reported previously in the article describing the main results of the trial. In the current analysis, treatment adverse events in patients who did and did not experience a cardiorenal end point are reported in Table 3. Gastrointestinal adverse events were common in both treatment groups but occurred more frequently with tirzepatide than dulaglutide. In the tirzepatide treatment group, 721 patients (46.0%) who experienced a cardiorenal end point had a gastrointestinal adverse event compared with 2016 patients (41.4%) who did not have the primary end point. There was no meaningful difference in occurrence of gastrointestinal adverse events among dulaglutide-treated patients who did and did not experience a cardiorenal end point. Treatment-emergent adverse events leading to drug discontinuation were more common in patients treated with tirzepatide and associated with occurrence of cardiorenal end points. Drug discontinuation for adverse events was less common with dulaglutide but was also associated with occurrence of cardiorenal end point. The occurrence of adverse events in patients who experienced a cardiorenal end point were broadly similar between the tirzepatide and dulaglutide treatment groups.
Table 3. Adverse Events Occurring in Participants Who Experienced a Cardiorenal End Point and Those Who Did Not.
| Eventa | No. (%) | |||
|---|---|---|---|---|
| Tirzepatide group (n = 6647) | Dulaglutide group (n = 6647) | |||
| Had end point (n = 1562) | No end point (n = 5085) | Had end point (n = 1805) | No end point (n = 4842) | |
| Any treatment-emergent adverse event | 1458 (93.3) | 4412 (86.8) | 1638 (90.7) | 4122 (85.1) |
| Serious treatment-emergent adverse events | 806 (51.6) | 1282 (25.2) | 920 (50.9) | 1141 (23.6) |
| Treatment-emergent adverse events leading to drug discontinuation | 318 (20.4) | 560 (11.0) | 282 (15.6) | 390 (8.1) |
| Gastrointestinal adverse event | 721 (46.0) | 2106 (41.4) | 667 (37.0) | 1720 (35.5) |
| Urinary tract infection | 161 (10.3) | 314 (6.2) | 177 (9.8) | 318 (6.6) |
| Dizziness | 124 (7.9) | 342 (6.2) | 154 (8.5) | 258 (5.3) |
| Hypotension | 107 (6.9) | 288 (5.7) | 85 (4.7) | 136 (2.8) |
| Anemia | 110 (7.0) | 152 (3.0) | 138 (7.6) | 145 (3.0) |
| Serious adverse events | ||||
| Pneumonia | 64 (4.1) | 54 (1.1) | 79 (4.4) | 62 (1.3) |
| Acute kidney injury | 58 (3.7) | 35 (0.7) | 63 (3.5) | 28 (0.6) |
| Angina unstable | 45 (2.9) | 44 (0.9) | 55 (3.0) | 45 (0.9) |
| Peripheral arterial occlusive disease | 24 (1.5) | 35 (0.7) | 34 (1.9) | 31 (0.6) |
| Cardiac failure chronic | 49 (3.1) | 9 (0.2) | 46 (2.5) | 16 (0.3) |
| Atrial fibrillation | 30 (1.9) | 27 (0.5) | 33 (1.8) | 22 (0.5) |
| Urinary tract infection | 28 (1.8) | 29 (0.6) | 27 (1.5) | 23 (0.5) |
| Acute cholecystitis | 22 (1.4) | 34 (0.7) | 14 (0.8) | 25 (0.5) |
All reported adverse events represent the investigator’s judgment. Specific guidance was not provided. Gastrointestinal adverse events included nausea, vomiting, and diarrhea.
Discussion
The SURPASS CVOT was designed to compare the effects of the dual GLP-1 and GIP agonist tirzepatide with the GLP-1 agonist dulaglutide in patients with diabetes and cardiovascular disease for a narrow 3-component end point consisting of cardiovascular death, MI, or stroke. The primary comparison of tirzepatide with dulaglutide showed an HR of 0.92 (95% CI, 0.83-1.01; P = .003 for noninferiority and P = .09 superiority). This trial was the first active-control cardiovascular outcome trial comparing alternative incretin-based therapies. Because several placebo-controlled trials of GLP-1 receptor agonists had previously demonstrated favorable effects on cardiovascular outcomes in patients with type 2 diabetes, it was deemed most appropriate to compare tirzepatide with an active-control treatment. Dulaglutide was chosen as a comparator because this drug had shown favorable effects on cardiovascular outcomes in a previous large cardiovascular outcome trial and could be supplied in an injection device indistinguishable from tirzepatide. The narrow 3-component end point was selected because the primary analysis of the dulaglutide cardiovascular outcome trial had reported results for this composite end point.
However, people with diabetes and obesity experience a broad range of adverse cardiorenal outcomes. A recent presidential advisory of the American Heart Association emphasized the importance of a more expansive cardiovascular-kidney-metabolic syndrome, particularly in patients with obesity and diabetes. The current post hoc study was undertaken to examine the association of tirzepatide and dulaglutide with outcomes for an expanded 6-component cardiorenal end point that included all-cause mortality, MI, stroke, revascularization, heart failure and adverse kidney outcomes. Analysis of this 6-component cardiorenal end point showed an absolute risk reduction of 3.7% in the tirzepatide group compared with dulaglutide, with a number needed to treat to prevent 1 event of 27. Each of the individual cardiorenal end points contributed to the association of tirzepatide with a reduction in morbidity and mortality compared with dulaglutide. Sensitivity analyses for a 5-component end point that excluded kidney events and a 4-component end point that excluded both kidney and heart failure events both showed an identical HR of 0.86. The findings from the current analysis provide a comprehensive comparison of the dual GLP-1/GIP incretin tirzepatide with the GLP-1 agonist dulaglutide on major cardiorenal adverse outcomes.
The rationale for use of a broad cardiorenal end point in the current analysis stems from emerging data suggesting that treatment of obesity and diabetes with incretin-based therapies may provide wide-ranging benefits. Recent studies comparing incretin-based therapies with placebo have demonstrated favorable effects on multiple sources of morbidity in patients with obesity with or without diabetes, including coronary revascularization, heart failure, and adverse kidney outcomes, but not all-cause mortality. There are also data demonstrating greater weight loss with the tirzepatide compared with the GLP-1 receptor agonist semaglutide. A placebo-controlled trial of tirzepatide in patients with obesity and heart failure with preserved ejection fraction showed that treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure. A post hoc analysis of a trial comparing tirzepatide with insulin glargine suggested a benefit on kidney outcomes. The inclusion of all-cause mortality in the 6 component composite was driven by data showing the association of obesity and diabetes with several sources of mortality, including death due to infections and malignancy.
Studies of metabolic surgery have suggested a broad range of benefits from weight loss, including a reduction in all-cause mortality. Although placebo-controlled trials of the GLP-1 receptor agonists semaglutide and dulaglutide showed a reduction in the 3-component composite of cardiovascular death, MI, or stroke in patients with diabetes and high cardiovascular risk, none of these trials showed a significant reduction in cardiovascular death or all-cause mortality. A trial of semaglutide in patients with obesity but without diabetes showed a reduction in the 3-component composite but not cardiovascular death and a possible reduction in all-cause mortality that was not considered statistically significant because of the multiplicity-controlled testing procedure. Although the current trial also did not show a significant reduction in cardiovascular death for tirzepatide treatment compared with dulaglutide, the current analysis shows a strong favorable association of tirzepatide for all-cause mortality. Additional data on the effects of tirzepatide on expanded cardiorenal outcomes including all-cause mortality will be forthcoming in a large placebo-controlled cardiovascular outcome trial involving patients with obesity but without diabetes.
Baseline characteristics of patients who experienced an adverse cardiorenal event were consistent with observations from epidemiological studies and other cardiovascular outcome trials. Older age, male sex, tobacco use, macroalbuminuria or microalbuminuria, and lower eGFR were all associated with a higher likelihood of a cardiorenal event. Most baseline characteristics associated with an end point event were broadly similar between treatment groups. Gastrointestinal adverse events were more common with tirzepatide compared with dulaglutide, more likely to lead to drug discontinuation, and associated with a slightly higher primary cardiorenal event rate. Other treatment-emergent adverse events leading to drug discontinuation were more common in patients treated with tirzepatide and associated with a slightly higher rate of occurrence of cardiorenal end points. Drug discontinuation for adverse events was less common with dulaglutide but also associated with occurrence of cardiorenal end point.
Limitations
The study has several limitations. First, this was a secondary analysis of a clinical trial with a narrower primary end point. Such post hoc analyses benefit from knowledge about the outcomes for the primary trial, which may bias selection of components of the broader analysis. However, each of the components of the current study were included in the trial design and most were centrally adjudicated. Second, the broader end point resulted in approximately double the number of events compared with the primary trial, which yielded much greater statistical power than intended by the original trial design. Third, the trial included only patients with high cardiovascular risk. The association of the studied treatments with this broader end point in lower-risk populations was not studied. Whether results would be similar in other populations cannot be assumed.
Conclusions
In this post hoc analysis of data for patients with type 2 diabetes and established cardiovascular disease, the dual GLP-1/GIP agonist tirzepatide, compared with the GLP-1 agonist dulaglutide was associated with a lower incidence of a broad 6-component cardiorenal end point that included all-cause mortality, MI, stroke, coronary revascularization, heart failure, and adverse kidney outcomes.
Trial protocol
Statistical analysis plan
eFigure 1. Demographic Subgroups for MACE-6 Primary Efficacy Endpoint
eFigure 2. Comorbidity Subgroups for MACE-6 Primary Efficacy Endpoint
Data sharing statement
References
- 1.Jastreboff AM, le Roux CW, Stefanski A, et al. ; SURMOUNT-1 Investigators . Tirzepatide for obesity treatment and diabetes prevention. N Engl J Med. 2025;392(10):958-971. doi: 10.1056/NEJMoa2410819 [DOI] [PubMed] [Google Scholar]
- 2.Packer M, Zile MR, Kramer CM, et al. ; SUMMIT Trial Study Group . Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392(5):427-437. doi: 10.1056/NEJMoa2410027 [DOI] [PubMed] [Google Scholar]
- 3.Gerstein HC, Sattar N, Rosenstock J, et al. ; AMPLITUDE-O Trial Investigators . Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385(10):896-907. doi: 10.1056/NEJMoa2108269 [DOI] [PubMed] [Google Scholar]
- 4.Perkovic V, Tuttle KR, Rossing P, et al. ; FLOW Trial Committees and Investigators . Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. doi: 10.1056/NEJMoa2403347 [DOI] [PubMed] [Google Scholar]
- 5.Krumholz HM, de Lemos JA, Sattar N, et al. Tirzepatide and blood pressure reduction: stratified analyses of the SURMOUNT-1 randomised controlled trial. Heart. 2024;110(19):1165-1171. doi: 10.1136/heartjnl-2024-324170 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kanbay M, Copur S, Siriopol D, et al. Effect of tirzepatide on blood pressure and lipids: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2023;25(12):3766-3778. doi: 10.1111/dom.15272 [DOI] [PubMed] [Google Scholar]
- 7.Marso SP, Daniels GH, Brown-Frandsen K, et al. ; LEADER Steering Committee; LEADER Trial Investigators . Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Marso SP, Bain SC, Consoli A, et al. ; SUSTAIN-6 Investigators . Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141 [DOI] [PubMed] [Google Scholar]
- 9.Gerstein HC, Colhoun HM, Dagenais GR, et al. ; REWIND Investigators . Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. doi: 10.1016/S0140-6736(19)31149-3 [DOI] [PubMed] [Google Scholar]
- 10.Hernandez AF, Green JB, Janmohamed S, et al. ; Harmony Outcomes committees and investigators . Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519-1529. doi: 10.1016/S0140-6736(18)32261-X [DOI] [PubMed] [Google Scholar]
- 11.McGuire DK, Marx N, Mulvagh SL, et al. ; SOUL Study Group . Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. 2025;392(20):2001-2012. doi: 10.1056/NEJMoa2501006 [DOI] [PubMed] [Google Scholar]
- 12.Nogueiras R, Nauck MA, Tschöp MH. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat Metab. 2023;5(6):933-944. doi: 10.1038/s42255-023-00812-z [DOI] [PubMed] [Google Scholar]
- 13.Nicholls SJ, Bhatt DL, Buse JB, et al. ; SURPASS-CVOT investigators . Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. Am Heart J. 2024;267:1-11. doi: 10.1016/j.ahj.2023.09.007 [DOI] [PubMed] [Google Scholar]
- 14.Nicholls SJ, Pavo I, Bhatt DL, et al. ; SURPASS-CVOT Investigators . Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med. 2025;393(24):2409-2420. doi: 10.1056/NEJMoa2505928 [DOI] [PubMed] [Google Scholar]
- 15.Ndumele CE, Rangaswami J, Chow SL, et al. ; American Heart Association . Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation. 2023;148(20):1606-1635. doi: 10.1161/CIR.0000000000001184 [DOI] [PubMed] [Google Scholar]
- 16.Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. ; SELECT Trial Investigators . Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi: 10.1056/NEJMoa2307563 [DOI] [PubMed] [Google Scholar]
- 17.Aronne LJ, Horn DB, le Roux CW, et al. ; SURMOUNT-5 Trial Investigators . Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393(1):26-36. doi: 10.1056/NEJMoa2416394 [DOI] [PubMed] [Google Scholar]
- 18.Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(11):774-785. doi: 10.1016/S2213-8587(22)00243-1 [DOI] [PubMed] [Google Scholar]
- 19.Lee MMY, Sattar N, Pop-Busui R, et al. ; SOUL Trial Investigators . Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized trials. Diabetes Care. 2025;48(5):846-859. doi: 10.2337/dc25-0241 [DOI] [PubMed] [Google Scholar]
- 20.Yang WS, Chang YC, Chang CH, Wu LC, Wang JL, Lin HH. The association between body mass index and the risk of hospitalization and mortality due to infection: a prospective cohort study. Open Forum Infect Dis. 2020;8(1):ofaa545. doi: 10.1093/ofid/ofaa545 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356:j477. doi: 10.1136/bmj.j477 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Aminian A, Zajichek A, Arterburn DE, et al. Association of metabolic surgery with major adverse cardiovascular outcomes in patients with type 2 diabetes and obesity. JAMA. 2019;322(13):1271-1282. doi: 10.1001/jama.2019.14231 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lam CSP, Rodriguez A, Aminian A, et al. Tirzepatide for reduction of morbidity and mortality in adults with obesity: rationale and design of the SURMOUNT-MMO trial. Obesity (Silver Spring). 2025;33(9):1645-1656. doi: 10.1002/oby.24332 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
Statistical analysis plan
eFigure 1. Demographic Subgroups for MACE-6 Primary Efficacy Endpoint
eFigure 2. Comorbidity Subgroups for MACE-6 Primary Efficacy Endpoint
Data sharing statement
