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. 2025 Sep 29;27(12):7385–7394. doi: 10.1111/dom.70143

Tirzepatide and the 10‐year predicted risk of cardiovascular disease and type 2 diabetes in adults with obesity and prediabetes: A post hoc analysis from the three‐year SURMOUNT‐1 trial

Emily R Hankosky 1, Jeremie Lebrec 2, Clare J Lee 1, Georgios K Dimitriadis 1, Irina Jouravskaya 1, Adam Stefanski 1, W Timothy Garvey 3,✉
PMCID: PMC12587230  PMID: 41017451

Abstract

Aim

We assessed the association between tirzepatide and the 10‐year predicted risk of developing cardiovascular disease (CVD) and type 2 diabetes (T2D) among three‐year SURMOUNT‐1 trial participants.

Materials and Methods

This post hoc analysis applied validated risk engines that predict 10‐year CVD (atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], and total CVD) and T2D risk to the three‐year SURMOUNT‐1 clinical trial data at baseline and 176 weeks. In the trial, participants with obesity and prediabetes at baseline were randomly assigned to once weekly tirzepatide (5/10/15 mg) or placebo for 176 weeks of treatment. Changes in risk scores from baseline to week 176 were compared between tirzepatide and placebo using a mixed model of repeated measures.

Results

Tirzepatide treatment was associated with greater reductions in the 10‐year predicted risk of CVD and T2D compared with placebo. Mean percent change from baseline to week 176 in predicted ASCVD risk score was greater in tirzepatide‐treated groups using the ACC/AHA (5 mg: −4.6%; 10 mg: −7.5%; 15 mg: −9.2%) and PREVENT risk equations (5 mg: −3.7%; 10 mg: −6.3%; 15 mg: −8.8%) versus increased risk in placebo (57.9% and 40.5%, respectively; p < 0.0001 for all). Mean absolute change in T2D risk scores from baseline to week 176 using Cardiometabolic Disease Staging (CMDS) was greater in tirzepatide‐treated groups (5 mg: −17.0%; 10 mg: −19.6%; 15 mg: −19.5%) versus placebo (−4.3%, p < 0.0001).

Conclusion

Tirzepatide treatment was associated with a reduction in the 10‐year predicted risk of both cardiovascular outcomes and T2D in people with obesity and prediabetes.

Keywords: atherosclerosis, cardiovascular risk, incretins, obesity management, obesity management medication, prediabetic state

1. INTRODUCTION

Obesity is a chronic, neuroendocrine disease with a rising prevalence worldwide. 1 In the United States (US), the prevalence of obesity has nearly tripled over the last three decades, increasing from <14.0% in 1990 to 40.3% in 2023. 1 , 2 , 3 Obesity and its related complications are interconnected, forming a group of interdependent risk factors that drive the progression of metabolic and cardiovascular disease (CVD) outcomes. 4 , 5 , 6 As a central driver, obesity exacerbates insulin resistance, leading eventually to beta‐cell dysfunction, thus underpinning the development of prediabetes and ultimately, type 2 diabetes (T2D). 5 , 7 Prediabetes is a significant global health concern, affecting approximately 38% of US adults. 8 , 9 The progression from insulin resistance to prediabetes to overt T2D increases the risk of long‐term vascular disease, including atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), CVD‐related mortality, and all‐cause mortality compared to those with normoglycemia. 10 , 11 , 12 , 13

Weight reduction can help prevent and treat T2D and CVD outcomes associated with obesity. 14 The American Diabetes Association Standards of Care and the American Association of Clinical Endocrinology obesity care guidelines indicate that modest, sustained weight reduction of 3–7% may improve insulin sensitivity and beta‐cell function, while weight reduction of 35–315% is often needed to ameliorate many obesity‐related complications. 14 , 15 To achieve these goals, clinical guidelines recommend treatment with obesity management medications as an adjunct to lifestyle interventions for people with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one obesity‐related complication. 14

Tirzepatide, a long‐acting glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA), has been approved in many countries for weight management and for the treatment of T2D. 16 , 17 , 18 , 19 In SURMOUNT‐1, tirzepatide treatment resulted in substantial body weight reduction in people with obesity or overweight with at least one weight‐related complication, over a 72‐week treatment period. 20 An extension of this study (three‐year SURMOUNT‐1 trial) showed that 176 weeks of treatment with tirzepatide in participants with obesity and prediabetes resulted in up to 22.9% sustained weight reduction compared to 2.1% in placebo (efficacy estimand). 21 Additionally, a 94% reduction in the risk of developing T2D after tirzepatide treatment compared to the placebo group was observed (1.2% vs. 12.6% [efficacy estimand]; hazard ratio [HR], 0.06; 95% CI, [0.03, 0.13]). 21 In post hoc analyses from the SURMOUNT‐1 primary trial (72‐week), tirzepatide treatment was associated with a significant decrease in the 10‐year predicted risk of ASCVD and T2D compared with placebo. 22 , 23

Despite growing evidence supporting the efficacy of tirzepatide for chronic weight management and reducing cardiometabolic risk factors, the effect of extended tirzepatide treatment (>3 years) on 10‐year risk estimates of CVD outcomes (ASCVD, HF, and total CVD) and progression to T2D is still unknown. 24 , 25 Most existing studies have focused on treatment durations of <2 years and have primarily reported endpoints such as body weight reduction, glycemic outcomes, and cardiometabolic parameters. 22 , 23 , 26 , 27 , 28 , 29 This represents a gap in existing knowledge, particularly for individuals with obesity and prediabetes who may have elevated long‐term cardiometabolic risk. Therefore, the goal of this study was to understand the association between extended tirzepatide treatment and the long‐term predicted risk for CVD outcomes and T2D using validated risk prediction engines. Specifically, the study objectives were to describe and compare the predicted risk of long‐term outcomes (ASCVD, HF, total CVD, and T2D) between tirzepatide and placebo at 176 weeks among participants in the three‐year SURMOUNT‐1 trial, that is, people with obesity or overweight and prediabetes at baseline.

2. MATERIALS AND METHODS

2.1. Study design and population

These post hoc analyses of the three‐year SURMOUNT‐1 trial (NCT04184622) utilised patient‐level data to compare the change in risk for long‐term CVD outcomes (ASCVD, HF, and total CVD) and T2D at 176 weeks between tirzepatide and placebo groups among people with prediabetes at baseline. Data from a phase 3, randomised trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive once weekly tirzepatide (5 mg, 10 mg, or 15 mg) or placebo. The details of the 72‐week and three‐year SURMOUNT‐1 trials have been previously published. 20 , 21

The three‐year SURMOUNT‐1 trial was conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki. Protocols were approved by institutional review boards or independent ethics committees. The original participant consent also covered the current analyses.

2.2. Variables and outcomes

Demographic and clinical characteristics of three‐year SURMOUNT‐1 participants were used to quantify risks in both the tirzepatide and placebo groups. Specifically, we assessed: (a) 10‐year predicted risk scores of CVD outcomes and T2D using validated risk engines at baseline and week 176, and (b) change from baseline in predicted risk of CVD outcomes and T2D in tirzepatide and placebo groups at 176 weeks. For cardiovascular risk prediction, individuals with prior CVD history were excluded. For T2D risk prediction, individuals with prior T2D were already excluded from the study population by design of the SURMOUNT‐1 trial. The 10‐year risk of developing these outcomes was predicted using the following validated risk prediction engines (Table S1):

  1. ASCVD: the American College of Cardiology/American Heart Association (ACC/AHA) risk equation. 30

  2. Total CVD (a composite of ASCVD and HF), ASCVD, and HF: The Predicting Risk of CVD Events (PREVENT) equation. 31 , 32

  3. T2D: Cardiometabolic Disease Staging (CMDS) risk engine. 33 , 34

Missing predictors were not imputed, and risk scores for participants with missing predictors were not calculated.

2.3. Statistical analysis

This study utilised the efficacy analysis set, which included data from all modified‐intent‐to‐treat (mITT) randomised participants who had received at least one dose of the study intervention during the treatment period, excluding data after study drug discontinuation. Categorical variables were presented using frequencies and percentages; continuous variables were described using means and SD. Median and mean risk scores are presented for the ASCVD and T2D risk assessments, respectively. For the primary analysis, the mean change in predicted risk scores from baseline was derived using a mixed model for repeated measures (MMRM). The MMRM model terms were baseline risk score, country, treatment group, timepoint, and treatment by timepoint interaction. The least squares (LS) mean, mean change from baseline, and percent change from baseline were assessed.

The ACC/AHA and PREVENT risk scores were grouped into low (risk score <5%), borderline (≥5 to <7.5%), intermediate (≥7.5–<20%), or high (≥20%) risk categories. The change in the risk categories from baseline to week 176 was also analysed using a proportional odds model 35 , 36 on the following three ordered outcomes:

  1. Improved risk profile: shift from a higher‐risk to a lower‐risk category from baseline to week 176.

  2. Stable risk profile: same risk category at baseline and week 176, and

  3. Worsening risk profile: shift from a lower‐risk to higher‐risk category from baseline to week 176.

Additional sensitivity analyses were performed to assess the robustness of the findings:

  1. The change in predicted risk scores for ASCVD and HF, using the PREVENT risk equation.

  2. The predicted risk of T2D was estimated after including people who developed T2D prior to 176 weeks in the analysis, who were assigned a CMDS risk value of 1.

  3. All doses of tirzepatide were pooled and analysed for the risk of ASCVD, total CVD, and T2D versus the placebo group.

  4. The analyses were performed among narrower populations in which the models were developed and validated:

  • ASCVD (ACC/AHA): White or Black/African American participants ≥40–79 years at baseline.

  • T2D (CMDS): White or Black/African American participants ≥45 years at baseline.

  • Total CVD (PREVENT): Participants aged ≥30 to ≤79 years.

p = 0.05 was used as a guidance threshold for significance. Analyses were conducted using SAS Enterprise Guide 8.2. (SAS Institute Inc., Cary, NC). 36

3. RESULTS

Among the 2539 participants in the primary SURMOUNT‐1 trial, 1032 (5 mg, n = 247; 10 mg, n = 262; 15 mg, n = 253; placebo, n = 270) had prediabetes at baseline, and only those with prediabetes were included in the three‐year SURMOUNT‐1 trial (Table 1 and Figure S1). Table 1 summarises the participants' demographic and baseline clinical characteristics: mean (SD) age: 48.2 (11.8) years; female: 63.9%; and mean (SD) BMI: 38.8 (7.1) kg/m2.

TABLE 1.

Demographic and clinical characteristics of the three‐year SURMOUNT‐1 study participants with prediabetes at baseline.

Characteristics Placebo (n = 270) TZP 5 mg (n = 247) TZP 10 mg (n = 262) TZP 15 mg (n = 253) Total (N = 1032)
Age, years 47.7 ± 11.9 49.3 ± 12.2 47.4 ± 11.6 48.4 ± 11.7 48.2 ± 11.8
Female a 170 (63.0) 160 (64.8) 168 (64.1) 161 (63.6) 659 (63.9)
Country/Region a
White 193 (71.5) 182 (73.7) 198 (75.6) 185 (73.1) 758 (73.4)
Asian 30 (11.1) 22 (8.9) 27 (10.3) 26 (10.3) 105 (10.2)
Black or African American 23 (8.5) 19 (7.7) 15 (5.7) 20 (7.9) 77 (7.5)
Native Hawaiian or other Pacific islander 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 4 (0.4)
American Indian or Alaska native 18 (6.7) 18 (7.3) 20 (7.6) 19 (7.5) 75 (7.3)
Multiple 5 (1.9) 5 (2.0) 1 (0.4) 2 (0.8) 13 (1.3)
Ethnicity a
Hispanic or Latino 127 (47.0) 118 (47.8) 120 (45.8) 117 (46.2) 482 (46.7)
Not reported 21 (7.8) 15 (6.1) 21 (8.0) 23 (9.1) 80 (7.8)
Duration of education (years) 14.3 (4.4) 14.1 (3.6) 14.2 (3.6) 14.0 (4.0) 14.2 (3.9)
Current smoker a 30 (11.1) 27 (10.9) 29 (11.1) 30 (11.9) 116 (11.2)
HbA1c, (%) 5.8 (0.3) 5.8 (0.3) 5.7 (0.3) 5.8 (0.4) 5.8 (0.3)
BMI, kg/m2 39.1 (7.1) 37.8 (6.6) 39.0 (7.2) 39.2 (7.4) 38.8 (7.1)
BMI category a
kgm2 89 (33.0) 96 (38.9) 91 (34.7) 82 (32.4) 358 (34.7)
≥35 kg/m2 181 (67.0) 151 (61.1) 171 (65.3) 171 (67.6) 674 (65.3)
BMI category a
kgm2 162 (60.0) 170 (68.8) 158 (60.3) 158 (62.5) 648 (62.8)
≥40 kg/m2 108 (40.0) 77 (31.2) 104 (39.7) 95 (37.5) 384 (37.2)
Use of antihypertensive medications a 103 (38.1) 103 (41.7) 97 (37.0) 101 (39.9) 404 (39.1)
Use of statins 53 (19.6) 60 (24.3) 29 (11.1) 44 (17.4) 186 (18.0)
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Note: Data are presented as mean (SD) unless otherwise mentioned.

Abbreviations: BMI, body mass index; HbA1c, Glycated Haemoglobin; N, number of participants in total population; n = number of participants in treatment group; TZP, tirzepatide.

a

Data are presented as n (%).

3.1. 10‐year predicted risk of cardiovascular outcomes using the ACC/AHA and PREVENT equations

Among the 1,032 mITT participants with prediabetes at baseline, 47 (4.6%) had a CVD history and were excluded from the ACC/AHA and PREVENT analyses. The demographic and baseline characteristics of the 985 participants (5 mg, n = 235; 10 mg, n = 251; 15 mg, n = 242; placebo, n = 257) were similar across the treatment groups (Table S2). The mean (SD) age of participants was 47.7 (11.8) years, 65.3% were female, and the mean BMI (SD) was 38.8 (7.0) kg/m2.

3.1.1. ACC/AHA results

At week 176, 455 (46.2%) participants had missing ASCVD risk scores. The proportion of participants with missing data was higher in the placebo group (n = 152 [59.1%]) than in the tirzepatide groups (5 mg: 103 [43.8%], 10 mg: 101 [40.2%], 15 mg: 99 [40.9%]), consistent with those who withdrew from the study over the three‐year extension period of the SURMOUNT‐1 trial. 21 The median 10‐year predicted ASCVD risk scores at baseline were comparable between the placebo and tirzepatide‐treated groups (range: 1.8%–2.6%, Figure 1A). At week 176, the median ASCVD risk scores were 5 mg: 2.2%, 10 mg: 1.8%, 15 mg: 2.1%, and placebo: 3.7%. The LS mean percent decrease in predicted ASCVD risk score from baseline to week 176 was significantly greater in the tirzepatide‐treated groups (5 mg: −4.6%, 10 mg: −7.5%, 15 mg: −9.2%) compared with the increase in risk observed in the placebo group (57.9%, p < 0.0001; Figure 1A).

FIGURE 1.

FIGURE 1

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Effect of tirzepatide on 10‐year predicted risk of cardiovascular outcomes in participants with obesity or overweight and prediabetes. (A) Percent change in 10‐year predicted risk of ASCVD at week 176 in participants with obesity or overweight and prediabetes, using the ACC/AHA risk engine; median ASCVD risk scores at baseline, week 176, change, and percent change at week 176 are presented in the table below the plot. (B) Percent change in 10‐year predicted risk of ASCVD, HF, total CVD at week 176 in participants with obesity or overweight and prediabetes, using the PREVENT risk engine; median risk scores at baseline, week 176, and percent change at week 176 from baseline are presented in the table below the plot. All comparisons of risk reductions from baseline between tirzepatide dose groups and placebo were significant at *p < 0.0001 vs. placebo. The percent change in predicted risk from baseline to week 176 was derived from an MMRM analysis using the SURMOUNT‐1 (3‐year trial) efficacy analysis set. It included data obtained during the treatment period from the mITT (all randomized participants who received at least 1 dose of the study drug), excluding data after discontinuation of the study drug (last dose date +7 days). Source: Only participants with at least one non‐missing post‐baseline value of the response variable were included in the analysis. Change in predicted risk for ASCVD and HF using the PREVENT risk engine was planned as a sensitivity analysis. ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CVD, cardiovascular disease; N, number of subjects in the population with baseline and post‐baseline value at the specified time point; MMRM, mixed model for repeated measures; mITT, modified intent to treat; TZP, tirzepatide.

At baseline, the majority of participants (73.4%) were in the ASCVD low‐risk group, 14.2% in the borderline, 11.1% in the intermediate, and only 1.3% of participants were in the high‐risk group. At week 176, a higher proportion of participants in the placebo group (23.8%) compared to those treated with pooled tirzepatide (11.8%) had a worsened ASCVD risk category profile than at baseline. Additionally, we observed 2.4 times greater odds (95% CI, [1.4, 4.0]; p < 0.001) of improvement in the tirzepatide‐treated group relative to the placebo (Table 2).

TABLE 2.

Summary of shift in ASCVD risk categories from baseline to week 176.

Visit/time Risk outcome Observed proportion, n (%) Odds ratio a (vs. placebo) p value
Placebo Pooled TZP Estimate (95% CI)
ACC/AHA risk equation analysis
Week 176 Improved 2 (1.9) 24 (5.6) 2.4 (1.4, 4.0) <0.001
Stable 78 (74.3) 351 (82.6)
Worsened 25 (23.8) 50 (11.8)
Total, N 105 425
PREVENT risk equation analysis
Week 176 Improved 3 (3.1) 11 (2.9) 3.5 (1.6, 7.4) 0.001
Stable 79 (82.3) 352 (93.6)
Worsened 14 (14.6) 13 (3.5)
Total, N 96 376
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Note: The ACC/AHA and PREVENT risk scores were grouped into low (<5%), borderline (≥5 to <7.5%), intermediate (≥7.5 to <20%), or high (≥20%) risk categories. Improved: Participant shifts from a higher risk category at baseline to a lower risk category at week 176; Stable: Participant stays in the same risk category at baseline and week 176; Worse: Participant shifts from a lower risk category at baseline to a higher risk category at week 176. The adjusted proportion and odds ratio were estimated from a proportional odds model where the ordered outcome category was modelled. The model terms included baseline risk score, treatment group. The summary of shifts in ASCVD risk categories for each treatment group is reported in Table S3. Participants who had a baseline CVD history or had a CVD event prior to week 176 were excluded from the analysis.

Abbreviations: ACC/AHA, the American College of Cardiology/American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CVD, cardiovascular; n, number of participants; PREVENT, The Predicting Risk of CVD Events; TZP, tirzepatide.

a

Cumulative odds ratio (Pooled tirzepatide vs. Placebo) for ‘Improved’ vs. ‘Stable or Worsened’. Note that in the proportional odds model, the previous odds ratio is assumed to equal that for ‘Improved or Stable’ vs. ‘Worsened’.

Two sensitivity analyses were conducted using the ACC/AHA risk engine. First, where all doses of tirzepatide were pooled, and second, among the narrower population in which the ACC/AHA risk engine was developed (White or Black participants aged ≥40–79 years old). The results of both sensitivity analyses were consistent with the primary analysis (Figure S1A,B).

3.1.2. PREVENT results

At baseline, the median risk scores for ASCVD (range: 1.5%–1.9%) and HF (0.9%–1.5%) were comparable between the tirzepatide and placebo groups. Figure 1B presents the median risk scores at week 176 for ASCVD (5 mg: 1.8%, 10 mg: 1.5%, 15 mg: 2.0%, and placebo: 2.9%) and HF (1.3%, 1.3%, 1.5%, and 2.4%). The LS mean percent change from baseline to week 176 in the risk of ASCVD or HF was greater in the tirzepatide‐treated groups (ASCVD: −3.7%, −6.3%, −8.8%; HF: −0.7%, 1.6%, −5.4%) compared to the increased risk estimate in the placebo group (ASCVD: 40.5%; HF: 56.3%; p < 0.0001, Figure 1B).

At baseline, the majority of participants (88.3%) were in the ASCVD low‐risk group, 7.6% in the borderline group, 4.0% in the intermediate‐risk group, and none in the high‐risk category when analysed using the PREVENT equation. Similar to the results obtained from the ACC/AHA equation, more participants in the placebo group (14.6%) had a worsened ASCVD risk profile at week 176 from baseline compared to tirzepatide‐treated participants (3.5%). Furthermore, tirzepatide‐treated participants had 3.5 times greater odds (95% CI [1.6, 7.4]; p = 0.001) of improvement in the ASCVD risk category from baseline to week 176 than those in the placebo group (Table 2).

The median risk scores for total CVD (composite of ASCVD and/or HF) at baseline were comparable for the tirzepatide and placebo groups (range: 2.3%–2.9%). At week 176, the median risk scores were: 5 mg: 2.9%, 10 mg: 2.5%, 15 mg: 3.2%, and placebo: 4.3% (Figure 1B). The LS mean percent change from baseline in the 10‐year predicted risk of total CVD to week 176 was greater in the tirzepatide‐treated groups (5 mg: 1.3%, 10 mg: 0.7%, 15 mg: 2.4%) compared with the increased risk estimate in the placebo (43.8%, p < 0.0001, Figure 1B).

Additional sensitivity analyses were also conducted, where tirzepatide doses were pooled and among the narrower population (age ≥ 30 and ≤ 79 years old) in which the PREVENT equation was developed. These results were consistent with the primary analysis (Figure S2A,B).

3.2. The 10‐year predicted risk of T2D using the CMDS risk engine

Among the 1,032 mITT participants who had prediabetes at baseline, 2 were excluded from the T2D risk prediction analysis as they were diagnosed with T2D at the randomisation visit (Table S4). The demographic and baseline characteristics of the remaining 1,030 participants (5 mg, n = 247; 10 mg, n = 262; 15 mg, n = 253; placebo, n = 268) were similar across the treatment groups (Table S4). The mean (SD) age of participants was 48.2 (11.8) years, 64.0% were female, and the mean BMI (SD) was 38.8 (7.1) kg/m2.

There were 505 (49.0%) participants with missing risk scores at week 176. The proportion of participants with missing data was higher in the placebo group (n = 179 [66.8%]) than in the tirzepatide groups (5 mg: 113 [45.7%], 10 mg: 105 [40.1%], 15 mg: 108 [42.7%]), consistent with those who withdrew from the study over the three‐year extension period of the SURMOUNT‐1 trial. At baseline, the LS mean 10‐year T2D predicted risk scores were comparable across the four treatment groups (range: 25.8%–27.1%; Figure 2A). At week 176, the LS mean scores were 5 mg: 8.9%, 10 mg: 6.3%, 15 mg: 6.4%, and placebo: 21.9% (Figure 2A). The LS mean change in predicted T2D risk scores from baseline to week 176 was significantly greater in the tirzepatide‐treated groups (5 mg: −17.0%, 10 mg: −19.6%, 15 mg: −19.5%) compared with placebo (−4.3%, p < 0.0001; Figure 2B). At week 176, the median relative risk reduction ranged from −69.0% to −75.7% for participants treated with tirzepatide compared with placebo (−16.0%).

FIGURE 2.

FIGURE 2

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Effect of tirzepatide on 10‐year predicted risk of T2D in participants with obesity or overweight and prediabetes. (A) LS mean T2D predicted risk scores at baseline, week 176. (B) LS mean change in T2D predicted risk scores from baseline at week 176. (C) LS mean change in T2D predicted risk scores where people with T2D were included and assigned a risk value of 1 (sensitivity analysis). All comparisons of risk reductions from baseline between tirzepatide dose groups and placebo were significant at *p < 0.0001 vs. placebo. The change in predicted risk from baseline to week 176 was derived from MMRM analysis using the SURMOUNT‐1 (3‐year trial) efficacy analysis set. It included data obtained during the treatment period from the mITT (all randomized participants who received at least 1 dose of the study drug), excluding data after discontinuation of the study drug (last dose date +7 days). Source: The analysis included only participants with at least one non‐missing post‐baseline value of the response variable. 14 participants who developed T2D during the study discontinued the treatment before week 176. LS, least squares; MMRM, mixed model for repeated measures; mITT, modified intent to treat; T2D, type 2 diabetes; TZP, tirzepatide.

In the first sensitivity analysis, 41 participants who developed T2D during the study period were included in the risk prediction analysis and assigned a risk value of 1. Of these, 14 participants discontinued the treatment before week 176. The results of the tirzepatide‐treated groups were numerically consistent with the primary analysis, where the LS mean change in predicted T2D risk scores from baseline to week 176 was greater compared with placebo (p < 0.0001; Figure 2C). However, the predicted risk of T2D at week 176 increased in the placebo group from baseline (1.1% vs. −4.3% reduction in the primary analysis) when people who developed T2D were included in the analysis. The other two sensitivity analyses examined the risk of developing T2D when all doses of tirzepatide were pooled versus placebo and among only White or Black/African American participants aged ≥45 years (Figure S2C,D). The results of these sensitivity analyses were also consistent with the primary analyses.

4. DISCUSSION

This is the first study evaluating the association between long‐term tirzepatide treatment and the predicted risk of CVD outcomes and progression to T2D, the two major end‐stage outcomes of progressive cardiometabolic disease, in people with obesity and prediabetes. Using data from 176 weeks of observation in SURMOUNT‐1, long‐term treatment with tirzepatide was associated with a significant reduction in the 10‐year predicted risk of CVD outcomes (ASCVD, HF, and total CVD) as well as a significant reduction in the risk of developing T2D in people with obesity and prediabetes. These results highlight the role of sustained metabolic health benefits that may be achieved with tirzepatide.

Regarding mechanisms explaining the reduction in risk scores, tirzepatide‐induced weight reduction was associated with markedly enhanced insulin sensitivity 37 and improvements in CVD risk factors that are properties of an insulin‐resistant state. 4 This, together with the effect of tirzepatide on improving glycemia, could explain the marked reductions in the T2D predicted risk scores. 28 With respect to reductions in CVD risk, tirzepatide‐treated groups may have experienced direct and indirect effects of tirzepatide on risk factors in addition to weight reduction. 38 A recent network meta‐analysis reported tirzepatide to be effective in reducing glycated haemoglobin, fasting glucose, triglyceride level, and waist circumference compared with placebo. 39 Our findings are congruent with other studies indicating that the CVD risk reduction associated with GLP‐1 RAs may involve mechanisms beyond weight reduction, specifically, those partly related to the physiological benefits of GLP‐1 receptor agonism, such as improvements in BMI, glycemia, waist circumference, inflammation, renal function, and blood pressure. 40 , 41 , 42 , 43

In the SELECT trial, treatment with semaglutide, a GLP‐1 RA, significantly reduced the risk of major adverse cardiovascular events (MACE‐3: non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death) by 20% compared with placebo (HR, 0.80; 95% CI [0.72, 0.90], p < 0.001) in individuals with obesity and preexisting CVD. 44 Recently released topline results from the SURPASS‐CVOT (NCT04255433) trial reported that tirzepatide was non‐inferior to dulaglutide with an 8% (HR, 0.92; 95.3% CI [0.83, 1.01]) lower rate of MACE‐3 events while demonstrating greater reductions in HbA1C and weight (detailed results are yet to be published). A pre‐specified indirect comparison of the REWIND and SURPASS‐CVOT studies found that tirzepatide reduced the risk of MACE‐3 by 28% (HR, 0.72; 95% CI [0.55–0.94]) compared to placebo. Furthermore, the effect of tirzepatide treatment on cardiovascular events and outcomes is currently being assessed in the SURMOUNT‐MMO (NCT05556512) trial. 45 , 46 In the absence of hard evidence of cardioprotective benefits, the current analyses showed that long‐term tirzepatide treatment significantly reduced the predicted risk of developing CVD outcomes compared with placebo. Our modelling results are consistent with the SUMMIT trial, which showed that tirzepatide treatment reduced the risk of worsening HF by 46% relative to placebo (HR, 0.54; 95% CI [0.34, 0.85]) in patients with heart failure with preserved ejection fraction and obesity. 29 , 45 , 46

We observed an increase in the predicted cardiovascular risk at week 176 in the placebo arm, likely due to the natural progression of obesity and prediabetes, despite the lifestyle interventions that participants underwent as part of the trial. 47 , 48 This finding is underscored by the fact that individuals with obesity and prediabetes have insulin resistance, hypertriglyceridemia, and dyslipidemia, among other risk factors. 49 In the absence of evidence‐based interventions, these risk factors may translate into advanced atherosclerotic vascular changes and an enhanced risk of developing long‐term CVDs. 49

The difference in predicted ASCVD risk with the PREVENT vs. ACC/AHA risk engine is in line with a recent study using the NHANES data that reported lower estimated ASCVD risk with the PREVENT equations (4.3%, 95% CI [4.1%, 4.5%]) compared to the ACC/AHA equation (8.0%, 95% CI [7.6%, 8.4%]). 50 The PREVENT equations exclude race and include measures such as renal function, statin use, and optional variables (HbA1c and uACR). Pooled cohort equations (ACC/AHA risk equation) often overestimate the ASCVD risk in some US cohorts, as they were developed using relatively older data, whereas the PREVENT equation uses more contemporary cohorts from electronic health records. 50 , 51 Notably, the association between tirzepatide and the predicted risk for ASCVD did not depend on the risk equation used.

Weight reduction is intricately linked with improved long‐term insulin sensitivity and glycaemic outcomes. Indeed, the post hoc risk‐prediction analysis of the 72‐week SURMOUNT‐1 trial among people with prediabetes at baseline demonstrated a significant reduction in the 10‐year risk of developing T2D relative to placebo (range: −16.0% to −20.3%). 23 Consistent with those findings, the current analysis showed a reduction in 10‐year predicted T2D risk after tirzepatide treatment ranging from −17.0% to −19.6% (absolute risk score). Together, these findings reflect the sustained benefits of extended tirzepatide treatment and obesity management on long‐term glycaemic control.

Although direct comparisons cannot be made, the T2D risk predicted at 176 weeks in the current study (tirzepatide: 6.3%–8.9%, placebo: 21.9%) is higher than the incident T2D observed in the three‐year SURMOUNT‐1 trial (tirzepatide: 1.2%, placebo: 12.6%). 21 One reason for the difference is that the CMDS model predicts a 10‐year risk of T2D, while SURMOUNT‐1 evaluated observed outcomes of T2D after about 3 years of tirzepatide treatment. Thus, as the cumulative incidence of T2D increased over a more extended time period, the observed outcomes may approximate the 10‐year risk prediction, which has been validated in large national cohorts. Alternatively, the underestimation of T2D risk suggests that there are underlying mechanisms of tirzepatide, beyond those captured by the CMDS model inputs, that contribute to the reduction in risk for T2D. This phenomenon, whereby risk prediction modelling does not fully capture the benefit of a treatment, is consistent with the observed underestimation of empagliflozin benefit on cardiovascular and kidney outcomes based on risk prediction. 51

This study was strengthened by several factors. First, this analysis utilised validated risk prediction models that incorporate multiple risk factors to quantitatively assess risk. The CMDS and ACC/AHA models were selected over the Framingham models due to their broader generalisability across populations and greater accuracy of prediction. 30 , 34 The PREVENT model is sex‐specific, independent of race, and incorporates renal function in its analyses. 32 Second, the study utilised a large, global sample from the three‐year SURMOUNT‐1 trial, which facilitates the generalisability of these results. Finally, the consistency of results across the three risk engines from the primary and sensitivity analyses supports the robustness of the findings.

5. LIMITATIONS

These findings should be interpreted with caution as the risk models generate predicted scores that may not be applicable to all real‐world scenarios or considered as confirmatory evidence against hard clinical outcomes after 10 years. The models were developed and validated in populations different from the trial population, though sensitivity analyses in the alternate populations were consistent with the primary analysis. The results should be interpreted with caution as the rate of missing data was high at week 176, due to discontinuation or withdrawal. Furthermore, repeated measurements were used for the analysis of risk score as a continuous variable, but not to analyse the shift in the participant's ASCVD risk categories from baseline to week 176 using the ACC/AHA and PREVENT risk engines.

The findings of our study warrant validation through randomized clinical trials and additional studies to characterize the impact of tirzepatide on cardiovascular outcomes. Tirzepatide has demonstrated promising results in terms of weight reduction and glycemic control, which in the long term may translate into cardiovascular benefits. 26 , 27 However, its precise cardiovascular effects remain to be fully elucidated and require further investigation through ongoing SURMOUNT‐MMO (NCT05556512) and future clinical trials. 44 , 45

6. CONCLUSION

This post hoc analysis of the three‐year SURMOUNT‐1 trial suggests that extended tirzepatide treatment (>3 years) is associated with a reduction in the 10‐year predicted risk of both CVD and T2D in people with obesity and prediabetes. The data support the long‐term benefits of tirzepatide in the prevention of cardiometabolic disease outcomes. However, long‐term studies are needed to confirm these results and to assess the impact of tirzepatide on the prevention of CVD events and incident T2D. The ongoing SURMOUNT‐MMO (NCT05556512) trial will contribute evidence in addressing hard outcomes, that is, morbidity and mortality in adults living with obesity. 44

AUTHOR CONTRIBUTIONS

Emily R. Hankosky: Conception and design of the work, interpretation of data for the work, and drafting of the work. Jeremie Lebrec: Analysis of data for the work and critical review of the work for important intellectual content. Clare J. Lee: Conception of the work, interpretation of data for the work, drafting of the work, and critical review of the work for important intellectual content. Georgios K. Dimitriadis: Conception and design of the work, interpretation of data for the work, and critical review of the work for important intellectual content. Irina Jouravskaya and Adam Stefanski: Acquisition of the data of the work, interpretation of data for the work, and critical rview of the work for important intellectual content. W. Timothy Garvey: Conception and design of the work, analysis of the work, interpretation of data for the work, drafting of the work, and critical review of the work for important intellectual content.

FUNDING INFORMATION

The study and all support for the manuscript were funded by Eli Lilly and Company, Indianapolis, United States.

CONFLICT OF INTEREST STATEMENT

Emily R. Hankosky, Clare Lee, Georgios K. Dimitriadis, Irina Jouravskaya, Adam Stefanski are employees and stockholders of Eli Lilly and Company, Indianapolis, United States. Jeremie Lebrec—works as a contractor for Eli Lilly and Company. W. Timothy Garvey: Dr. Garvey has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, Zealand, Allurion, Carmot/Roche, Terns Pharmaceuticals, Neurocrine, Keros Therapeutics, Gan & Lee, and Regeneron. He is a site principal investigator for multi‐centred clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly, Epitomee, Neurovalens, Zealand, Carmot/Roche, and Pfizer. He is a member of a Data Monitoring Committee for phase 3 clinical trials conducted by Boehringer‐Ingelheim and Eli Lilly.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70143.

Supporting information

FIGURE S1. Participant disposition.

FIGURE S2. Percent change in risk scores from baseline to week 176: results from sensitivity analyses.

TABLE S1. Details of the risk engines and their model input.

TABLE S2. Demographic and clinical characteristics of the three‐year SURMOUNT‐1 participants with no CVD history at baseline.

TABLE S3. Summary of shift in ASCVD risk categories from baseline to week 176 (all doses).

TABLE S4. Demographic and clinical characteristics of the three‐year SURMOUNT‐1 participants included in the T2D risk prediction analysis.

TABLE S5. Descriptive statistics of predictors/model inputs used in the ACC/AHA and PREVENT risk equations.

TABLE S6. Descriptive statistics of predictors/model inputs used in the CMDS risk engine.

DOM-27-7385-s001.docx (385.6KB, docx)

ACKNOWLEDGEMENTS

Era Seth of Eli Lilly Services India Pvt. Ltd. provided medical writing support which was funded by Eli Lilly and Company.

Hankosky ER, Lebrec J, Lee CJ, et al. Tirzepatide and the 10‐year predicted risk of cardiovascular disease and type 2 diabetes in adults with obesity and prediabetes: A post hoc analysis from the three‐year SURMOUNT‐1 trial. Diabetes Obes Metab. 2025;27(12):7385‐7394. doi: 10.1111/dom.70143

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

DATA AVAILABILITY STATEMENT

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request six months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms for the SURMOUNT‐1 study (NCT04184622) will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. A Website pertaining to Cardiometabolic Staging (CMDS) is available to the public and permits data entry providing individual 10‐year risk estimates for diabetes and for MACE cardiovascular outcomes https://cmdsrisk.uab.edu/

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

FIGURE S1. Participant disposition.

FIGURE S2. Percent change in risk scores from baseline to week 176: results from sensitivity analyses.

TABLE S1. Details of the risk engines and their model input.

TABLE S2. Demographic and clinical characteristics of the three‐year SURMOUNT‐1 participants with no CVD history at baseline.

TABLE S3. Summary of shift in ASCVD risk categories from baseline to week 176 (all doses).

TABLE S4. Demographic and clinical characteristics of the three‐year SURMOUNT‐1 participants included in the T2D risk prediction analysis.

TABLE S5. Descriptive statistics of predictors/model inputs used in the ACC/AHA and PREVENT risk equations.

TABLE S6. Descriptive statistics of predictors/model inputs used in the CMDS risk engine.

DOM-27-7385-s001.docx (385.6KB, docx)

Data Availability Statement

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request six months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms for the SURMOUNT‐1 study (NCT04184622) will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. A Website pertaining to Cardiometabolic Staging (CMDS) is available to the public and permits data entry providing individual 10‐year risk estimates for diabetes and for MACE cardiovascular outcomes https://cmdsrisk.uab.edu/

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