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. 2025 Mar 12;33(5):851–860. doi: 10.1002/oby.24254

Body weight reduction in women treated with tirzepatide by reproductive stage: a post hoc analysis from the SURMOUNT program

Beverly G Tchang 1, Andreea Ciudin Mihai 2, Adam Stefanski 3, Luis‐Emilio García‐Pérez 3, Donna Mojdami 3, Irina Jouravskaya 3, Sirel Gurbuz 3, Rebecca Taylor 3, Chrisanthi A Karanikas 3, Julia P Dunn 3,✉
PMCID: PMC12015656  PMID: 40074721

Abstract

Objective

Increases in adiposity and adverse changes in adipose distribution commonly occur in women during midlife and with the onset of menopause. This post hoc analysis assessed body weight changes with tirzepatide by reproductive stage.

Methods

Women participants from SURMOUNT‐1, ‐3, and ‐4 randomized to tirzepatide (15 mg or maximum tolerated dose) or placebo were retrospectively categorized as being in the pre‐, peri‐, or post‐menopause stages. Body weight and waist circumference changes, the proportion of participants achieving body weight‐reduction thresholds, and waist to height ratio (WHtR) category shift among those with baseline BMI < 35 kg/m2 were assessed at end of study treatment.

Results

In SURMOUNT‐1, significantly greater body weight reductions from baseline were observed with tirzepatide versus placebo in women in the premenopause (26% vs. 2%), perimenopause (23% vs. 3%), and postmenopause stages (23% vs. 3%; p < 0.001). Greater waist circumference reductions were also observed with tirzepatide across the subgroups (22 vs. 4 cm, 20 vs. 5 cm, and 20 vs. 4 cm, respectively; p < 0.001). Across the reproductive stage subgroups, 97% to 98% of participants achieved body weight reductions that were ≥5% with tirzepatide versus 29% to 33% with placebo. Furthermore, 30% to 52% of women among the reproductive stage subgroups who had baseline BMI < 35 kg/m2 reached WHtR ≤ 0.49 (low central adiposity) with tirzepatide. Similar results were observed in SURMOUNT‐3 and ‐4.

Conclusions

In this post hoc analysis, tirzepatide treatment was associated with significant body weight, waist circumference, and WHtR reductions versus placebo in women living with obesity or overweight and without type 2 diabetes, irrespective of reproductive stage.

graphic file with name OBY-33-851-g003.jpg

Tirzepatide provides consistent reduction in body weight and waist circumference across reproductive stages in women with obesity.

graphic file with name OBY-33-851-g002.jpg

Study Importance.

What is already known?

  • Tirzepatide, a once‐weekly glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist, is approved for the treatment of obesity and of type 2 diabetes.

  • In the SURMOUNT clinical trial program, robust weight reduction was observed with tirzepatide treatment in people with obesity or overweight, with and without type 2 diabetes, compared to placebo.

What are the new findings?

  • This post hoc analysis of the SURMOUNT program assessed treatment response by reproductive stage with tirzepatide versus placebo.

  • Tirzepatide treatment was associated with significant body weight, waist circumference, and waist‐to‐height ratio reductions versus placebo in women living with obesity or overweight without type 2 diabetes, irrespective of reproductive stage.

How might your results change the direction of research or the focus of clinical practice?

  • Results of this post hoc analysis may provide additional guidance to clinicians treating obesity in women of various reproductive stages.

INTRODUCTION

In midlife, women experience an average annual weight increase of 0.7 kg (1.5 lb) [1], and by 2030 it is projected that ~75% of US women will be living with obesity or overweight [2]. Moreover, during the peri‐ and post‐menopause stages, estrogen deficiency affects lipid metabolism, energy homeostasis, insulin resistance, and body fat distribution, which may lead to increased cardiometabolic risk [3], and the postmenopausal state may further increase cardiometabolic risk [4]. Approximately 75% of individuals undergoing medical weight management for obesity and excess weight are women [2, 5]. Clinical treatment of women requires particular attention on factors such as reproductive stage, especially regarding the influence of menopause on the effectiveness of treatment responses. Preclinical research has supported the central anorexigenic effects of estrogen [6], which suggests that fluctuations in estrogen levels, including during the menopausal transition, may affect downstream appetitive signaling and predispose women to weight changes.

Tirzepatide is a once‐weekly glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist approved for the treatment of obesity, type 2 diabetes, and obstructive sleep apnea (in the US). In the global phase 3 SURMOUNT clinical trials investigating tirzepatide in people with obesity or overweight, with and without type 2 diabetes (T2D), participants treated with tirzepatide at all doses studied demonstrated robust body weight reductions ranging from 13% to 6%, as well as improvements in other cardiometabolic parameters [7, 8, 9, 10]. However, it remains unknown whether reproductive stage impacts body weight reductions and improvements in cardiometabolic health in women receiving tirzepatide treatment for chronic weight management. This post hoc analysis assessed the changes in body weight in women treated with tirzepatide versus placebo in the SURMOUNT‐1, SURMOUNT‐3, and SURMOUNT‐4 clinical trials according to presumed reproductive stage.

METHODS

Study design

Study design and primary results were published [7, 9, 10]. The SURMOUNT clinical trial program included four phase 3, randomized, placebo‐controlled trials with treatment durations ranging from 72 to 176 weeks. In the current analysis, data from women living with obesity or overweight without T2D from the SURMOUNT‐1 (72‐week data), SURMOUNT‐3, and SURMOUNT‐4 trials are reported. Eligible participants were randomized to tirzepatide 5, 10, or 15 mg once weekly or the maximum tolerated dose (MTD) of 15 mg or 10 mg versus placebo. Treatment assignment was determined by a computer‐generated random sequence using an Interactive Web Response System. In SURMOUNT‐1, participants with obesity or overweight received 5, 10, or 15 mg of tirzepatide or placebo for 72 weeks [7]. SURMOUNT‐3 included participants who achieved at least 5% body weight reduction during a 12‐week intensive lifestyle intervention period [9]. SURMOUNT‐4 was a randomized withdrawal study with a 36‐week, open‐label, tirzepatide lead‐in period followed by a 52‐week, double‐blind, placebo‐controlled period [10].

Study participants

A full list of eligibility criteria from each study has been published in the primary manuscripts [7, 9, 10]. Briefly, adults aged ≥18 years with a body mass index (BMI) ≥ 30 kg/m2 or ≥27 kg/m2 with at least one weight‐related comorbidity were included in this analysis. Key exclusion criteria included people with diabetes mellitus, >5 kg body weight change within 90 days before screening, prior or planned surgical treatment for obesity, and treatment that promotes weight loss within 90 days before screening. Participants voluntarily reporting premature or artificial menopause or Mayer‐Rokitansky‐Küster‐Hauser syndrome were also excluded from this analysis, as was one participant aged <40 years with bilateral oophorectomy. The SURMOUNT‐2 trial included participants with T2D [8] and, therefore, was excluded from this analysis.

The SURMOUNT clinical trials included in this post hoc analysis were conducted in accordance with good clinical practice guidelines and the principles of the Declaration of Helsinki. Independent ethics committee or institutional review board approval was received for each of the participating sites. All participants provided written informed consent prior to trial participation.

Definition of reproductive stage

The studies did not require capturing the reproductive stage, and only a portion of women participants had a relevant diagnosis in medical history. The categorizations for these analyses were made retrospectively based on available details in the case report forms for the studies. Clinical study investigators were required to assess whether women participants were of childbearing potential. Participants were categorized into the following reproductive stages: 1) premenopause, defined as being aged <45 years without any indication of menopause, including medical history (e.g., menopausal symptoms, bilateral oophorectomy) or biochemical evidence; 2) perimenopause, defined as being aged 40 to 54 years with diagnosis of menopausal symptoms or evidence for clinical suspicion for menopause but not satisfying criteria for postmenopause (e.g., follicle‐stimulating hormone [FSH] was measured but was <40 mIU/mL when not prescribed hormone‐replacement therapy [HRT]) [11] or defined as being aged 45 to 54 years with no evidence for menopause; and 3) postmenopause, defined as being aged ≥40 years with documented medical history indicating menopause or bilateral oophorectomy, or FSH ≥ 40 mIU/mL without HRT, or being aged ≥55 years [12, 13, 14]. Most participants were categorized based on age without other indicators (Table S1). If a participant was on HRT, FSH value was not used to categorize the individual's reproductive status.

Outcome measures

Main outcomes of interest in this post hoc analysis were changes from baseline at Week 72 (SURMOUNT‐1 and SURMOUNT‐3) or Week 88 (SURMOUNT‐4) in percent body weight, waist circumference, and waist to height ratio (WHtR). The proportion of participants achieving weight‐reduction thresholds (≥5%, ≥10%, ≥15%, ≥20%, and ≥ 25%) at the primary endpoint of Week 72 or 88 was also evaluated. WHtR, which details risk category for degree of central adiposity among individuals with BMI < 35 kg/m2 and is a marker for early health risk [15], was assessed at baseline and end of study for each reproductive stage group and categorized according to National Institute for Health and Care Excellence (NICE) UK guidelines, using ≤0.49 for low risk, >0.49 to ≤0.59 for increased risk, and >0.59 for high risk [16]. Shift in WHtR for the entire cohort (i.e., irrespective of BMI) by reproductive stage was also assessed to provide an overarching perspective to the treatment effect for this measure. The overall safety profile from each study was assessed. Data reported in this post hoc analysis are from the tirzepatide 15 mg and MTD treatment arms compared to placebo.

Statistical analyses

Data were analyzed by trial (data could not be pooled due to the differences in study design across the SURMOUNT trials). All analyses were post hoc and performed on the modified intent‐to‐treat population from the efficacy analysis set, comprising all randomly assigned women with at least one dose of study drug exposure, excluding off‐treatment data. Only participants with nonmissing baseline values and at least one nonmissing postbaseline value of the response variable were included in this analysis.

Baseline demographics and clinical characteristics were summarized in participants in the pre‐, peri‐, and post‐menopause stages from the SURMOUNT‐1, SURMOUNT‐3, and SURMOUNT‐4 clinical trials (ANOVA for continuous variables and χ2 test for categorical variables).

Changes from baseline in body weight, waist circumference, and WHtR at Week 72 or 88 were assessed within each reproductive stage subgroup using a mixed model for repeated measures (MMRM) with baseline, analysis country, treatment group, visit, and treatment‐by‐visit interaction as the fixed effect. For analyses with SURMOUNT‐1, the MMRM was also adjusted for glycemic status (presence or absence of prediabetes) at randomization. The lead‐in period was included in the analysis for SURMOUNT‐4 and the MMRM was also adjusted for Interactive Web Response System MTD dose at Week 36, reproductive stage subgroup before first dose of study drug, and baseline weight (in kilograms) during the double‐blind period. Missing outcomes were not directly imputed but managed within the MMRM assuming that data are missing at random, and the missing data follow the same trend as the participants with the same treatment assignment and baseline characteristics. Sensitivity analyses with reproductive stage subgroup as an additional covariate in the model were also assessed in all randomized women per trial.

The proportions of participants who achieved weight‐reduction thresholds at the primary endpoint were estimated within each reproductive stage subgroup via logistic regression. Postbaseline values are the last nonmissing value, and the grand total was used as the denominator to calculate percentages in each treatment.

Safety parameters were summarized as count and proportion. All analyses presented are exploratory in nature. Analyses were performed using SAS version 9.4. (SAS Institute Inc.).

RESULTS

A total of 2542 women participants from the SURMOUNT‐1, SURMOUNT‐3, and SURMOUNT‐4 clinical trials were included in the analyses. Categorization of participants by reproductive status is provided in Table S1. In SURMOUNT‐1, 697 participants were in the premenopausal subgroup, 429 participants were in the perimenopausal subgroup, and 581 were in the postmenopausal subgroup. In SURMOUNT‐3, 143 participants were in the premenopausal subgroup, 101 participants were in the perimenopausal subgroup, and 119 were in the postmenopausal subgroup. In SURMOUNT‐4, 159 participants were in the premenopausal subgroup, 126 participants were in the perimenopausal subgroup, and 187 were in the postmenopausal subgroup.

FIGURE 1.

FIGURE 1

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Change in percent body weight and waist circumference by reproductive stage subgroup in SURMOUNT‐1. Data are proportion of participants who met weight‐reduction threshold at the primary endpoint. Logistic regression with missing value imputed by mixed model for repeated meaures (MMRM) at the primary endpoint was used to assess proportion of participants who met weight‐reduction thresholds. Data from the tirzepatide 15‐mg arm from SURMOUNT‐1 are shown vs. placebo. The denominator used to calculate proportion of participants achieving weight‐loss goals was the number of participants in imputed data. *p < 0.05 and **p < 0.001 vs. baseline and ## p < 0.001 vs. placebo.

Baseline characteristics

Overall, baseline demographics and clinical characteristics were generally similar to those reported in the primary studies [7, 9, 10]. In general, across the trials, BMI and waist circumference did not demonstrate a clear trend among the reproductive stage subgroups (Table 1 and Tables S2 and S3). In contrast, participants in the postmenopausal subgroup had higher systolic blood pressure and higher rates of preexisting comorbidities, including hypertension and dyslipidemia, compared with participants in the pre‐ and peri‐menopausal subgroups. Additionally, at baseline across the trials, participants in the postmenopausal subgroup had more concomitant medications but were less likely to be treated with hormonal therapy (i.e., replacement and contraceptives). In SURMOUNT‐1, more participants in the postmenopausal subgroup also had prediabetes, as defined in the main study [7].

TABLE 1.

Baseline demographics and clinical characteristics by reproductive stage subgroup in SURMOUNT‐1.

Premenopause Perimenopause Postmenopause Total
n = 697 n = 429 n = 581 N = 1707
Age, y 33.9 ± 7.0 45.4 ± 5.9 58.4 ± 6.5 45.1 ± 12.4
Race, n (%)
American Indian or Alaska Native 82 (12) 36 (8) 28 (5) 146 (9)
Asian 63 (9) 32 (8) 19 (3) 114 (7)
Black or African American 54 (8) 46 (11) 54 (9) 154 (9)
Native Hawaiian or other Pacific Islander 2 (0.3) 0 3 (1) 5 (0.3)
White 491 (70) 310 (72) 467 (80) 1268 (74)
Multiple 5 (1) 5 (1) 10 (2) 20 (1)
Treatment, n (%)
Tirzepatide 5 mg 160 (23) 115 (27) 148 (26) 423 (25)
Tirzepatide 10 mg 173 (25) 111 (26) 141 (24) 425 (25)
Tirzepatide 15 mg 162 (23) 110 (26) 152 (26) 424 (25)
Placebo 202 (29) 93 (22) 140 (24) 435 (26)
Duration of obesity, y 11.2 ± 7.9 15.7 ± 10.5 18.9 ± 13.5 14.9 ± 11.2
Body weight, kg 102.2 ± 19.8 101.7 ± 20.5 95.5 ± 16.7 99.8 ± 19.2
BMI, kg/m2 38.9 ± 6.8 38.8 ± 7.0 37.0 ± 5.9 38.2 ± 6.6
Waist circumference, cm 111.5 ± 14.2 111.8 ± 14.5 110.4 ± 12.3 111.2 ± 13.6
Systolic blood pressure, mm Hg 117.6 ± 11.8 121.8 ± 12.2 125.8 ± 13.4 121.5 ± 12.9
Diastolic blood pressure, mm Hg 78.3 ± 8.4 79.4 ± 7.9 78.9 ± 8.0 78.8 ± 8.2
eGFR, mL/min/1.73 m2 108.9 ± 15.5 98.9 ± 14.7 85.0 ± 14.2 98.3 ± 18.1
Total number of concomitant medications a 1.6 ± 2.0 2.1 ± 2.3 3.6 ± 3.3 2.4 ± 2.7
HRTC at first dose, n (%) 259 (37) 71 (17) 32 (6) 362 (21)
Polycystic ovary syndrome, n (%) b 31 (4) 5 (1) 3 (1) 39 (2)
Prediabetes, n (%) 204 (29) 161 (38) 293 (50) 658 (39)
Hypertension, n (%) b 79 (11) 136 (32) 267 (46) 482 (28)
Dyslipidemia, n (%) b 105 (15) 91 (21) 262 (45) 458 (27)
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Note: Data are mean ± SD or n (%) at baseline.

Abbreviations: eGFR, estimated glomerular filtration rate; HRTC, hormone‐replacement therapies and contraceptive.

a

Vaccines and vitamins not included.

b

Majority were “not reported.”

Change from baseline in percent body weight

Among the three studies included in these analyses, we describe SURMOUNT‐1 data as the main data given that it had the largest number of women participants, and we describe SURMOUNT‐3 and SURMOUNT‐4 as supportive evidence herein. In SURMOUNT‐1, among women in the pre‐, peri‐ and post‐menopausal subgroups, reductions from baseline in body weight ranging from 24% to 26% were significantly greater with tirzepatide compared to placebo (2%–3%) at Week 72 (p < 0.001 for all; Figure 1A). Change from baseline in percent body weight over time by reproductive stage is presented in Figures 2 and S1. In a sensitivity analysis that adjusted for reproductive stage subgroup as a covariate and assessed all randomized women together from SURMOUNT‐1, significantly greater reductions in body weight of 25% were observed with tirzepatide compared to placebo (3%; p < 0.001; Figure S2A). In the sensitivity analysis, across subgroups, a statistically significant difference of 0.22% more weight reduction in pre‐ versus post‐menopausal women was identified (p = 0.04). A similar relationship was not identified for SURMOUNT‐3 and SURMOUNT‐4.

FIGURE 2.

FIGURE 2

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Percent body weight change over time by reproductive stage subgroup in SURMOUNT‐1. Data are least squares mean (SE) percent change from baseline in body weight over time in participants treated with tirzepatide 15 mg.

Across all subgroups in SURMOUNT‐1, 97% to 98% of participants achieved body weight loss of ≥5% with tirzepatide versus 29% to 33% with placebo (69%–73% and 45%–50% of tirzepatide‐treated participants achieved body weight loss ≥20% and ≥25%, respectively; Figure 3). A significantly greater proportion of participants from all subgroups treated with tirzepatide exceeded all weight‐loss thresholds versus placebo.

FIGURE 3.

FIGURE 3

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Categorical weight‐loss outcomes by reproductive stage subgroup in SURMOUNT‐1. Data are proportion of participants who met weight‐reduction threshold at the primary endpoint. Logistic regression with missing value imputed by mixed model for repeated measures (MMRM) at the primary endpoint was used to assess proportion of participants who met weight‐reduction thresholds. Data from the tirzepatide 15‐mg arm from SURMOUNT‐1 are shown vs. placebo. The denominator used to calculate proportion of participants achieving weight‐loss goals was the number of participants in imputed data. # p < 0.05 and ## p < 0.001 vs. placebo.

Overall, reductions in body weight and proportion of participants achieving weight‐loss thresholds were similar in SURMOUNT‐3 and SURMOUNT‐4 across all reproductive stage subgroups (Figures S3A and S4).

Change from baseline in waist circumference

In SURMOUNT‐1 at Week 72, significantly greater reductions from baseline in waist circumference ranging from 20 to 22 cm were observed in all reproductive stage subgroups with tirzepatide vs. placebo (4–5 cm; p < 0.001 for all; Figure 1B). In a sensitivity analysis that adjusted for reproductive stage subgroup as a covariate and assessed all randomized women together from SURMOUNT‐1, significantly greater reductions in waist circumference of 21 cm were observed with tirzepatide compared to placebo (4 cm; p < 0.001; Figure S2B).

In the sensitivity analysis, a statistically significant difference of a 1.9‐cm greater reduction in waist circumference was observed in the pre‐ versus peri‐menopausal subgroups only in SURMOUNT‐4, whereas no difference across subgroups was observed in SURMOUNT‐1 or SURMOUNT‐3 (Figures S2B and S3B).

Shift in WHtR

In SURMOUNT‐1 at baseline, most participants did not have healthy WHtR, with only 2% of placebo‐treated participants with a baseline BMI < 35 kg/m2 from the premenopausal subgroup in a healthy WHtR range (Figure 4). At Week 72, significantly more participants in the tirzepatide group achieved a healthy WHtR compared to placebo irrespective of reproductive stage: 52%, 30%, and 30%, of participants in the pre‐, peri‐ and post‐menopausal subgroups, respectively, versus 6%, 0%, and 0% of placebo‐treated participants. Similarly, improvements in WHtR categories were observed in SURMOUNT‐3 and SURMOUNT‐4 (Figure S5).

FIGURE 4.

FIGURE 4

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WHtR by reproductive stage subgroup among participants with baseline BMI < 35 kg/m2 in SURMOUNT‐1. Data show shift in WHtR from baseline to the primary endpoint of 72 weeks. Postbaseline values are the last nonmissing value. Grand total was used as the denominator to calculate percentages in each treatment. WHtR, waist to height ratio.

In the total population (i.e., regardless of baseline BMI), significant improvements in WHtR category were observed in SURMOUNT‐1 with tirzepatide, with 24%, 18%, and 17% of participants in the pre‐, peri‐, and post‐menopausal subgroups achieving WHtR ≤ 0.49 versus 2%, 0%, and 0% of participants, respectively, on placebo (Figure S6). Similarly, more participants on tirzepatide achieved a healthy WHtR in SURMOUNT‐3 and SURMOUNT‐4 compared to placebo.

Safety

Treatment‐emergent adverse events (TEAEs) were assessed by trial. Across the trials analyzed, 60% to 88% of participants treated with tirzepatide 15 mg or MTD reported at least one TEAE versus 57% to 81% of participants treated with placebo (Table S4). Aside from reports of COVID‐19, the most frequently reported TEAEs were gastrointestinal in nature, including nausea and diarrhea, and were mostly mild to moderate in severity.

DISCUSSION

In this post hoc analysis of the SURMOUNT program, tirzepatide treatment was associated with significant body weight, waist circumference, and WHtR reductions compared to placebo in women living with obesity or overweight without T2D, irrespective of reproductive stage.

The menopausal transition is characterized by several physical and hormonal changes that result in weight or body composition changes. These body composition changes are largely described as a decrease in muscle mass, an increase in fat mass, and a redistribution of fat mass to more truncal locations [17]. In this analysis, tirzepatide treatment was associated with reduction not just in body weight but in waist circumference and WHtR, which are direct measures of central adiposity that are characteristically exacerbated during the perimenopause stage.

The decreases in WHtR that were observed with tirzepatide treatment are of clinical relevance due to the measure's association with obesity‐related complications and mortality [18, 19, 20] and its superiority to BMI in predicting cardiometabolic risk, particularly with some obesity‐related complications in women who are peri‐ and post‐menopausal [21, 22]. Recently, the American Medical Association released a statement regarding the limitations of BMI as a standalone clinical metric [23]. WHtR is an anthropometric measure that is readily applicable to clinical practice due to evidence supporting that the same three categories are appropriate irrespective of sex and race and ethnicity [16, 24]. In 2023, NICE UK updated its guidelines to recommend that the measure be used to classify people with excess adiposity and BMI < 35 kg/m2 [16]. More recently, the European Association for the Study of Obesity further emphasized the role of WHtR in clinical practice over waist circumference [25] due to its superiority as a screening marker cardiometabolic disease risk [24]. However, this may not be a useful addition for predicting health risks in people with a BMI > 35 kg/m2, as this group is always likely to have a high WHtR [16]. In this post hoc analysis, 17% to 38% of all women participants shifted to a healthy range for WHtR with tirzepatide compared to 0% to 3% who received placebo. Achieving this healthy range supports the potential health benefit of tirzepatide treatment. Improving their health remains among the top reasons why people with obesity or overweight seek obesity treatment [25, 26, 27, 28]. The current data encourage clinicians to use WHtR as discussion points with patients to address the obesity pathophysiology more directly in menopause (i.e., central adiposity) and to target patients' health goals of reducing cardiometabolic risk.

A commonly applied approach in obesity management is to recommend percentage of body weight reduction based on individualized obesity‐related complication assessments [29]. The current analysis supports that tirzepatide treatment is associated with substantial categorical body weight reductions, as 92% to 95% and 69% to 73% of women achieved ≥10% and ≥20% body weight reduction, respectively, in SURMOUNT‐1. For specific obesity‐related complications such as metabolic dysfunction‐associated steatohepatitis and cardiovascular disease prevention, the recommended higher magnitudes of weight reduction have been clinically challenging to achieve and maintain outside of procedures such as bariatric surgery. Newer obesity‐management medications such as tirzepatide can potentially assist in more effectively achieving individualized weight‐reduction thresholds [30]. The safety profile of tirzepatide treatment in women participants was similar to what has been reported for the three clinical study populations [7, 9, 10]. This was expected, as women participants made up 63% to 71% of the entire study populations in the SURMOUNT studies that were included in the current analyses [7, 9, 10]. Gastrointestinal adverse events were the most reported TEAEs, including nausea, diarrhea, constipation, and vomiting. As typically observed with incretin‐based therapies, gastrointestinal‐related adverse events were higher among participants treated with tirzepatide compared to placebo. This is consistent with incidences of gastrointestinal‐related adverse events that have been reported in the primary studies, which were generally transient and mostly mild to moderate in severity and primarily occurred during the dose‐escalation period [7, 9, 10]. Reports of COVID‐19 infections were also common and expected, as all three studies were conducted between 2019 and 2023. The rates of COVID‐19 infections were similar for those who received tirzepatide and placebo.

Despite women comprising the majority of patients receiving obesity management [31], and that women live about one‐half of their lives in the peri‐ to post‐menopause stages, current obesity guidelines [29, 32] do not discuss how obesity may worsen menopausal symptoms or how menopause may increase the risk of incident obesity. In a longitudinal study of ~1800 women in midlife, increased adiposity was associated with increased vasomotor symptoms [33]. In another study of only postmenopausal women, abdominal obesity predicted reporting vasomotor symptoms, depression, and muscle and joint pain [34]. Tirzepatide treatment was associated with improvements in aspects of quality of life, including pain, mental health, and physical function, in participants from SURMOUNT‐1, SURMOUNT‐3, and SURMOUNT‐4 [9, 35, 36, 37]. Future research into menopausal‐specific symptoms and various obesity‐management modalities, including resistance training with and without highly effective obesity‐management medications, may provide additional options to a holistic approach in women with obesity and menopausal symptoms.

This post hoc analysis is limited by certain factors intrinsic to its study design. Participants were retrospectively categorized by reproductive stage, which was defined by age and some clinical and biochemical characteristics. Whereas premenopausal and postmenopausal categories may have been more reliably delineated, individuals in the perimenopause subgroup may have been miscategorized (e.g., if they had undiagnosed polycystic ovary syndrome, then they may be premenopausal with polycystic ovary syndrome rather than perimenopausal). The design of the original SURMOUNT studies did not explicitly capture reproductive stage, which created an inherent limitation in this post hoc analysis. However, this limitation reflects real‐life clinical scenarios in which the perimenopause transition is variably experienced by patients and documented by clinicians. The current study's method to use age, biochemical markers, and medical history is likely demonstrative of real‐world experiences in the care of a woman in midlife. Furthermore, there remains a gap in the literature regarding the sex perspective and even less research on women's physiology and sex response to treatments in large clinical trials. Future studies are needed to focus on sex‐specific aspects that may influence treatment response and pave the way toward a personalized approach in the management of obesity and related complications. Additionally, studies have suggested that the weight changes occurring in the menopausal transition are not due to menopause per se. A meta‐analysis that included over 1 million women concluded that the increase in fat mass between premenopausal and postmenopausal women was predominately due to aging [38, 39]. As such, the validity of the primary findings that body weight reduction with tirzepatide treatment was similar across the reproductive stages is likely limitedly impacted by lack of biochemical data to confirm menopausal status. In the sensitivity analyses, we did not find a consistent relationship to support that tirzepatide‐induced reductions in weight or waist circumference are influenced by reproductive stage to a degree that is clinically meaningful. Furthermore, the SURMOUNT clinical trial program only included participants living with obesity or overweight at the time of enrollment; therefore, the findings from this post hoc analysis may not be generalizable to all women. Finally, due to the analyses' exploratory nature, we are unable to draw conclusions regarding treatment responses according to reproductive stage.

CONCLUSION

In this post hoc analysis of the SURMOUNT program, treatment with tirzepatide was associated with significant and clinically relevant body weight, waist circumference, and WHtR reductions compared to placebo in women living with obesity or overweight without T2D, irrespective of reproductive stage.

FUNDING INFORMATION

Funding for this post hoc analysis was provided by Eli Lilly and Company.

CLINICAL TRIAL REGISTRATION

ClinicalTrials.gov identifiers NCT04184622, NCT04657016, NCT04660643.

CONFLICT OF INTEREST STATEMENT

Beverly G. Tchang reports receiving consulting fees as an advisor for Novo Nordisk, Skye Bioscience, and Roman Health Ventures. Andreea Ciudin Mihai reports honoraria from AstraZeneca plc, Boehringer Ingelheim, Eli Lilly and Company, Esteve, and Novo Nordisk A/S for scientific talks, advisory board sessions, and attendance to congresses and is a member of the data monitoring committee for Boehringer Ingelheim clinical trials in obesity. Luis‐Emilio García‐Pérez, Adam Stefanski, Donna Mojdami, Irina Jouravskaya, Sirel Gurbuz, Rebecca Taylor, Chrisanthi A. Karanikas, and Julia P. Dunn are employees and shareholders of Eli Lilly and Company.

Supporting information

Data S1. Supporting information.

OBY-33-851-s001.docx (832.7KB, docx)

Tchang BG, Mihai AC, Stefanski A, et al. Body weight reduction in women treated with tirzepatide by reproductive stage: a post hoc analysis from the SURMOUNT program. Obesity (Silver Spring). 2025;33(5):851‐860. doi: 10.1002/oby.24254

DATA AVAILABILITY STATEMENT

Lilly 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 6 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, and 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.

OBY-33-851-s001.docx (832.7KB, docx)

Data Availability Statement

Lilly 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 6 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, and 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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